WO2018176082A1 - Prédiction de progression de détérioration cognitive - Google Patents

Prédiction de progression de détérioration cognitive Download PDF

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WO2018176082A1
WO2018176082A1 PCT/AU2018/050226 AU2018050226W WO2018176082A1 WO 2018176082 A1 WO2018176082 A1 WO 2018176082A1 AU 2018050226 W AU2018050226 W AU 2018050226W WO 2018176082 A1 WO2018176082 A1 WO 2018176082A1
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qsm
cognitive
magnetic susceptibility
measure
patient
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PCT/AU2018/050226
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English (en)
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Scott Jonathan AYTON
Amir FAZIOLLHI
Olivier Salvado
Ashley Ian Bush
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Crc For Mental Health Ltd
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Priority claimed from AU2017901114A external-priority patent/AU2017901114A0/en
Application filed by Crc For Mental Health Ltd filed Critical Crc For Mental Health Ltd
Publication of WO2018176082A1 publication Critical patent/WO2018176082A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/05—Detecting, measuring or recording for diagnosis by means of electric currents or magnetic fields; Measuring using microwaves or radio waves 
    • A61B5/055—Detecting, measuring or recording for diagnosis by means of electric currents or magnetic fields; Measuring using microwaves or radio waves  involving electronic [EMR] or nuclear [NMR] magnetic resonance, e.g. magnetic resonance imaging
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/40—Detecting, measuring or recording for evaluating the nervous system
    • A61B5/4076—Diagnosing or monitoring particular conditions of the nervous system
    • A61B5/4088—Diagnosing of monitoring cognitive diseases, e.g. Alzheimer, prion diseases or dementia
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01R—MEASURING ELECTRIC VARIABLES; MEASURING MAGNETIC VARIABLES
    • G01R33/00—Arrangements or instruments for measuring magnetic variables
    • G01R33/20—Arrangements or instruments for measuring magnetic variables involving magnetic resonance
    • G01R33/44—Arrangements or instruments for measuring magnetic variables involving magnetic resonance using nuclear magnetic resonance [NMR]
    • G01R33/48—NMR imaging systems
    • G01R33/50—NMR imaging systems based on the determination of relaxation times, e.g. T1 measurement by IR sequences; T2 measurement by multiple-echo sequences

Definitions

  • the present invention relates to methods for predicting progression or a trajectory of cognitive deterioration relating to the areas of dementias, cognitive disorders and/or affective disorders and/or behavioural dysfunction, Alzheimer's Disease (AD) and related dementias in patients with amyloid deposition in the brain by determining a measure of magnetic susceptibility and/or transverse relaxation in hippocampus of the brain.
  • the invention is also applicable to monitoring progression of cognitive deterioration and stratifying an individual into one or more classes depending on the diagnosis or prognosis of the cognitive deterioration.
  • AD Alzheimer's disease
  • ⁇ amyloid ⁇
  • AD brain pathology starts developing approximately two decades prior to the onset of cognitive symptoms. Consequently, anti-AD therapies may have the best chance of success when given in this preclinical period. There is a need to identify biomarkers that predict cognitive deterioration early or the potential rate of deterioration.
  • Amyloid PET imaging is the most advanced biomarker of geriatric cognitive deterioration.
  • High ⁇ burden ( ⁇ +) identified by PiB, flutemetamol, or florbetapir radioligands, predicts cognitive decline with an average effect size (difference between slopes) of ⁇ 0.5 on memory composite scores in cognitively normal (CN) subjects over 3+ years.
  • ⁇ imaging can be a sensitive predictor (98%) of cognitive decline but studies have shown repeatedly a large prevalence ( ⁇ 20-30%) of cognitive unimpaired people over age 60 with already high ⁇ burden in the brain.
  • AD Alzheimer's disease
  • ⁇ ⁇ -amyloid burden identified by PET predicts pre-clinical cognitive decline (Pietrzak et a/., 2015), but the large variability between individuals in the rate of decline indicates that other injuries might combine with ⁇ to accelerate clinical deterioration.
  • Cortical iron accumulation also a pathological feature of AD (Ayton et a/., 2014), has the potential to promote neurodegeneration though oxidative damage. Indeed, we showed recently that elevated CSF ferritin (reporting brain iron burden) predicted poorer cognition, and increased the risk of developing AD (Ayton et a/., 2015; Ayton et a/., 2016).
  • CSF ferritin reporting brain iron burden
  • the ability to detect preclinical or early stage disease through reliable measurement of markers present in biological samples from a subject suspected of having AD would also allow treatment and management of the disease to begin earlier.
  • the same tests can be used to monitor the progression of decline or the possible rate of decline without the need for expensive equipment, discomfort and side effects experienced in the present available methods of diagnosis and prognosis.
