WO2023172561A1

WO2023172561A1 - Use of blink reflex for parkinson's disease response monitoring and/or treatment selection

Info

Publication number: WO2023172561A1
Application number: PCT/US2023/014720
Authority: WO
Inventors: Jeffrey RILEY; Douglas CARNES; Jennifer FIORINI; Andrew MASSEY
Original assignee: Blinktbi, Inc.
Priority date: 2022-03-07
Filing date: 2023-03-07
Publication date: 2023-09-14

Abstract

The disclosure relates to, in part, method of diagnosing whether a patient is afflicted with Parkinson's disease and/or selecting Parkinson's treatment for a patient afflicted with Parkinson's disease and/or monitoring response of Parkinson's symptoms in patient to a Parkinson's treatment by measuring a blink reflex in a patient. The measurement comprising: applying a non-electrical stimulus to an eye of the patient to induce a blink reflex and assessing one or more blink-associated parameters. The patient is then diagnosed as afflicted with Parkinson's disease or not afflicted with Parkinson's disease by comparing the one or more blink associated parameters to equivalent one or more blink associated parameters from a patient who is not afflicted with Parkinson's disease.

Description

USE OF BLINK REFLEX FOR PARKINSON’S DISEASE RESPONSE MONITORING AND/OR TREATMENT SELECTION

FIELD

The present disclosure provides methods for Parkinson’s disease diagnosis, monitoring, and/or treatment selection in a patient.

RELATED APPLICATIONS

The application claims the benefit of, and priority to, U.S. Provisional Application No. 63/317,241 , filed March 07, 2022, the contents of which are hereby incorporated by reference in their entirety.

BACKGROUND

Parkinson’s Disease (PD) is a progressive neurodegenerative disease of the central nervous system (CNS) producing sensory and motor symptoms. In Parkinson’s disease, neurons in the brain gradually break down or die. Many of the symptoms of Parkinson’s are due to a loss of neurons that produce dopamine. When dopamine levels decrease, it causes abnormal brain activity, leading to impaired movement and other symptoms of Parkinson’s disease. Parkinson’s disease signs and symptoms can be different for everyone. Currently, the tools and methods for diagnosing whether a patient is afflicted with Parkinson’s are unreliable and expensive. There is a need for effective methods of diagnosing, predicting, and/or treating Parkinson’s in a patient. Moreover, there is a need for effective methods of selecting treatment and/or monitoring response to treatment in patient afflicted with Parkinson’s disease.

SUMMARY

Accordingly, the present disclosure provides a method of diagnosing whether a patient is afflicted with Parkinson’s disease, comprising: (a) measuring a blink reflex in a patient suspected to be afflicted with Parkinson’s disease, the measurement comprising: (i) applying a non-electrical stimulus to an eye of the patient to induce a blink reflex and (ii) assessing one or more blink-associated parameters; and (b) diagnosing the patient as afflicted with Parkinson’s disease or not afflicted with Parkinson’s disease by comparing the one or more blink-associated parameters to equivalent one or more blink-associated parameters from a patient who is not afflicted with Parkinson’s disease.

In aspects, the present disclosure provides a method of diagnosing and treating a patient afflicted with Parkinson’s disease, comprising: (a) measuring a blink reflex in a patient suspected to be afflicted with Parkinson’s disease, the measurement comprising: (i) applying a non-electrical stimulus to an eye of the patient to induce a blink reflex and (ii) assessing one or more blink-associated parameters; and (b) diagnosing the patient as afflicted with Parkinson’s disease or not afflicted with Parkinson’s disease by comparing the one or more blink-associated parameters to equivalent one or more blink-associated parameters from a patient who is not afflicted with Parkinson’s disease; and (c) administering an effective amount of a Parkinson’s disease treatment to a patient diagnosed as afflicted with Parkinson’s disease.

In aspects, the present disclosure provides a method of selecting a Parkinson’s disease treatment for a patient afflicted with Parkinson’s disease, comprising: (a) measuring a blink reflex in the patient afflicted with Parkinson’s disease, the measurement comprising: (i) applying a non-electrical stimulus to an eye of the patient to induce a blink reflex and (ii) assessing one or more blink-associated parameters; and (b) selecting a Parkinson’s disease treatment for the patient afflicted with Parkinson’s disease by comparing the one or more blink-associated parameters to equivalent one or more blink-associated parameters from the patient when not experiencing symptoms of Parkinson’s disease and/or the patient when receiving the Parkinson’s disease treatment.

In aspects, the present disclosure provides a method of monitoring response of Parkinson’s disease in patient to a Parkinson’s disease treatment, comprising (a) measuring a blink reflex in the patient afflicted with a Parkinson’s disease and who has undergone or is undergoing treatment with the Parkinson’s disease treatment, the measurement comprising: (i) applying a non-electrical stimulus to an eye of the patient to induce a blink reflex and (ii) assessing one or more blink-associated parameters; and (b) determining a response to the Parkinson’s disease treatment by comparing the one or more blink-associated parameters to equivalent one or more blink-associated parameters from the patient when not experiencing symptoms of Parkinson’s disease and/or the patient before receiving the Parkinson’s disease treatment.

The details of the invention are set forth in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, illustrative methods and materials are now described. Other features, objects, and advantages of the invention will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 depicts graphical representations of the quantitative differences in blink rate parameters between patients with Parkinson’s Disease (PD) (n = 81 , mean age = 71.0 ± 8.8 yrs.) and an age- matched healthy adult control group (n = 106, mean age = 69.1 ± 10.5 yrs.). Data represent the median ± 95% confidence intervals (Cl). Statistical evaluation is summarized in Table 1 .

Figs. 2A-2D depict graphical representations of the quantitative correlation between the duration of PD in subjects diagnosed with PD (n = 81, mean age = 71.0 ± 8.8 yrs.). Fig. 2A depicts time to open, Fig. 2B depicts time to close, Fig. 2C depicts number of oscillations, Fig. 2D depicts mean oscillation rate. Curves represent approximation functions ± 95% confidence interval (Cl). Statistical evaluation indicates strong correlation between time since diagnosis and effect on blink reflex parameter (P < 0.001).

Figs. 3A-3B depict graphical representations of the quantitative evaluation of the effects of PD and healthy aging on the number of oscillations. Fig. 3A shows the statistical difference between number of oscillations and oscillation rate between patients with PD and (n = 81, mean age = 71.0 ± 8.8 yrs.) and an age-matched healthy adult control group (n = 106, mean age = 69.1 ± 10.5 yrs.); left bar is Parkinson’s disease; right bar is control group. Fig. 3B shows the natural degradation of the number of oscillations in the blink reflex as a function of healthy aging. Curve represents approximation function.

DETAILED DESCRIPTION

In aspects, the present disclosure provides a method of diagnosing whether a patient is afflicted with Parkinson’s disease, comprising: (a) measuring a blink reflex in a patient suspected to be afflicted with Parkinson’s disease, the measurement comprising: (i) applying a non-electrical stimulus to an eye of the patient to induce a blink reflex and (II) assessing one or more blink-associated parameters; and (b) diagnosing the patient as afflicted with Parkinson’s disease or not afflicted with Parkinson’s disease by comparing the one or more blink-associated parameters to equivalent one or more blink-associated parameters from a patient who is not afflicted with Parkinson’s disease. In aspects, the present disclosure provides a method of diagnosing and treating a patient afflicted with Parkinson’s disease, comprising: (a) measuring a blink reflex in a patient suspected to be afflicted with Parkinson’s disease, the measurement comprising: (i) applying a non-electrical stimulus to an eye of the patient to induce a blink reflex and (ii) assessing one or more blink-associated parameters; and (b) diagnosing the patient as afflicted with Parkinson’s disease or not afflicted with Parkinson’s disease by comparing the one or more blink-associated parameters to equivalent one or more blink-associated parameters from a patient who is not afflicted with Parkinson’s disease; and (c) administering an effective amount of a Parkinson’s disease treatment to a patient diagnosed as afflicted with Parkinson’s disease.

In aspects, the present disclosure provides a method of selecting a Parkinson’s disease treatment for a patient afflicted with Parkinson’s disease, comprising: (a) measuring a blink reflex in the patient afflicted with Parkinson's disease, the measurement comprising: (i) applying a non-electrical stimulus to an eye of the patient to induce a blink reflex and (ii) assessing one or more blink-associated parameters; and (b) selecting a Parkinson’s disease treatment for the patient afflicted with Parkinson’s disease by comparing the one or more blink-associated parameters to equivalent one or more blink-associated parameters from the patient when not experiencing symptoms of Parkinson’s disease and/or the patient when receiving the Parkinson’s disease treatment.

In aspects, the present disclosure provides a method of screening a subject for early Parkinson’s disease and/or risk of future development of Parkinson’s disease, comprising: (a) measuring a blink reflex in a subject, the measurement comprising: (i) applying a non-electrical stimulus to an eye of the subject to induce a blink reflex and (ii) assessing one or more blink-associated parameters; and (b) identifying the subject as afflicted with early Parkinson’s disease, having risk of future development of Parkinson’s disease, or neither by comparing the one or more blink-associated parameters to equivalent one or more blink-associated parameters from a subject who is not afflicted with Parkinson’s disease.

In embodiments, the subject identified as afflicted with early Parkinson’s disease or having risk of future development of Parkinson’s disease is administered with preventative medications and/or lifestyle changes.

In aspects, the present disclosure provides a method of screening a subject for Parkinson’s disease and/or atypical Parkinsonism disorders, comprising: (a) measuring a blink reflex in a subject, the measurement comprising: (i) applying a non-electrical stimulus to an eye of the subject to induce a blink reflex and (ii) assessing one or more blink-associated parameters; and (b) identifying the subject as afflicted with Parkinson’s disease, atypical Parkinsonism disorders, or neither by comparing the one or more blink-associated parameters to equivalent one or more blink-associated parameters from a subject who is not afflicted with Parkinson’s disease.

In embodiments, the subject identified as afflicted with atypical Parkinsonism disorders comprise symptoms selected from Multiple System Atrophy, Progressive Supranuclear Palsy, Corticobasal Syndrome, Dementia with Lewy Bodies, drug-induced Parkinsonism, and vascular Parkinsonism.

In embodiments, the diagnosing comprises: diagnosis of disease onset; determination of disease stage and/or severity; determination of disease progress; and/or determination of cognitive state and/or mental capacity.

In embodiments, the method is carried out remotely, optionally with a telehealth device. In embodiments, the method is adapted for point-of-care application.

In embodiments, an information collected can predict correlation of Parkinson’s disease to the occurrence of a future disease of the central nervous system, optionally dementia.

In embodiments, an information collected further allows for assessing the therapeutic efficacy of pharmaceutical and/or medical and/or surgical treatment modalities.

In embodiments, the methods of the present disclosure provide information that may inform modifying the patient’s treatment (e.g., without limitation, changing treatment (e.g., adding or removing one or more Parkinson’s treatments), altering dosage of the Parkinson’s treatment(s), and/or altering the Parkinson’s treatment regimen (e.g., altering frequency and/or duration of dosing).

In embodiments, the methods of the present disclosure may be able to identify a patient’s susceptibility to Parkinson’s at least 1 year, at least 3 years, at least 5 years, at least 10 years, at least 15 years, at least 20 years, at least 25 years, at least 30 years, at least 35 years, at least 40 years, at least 45 years, at least 50 years, at least 55 years, at least 60 years, at least 65 years, at least 70 years, at least 75 years, at least 80 years, at least 85 years, at least 90 years, at least 95 years, and/or at least 100 years before the first sign and/or symptom of Parkinson’s occurs.

Blink Measurements

In embodiments, the method of the present disclosure measures latency until physiological response to stimulus. In embodiments, the blink reflex correlates with functionality of one or more of the trigeminal and facial nerves.