  • a test which can provide assistance to clinicians in reaching an early stage prognosis prior to the portrayal of detectable clinical indicators and which would obviate the need for actual confirmatory brain imaging tests would be useful.
  • therapies for neurological disorders undergoing clinical trials, there is a social and economic imperative to identify progression of the disease in at- risk individuals in the earliest possible stage, so therapies can be administered at a time when the disease burden is mild and it may prevent or delay functional and irreversible cognitive loss.
  • Measuring cognitive deterioration before the onset of AD may enable early treatment with drugs that could delay disease progression.
  • a method for predicting or diagnosing cognitive deterioration in a patient with amyloid deposition in the brain comprising determining a measure of magnetic susceptibility and/or transverse relaxation in hippocampus of the patient wherein the measure of magnetic susceptibility and/or transverse relaxation is an indication of cognitive deterioration.
  • the measure of magnetic susceptibility and/or transverse relaxation can be performed using any method which can measure magnetic properties of tissues. These may include QSM, T2* T2, or NMR frequency.
  • the method used to measure magnetic susceptibility is QSM.
  • the method to measure transverse relaxation is T2 * Applicants have demonstrated a QSM value in hippocampus as an alternative/adjunct prognostic for cognitive deterioration. They show that the QSM value in patients with amyloid deposition in the brain can predict the trajectory and rate of cognitive decline in these patients from the QSM value in hippocampus.
  • QSM is a measure of magnetic susceptibility
  • any method available to the skilled addressee for measuring magnetic susceptibility in hippocampus may be used.
  • methods such as T2* which measure the transverse relaxation speed of molecules may be used since molecules such as iron which may be present in hippocampus will also affect the transverse relaxation of tissue.
  • relaxation maps of tissue such as those obtained from T2* T2, T1 , or T2' maps may also provide an indication of the presence of molecules such as iron in tissues of patients with amyloid deposition thereby enabling a prediction of cognitive deterioration.
  • the changes in magnetic susceptibility preferably the QSM values in hippocampus can additionally be used in assessing for any changes in cognitive deterioration of a patient. Accordingly, in the monitoring of the magnetic susceptibility or preferably QSM values in hippocampus, it is possible to monitor for the presence of cognitive deterioration over a period of time, or to track cognitive deterioration progression in a patient by the measurement of QSM in hippocampus.
  • a method for monitoring progression of cognitive deterioration in a patient with amyloid deposition in the brain comprising determining a first measure of magnetic susceptibility and/or transverse relaxation in hippocampus from in the patient at a first time point;
  • the changes in the level of magnetic susceptibility or preferably QSM values and/or transverse relaxation in hippocampus of a patient with amyloid deposition in the brain can also be used to stratify a patient (i.e., sorting a patient with cognitive deterioration into different classes of the condition).
  • a method for stratifying a patient with amyloid deposition in the brain for cognitive deterioration said method comprising determining a measure of magnetic susceptibility and/or transverse relaxation in hippocampus of the patient;
  • Figure 1 shows a graphical representation of the impact of baseline QSM upon change of cognition, measured by cognitive composite scores of episodic memory (CVLT-delayed, Logical Memory Test-delayed, RCFT-Long Delay), executive function (FAS, Category Fluency Switching), and language (Boston Naming Test, Category Fluency [animals + boys names]).
  • A Baseline QSM in the hippocampus was negatively associated with annual rate of change in episodic memory ⁇ +ve subjects, and positively associated with rate of change in ⁇ -ve subjects.
  • B Baseline QSM in hippocampus was negatively associated with annual rate of change in executive function in ⁇ +ve subjects.
  • Predicting a rate or progression of cognitive deterioration before the onset of AD may enable early treatment intervention to delay disease progression.
  • Anti-AD therapies given in the pre-clinical period will have the best chance of success.
  • dementia or AD may not fully develop, but the patient displays symptoms of Mild Cognitive Impairment (MCI) or are cognitively normal elders who may eventually experience cognitive deterioration.
  • MCI Mild Cognitive Impairment
  • Monitoring progression and predicting or diagnosing a trajectory of cognitive deterioration will be imperative for managing the cognitive deterioration over time.
  • a method for predicting or diagnosing cognitive deterioration in a patient with amyloid deposition in hippocampus comprising determining a measure of magnetic susceptibility and/or transverse relaxation in brain tissue for the patient wherein the measure of magnetic susceptibility and/or transverse relaxation is an indication of cognitive deterioration.
  • ⁇ or amyloid alone or any measure of magnetic susceptibility or transverse relaxation alone has been shown to be insufficient as a marker for cognitive deterioration since there exist a large number of cognitively unimpaired people with high ⁇ levels in the brain.