In embodiments, the stimulus is non-electrical. In embodiments, the non-electrical stimulus is one or more physical stimuli. In embodiments, the one or more physical stimuli are mechanical, visual, and/or acoustic. In embodiments, the one or more physical stimuli are light, heat, and/or sound. In embodiments, the one or more physical stimuli are a puff of air, a flash of light, a noise, and/or a vibration. In embodiments, wherein the stimulus is a sound, the stimulus triggers blink reflex when the sound is about 40 to about 60 dB greater than the minimum dB level for the patient. In embodiments, the puff of air is a short light gust of air. In embodiments, the puff of air is a tactile stimulus. In embodiments, the air is or comprises compressed air. In embodiments, the compressed air is delivered to the user’s and/or patient’s eye at a predetermined pressure. In embodiments, the puff of air has a pressure of about 3.75psi (~25kPa) to about 60psi -415 kPa) (e.g., about 5 kPa, or about 10 kPa, or about 15 kPa, or about 20 kPa, or about 25 kPa). In embodiments, the puff of air is delivered at a duration of about 100 ms and a peak pressure of about 60psi (-415 kPa). In embodiments, the air is or comprises carbon dioxide. In embodiments, the air is or comprises nitrogen. In embodiments, the air is or comprises oxygen. In embodiments, the air puff stimulus is delivered from an air source. In embodiments, air source comprises an air compressor. In embodiments, air source comprises an air compression system. In embodiments, air source comprises a tank of industrial air. In embodiments, the air is purified air, usually food grade versions of air, CO2, nitrogen, etc., are used. In embodiments, the air compression system may include a gas source, holding tank, power source, and regulator. In embodiments, the holding tank may be coupled to gas source and may receive gas outputted from gas source. In embodiments, the regulator controls gas source and outputs gas from gas source into holding tank prior to being release to the user or patient to initiate a blink reflex. In embodiments, the regulator may be a valve and may be coupled to power source and gas source. In embodiments, the regulator may be coupled to gas source or may be integrally formed with gas source. In embodiments, the regulator may be configured to reduce the pressure of the gas outputted by gas source. For example, the regulator may be configured to step down the pressure outputted from gas source to under 100 PSI. In embodiments, the pressure of the gas outputted by gas source is approximately 900 PSI and regulator is configured to step down the pressure from gas source to less than 100 PSI. However, the regulator may be configured to step down the pressure to less than about 500 PSI, less than about 400 PSI, less than about 200 PSI, or less than about 50 PSI. In embodiments, the regulator is configured to allow certain amounts of pressure into holding tank that can then be released at different pressures to initiate one or more blink reflexes. In embodiments, the regulator may be configured to allow for different outputs of pressure of gas for different users or patients of blink reflex device.

In embodiments, the regulator may be configured to fine tune the pressure of gas outputted by blink reflex that initiates the blink reflex of the user or patient. In embodiments, the regulator may be configured to output gas (via gas source) at the minimum pressure required to initiate a blink reflex. For example, regulator may be configured to output gas at a pressure of less than about 50 PSI. In embodiments, the regulator is configured to received compressed gas from gas source and output compressed gas from blink reflex device at a predetermined pressure for a predetermined duration. For example, the regulator may be configured to output compressed gas at a pressure of about 3 PSI to about 60 PSI or at a pressure of about 30 PSI to about 50 PSI. However, regulator may be configured to output gas at a pressure of about 10 PSI to about 100 PSI, about 20 PSI to about 80 PSI, or about 40 PSI to about 60 PSI. In embodiments, regulator outputs a first puff of compressed gas at a first pressure and then a second puff of compressed air at a second pressure. In embodiments, the first pressure may be less than the second pressure. In embodiments, the regulator outputs compressed gas at the first pressure for one or more puffs and then outputs compressed gas at the second pressure for one or more puffs. In embodiments, the regulator is to be configured to determine the minimum pressure required to initiate a blink reflex. During use, the regulator may initially output compressed gas at a low pressure and gradually increase the pressure of compressed gas outputted until a blink reflex is detected. In embodiments, the regulator increases the pressure of compressed gas by about 1 to about 3 PSI. However, regulator may increase the pressure of compressed gas by about 0.5 PSI to about 5 PSI, about 1 PSI to about 3 PSI, or less than about 0.5 PSI.

In embodiments, the stimulus is delivered to the desired location, e.g., without limitation, on the face of the subject. In embodiments, the stimulus is delivered to the forehead. In embodiments, the stimulus is delivered to the cheek. In embodiments, the compressed air is applied across the left eye, the right eye, and/or both eyes. In embodiments, the compressed air is applied across the eye. In embodiments, the non-electrical stimulus is applied to the canthus, outer canthus, inner canthus, lateral canthus, or medial canthus. In embodiments, applying the non-electrical stimulus to the canthus or the outer canthus produces a robust blink reflex. In embodiments, the non-electrical stimulus is not applied directly onto the cornea.

In embodiments, the blink reflex is measured with a high-speed camera. In embodiments, the blink reflex is measured by capturing and analyzing high-definition images. In embodiments, the present measurement, e.g., via a device for measuring, capturing, and analyzing high-definition images is further capable of distinguishing between the desired blink and undesired blink. In embodiments, the desired blink is triggered as a result of a blink reflex. In embodiments, the desired blink is triggered by a stimulus (e.g., without limitation, a puff of air, light, heat, and/or sound). In embodiments, the undesired blink is a false-positive blink, a false-negative blink, or an abnormal blink. In embodiments, the desired blink is or comprises an induced blink. In embodiments, the undesired blink is or comprises spontaneous and/or voluntary blink. In embodiments, the present measurement, e.g., via a device for measuring, capturing, and analyzing high-definition images, omits or flags the undesired blink (e.g., without limitation, a false-positive blink, a false-negative blink, or an abnormal blink) from the final results generated. In embodiments, the present measurement, e.g., via a device for measuring, capturing, and analyzing high-definition images, includes the undesired blink (e.g., without limitation, a spontaneous and/or voluntary blink) in the final results generated. In embodiments, the present measurement, e.g., via a device for measuring, capturing, and analyzing high-definition images, includes the desired blink (e.g., without limitation, an induced blink) in the final results generated. In embodiments, the blink reflex is not measured with an EMG sensor. In embodiments, the blink reflex is measured with a blink reflex monitoring device. In embodiments, the blink reflex monitoring device is a wearable device or a handheld device or can be placed on a tripod, on a desk, or the like. In embodiments, the handheld device involves a smartphone app. In embodiments, the blink reflex monitoring device is simply placed on a stool or a chair. In embodiments, the blink reflex monitoring device is simply hung on a wall such that the device is able to monitor and record the blink reflex of the user’s and/or patient’s eye. In embodiments, the blink reflex monitoring device is a wearable device. In embodiments, the blink reflex monitoring device can be worn by a user and/or patient. In embodiments, the blink reflex monitoring device is secured to a user’s and/or patient’s head via one or more straps. In embodiments, the blink reflex monitoring device is portable. In embodiments, the blink reflex monitoring device may be configured to be disposed on a mount or stand to easily allow for consecutive uses by multiple users. In embodiments, securing the blink reflex monitoring device to a tripod or stand allows for multiple users or patients to each quickly and efficiently use the device without having to constantly remove the device from a user’s or patient’s head.

In embodiments, the blink reflex monitoring device has or comprises: a front end, a back end, a first plane extending through the front end and the back end, a second plane intersecting the first plane between the front end and the back end, the back end configured to receive a portion of a face of a user and disposed opposite the front end; and a strap coupled to the blink reflex monitoring device and having a first position and a second position, wherein in the first position the strap extends away from the blink reflex monitoring device along the first plane end and is configured to secure the blink reflex monitoring device to a head of a user and in the second position the strap extends below the blink reflex monitoring device along the second plane and is configured to support the blink reflex monitoring device above a surface.

In embodiments, the blink reflex monitoring device has or comprises: a front end and a back end, the back end configured to receive a portion of a face of a user and disposed opposite the front end; at least one strap coupled to the blink reflex monitoring device proximate the back end, the at least one strap configured to be secured around a head of a user; and an air compression system including a source of compressed air and a valve, the air compression system disposed within the blink reflex monitoring device and the valve configured to output compressed air from the back end at a pressure of about 3 PSI to about 60 PSI.

In embodiments, the air compression system disposed within the blink reflex monitoring device and the valve configured to output compressed air from the back end at a pressure of about 30 PSI to about 50 PSI.

In embodiments, the blink reflex is not measured with an electromyography (EMG) device. In embodiments, the blink reflex is measured with a high-speed camera. In embodiments, the blink reflex is not measured with an EMG sensor.

In embodiments, the measuring of a blink reflex, comprises: providing a blink reflex monitoring device to a user, the blink reflex monitoring device having an air compression system including a compressed air source and a valve; outputting a first burst of compressed air from the compressed air source through the valve at a first pressure; detecting a presence or an absence of a blink in response to the first burst of compressed air source at the first pressure; if the blink is present, then measuring a duration between the output of the first burst of compressed air at the first pressure and the blink to determine the blink reflex; and if the blink is absent, then outputting a second burst of compressed air from the compressed air source at a second pressure, the second pressure being greater than the first pressure and measuring a duration between the output of the second burst of compressed air at the second pressure and the blink to determine the blink reflex.

In embodiments, the method of the present disclosure detects a blink reflex. In embodiments, the method of the present disclosure detects a blink reflex and distinguish the blink reflex from a falsepositive or a false-negative blink. In embodiments, the method of the present disclosure detects a blink reflex and distinguish the blink reflex from an abnormal blink. In embodiments, the abnormal blink includes double blink, excessive blink, blinking during micro-sleep, and the like. Abnormal blink may occur when one or both eyes transition from the open state to the close state and begin returning to the open state at rate that is substantially slower than that associated with a normal blink. Such abnormal blink may be an indication of the user or patient experiencing fatigue and/or may occur over a period of that that is substantially longer than the normal blink reflex (e.g., without limitation, 5 times longer, 10 times longer, or 20 times longer). In embodiments, the method of the present disclosure omits or flags the abnormal blink from the final results generated.

In a non-limiting embodiment, the one or more blink-associated parameters are measured in one or more of the right and left eyes.

In embodiments, the one or more blink-associated parameters are selected from:

(a) latency, optionally in milliseconds, comprising a time differential between stimulation and eyelid movement, e.g., one or more of upper eyelid or lower eyelid;

(b) differential latency, optionally in milliseconds, comprising a time differential between the start of ipsilateral eye movement and the start of contralateral eye movement;

(c) delta 30, comprising a time difference between ipsilateral eye and contralateral eye movement;

(d) eyelid excursion, optionally in pixels, comprising a distance traveled by the eyelid from the tonic lid position to closed position;

(e) initial lid velocity, optionally in pixels/msec, comprising an average eyelid speed following start of eyelid movement, e.g., the first about 5 frames, the first about 7 frames, or the first about 10 frames;

(f) time to close, optionally in log scale, comprising a time for lid to travel from tonic lid position to the closed position;

(g) time to open, optionally in log scale, comprising a time for lid to travel from closed position back to tonic lid position;

(h) time under threshold, optionally in log scale, comprising a time that the eyelid spends below the threshold position; (i) number of oscillations, comprising cycles of up and down upper eyelid movement after a stimulated blink;

(j) total blink time, optionally in log scale, comprising a time from start of eyelid movement until it returns to its tonic lid position;

(k) number of blinks;

(l) blink rate, optionally per minute;

(m) area under curve, optionally in pixels;

(n) maximum closing velocity, optionally in milliseconds, comprising a maximum velocity during eyelid closure;

(o) maximum opening velocity, optionally in milliseconds, comprising a maximum velocity during eyelid opening;

(p) time to first oscillation, optionally in log scale, comprising the elapsed time between the eyelid returning within threshold of a tonic position for a stimulated blink and the onset of the next unstimulated blink;

(q) prepulse inhibition, optionally comprising the inhibitory effect caused by a stimulus of an intensity low enough not to induce a response by itself on the response elicited by a subsequent stimulus;

(r) blink reflex recovery cycle, optionally comprising the size of the test response as a percentage of that of the first conditioning response at each interval (such blink reflex recovery cycle is determined by altering the interstimulus interval to find the point at which blink reflex excitability normalizes);

(s) interstimulus interval, optionally comprising the time between the onset of the conditioning stimulus and the onset of the unconditioned stimulus; and

(t) blink reflex excitability, optionally comprising the outcome of the relationship between the blink reflex to trigeminal nerve stimulation as modulated by the brainstem (such blink reflex excitability is determined by presenting pairs of identical stimuli with a short interstimulus interval, and comparing the magnitude of the lid movement evoked by the second (test) stimulus to that evoked by the first (condition) stimulus). In a non-limiting embodiment, the one or more blink-associated parameters are measured in one or more of the right and left eyes.

In embodiments, in comparison of the patient before receiving the Parkinson’s disease treatment to after receiving the Parkinson’s disease treatment: latency increases or decreases; differential latency increases or decreases; delta 30 increases or decreases; eyelid excursion increases or decreases; initial lid velocity increases or decreases; time to close increases or decreases; time to open increases or decreases; time under threshold increases or decreases; number of oscillations increases or decreases; total blink time increases or decreases; number of blinks increases or decreases; blink rate increases or decreases; area under curve increases or decreases; maximum closing velocity increases or decreases; maximum opening velocity increases or decreases; time to first oscillation increases or decreases; prepulse inhibition increases or decreases; blink reflex recovery cycle increases or decreases; interstimulus interval increases or decreases; and/or blink reflex excitability increases or decreases. In embodiments, by “increase” or “decreases”, e.g., in comparison of the one or more blink- associated parameters from a patient before receiving the Parkinson’s treatment to after receiving the Parkinson’s treatment, the disclosure refers to values that change over time or relative to each other. In embodiments “increase” is synonymous with “is more than” and/or reflects a non-static value that has changed. In embodiments “decrease” is synonymous with “is less than” and/or reflects a non-static value that has changed. In embodiments, assessment of whether a value “increases” or “is more than” or “decreases” or “is less than”, e.g., in comparison of the one or more blink- associated parameters from a patient before receiving the Parkinson’s treatment to after receiving the Parkinson’s treatment, involves comparing a measured value at two different time points.

In embodiments, in comparison of the patient before receiving the Parkinson’s disease treatment to after receiving the Parkinson’s disease treatment latency increases or decreases by about or at least about 1%, or by about or at least about 2%, or by about or at least about 3%, or by about or at least about 4%, or by about or at least about 5%, or by about or at least about 10%, or by about or at least about 15%, or by about or at least about 20%, or by about or at least about 25%, or by about or at least about 30%, or by about or at least about 35%, or by about or at least about 40%, or by about or at least about 45%, or by about or at least about 50%, or by about or at least about 55%, or by about or at least about 60%, or by about or at least about 65%, or by about or at least about 70%, or by about or at least about 75%, or by about or at least about 80%, or by about or at least about 85%, or by about or at least about 90%, or by about or at least about 95%.

In embodiments, in comparison of the patient before receiving the Parkinson’s disease treatment to after receiving the Parkinson’s disease treatment differential latency increases or decreases by about or at least about 1%, or by about or at least about 2%, or by about or at least about 3%, or by about or at least about 4%, or by about or at least about 5%, or by about or at least about 10%, or by about or at least about 15%, or by about or at least about 20%, or by about or at least about 25%, or by about or at least about 30%, or by about or at least about 35%, or by about or at least about 40%, or by about or at least about 45%, or by about or at least about 50%, or by about or at least about 55%, or by about or at least about 60%, or by about or at least about 65%, or by about or at least about 70%, or by about or at least about 75%, or by about or at least about 80%, or by about or at least about 85%, or by about or at least about 90%, or by about or at least about 95%. In embodiments, in comparison of the patient before receiving the Parkinson’s disease treatment to after receiving the Parkinson’s disease treatment delta 30 increases or decreases by about or at least about 1%, or by about or at least about 2%, or by about or at least about 3%, or by about or at least about 4%, or by about or at least about 5%, or by about or at least about 10%, or by about or at least about 15%, or by about or at least about 20%, or by about or at least about 25%, or by about or at least about 30%, or by about or at least about 35%, or by about or at least about 40%, or by about or at least about 45%, or by about or at least about 50%, or by about or at least about 55%, or by about or at least about 60%, or by about or at least about 65%, or by about or at least about 70%, or by about or at least about 75%, or by about or at least about 80%, or by about or at least about 85%, or by about or at least about 90%, or by about or at least about 95%.

In embodiments, in comparison of the patient before receiving the Parkinson’s disease treatment to after receiving the Parkinson’s disease treatment eyelid excursion increases or decreases by about or at least about 1%, or by about or at least about 2%, or by about or at least about 3%, or by about or at least about 4%, or by about or at least about 5%, or by about or at least about 10%, or by about or at least about 15%, or by about or at least about 20%, or by about or at least about 25%, or by about or at least about 30%, or by about or at least about 35%, or by about or at least about 40%, or by about or at least about 45%, or by about or at least about 50%, or by about or at least about 55%, or by about or at least about 60%, or by about or at least about 65%, or by about or at least about 70%, or by about or at least about 75%, or by about or at least about 80%, or by about or at least about 85%, or by about or at least about 90%, or by about or at least about 95%.

In embodiments, in comparison of the patient before receiving the Parkinson’s disease treatment to after receiving the Parkinson’s disease treatment initial lid velocity increases or decreases by about or at least about 1%, or by about or at least about 2%, or by about or at least about 3%, or by about or at least about 4%, or by about or at least about 5%, or by about or at least about 10%, or by about or at least about 15%, or by about or at least about 20%, or by about or at least about 25%, or by about or at least about 30%, or by about or at least about 35%, or by about or at least about 40%, or by about or at least about 45%, or by about or at least about 50%, or by about or at least about 55%, or by about or at least about 60%, or by about or at least about 65%, or by about or at least about 70%, or by about or at least about 75%, or by about or at least about 80%, or by about or at least about 85%, or by about or at least about 90%, or by about or at least about 95%. In embodiments, in comparison of the patient before receiving the Parkinson’s disease treatment to after receiving the Parkinson’s disease treatment time to close increases or decreases by about or at least about 1%, or by about or at least about 2%, or by about or at least about 3%, or by about or at least about 4%, or by about or at least about 5%, or by about or at least about 10%, or by about or at least about 15%, or by about or at least about 20%, or by about or at least about 25%, or by about or at least about 30%, or by about or at least about 35%, or by about or at least about 40%, or by about or at least about 45%, or by about or at least about 50%, or by about or at least about 55%, or by about or at least about 60%, or by about or at least about 65%, or by about or at least about 70%, or by about or at least about 75%, or by about or at least about 80%, or by about or at least about 85%, or by about or at least about 90%, or by about or at least about 95%.

In embodiments, in comparison of the patient before receiving the Parkinson’s disease treatment to after receiving the Parkinson’s disease treatment time to open increases or decreases by about or at least about 1%, or by about or at least about 2%, or by about or at least about 3%, or by about or at least about 4%, or by about or at least about 5%, or by about or at least about 10%, or by about or at least about 15%, or by about or at least about 20%, or by about or at least about 25%, or by about or at least about 30%, or by about or at least about 35%, or by about or at least about 40%, or by about or at least about 45%, or by about or at least about 50%, or by about or at least about 55%, or by about or at least about 60%, or by about or at least about 65%, or by about or at least about 70%, or by about or at least about 75%, or by about or at least about 80%, or by about or at least about 85%, or by about or at least about 90%, or by about or at least about 95%.

In embodiments, in comparison of the patient before receiving the Parkinson’s disease treatment to after receiving the Parkinson’s disease treatment time under threshold of 20 increases or decreases by about or at least about 1%, or by about or at least about 2%, or by about or at least about 3%, or by about or at least about 4%, or by about or at least about 5%, or by about or at least about 10%, or by about or at least about 15%, or by about or at least about 20%, or by about or at least about 25%, or by about or at least about 30%, or by about or at least about 35%, or by about or at least about 40%, or by about or at least about 45%, or by about or at least about 50%, or by about or at least about 55%, or by about or at least about 60%, or by about or at least about 65%, or by about or at least about 70%, or by about or at least about 75%, or by about or at least about 80%, or by about or at least about 85%, or by about or at least about 90%, or by about or at least about 95%. In embodiments, in comparison of the patient before receiving the Parkinson’s disease treatment to after receiving the Parkinson’s disease treatment number of oscillations increases or decreases by about or at least about 1%, or by about or at least about 2%, or by about or at least about 3%, or by about or at least about 4%, or by about or at least about 5%, or by about or at least about 10%, or by about or at least about 15%, or by about or at least about 20%, or by about or at least about 25%, or by about or at least about 30%, or by about or at least about 35%, or by about or at least about 40%, or by about or at least about 45%, or by about or at least about 50%, or by about or at least about 55%, or by about or at least about 60%, or by about or at least about 65%, or by about or at least about 70%, or by about or at least about 75%, or by about or at least about 80%, or by about or at least about 85%, or by about or at least about 90%, or by about or at least about 95%.

In embodiments, in comparison of the patient before receiving the Parkinson’s disease treatment to after receiving the Parkinson’s disease treatment number of blinks increases or decreases by about or at least about 1%, or by about or at least about 2%, or by about or at least about 3%, or by about or at least about 4%, or by about or at least about 5%, or by about or at least about 10%, or by about or at least about 15%, or by about or at least about 20%, or by about or at least about 25%, or by about or at least about 30%, or by about or at least about 35%, or by about or at least about 40%, or by about or at least about 45%, or by about or at least about 50%, or by about or at least about 55%, or by about or at least about 60%, or by about or at least about 65%, or by about or at least about 70%, or by about or at least about 75%, or by about or at least about 80%, or by about or at least about 85%, or by about or at least about 90%, or by about or at least about 95%.

In embodiments, in comparison of the patient before receiving the Parkinson’s disease treatment to after receiving the Parkinson’s disease treatment blink rate increases or decreases by about or at least about 1%, or by about or at least about 2%, or by about or at least about 3%, or by about or at least about 4%, or by about or at least about 5%, or by about or at least about 10%, or by about or at least about 15%, or by about or at least about 20%, or by about or at least about 25%, or by about or at least about 30%, or by about or at least about 35%, or by about or at least about 40%, or by about or at least about 45%, or by about or at least about 50%, or by about or at least about 55%, or by about or at least about 60%, or by about or at least about 65%, or by about or at least about 70%, or by about or at least about 75%, or by about or at least about 80%, or by about or at least about 85%, or by about or at least about 90%, or by about or at least about 95%. In embodiments, in comparison of the patient before receiving the Parkinson’s disease treatment to after receiving the Parkinson’s disease treatment area under curve increases or decreases by about or at least about 1%, or by about or at least about 2%, or by about or at least about 3%, or by about or at least about 4%, or by about or at least about 5%, or by about or at least about 10%, or by about or at least about 15%, or by about or at least about 20%, or by about or at least about 25%, or by about or at least about 30%, or by about or at least about 35%, or by about or at least about 40%, or by about or at least about 45%, or by about or at least about 50%, or by about or at least about 55%, or by about or at least about 60%, or by about or at least about 65%, or by about or at least about 70%, or by about or at least about 75%, or by about or at least about 80%, or by about or at least about 85%, or by about or at least about 90%, or by about or at least about 95%.

In embodiments, in comparison of the patient before receiving the Parkinson’s disease treatment to after receiving the Parkinson’s disease treatment maximum opening velocity increases or decreases by about or at least about 1%, or by about or at least about 2%, or by about or at least about 3%, or by about or at least about 4%, or by about or at least about 5%, or by about or at least about 10%, or by about or at least about 15%, or by about or at least about 20%, or by about or at least about 25%, or by about or at least about 30%, or by about or at least about 35%, or by about or at least about 40%, or by about or at least about 45%, or by about or at least about 50%, or by about or at least about 55%, or by about or at least about 60%, or by about or at least about 65%, or by about or at least about 70%, or by about or at least about 75%, or by about or at least about 80%, or by about or at least about 85%, or by about or at least about 90%, or by about or at least about 95%.