  • Approximately 30% of ⁇ carrying subjects do not have objective cognitive impairment, suggesting that amyloid is not sufficient to precipitate dementia, however amyloid acts in concert with other pathogenic factors to drive disease progression.
  • the present invention demonstrates that measures of magnetic susceptibility such as QSM and/or transverse relaxation in hippocampus may also predict the trajectory of cognitive decline in ⁇ carrying subjects depending on a measure of magnetic susceptibility or preferably QSM value and/or transverse relaxation determined.
  • amyloid along with a measure of magnetic susceptibility enables a prediction of a trajectory of the decline. For instance, when amyloid is present in the brain, having higher than average magnetic susceptibility (but still may be within normal limits) as measured for instance by QSM puts the patient at risk of decline.
  • QSM measures of magnetic susceptibility or preferably QSM and/or transverse relaxation in hippocampus to be used in combination with PET imaging for AD-prognostics to provide an indication of how quickly the patient will decline.
  • Magnetic susceptibility is a measure of the magnetic properties of a material including tissue.
  • the susceptibility indicates whether a material is attracted into or repelled out of a magnetic field. It can also be a measure the degree of magnetization of a material in response to an applied magnetic field. Hence, it often reflects iron levels in tissue where iron is the most abundant magnetic material in the tissue.
  • Measuring magnetic susceptibility can be conducted by several methods available to the skilled addressee aiming to measure the magnetic properties of tissue. Methods such as QSM and MRI are the most common methods used. Preferably, QSM is used as it is a superior method for measuring magnetic susceptibility.
  • Transverse relaxation T2 or T2*
  • T2 Transverse relaxation
  • both measures such as QSM and T2/T2* are a surrogate measure of the presence of iron in the brain and in particular, for the present invention, the presence of iron is measured in the hippocampus which has been identified by the Applicants as predictive of cognitive deterioration and a trajectory for deteriorating cognitive performance using QSM values.
  • the present invention relates to assessing, predicting or diagnosing cognitive deterioration in patients with amyloid deposition in the brain as measured by magnetic susceptibility or preferably QSM and/or transverse relaxation as an indicator of the rate of decline in cognitive capacity for these patients.
  • a patient's cognitive capacity declines changes occur which give rise to a variety of symptoms associated with aging, such as forgetfulness, decreased ability to maintain focus, and decreased problem solving capability. Symptoms oftentimes progress into more serious conditions, such as dementia and depression, or even Alzheimer's disease.
  • cognitive deterioration includes mild cognitive impairment (MCI), MCI conversion to Alzheimer's Disease (AD), and AD.
  • MCI mild cognitive impairment
  • AD Alzheimer's Disease
  • the invention also relates broadly to the areas of dementias, cognitive disorders and/or affective disorders and/or behavioural dysfunction, Alzheimer's Disease and related dementias associated with a decline in cognitive function.
  • cognitive deterioration may be used interchangeably with “cognitive decline”.
  • the term also includes and refers to a rate of decline or deterioration or a trajectory for deteriorating cognitive performance.
  • Mild cognitive impairment (MCI) is an intermediate stage between the expected cognitive decline of normal aging and the more serious decline of dementia. It can involve problems with memory, language, thinking and judgment that are greater than normal age-related changes.
  • Mild cognitive impairment causes cognitive changes that are serious enough to be noticed by the individuals experiencing them or to other people, but the changes are not severe enough to interfere with daily life or independent function.
  • MCI cognitive deterioration
  • Alzheimer's Disease and related dementias generally requires an evaluation of medical history and physical examination to determine the extent of cognitive function including neurological, neuropsychological and psychiatric assessment including memory and/or psychological tests, assessment of language impairment and/or other focal cognitive deficits (such as apraxia, acalculia and left-right disorientation), assessment of impaired judgment and general problem-solving difficulties, assessment of personality changes ranging from progressive passivity to marked agitation, as well as various biological, radiological and electrophysiological tests, such as for instance measuring brain volume or activity measurements derived from neuroimaging modalities such as magnetic resonance imaging (MRI) or positron emission tomography (PET) of relevant brain regions.
  • MRI magnetic resonance imaging
  • PET positron emission tomography
  • the cognitive deterioration is determined by cognitive composite scores of episodic memory (CVLT-delayed, Logical Memory Test-delayed, RCFT-Long Delay), executive function (FAS, Category Fluency Switching), and language (Boston Naming Test, Category Fluency [animals + boys names]) were used as outcome variables, as previously described Lim YY, Maruff P, Pietrzak RH, Ames D, Ellis KA, Harrington K, et al. Effect of amyloid on memory and non-memory decline from preclinical to clinical Alzheimer's disease. Brain : a journal of neurology 2014; 137(Pt 1 ): 221 -31 .