In embodiments, in comparison of the patient before receiving the Parkinson’s disease treatment to after receiving the Parkinson’s disease treatment time to first oscillation increases or decreases by about or at least about 1%, or by about or at least about 2%, or by about or at least about 3%, or by about or at least about 4%, or by about or at least about 5%, or by about or at least about 10%, or by about or at least about 15%, or by about or at least about 20%, or by about or at least about 25%, or by about or at least about 30%, or by about or at least about 35%, or by about or at least about 40%, or by about or at least about 45%, or by about or at least about 50%, or by about or at least about 55%, or by about or at least about 60%, or by about or at least about 65%, or by about or at least about 70%, or by about or at least about 75%, or by about or at least about 80%, or by about or at least about 85%, or by about or at least about 90%, or by about or at least about 95%. In embodiments, in comparison of the patient before receiving the Parkinson’s disease treatment to after receiving the Parkinson’s disease treatment prepulse inhibition increases or decreases by about or at least about 1%, or by about or at least about 2%, or by about or at least about 3%, or by about or at least about 4%, or by about or at least about 5%, or by about or at least about 10%, or by about or at least about 15%, or by about or at least about 20%, or by about or at least about 25%, or by about or at least about 30%, or by about or at least about 35%, or by about or at least about 40%, or by about or at least about 45%, or by about or at least about 50%, or by about or at least about 55%, or by about or at least about 60%, or by about or at least about 65%, or by about or at least about 70%, or by about or at least about 75%, or by about or at least about 80%, or by about or at least about 85%, or by about or at least about 90%, or by about or at least about 95%.

In embodiments, in comparison of the patient before receiving the Parkinson’s disease treatment to after receiving the Parkinson’s disease treatment blink reflex recovery cycle increases or decreases by about or at least about 1%, or by about or at least about 2%, or by about or at least about 3%, or by about or at least about 4%, or by about or at least about 5%, or by about or at least about 10%, or by about or at least about 15%, or by about or at least about 20%, or by about or at least about 25%, or by about or at least about 30%, or by about or at least about 35%, or by about or at least about 40%, or by about or at least about 45%, or by about or at least about 50%, or by about or at least about 55%, or by about or at least about 60%, or by about or at least about 65%, or by about or at least about 70%, or by about or at least about 75%, or by about or at least about 80%, or by about or at least about 85%, or by about or at least about 90%, or by about or at least about 95%.

In embodiments, in comparison of the patient before receiving the Parkinson’s disease treatment to after receiving the Parkinson’s disease treatment interstimulus interval increases or decreases by about or at least about 1%, or by about or at least about 2%, or by about or at least about 3%, or by about or at least about 4%, or by about or at least about 5%, or by about or at least about 10%, or by about or at least about 15%, or by about or at least about 20%, or by about or at least about 25%, or by about or at least about 30%, or by about or at least about 35%, or by about or at least about 40%, or by about or at least about 45%, or by about or at least about 50%, or by about or at least about 55%, or by about or at least about 60%, or by about or at least about 65%, or by about or at least about 70%, or by about or at least about 75%, or by about or at least about 80%, or by about or at least about 85%, or by about or at least about 90%, or by about or at least about 95%. In embodiments, in comparison of the patient before receiving the Parkinson’s disease treatment to after receiving the Parkinson’s disease treatment blink reflex excitability increases or decreases by about or at least about 1%, or by about or at least about 2%, or by about or at least about 3%, or by about or at least about 4%, or by about or at least about 5%, or by about or at least about 10%, or by about or at least about 15%, or by about or at least about 20%, or by about or at least about 25%, or by about or at least about 30%, or by about or at least about 35%, or by about or at least about 40%, or by about or at least about 45%, or by about or at least about 50%, or by about or at least about 55%, or by about or at least about 60%, or by about or at least about 65%, or by about or at least about 70%, or by about or at least about 75%, or by about or at least about 80%, or by about or at least about 85%, or by about or at least about 90%, or by about or at least about 95%.

In embodiments, in comparison of a patient who is not afflicted with Parkinson’s disease with a patient who is afflicted with Parkinson’s disease: latency increases or decreases; differential latency increases or decreases; delta 30 increases or decreases; eyelid excursion increases or decreases; initial lid velocity increases or decreases; time to close increases or decreases; time to open increases or decreases; time under threshold increases or decreases; number of oscillations increases or decreases; total blink time increases or decreases; number of blinks increases or decreases; blink rate increases or decreases; area under curve increases or decreases; maximum closing velocity increases or decreases; maximum opening velocity increases or decreases; time to first oscillation increases or decreases; prepulse inhibition increases or decreases; blink reflex recovery cycle increases or decreases; interstimulus interval increases or decreases; and/or blink reflex excitability increases or decreases.

In embodiments, by “increase” or “decreases”, e.g., in comparison of a patient who is not afflicted with a Parkinson’s with a patient who is afflicted with a Parkinson’s, the one or more blink-associated parameters do not change but one or more are static values that are compared to each other. In embodiments “increase” is synonymous with “is more than”. In embodiments “decrease” is synonymous with “is less than”. In embodiments, assessment of whether a value “increases” or “is more than” or “decreases” or “is less than”, e.g., in comparison of a patient who is not afflicted with a Parkinson’s with a patient who is afflicted with a Parkinson’s, involves comparing a measured value, e.g., from a patient who is afflicted with a Parkinson’s, with a reference standard, e.g., from a patient or population of patients who are not afflicted with a Parkinson’s. Accordingly, in embodiments, the one or more blink-associated parameters of a patient or population of patients who is not afflicted with a Parkinson’s are a reference value.

In embodiments, in comparison of a patient who is not afflicted with Parkinson’s disease with a patient who is afflicted with Parkinson’s disease latency increases or decreases by about or at least about 1%, or by about or at least about 2%, or by about or at least about 3%, or by about or at least about 4%, or by about or at least about 5%, or by about or at least about 10%, or by about or at least about 15%, or by about or at least about 20%, or by about or at least about 25%, or by about or at least about 30%, or by about or at least about 35%, or by about or at least about 40%, or by about or at least about 45%, or by about or at least about 50%, or by about or at least about 55%, or by about or at least about 60%, or by about or at least about 65%, or by about or at least about 70%, or by about or at least about 75%, or by about or at least about 80%, or by about or at least about 85%, or by about or at least about 90%, or by about or at least about 95%. In embodiments, in comparison of a patient who is not afflicted with Parkinson’s disease with a patient who is afflicted with Parkinson’s disease differential latency increases or decreases by about or at least about 1%, or by about or at least about 2%, or by about or at least about 3%, or by about or at least about 4%, or by about or at least about 5%, or by about or at least about 10%, or by about or at least about 15%, or by about or at least about 20%, or by about or at least about 25%, or by about or at least about 30%, or by about or at least about 35%, or by about or at least about 40%, or by about or at least about 45%, or by about or at least about 50%, or by about or at least about 55%, or by about or at least about 60%, or by about or at least about 65%, or by about or at least about 70%, or by about or at least about 75%, or by about or at least about 80%, or by about or at least about 85%, or by about or at least about 90%, or by about or at least about 95%.

In embodiments, in comparison of a patient who is not afflicted with Parkinson’s disease with a patient who is afflicted with Parkinson’s disease delta 30 increases or decreases by about or at least about 1%, or by about or at least about 2%, or by about or at least about 3%, or by about or at least about 4%, or by about or at least about 5%, or by about or at least about 10%, or by about or at least about 15%, or by about or at least about 20%, or by about or at least about 25%, or by about or at least about 30%, or by about or at least about 35%, or by about or at least about 40%, or by about or at least about 45%, or by about or at least about 50%, or by about or at least about 55%, or by about or at least about 60%, or by about or at least about 65%, or by about or at least about 70%, or by about or at least about 75%, or by about or at least about 80%, or by about or at least about 85%, or by about or at least about 90%, or by about or at least about 95%.

In embodiments, in comparison of a patient who is not afflicted with Parkinson’s disease with a patient who is afflicted with Parkinson’s disease eyelid excursion increases or decreases by about or at least about 1%, or by about or at least about 2%, or by about or at least about 3%, or by about or at least about 4%, or by about or at least about 5%, or by about or at least about 10%, or by about or at least about 15%, or by about or at least about 20%, or by about or at least about 25%, or by about or at least about 30%, or by about or at least about 35%, or by about or at least about 40%, or by about or at least about 45%, or by about or at least about 50%, or by about or at least about 55%, or by about or at least about 60%, or by about or at least about 65%, or by about or at least about 70%, or by about or at least about 75%, or by about or at least about 80%, or by about or at least about 85%, or by about or at least about 90%, or by about or at least about 95%. In embodiments, in comparison of a patient who is not afflicted with Parkinson’s disease with a patient who is afflicted with Parkinson’s disease initial lid velocity increases or decreases by about or at least about 1%, or by about or at least about 2%, or by about or at least about 3%, or by about or at least about 4%, or by about or at least about 5%, or by about or at least about 10%, or by about or at least about 15%, or by about or at least about 20%, or by about or at least about 25%, or by about or at least about 30%, or by about or at least about 35%, or by about or at least about 40%, or by about or at least about 45%, or by about or at least about 50%, or by about or at least about 55%, or by about or at least about 60%, or by about or at least about 65%, or by about or at least about 70%, or by about or at least about 75%, or by about or at least about 80%, or by about or at least about 85%, or by about or at least about 90%, or by about or at least about 95%.

In embodiments, in comparison of a patient who is not afflicted with Parkinson’s disease with a patient who is afflicted with Parkinson’s disease time to close increases or decreases by about or at least about 1%, or by about or at least about 2%, or by about or at least about 3%, or by about or at least about 4%, or by about or at least about 5%, or by about or at least about 10%, or by about or at least about 15%, or by about or at least about 20%, or by about or at least about 25%, or by about or at least about 30%, or by about or at least about 35%, or by about or at least about 40%, or by about or at least about 45%, or by about or at least about 50%, or by about or at least about 55%, or by about or at least about 60%, or by about or at least about 65%, or by about or at least about 70%, or by about or at least about 75%, or by about or at least about 80%, or by about or at least about 85%, or by about or at least about 90%, or by about or at least about 95%.

In embodiments, in comparison of a patient who is not afflicted with Parkinson’s disease with a patient who is afflicted with Parkinson’s disease time to open increases or decreases by about or at least about 1%, or by about or at least about 2%, or by about or at least about 3%, or by about or at least about 4%, or by about or at least about 5%, or by about or at least about 10%, or by about or at least about 15%, or by about or at least about 20%, or by about or at least about 25%, or by about or at least about 30%, or by about or at least about 35%, or by about or at least about 40%, or by about or at least about 45%, or by about or at least about 50%, or by about or at least about 55%, or by about or at least about 60%, or by about or at least about 65%, or by about or at least about 70%, or by about or at least about 75%, or by about or at least about 80%, or by about or at least about 85%, or by about or at least about 90%, or by about or at least about 95%. In embodiments, in comparison of a patient who is not afflicted with Parkinson’s disease with a patient who is afflicted with Parkinson’s disease time under threshold of 20 increases or decreases by about or at least about 1%, or by about or at least about 2%, or by about or at least about 3%, or by about or at least about 4%, or by about or at least about 5%, or by about or at least about 10%, or by about or at least about 15%, or by about or at least about 20%, or by about or at least about 25%, or by about or at least about 30%, or by about or at least about 35%, or by about or at least about 40%, or by about or at least about 45%, or by about or at least about 50%, or by about or at least about 55%, or by about or at least about 60%, or by about or at least about 65%, or by about or at least about 70%, or by about or at least about 75%, or by about or at least about 80%, or by about or at least about 85%, or by about or at least about 90%, or by about or at least about 95%.

In embodiments, in comparison of a patient who is not afflicted with Parkinson’s disease with a patient who is afflicted with Parkinson’s disease number of oscillations increases or decreases by about or at least about 1%, or by about or at least about 2%, or by about or at least about 3%, or by about or at least about 4%, or by about or at least about 5%, or by about or at least about 10%, or by about or at least about 15%, or by about or at least about 20%, or by about or at least about 25%, or by about or at least about 30%, or by about or at least about 35%, or by about or at least about 40%, or by about or at least about 45%, or by about or at least about 50%, or by about or at least about 55%, or by about or at least about 60%, or by about or at least about 65%, or by about or at least about 70%, or by about or at least about 75%, or by about or at least about 80%, or by about or at least about 85%, or by about or at least about 90%, or by about or at least about 95%.

In embodiments, in comparison of a patient who is not afflicted with Parkinson’s disease with a patient who is afflicted with Parkinson’s disease number of blinks increases or decreases by about or at least about 1%, or by about or at least about 2%, or by about or at least about 3%, or by about or at least about 4%, or by about or at least about 5%, or by about or at least about 10%, or by about or at least about 15%, or by about or at least about 20%, or by about or at least about 25%, or by about or at least about 30%, or by about or at least about 35%, or by about or at least about 40%, or by about or at least about 45%, or by about or at least about 50%, or by about or at least about 55%, or by about or at least about 60%, or by about or at least about 65%, or by about or at least about 70%, or by about or at least about 75%, or by about or at least about 80%, or by about or at least about 85%, or by about or at least about 90%, or by about or at least about 95%. In embodiments, in comparison of a patient who is not afflicted with Parkinson’s disease with a patient who is afflicted with Parkinson’s disease blink rate increases or decreases by about or at least about 1%, or by about or at least about 2%, or by about or at least about 3%, or by about or at least about 4%, or by about or at least about 5%, or by about or at least about 10%, or by about or at least about 15%, or by about or at least about 20%, or by about or at least about 25%, or by about or at least about 30%, or by about or at least about 35%, or by about or at least about 40%, or by about or at least about 45%, or by about or at least about 50%, or by about or at least about 55%, or by about or at least about 60%, or by about or at least about 65%, or by about or at least about 70%, or by about or at least about 75%, or by about or at least about 80%, or by about or at least about 85%, or by about or at least about 90%, or by about or at least about 95%.

In embodiments, in comparison of a patient who is not afflicted with Parkinson’s disease with a patient who is afflicted with Parkinson’s disease area under curve increases or decreases by about or at least about 1%, or by about or at least about 2%, or by about or at least about 3%, or by about or at least about 4%, or by about or at least about 5%, or by about or at least about 10%, or by about or at least about 15%, or by about or at least about 20%, or by about or at least about 25%, or by about or at least about 30%, or by about or at least about 35%, or by about or at least about 40%, or by about or at least about 45%, or by about or at least about 50%, or by about or at least about 55%, or by about or at least about 60%, or by about or at least about 65%, or by about or at least about 70%, or by about or at least about 75%, or by about or at least about 80%, or by about or at least about 85%, or by about or at least about 90%, or by about or at least about 95%.

In embodiments, in comparison of a patient who is not afflicted with Parkinson’s disease with a patient who is afflicted with Parkinson’s disease maximum closing velocity increases or decreases by about or at least about 1%, or by about or at least about 2%, or by about or at least about 3%, or by about or at least about 4%, or by about or at least about 5%, or by about or at least about 10%, or by about or at least about 15%, or by about or at least about 20%, or by about or at least about 25%, or by about or at least about 30%, or by about or at least about 35%, or by about or at least about 40%, or by about or at least about 45%, or by about or at least about 50%, or by about or at least about 55%, or by about or at least about 60%, or by about or at least about 65%, or by about or at least about 70%, or by about or at least about 75%, or by about or at least about 80%, or by about or at least about 85%, or by about or at least about 90%, or by about or at least about 95%. In embodiments, in comparison of a patient who is not afflicted with Parkinson’s disease with a patient who is afflicted with Parkinson’s disease maximum opening velocity increases or decreases by about or at least about 1%, or by about or at least about 2%, or by about or at least about 3%, or by about or at least about 4%, or by about or at least about 5%, or by about or at least about 10%, or by about or at least about 15%, or by about or at least about 20%, or by about or at least about 25%, or by about or at least about 30%, or by about or at least about 35%, or by about or at least about 40%, or by about or at least about 45%, or by about or at least about 50%, or by about or at least about 55%, or by about or at least about 60%, or by about or at least about 65%, or by about or at least about 70%, or by about or at least about 75%, or by about or at least about 80%, or by about or at least about 85%, or by about or at least about 90%, or by about or at least about 95%.

In embodiments, in comparison of a patient who is not afflicted with Parkinson’s disease with a patient who is afflicted with Parkinson’s disease prepulse inhibition increases or decreases by about or at least about 1%, or by about or at least about 2%, or by about or at least about 3%, or by about or at least about 4%, or by about or at least about 5%, or by about or at least about 10%, or by about or at least about 15%, or by about or at least about 20%, or by about or at least about 25%, or by about or at least about 30%, or by about or at least about 35%, or by about or at least about 40%, or by about or at least about 45%, or by about or at least about 50%, or by about or at least about 55%, or by about or at least about 60%, or by about or at least about 65%, or by about or at least about 70%, or by about or at least about 75%, or by about or at least about 80%, or by about or at least about 85%, or by about or at least about 90%, or by about or at least about 95%.

In embodiments, in comparison of a patient who is not afflicted with Parkinson’s disease with a patient who is afflicted with Parkinson’s disease blink reflex recovery cycle increases or decreases by about or at least about 1%, or by about or at least about 2%, or by about or at least about 3%, or by about or at least about 4%, or by about or at least about 5%, or by about or at least about 10%, or by about or at least about 15%, or by about or at least about 20%, or by about or at least about 25%, or by about or at least about 30%, or by about or at least about 35%, or by about or at least about 40%, or by about or at least about 45%, or by about or at least about 50%, or by about or at least about 55%, or by about or at least about 60%, or by about or at least about 65%, or by about or at least about 70%, or by about or at least about 75%, or by about or at least about 80%, or by about or at least about 85%, or by about or at least about 90%, or by about or at least about 95%. In embodiments, in comparison of a patient who is not afflicted with Parkinson’s disease with a patient who is afflicted with Parkinson’s disease interstimulus interval increases or decreases by about or at least about 1%, or by about or at least about 2%, or by about or at least about 3%, or by about or at least about 4%, or by about or at least about 5%, or by about or at least about 10%, or by about or at least about 15%, or by about or at least about 20%, or by about or at least about 25%, or by about or at least about 30%, or by about or at least about 35%, or by about or at least about 40%, or by about or at least about 45%, or by about or at least about 50%, or by about or at least about 55%, or by about or at least about 60%, or by about or at least about 65%, or by about or at least about 70%, or by about or at least about 75%, or by about or at least about 80%, or by about or at least about 85%, or by about or at least about 90%, or by about or at least about 95%.

In embodiments, in comparison of a patient who is not afflicted with Parkinson’s disease with a patient who is afflicted with Parkinson’s disease blink reflex excitability increases or decreases by about or at least about 1%, or by about or at least about 2%, or by about or at least about 3%, or by about or at least about 4%, or by about or at least about 5%, or by about or at least about 10%, or by about or at least about 15%, or by about or at least about 20%, or by about or at least about 25%, or by about or at least about 30%, or by about or at least about 35%, or by about or at least about 40%, or by about or at least about 45%, or by about or at least about 50%, or by about or at least about 55%, or by about or at least about 60%, or by about or at least about 65%, or by about or at least about 70%, or by about or at least about 75%, or by about or at least about 80%, or by about or at least about 85%, or by about or at least about 90%, or by about or at least about 95%.

In embodiments, the patient who is afflicted with Parkinson’s disease (PD) exhibits one or more changes in blink reflex parameters relative to a healthy adult (e.g., without PD). In embodiments, these changes include increased time to open, increased oscillations, increased area under the curve, increased time under 20, increased oscillation rate, and/or decreased excursions (e.g., as shown in Table 1 and Fig. 1). In embodiments, the patient who is afflicted with Parkinson’s disease exhibits changes in blink reflex parameters that relate to increased time to open, increased oscillations, increased area under the curve, increased time under 20, increased oscillation rate, and decreased excursions.

In embodiments, the blink reflex correlates with duration of Parkinson’s disease (PD). In embodiments, the blink reflex is used to determine an estimation of how long a patient has been afflicted with PD, or to confirm a recent diagnosis of PD. In embodiments, the blink reflex that correlates with duration of PD includes one or more of increased time to open, decreased time to open, increased number of oscillations, and/or increased mean oscillation rate.

In embodiments, the blink reflex correlates with the sex of the patient. In embodiments, the blink reflex that correlates with sex comprises one or more of excursion, max opening velocity, number of oscillations, oscillation rate, and/or latency. In embodiments, females have a lower incidence of PD, a later age of onset of symptomatic PD, and have slower progression than males, as evidenced by blink reflex parameters. In embodiments, the patient is male. In embodiments, the patient is female.

In embodiments, blink reflex parameter datasets used for diagnosing, monitoring, and/or treatment selection for subjects with PD, or suspected of having PD, are bifurcated based on sex and/or segmented based on age and/or health.

Medications/Treatments

In embodiments, the Parkinson’s disease treatment is or comprises a medication or surgery. In embodiments, the Parkinson’s disease treatment is or comprises deep brain stimulation. In embodiments, the Parkinson’s disease treatment is an electrode-based therapy or device, optionally implantable.

In embodiments, the medication reduces a motor symptom. In embodiments, the medication is or comprises one or more of levodopa (L-DOPA), MAO-B inhibitors, and/or dopamine agonists.

In embodiments, the medication is or comprises one or more of levodopa (optionally, in combination with tolcapone, entacapone, carbidopa, or benserazide), dopamine agonists (optionally, selected from apomorphine, bromocriptine, pergolide, pramipexole, ropinirole, piribedil, cabergoline, apomorphine, and lisuride), MAO-B inhibitors (optionally, deprenyls, optionally, selected from selegiline and rasagiline), Piribedil, pramipexole (optionally, selected from MIRAPEX, MIRAPEXIN, and SIFROL), bromocriptine (optionally, selected from PARLODEL, CYCLOSET, and BROTIN), Ropinirole (optionally, selected from REQUIP, REPREVE, RONIROL, and ADARTREL), sumanirole (optionally, PNU-95,666), aplindore (optionally, DAB-452), amantadine, anticholinergics (optionally, selected from artane and Cogentin), quetiapine, cholinesterase inhibitors, modafinil, tyrosine hydroxylase, N-phenyl-7-(hydroxylimino)cyclopropa[b]chromen-1 a-carboxamide (PHCCC), and nonsteroidal anti-inflammatory drugs. Scales

In embodiments, the Parkinson’s disease is evaluated by or characterized by the Unified Parkinson’s Disease Rating Scale (UPDRS). In embodiments, the Parkinson’s disease is evaluated by or characterized by the Hoehn and Yahr scale. In embodiments, the Parkinson’s disease is evaluated by or characterized by the Schwab and England ADL (Activities of Daily Living) scale.

Symptoms Prior to Treatment

In embodiments, the Parkinson’s disease is characterized by early symptoms, optionally selected from tremor, rigidity, slowness of movement, and/or difficulty with walking. In embodiments, the patient is experiencing symptoms associated with dyskinesia. In embodiments, the dyskinesia is or comprises one or more of dystonia, chorea, movements, and/or tremors. In embodiments, the movements comprise mild bradykinesia, moderate bradykinesia, severe bradykinesia, and/or morning akinesia.

In embodiments, the tremors comprise unilateral or bilateral mild tremors, bilateral or midline moderate tremors, and/or intractable tremors. In embodiments, the dyskinesia ranges from mild to severe. In embodiments, the patient is experiencing symptoms associated with changes in balance, optionally selected from impaired balance, impaired righting reflexes, and/or significant balance disorder or falling.

In embodiments, the patient is experiencing a reduction in quality of life. In embodiments, the patient has a moderate impact on quality of life (optionally experiencing some limitations to activities of daily living). In embodiments, the patient’s quality of life has been diminished (optionally by illness). In embodiments, the patient has experienced a change in non-motor symptoms.

In embodiments, the patient has mild to moderate cognitive impairment. In embodiments, the patient has significant cognitive impairment such as dementia, optionally including behavioral disturbances, optionally hallucinations. In embodiments, the patient has medically refractory motor fluctuations, optionally consisting of “wearing off” and/or levodopa-induced dyskinesias, optionally causing significant disability.

In embodiments, the patient is experiencing symptoms associated with rigidity. In embodiments, the patient is experiencing symptoms associated with slowness of movement. In embodiments, the patient is experiencing symptoms associated with difficulty walking. In embodiments, the patient is experiencing symptoms associated with behavioral problems. In embodiments, the patient is experiencing complications associated with dementia. In embodiments, the patient is experiencing complications associated with depression. In embodiments, the patient is experiencing complications associated with anxiety.

In embodiments, the Parkinson’s disease is or comprises one or more of idiopathic Parkinson’s disease. In embodiments, the Parkinson’s disease is or comprises vascular parkinsonism. In embodiments, the Parkinson’s disease is or comprises drug-induced parkinsonism. In embodiments, the Parkinson’s disease is or comprises dementia with Lewy bodies. In embodiments, the Parkinson’s disease is or comprises inherited Parkinson’s. In embodiments, the Parkinson’s disease is or comprises juvenile Parkinson’s. In embodiments, the Parkinson’s disease is or comprises Parkinson’s disease dementia.

Improvement After Treatment

In embodiments, the method detects, indirectly or directly, a reduction of the total score of a Parkinson’s disease rating scale in patient after treatment. In embodiments, in comparison of the patient before receiving the Parkinson’s disease treatment to after receiving the Parkinson’s disease treatment, the total score on a Parkinson’s disease rating scale decreases. In embodiments, in comparison of the patient before receiving the Parkinson’s disease treatment to after receiving the Parkinson’s disease treatment, the patient’s UPDRS-III medication score decreases.

In embodiments, in comparison of the patient before receiving the Parkinson’s disease treatment to after receiving the Parkinson’s disease treatment, the patient’s UPDRS-III medication score decreases by about or at least about 5%, or by about or at least about 10%, or by about or at least about 15%, or by about or at least about 20%, or by about or at least about 25%, or by about or at least about 30%, or by about or at least about 35%, or by about or at least about 40%, or by about or at least about 45%, or by about or at least about 50%, or by about or at least about 55%, or by about or at least about 60%, or by about or at least about 65%, or by about or at least about 70%, or by about or at least about 75%, or by about or at least about 80%, or by about or at least about 85%, or by about or at least about 90%, or by about or at least about 95%.

In embodiments, in comparison of the patient before receiving the Parkinson’s disease treatment to after receiving the Parkinson’s disease treatment, the patients quality of life, mood, cognitive function, dyskinesia, compulsive behavior, and/or sleep quality improve. Improvements and Scales Used

In embodiments, the patient’s improvement in dyskinesia is assessed using the Unified Dyskinesia Rating Scale (UDysRS). In embodiments, the patient’s improvement in dyskinesia is assessed using the Hauser motor diaries. In embodiments, the patient’s improvement in mood is assessed using the Beck Depression Inventory II (BDI-II). In embodiments, the patient’s improvement in cognitive function is assessed using the Montreal Cognitive Assessment (MoCA). In embodiments, the patient’s improvement in cognitive function is assessed using the Mattis Dementia Rating Scale- Second Edition (MDRS-2).

In embodiments, the patient’s improvement in compulsive behaviors is assessed using the Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease- Rating Scale (QUIP-RS). In embodiments, the patient’s improvement in sleep quality and disturbance is assessed using the Parkinson’s Disease Sleep Scale 2 (PDSS-2). In embodiments, the patient’s improvement in quality of life is assessed using the Parkinson’s Disease Questionnaire (PDQ39). In embodiments, the patient’s improvement in quality of life is assessed using the Schwab and England scale. In embodiments, the patient’s improvement in quality of life is assessed using the Clinical Global Impression (CGI). In embodiments, the patient’s improvement in quality of life is assessed using the Patient Global Impression (PGI).

In embodiments, there is provided methods of treatment of Parkinson’s symptoms (e.g., without limitation, shaking, stiffness, and lack of coordination) and/or selection of agents for treatment of Parkinson’s symptoms and/or monitoring if agents are having efficacy in treatment of Parkinson’s symptoms. In embodiments, the treatment includes one or more of lessening severity, alleviation of pain intensity, and other associated symptoms, reducing frequency of recurrence, increasing the quality of life, and decreasing dose and/or frequency of administration of medications to treat the Parkinson’s disease.

In embodiments, there is provided methods of reducing incidence of Parkinson’s and/or selecting agents to reduce incidence of Parkinson’s. In embodiments, reducing incidence includes reducing one or more of severity (e.g., reducing need for and/or amount of therapies used in treatment), duration, and frequency (including, e.g., delaying or increasing time to next episodic attack in a subject). In embodiments, there is provided methods of ameliorating Parkinson’s or one or more symptoms of Parkinson’s and/or selection of agents for ameliorating Parkinson’s or one or more symptoms of Parkinson’s and/or monitoring if agents are having efficacy in ameliorating Parkinson’s or one or more symptoms of Parkinson’s. In embodiments, ameliorating Parkinson’s or one or more symptoms of Parkinson’s includes lessening or improvement of one or more symptoms of Parkinson’s as compared to without treatment. In embodiments, ameliorating Parkinson’s or one or more symptoms of Parkinson’s includes shortening or reduction in duration of a symptom. For example, in embodiments, Parkinson’s is ameliorated by at least about 10%, or least about 20%, or least about 30%, or least about 40%, or least about 50%, or least about 60%, or least about 70% in the individual as compared to the level before treatment.

In embodiments, there is provided methods of controlling Parkinson’s and/or selection of agents for controlling Parkinson’s and/or monitoring if agents are having efficacy controlling Parkinson’s. In embodiments, controlling Parkinson’s includes maintaining or reducing severity or duration of one or more symptoms of Parkinson’s or frequency of Parkinson’s symptoms in an individual (as compared to the level before treatment). For example, in embodiments, a duration or severity of discomforts, or frequency of movements is reduced by at least about 10%, or least about 20%, or least about 30%, or least about 40%, or least about 50%, or least about 60%, or least about 70% in the individual as compared to the level before treatment.

In embodiments, there is provided methods of delaying the development of Parkinson’s or one or more symptoms of Parkinson’s and/or selection of agents having efficacy in delaying the development of Parkinson’s or one or more symptoms of Parkinson’s and/or monitoring if agents are having efficacy in delaying the development of Parkinson’s or one or more symptoms of Parkinson’s. In embodiments, delaying the development of Parkinson’s or one or more symptoms of Parkinson’s includes hindering, slowing, stabilizing, and/or postponing progression of the disease. This delay can be of varying lengths of time, depending on the history of the disease and/or individuals being treated.

In embodiments, assessment of Parkinson’s may be performed based on one or more subjective measures, such as patient characterization of symptoms, e.g., tremor or shaking lasting about 4 to about 72 hours with two or more of the following symptoms: loss of automatic movements, impaired posture and balance, slowed movement (bradykinesia), and muscle stiffness of moderate or severe intensity.

The following definitions are used in connection with the invention disclosed herein. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of skill in the art to which this invention belongs.

As used herein, “a,” “an,” or “the” can mean one or more than one.

The term “alleviating” means a reduction in the occurrence of a symptom, e.g. , without limitation, of undergoing symptoms of Parkinson’s disease.

The term “treating” means to alleviate (or to eliminate) at least one symptom of Parkinson’s (such as, by nonlimiting illustration, a tremor), either temporarily or permanently.

Further, the term “about” when used in connection with a referenced numeric indication means the referenced numeric indication plus or minus up to 10% of that referenced numeric indication. For example, the language “about 50” covers the range of 45 to 55.

An “effective amount,” when used in connection with medical uses is an amount that is effective for providing a measurable treatment, prevention, or reduction in the rate of pathogenesis of a disease of interest.

The term “in vivo" refers to an event that takes place in a subject’s body.

The term “ex vivo" refers to an event which involves treating or performing a procedure on a cell, tissue and/or organ which has been removed from a subject’s body. Aptly, the cell, tissue and/or organ may be returned to the subject’s body in a method of treatment or surgery.

“Carrier” or “vehicle” as used herein refer to carrier materials suitable for drug administration. Carriers and vehicles useful herein include any such materials known in the art, e.g., any liquid, gel, solvent, liquid diluent, solubilizer, surfactant, lipid, or the like, which is nontoxic, and which does not interact with other components of the composition in a deleterious manner.

The phrase “pharmaceutically acceptable” refers to those compounds, materials, compositions, and/or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit/risk ratio. The terms “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” are intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and inert ingredients. The use of such pharmaceutically acceptable carriers or pharmaceutically acceptable excipients for active pharmaceutical ingredients is well known in the art. Except insofar as any conventional pharmaceutically acceptable carrier or pharmaceutically acceptable excipient is incompatible with the active pharmaceutical ingredient, its use in the therapeutic compositions of the disclosure is contemplated. Additional active pharmaceutical ingredients, such as other drugs, can also be incorporated into the described compositions and methods.

As referred to herein, all compositional percentages are by weight of the total composition, unless otherwise specified. As used herein, the word “include,” and its variants, is intended to be nonlimiting, such that recitation of items in a list is not to the exclusion of other like items that may also be useful in the compositions and methods of this technology. Similarly, the terms “can” and “may” and their variants are intended to be non-limiting, such that recitation that an embodiment can or may comprise certain elements or features does not exclude other embodiments of the present technology that do not contain those elements or features.

Although the open-ended term “comprising,” as a synonym of terms such as including, containing, or having, is used herein to describe and claim the invention, the present invention, or embodiments thereof, may alternatively be described using alternative terms such as “consisting of” or “consisting essentially of.”

As used herein, the words “preferred” and “preferably” refer to embodiments of the technology that afford certain benefits, under certain circumstances. However, other embodiments may also be preferred, under the same or other circumstances. Furthermore, the recitation of one or more preferred embodiments does not imply that other embodiments are not useful and is not intended to exclude other embodiments from the scope of the technology.

The amount of compositions described herein needed for achieving a therapeutic effect may be determined empirically in accordance with conventional procedures for the particular purpose. Generally, for administering therapeutic agents for therapeutic purposes, the therapeutic agents are given at a pharmacologically effective dose. A “pharmacologically effective amount,” “pharmacologically effective dose,” “therapeutically effective amount,” or “effective amount” refers to an amount sufficient to produce the desired physiological effect or amount capable of achieving the desired result, particularly for treating the disorder or disease. An effective amount as used herein would include an amount sufficient to, for example, delay the development of a symptom of the disorder or disease, alter the course of a symptom of the disorder or disease (e.g., slow the progression of a symptom of the disease), reduce or eliminate one or more symptoms or manifestations of the disorder or disease, and reverse a symptom of a disorder or disease. Therapeutic benefit also includes halting or slowing the progression of the underlying disease or disorder, regardless of whether improvement is realized.

As used herein, “methods of treatment” are equally applicable to use of a composition for treating the diseases or disorders described herein and/or compositions for use and/or uses in the manufacture of a medicaments for treating the diseases or disorders described herein.

This invention is further illustrated by the following non-limiting examples.

EXAMPLES

Hereinafter, the present disclosure will be described in further detail with reference to examples. These examples are illustrative purposes only and are not to be construed to limit the scope of the present invention. In addition, various modifications and variations can be made without departing from the technical scope of the present invention.

Example 1 - Measuring Blink Reflex Response for Diagnosis of Parkinson’s Disease (PD)

A cross-sectional study was performed that compared the blink reflex between patients with PD (n = 81 , mean age 71.0 ± 8.8 yrs.) to age-matched healthy adult controls without PD (n = 106, mean age 69.1 ± 10.5 yrs.). Table 1 below summarizes the baseline latency (ms), differential latency (ms), delta 30 (ms), eyelid excursion (pixels), initial lid velocity (pixels/ms), time to close, time to open, time under threshold, number of oscillations, oscillation rate, time to first oscillation, number of blinks, blink rate (per minute), area under the curve (pixels), maximum closing velocity (ms), maximum opening velocity, excursion, and closure indicator for each patient population.

Table 1 : Blink reflex comparison between PD and Controls. Data are median ± 95% confidence interval (Cl). Statistical evaluation is done using a parametric t-test (significance cutoff of p < 0.05).

The results (e.g., as summarized in Table 1) indicate a statistically significant difference in blink reflex parameters in several categories. Fig. 1 illustrates the results indicating that PD patients exhibited a statistically significantly increased time to open, time under 20, number of oscillations, oscillation rate, and area under the curve, relative to the control population; PD patients exhibited a statistically significantly decreased excursion in comparison to the control population.

Next, blink reflex parameters were analyzed for correlation to duration of PD pathology in patients with PD to evaluate if measuring blink reflex can provide a quantitative measure of the severity of diagnosis and/or progression of pathology. As shown in Figs. 2A-2D, a strong statistical correlation exists for several blink reflex parameters with respect to the diagnosis of patients with PD. Figs. 2A- 2D depict the time to open, time to close, number of oscillations, and mean oscillation rate as a function of years since PD diagnosis, respectively, with each indicating a correlation with a p < 0.001 . From the data, it was observed that the blink reflex parameters correlate to the time after diagnosis, and thus the progression of PD, particularly with respect to increased time to open, decreased time to close, increased number of oscillations, and increased mean oscillation rate.

In conclusion, it was demonstrated that several blink reflex parameters successfully discriminated between patients based on PD status. Moreover, blink reflex parameters are effective at determining the extent, or severity, of PD, by providing an estimation of time since manifestation of PD symptoms or pathology (or suspected PD pathology). Overall, the data indicated that measuring the blink reflex is an effective method for diagnosing, monitoring, and selecting treatments for patients suspected of having PD, or for patients that have PD.

Example 2 - Measuring Sex-Based and Age-Based Blink Reflex Response Differences

A cross-sectional study of consecutive healthy participants with no diagnosis of PD was performed (n = 365, 61 % female, 90% white, mean age = 48.5 ± 19.9 yrs.). The study analyzed blink reflex parameters with respect to age, sex, and race to identify population-based differences in blink reflex. The same blink reflex parameters indicated in Example 1 were measured.

It was observed that the blink reflex naturally changed with age, but overall, was not affected by participant sex. The most discriminate variable was the number of oscillations, which was significantly higher in patients with PD (e.g., as shown in Fig. 3A), whereas it naturally decreased with healthy aging (e.g., as shown in Fig. 3B). This further demonstrated the measured discrepancy in number of oscillations between an aging population with PD and a healthily aging population.

The data, when stratified by sex, indicated differences between male and female blink reflex parameters in those with PD (e.g., as summarized in Table 2).

Table 2: Sex-based differences in blink reflex comparison between males and females with PD.

Males with PD exhibited lower excursions/slower eyelid motion, whereas females with PD exhibited higher oscillations (cycles of up and down upper eyelid movement).

In conclusion, it was demonstrated that several blink reflex parameters were able to discriminate between PD patients based on sex, indicating that measuring the blink reflex is an effective method for diagnosing, monitoring, and selecting treatments for patients suspected of having PD, or having PD, based on datasets that can be further segmented by sex and/or age for increased accuracy.

EQUIVALENTS

While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure as come within known or customary practice within the art to which the invention pertains and as may be applied to the essential features herein set forth and as follows in the scope of the appended claims.

Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific embodiments described specifically herein. Such equivalents are intended to be encompassed in the scope of the following claims.

INCORPORATION BY REFERENCE

All patents and publications referenced herein are hereby incorporated by reference in their entireties.

The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention.

As used herein, all headings are simply for organization and are not intended to limit the disclosure in any manner. The content of any individual section may be equally applicable to all sections.

Claims

What is claimed is:

1 . A method of diagnosing whether a patient is afflicted with Parkinson’s disease, comprising:

(a) measuring a blink reflex in a patient suspected to be afflicted with Parkinson’s disease, the measurement comprising:

(i) applying a non-electrical stimulus to an eye of the patient to induce a blink reflex and

(ii) assessing one or more blink-associated parameters; and

(b) diagnosing the patient as afflicted with Parkinson’s disease or not afflicted with Parkinson’s disease by comparing the one or more blink-associated parameters to equivalent one or more blink-associated parameters from a patient who is not afflicted with Parkinson’s disease.

2. A method of diagnosing and treating a patient afflicted with Parkinson’s disease, comprising:

(ii) assessing one or more blink-associated parameters; and

(b) diagnosing the patient as afflicted with Parkinson’s disease or not afflicted with Parkinson’s disease by comparing the one or more blink-associated parameters to equivalent one or more blink-associated parameters from a patient who is not afflicted with Parkinson’s disease; and

(c) administering an effective amount of a Parkinson’s disease treatment to a patient diagnosed as afflicted with Parkinson’s disease.

3. A method of selecting a Parkinson’s disease treatment for a patient afflicted with Parkinson’s disease, comprising: (a) measuring a blink reflex in the patient afflicted with Parkinson’s disease, the measurement comprising:

(II) assessing one or more blink-associated parameters; and

(b) selecting a Parkinson’s disease treatment for the patient afflicted with Parkinson’s disease by comparing the one or more blink-associated parameters to equivalent one or more blink-associated parameters from the patient when not experiencing symptoms of Parkinson’s disease and/or the patient when receiving the Parkinson’s disease treatment.

4. A method of monitoring response of Parkinson’s disease in patient to a Parkinson’s disease treatment, comprising

(a) measuring a blink reflex in the patient afflicted with a Parkinson’s disease and who has undergone or is undergoing treatment with the Parkinson’s disease treatment, the measurement comprising:

(ii) assessing one or more blink-associated parameters; and

(b) determining a response to the Parkinson’s disease treatment by comparing the one or more blink-associated parameters to equivalent one or more blink-associated parameters from the patient when not experiencing symptoms of Parkinson’s disease and/or the patient before receiving the Parkinson’s disease treatment.

5. A method of screening a subject for early Parkinson’s disease and/or risk of future development of Parkinson’s disease, comprising:

(a) measuring a blink reflex in a subject, the measurement comprising:

(i) applying a non-electrical stimulus to an eye of the subject to induce a blink reflex and

(ii) assessing one or more blink-associated parameters; and (b) identifying the subject as afflicted with early Parkinson’s disease, having risk of future development of Parkinson’s disease, or neither by comparing the one or more blink- associated parameters to equivalent one or more blink-associated parameters from a subject who is not afflicted with Parkinson’s disease.

6. The method of claim 5, wherein the subject identified as afflicted with early Parkinson’s disease or having risk of future development of Parkinson’s disease is administered with preventative medications and/or lifestyle changes.

7. A method of screening a subject for Parkinson’s disease and/or atypical Parkinsonism disorders, comprising:

(a) measuring a blink reflex in a subject, the measurement comprising:

(ii) assessing one or more blink-associated parameters; and

(b) identifying the subject as afflicted with Parkinson’s disease, atypical Parkinsonism disorders, or neither by comparing the one or more blink-associated parameters to equivalent one or more blink-associated parameters from a subject who is not afflicted with Parkinson’s disease.

8. The method of claim 7, wherein the subject identified as afflicted with atypical Parkinsonism disorders comprise symptoms selected from Multiple System Atrophy, Progressive Supranuclear Palsy, Corticobasal Syndrome, Dementia with Lewy Bodies, drug-induced Parkinsonism, and vascular Parkinsonism.

9. The method of any one of claims 1 -8, wherein the diagnosing comprises: diagnosis of disease onset; determination of disease stage and/or severity; determination of disease progress; and/or determination of cognitive state and/or mental capacity.

10. The method of any one of claims 1-9, wherein the method is carried out remotely, optionally with a telehealth device.

11. The method of any one of claims 1-10, wherein the method is adapted for point-of-care application.

12. The method of any one of claims 1-11 , wherein an information collected can predict correlation of Parkinson’s disease to the occurrence of a future disease of the central nervous system, optionally dementia.

13. The method of any one of claims 1-12, wherein an information collected further allows for assessing the therapeutic efficacy of pharmaceutical and/or medical and/or surgical treatment modalities.

14. The method of any one of claims 1-13, wherein the method measures latency until physiological response to stimulus.

15. The method of any one of claims 1-14, wherein the blink reflex correlates with functionality of one or more of the trigeminal and facial nerves.

16. The method of any one of claims 1-15, wherein the non-electrical stimulus is one or more physical stimuli.

17. The method of any one of claims 1-16, wherein the one or more physical stimuli are a puff of air, a flash of light, a noise, and/or a vibration.

18. The method of claim 17, wherein the air is or comprises compressed air.

19. The method of claim 17 or claim 18, wherein the air is or comprises carbon dioxide.

20. The method of claim 18 or claim 19, wherein the compressed air is applied across the eye.

21. The method of claim 20, wherein the non-electrical stimulus is applied to the canthus or outer canthus.

22. The method of any one of claims 1-21, wherein the blink reflex is measured with a high-speed camera.

23. The method of any one of claims 1-22, wherein the blink reflex is not measured with an EMG sensor.

24. The method of any one of claims 1-23, wherein the blink reflex is measured with a blink reflex monitoring device.

25. The method of any one of claims 1-24, wherein the blink reflex monitoring device is a wearable device or a handheld device or can be placed on a tripod, on a desk, or the like.

26. The method of any one of claims 1-25, wherein the blink reflex monitoring device is a wearable device. The method of any one of claims 1-26, wherein the blink reflex monitoring device has or comprises: a front end, a back end, a first plane extending through the front end and the back end, a second plane intersecting the first plane between the front end and the back end, the back end configured to receive a portion of a face of a user and disposed opposite the front end; and a strap coupled to the blink reflex monitoring device and having a first position and a second position, wherein in the first position the strap extends away from the blink reflex monitoring device along the first plane end and is configured to secure the blink reflex monitoring device to a head of a user and in the second position the strap extends below the blink reflex monitoring device along the second plane and is configured to support the blink reflex monitoring device above a surface. The method of any one of claims 1-27, wherein the blink reflex monitoring device has or comprises: a front end and a back end, the back end configured to receive a portion of a face of a user and disposed opposite the front end; at least one strap coupled to the blink reflex monitoring device proximate the back end, the at least one strap configured to be secured around a head of a user; and an air compression system including a source of compressed air and a valve, the air compression system disposed within the blink reflex monitoring device and the valve configured to output compressed air from the back end at a pressure of about 3 PSI to about 60 PSI. The method of any one of claims 1-28, wherein the air compression system disposed within the blink reflex monitoring device and the valve configured to output compressed air from the back end at a pressure of about 30 PSI to about 50 PSI. The method of any one of claims 1-29, wherein the air compression system disposed within the blink reflex monitoring device and the valve configured to output compressed air from the back end at a pressure of about 35 PSI to about 45 PSI. The method of any one of claims 1-30, wherein the air compression system disposed within the blink reflex monitoring device and the valve configured to output compressed air from the back end at a pressure of about 38 PSI to about 43 PSI. The method of any one of claims 1-31 , wherein the air compression system disposed within the blink reflex monitoring device and the valve configured to output compressed air from the back end at a pressure of about 40 PSI to about 41 PSI. The method of any one of claims 1-32, wherein the measuring of a blink reflex, comprises: providing a blink reflex monitoring device to a user, the blink reflex monitoring device having an air compression system including a compressed air source and a valve; outputting a first burst of compressed air from the compressed air source through the valve at a first pressure; detecting a presence or an absence of a blink in response to the first burst of compressed air source at the first pressure; if the blink is present, then measuring a duration between the output of the first burst of compressed air at the first pressure and the blink to determine the blink reflex; and if the blink is absent, then outputting a second burst of compressed air from the compressed air source at a second pressure, the second pressure being greater than the first pressure and measuring a duration between the output of the second burst of compressed air at the second pressure and the blink to determine the blink reflex. The method of any one of claims 1-33, wherein the one or more blink-associated parameters are selected from:

(c) delta 30, comprising a time difference between ipsilateral eye and contralateral eye movement; (d) eyelid excursion, optionally in pixels, comprising a distance traveled by the eyelid from the tonic lid position to closed position;

(e) initial lid velocity, optionally in pixels/msec, comprising an average eyelid speed following start of eyelid movement, optionally within the first about 5 frames, the first about 7 frames, or the first about 10 frames;

(h) time under threshold, optionally in log scale, comprising a time that the eyelid spends below the threshold position;

(i) number of oscillations, comprising cycles of up and down upper eyelid movement after a stimulated blink;

0) total blink time, optionally in log scale, comprising a time from start of eyelid movement until it returns to its tonic lid position;

(k) number of blinks;

(l) blink rate, optionally per minute;

(m) area under curve, optionally in pixels;

(p) time to first oscillation, optionally in log scale, comprising the elapsed time between the eyelid returning within threshold of a tonic position for a stimulated blink and the onset of the next unstimulated blink; (q) prepulse inhibition, optionally comprising the inhibitory effect caused by a stimulus of an intensity low enough not to induce a response by itself on the response elicited by a subsequent stimulus;

(t) blink reflex excitability, optionally comprising the outcome of the relationship between the blink reflex to trigeminal nerve stimulation as modulated by the brainstem (such blink reflex excitability is determined by presenting pairs of identical stimuli with a short interstimulus interval, and comparing the magnitude of the lid movement evoked by the second (test) stimulus to that evoked by the first (condition) stimulus).

35. The method of any one of claims 1-34, wherein in comparison of the patient before receiving the Parkinson’s disease treatment to after receiving the Parkinson’s disease treatment: latency increases or decreases; differential latency increases or decreases; delta 30 increases or decreases; eyelid excursion increases or decreases; initial lid velocity increases or decreases; time to close increases or decreases; time to open increases or decreases; time under threshold increases or decreases; number of oscillations increases or decreases; total blink time increases or decreases; number of blinks increases or decreases; blink rate increases or decreases; area under curve increases or decreases; maximum closing velocity increases or decreases; maximum opening velocity increases or decreases; time to first oscillation increases or decreases; prepulse inhibition increases or decreases; blink reflex recovery cycle increases or decreases; interstimulus interval increases or decreases; and/or blink reflex excitability increases or decreases.

36. The method of any one of claims 1-35, wherein in comparison of a patient who is not afflicted with Parkinson’s disease with a patient who is afflicted with Parkinson’s disease: latency increases or decreases; differential latency increases or decreases; delta 30 increases or decreases; eyelid excursion increases or decreases; initial lid velocity increases or decreases; time to close increases or decreases; time to open increases or decreases; time under threshold increases or decreases; number of oscillations increases or decreases; total blink time increases or decreases; number of blinks increases or decreases; blink rate increases or decreases; area under curve increases or decreases; maximum closing velocity increases or decreases; maximum opening velocity increases or decreases; time to first oscillation increases or decreases; prepulse inhibition increases or decreases; blink reflex recovery cycle increases or decreases; interstimulus interval increases or decreases; and/or blink reflex excitability increases or decreases.

37. The method of any one of claims 1-36, wherein the patient who is afflicted with Parkinson’s disease exhibits one or more changes in blink reflex parameters of increased time to open, increased oscillations, increased area under the curve, increased time under 20, increased oscillation rate, and/or decreased excursions.

38. The method of any one of claims 1-37, wherein the blink reflex correlates with duration of Parkinson’s Disease.

39. The method of claim 38, wherein the blink reflex that correlates with duration of Parkinson’s Disease comprises one or more of increased time to open, decreased time to open, increased number of oscillations, and/or increased mean oscillation rate.

40. The method of any one of claims 1-39, wherein the blink reflex correlates with sex.

41 . The method of claim 40, wherein the blink reflex that correlates with sex comprises one or more of excursion, max opening velocity, number of oscillations, oscillation rate, and/or latency.

42. The method of any one of claims 1-41, wherein the patient is female.

43. The method of any one of claims 1-41, wherein the patient is male.

44. The method of any one of claims 1-43, wherein the Parkinson’s disease treatment is or comprises a medication or surgery.

45. The method of any one of claims 1-44, wherein the Parkinson’s disease treatment is or comprises deep brain stimulation.

46. The method of any one of claims 1-44, wherein the Parkinson’s disease treatment is an electrode-based therapy or device, optionally implantable.

47. The method of any one of claims 1-46, wherein the medication reduces a motor symptom.

48. The method of any one of claims 1-47, wherein the medication is or comprises one or more of levodopa (L-DOPA), MAO-B inhibitors, and/or dopamine agonists.

49. The method of any one of claims 1-48, wherein the medication is or comprises one or more of levodopa; a combination of levodopa and one or more of tolcapone, entacapone, carbidopa, or benserazide; a dopamine agonist (apomorphine, bromocriptine, pergolide, pramipexole, ropinirole, piribedil, cabergoline, apomorphine, or lisuride); a MAO-B inhibitor, (deprenyls, selegiline, or rasagiline); Piribedil, pramipexole (MIRAPEX, MIRAPEXIN, and SIFROL), bromocriptine (PARLODEL, CYCLOSET, and BROTIN), Ropinirole (REQUIP, REPREVE, RONIROL, and ADARTREL), sumanirole (PNU-95,666), aplindore (DAB-452), amantadine, anticholinergics (artane and Cogentin), quetiapine, cholinesterase inhibitors, modafinil, tyrosine hydroxylase, N-phenyl-7-(hydroxylimino)cyclopropa[b]chromen-1a-carboxamide (PHCCC), and non-steroidal anti-inflammatory drugs.

50. The method of any one of claims 1-49, wherein the Parkinson’s disease is evaluated by or characterized by the Unified Parkinson’s Disease Rating Scale (UPDRS).

51. The method of any one of claims 1-50, wherein the Parkinson’s disease is evaluated by or characterized by the Hoehn and Yahr scale.

52. The method of any one of claims 1-51 , wherein the Parkinson’s disease is evaluated by or characterized by the Schwab and England ADL (Activities of Daily Living) scale.

53. The method of any one of claims 1-52, wherein the Parkinson’s disease is characterized by early symptoms, optionally selected from tremor, rigidity, slowness of movement, and/or difficulty with walking.

54. The method of any one of claims 1-53, wherein the patient is experiencing symptoms associated with dyskinesia.

55. The method of any one of claims 1-54, wherein the dyskinesia is or comprises one or more of dystonia, chorea, movements, and/or tremors.

56. The method of any one of claims 1-55, wherein the movements comprise mild bradykinesia, moderate bradykinesia, severe bradykinesia, and/or morning akinesia.

57. The method of any one of claims 1-56, wherein the tremors comprise unilateral or bilateral mild tremors, bilateral or midline moderate tremors, and/or intractable tremors.

58. The method of any one of claims 1-57, wherein the dyskinesia ranges from mild to severe.

59. The method of any one of claims 1-58, wherein the patient is experiencing symptoms associated with changes in balance, optionally selected from impaired balance, impaired righting reflexes, and/or significant balance disorder or falling.

60. The method of any one of claims 1-59, wherein the patient is experiencing a reduction in quality of life.

61. The method of any one of claims 1-60, wherein the patient has a moderate impact on quality of life.

62. The method of any one of claims 1 -61 , wherein the patient’s quality of life is diminished.

63. The method of any one of claims 1-62, wherein the patient has experienced a change in nonmotor symptoms.

64. The method of any one of claims 1-63, wherein the patient has mild to moderate cognitive impairment.

65. The method of any one of claims 1-64, wherein the patient has significant cognitive impairment such as dementia, behavioral disturbances, and/or hallucinations.

66. The method of any one of claims 1-65, wherein the patient has medically refractory motor fluctuations, “wearing off” and/or levodopa-induced dyskinesias, and/or disability.

67. The method of any one of claims 1-66, wherein the patient is experiencing symptoms associated with rigidity.

68. The method of any one of claims 1-67, wherein the patient is experiencing symptoms associated with slowness of movement.

69. The method of any one of claims 1-68, wherein the patient is experiencing symptoms associated with difficulty walking.

70. The method of any one of claims 1-69, wherein the patient is experiencing symptoms associated with behavioral problems.

71. The method of any one of claims 1-70, wherein the patient is experiencing complications associated with dementia.

72. The method of any one of claims 1-71, wherein the patient is experiencing complications associated with depression.

73. The method of any one of claims 1-72, wherein the patient is experiencing complications associated with anxiety.

74. The method of any one of claims 1-73, wherein the Parkinson’s disease is or comprises one or more of idiopathic Parkinson’s disease.

75. The method of any one of claims 1-74, wherein the Parkinson’s disease is or comprises vascular parkinsonism.

76. The method of any one of claims 1-75, wherein the Parkinson’s disease is or comprises drug- induced parkinsonism.

77. The method of any one of claims 1-76, wherein the Parkinson’s disease is or comprises dementia with Lewy bodies.

78. The method of any one of claims 1-77, wherein the Parkinson’s disease is or comprises inherited Parkinson’s.

79. The method of any one of claims 1-78, wherein the Parkinson’s disease is or comprises juvenile Parkinson’s.

80. The method of any one of claims 1-79, wherein the Parkinson’s disease is or comprises Parkinson’s disease dementia.

81. The method of any one of claims 1-80, wherein the method detects, indirectly or directly, a reduction of the total score of a Parkinson’s disease rating scale in the patient after treatment.

82. The method of any one of claims 1-81 , wherein in comparison of the patient before receiving the Parkinson’s disease treatment to after receiving the Parkinson’s disease treatment, the total score on a Parkinson’s disease rating scale decreases.

83. The method of any one of claims 1-82, wherein in comparison of the patient before receiving the Parkinson’s disease treatment to after receiving the Parkinson’s disease treatment, the patient’s UPDRS-II I medication score decreases.

84. The method of any one of claims 1-83, wherein in comparison of the patient before receiving the

Parkinson’s disease treatment to after receiving the Parkinson’s disease treatment, the patient’s UPDRS-II I medication score decreases by about or at least about 5%, or by about or at least about 10%, or by about or at least about 15%, or by about or at least about 20%, or by about or at least about 25%, or by about or at least about 30%, or by about or at least about 35%, or by about or at least about 40%, or by about or at least about 45%, or by about or at least about

50%, or by about or at least about 55%, or by about or at least about 60%, or by about or at least about 65%, or by about or at least about 70%, or by about or at least about 75%, or by about or at least about 80%, or by about or at least about 85%, or by about or at least about

90%, or by about or at least about 95%.

85. The method of any one of claims 1-84, wherein in comparison of the patient before receiving the Parkinson’s disease treatment to after receiving the Parkinson’s disease treatment, the patient’s quality of life, mood, cognitive function, dyskinesia, compulsive behavior, and/or sleep quality improve.

86. The method of any one of claims 1-85, wherein the patient’s improvement in dyskinesia is assessed using the Unified Dyskinesia Rating Scale (UDysRS).

87. The method of any one of claims 1-86, wherein the patient’s improvement in dyskinesia is assessed using the Hauser motor diaries.

88. The method of any one of claims 1-87, wherein the patient’s improvement in mood is assessed using the Beck Depression Inventory II (BDI-II).

89. The method of any one of claims 1-88, wherein the patient’s improvement in cognitive function is assessed using the Montreal Cognitive Assessment (MoCA).

90. The method of any one of claims 1-89, wherein the patient’s improvement in cognitive function is assessed using the Mattis Dementia Rating Scale-Second Edition (MDRS-2).

91. The method of any one of claims 1-90, wherein the patient’s improvement in compulsive behaviors is assessed using the Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease- Rating Scale (QUIP-RS).

92. The method of any one of claims 1-91, wherein the patient’s improvement in sleep quality and disturbance is assessed using the Parkinson’s Disease Sleep Scale 2 (PDSS-2).

93. The method of any one of claims 1-92, wherein the patient’s improvement in quality of life is assessed using the Parkinson’s Disease Questionnaire (PDQ39).

94. The method of any one of claims 1-93, wherein the patient’s improvement in quality of life is assessed using the Schwab and England scale.

95. The method of any one of claims 1-94, wherein the patient’s improvement in quality of life is assessed using the Clinical Global Impression (CGI).

96. The method of any one of claims 1-95, wherein the patient’s improvement in quality of life is assessed using the Patient Global Impression (PGI).