  • a risk or rate of cognitive deterioration may be assessed relative to a cognitively normal (CN) patient which will provide a reference level.
  • Patients who are at risk of cognitive deterioration and/or Alzheimer's Disease include those with family histories, genetic vulnerability and deficiency alleles. They may be vulnerable and carry genes which predispose them to a more rapid cognitive deterioration leading to dementia and AD. Being able to determine an onset of rapid decline will enable better management of the cognitive deterioration.
  • CN patient means a subject which has no significant cognitive impairment or impaired activities of daily living. Patients that are suspected of, or are at risk of cognitive deterioration may be compared against a CN patient. This includes patients that are cognitively normal but show changed levels of a marker indicative of a neurological disease such as amyloid loading in the brain (preferably determined by PET imaging or CSF analysis of tau and ⁇ ). The characteristics of a CN patient may assist in providing a reference level or reference value to which deterioration from normal can be determined.
  • Applicants have demonstrated that a measure of magnetic susceptibility or preferably QSM in hippocampus of the brain in patients with amyloid deposition in the brain predicts a propensity for cognitive deterioration and a trajectory of cognitive deterioration in these patients which enables a simple assessment of the risk for cognitive deterioration and the progression of the condition in patients.
  • T2/T2* transverse relaxation
  • these data support (1 ) the utility of a measure of magnetic susceptibility or preferably QSM and/or transverse relaxation in hippocampus as a prognostic test for cognitive impairment in AD and a prediction of a rate of deterioration in patients with amyloid deposition in the brain, and (2) a possibility of therapeutically lowering brain iron levels to delay disease progression.
  • QSM provides a contrast mechanism in Magnetic Resonance Imaging (MRI) derived from phase processing of gradient echo acquisition, and is a relatively new MRI technique that has been validated with post mortem studies. It has been used for a number of applications including differentiating calcification from iron, standardized quantitative stratification of cerebral microbleeds, gadolinium quantification in contrast enhanced MRI, and direct monitoring of targeted theranostic drug biodistribution in nanomedicine. However, its use on hippocampus to predict a trajectory for deteriorating cognitive performance in patients with amyloid loading has not been previously established.
  • MRI Magnetic Resonance Imaging
  • a QSM value may be obtained for patients and individuals with amyloid loading that can be used to determine whether there is a change in cognitive deterioration or trajectory of cognitive deterioration. These values may be compared against a reference level such as from a cognitively normal individual or an internal sample taken the same individual. Alternatively, the QSM reference values can derive from diseased participants and healthy controls (HC). Like any measure of magnetic susceptibility, QSM values may be stratified into categories such as, but not limited to high or low QSM values. A high QSM value may be indicative of a high iron loading in the brain. Conversely low QSM value may indicate a low iron loading in the brain. Consequently, high or elevated QSM values or elevated magnetic susceptibility values will indicate a trajectory for deteriorating cognitive performance in participants with an amyloid load, whereas low QSM or negative magnetic susceptibility may be associated with stable cognitive performance in patients with amyloid loading.
  • the QSM values need not be abnormally high for magnetic susceptibility or QSM to act as an indicator of cognitive deterioration and a trajectory of cognitive deterioration.
  • QSM magnetic susceptibility
  • the magnetic susceptibility or preferably QSM values in hippocampus can assist in assessing cognitive deterioration or a trajectory for cognitive deterioration in patients with amyloid loading in the brain since a stratified magnetic susceptibility or preferably QSM will allow for a prediction of the severity of deteriorating cognitive performance in participants with amyloid load.
  • a stratified magnetic susceptibility or preferably QSM will allow for a prediction of the severity of deteriorating cognitive performance in participants with amyloid load.
  • severe deterioration may be indicated by high QSM values and manageable deterioration or stable deterioration may be indicated by low QSM values.
  • the magnetic susceptibility or preferably QSM values will also enable a diagnosis of the cognitive deterioration in patients with amyloid loading as being deteriorating or stable cognitive performance.
  • the QSM values from hippocampus are particularly useful for predicting a trajectory for deteriorating cognitive performance.
  • the QSM value from hippocampus correlates with iron loading
  • a correlation that is indicative of high iron loading in hippocampus will be a predictor of a greater trajectory for deteriorating cognitive performance.
  • changes in transverse relaxation or T2/T2* may indicate changes in excitability of molecules in the hippocampus of the brain caused by the presence of other molecules such as but not limited to iron content of the brain
  • determining generally refer to any form of measurement. These terms include both quantitative and/or qualitative determinations, which require sample processing and transformation steps of the biological sample. Assessing may be relative or absolute.
  • the measure of magnetic susceptibility or preferably QSM value and/or transverse relaxation is an indication of a rate of cognitive deterioration.
  • diagnosis or “diagnosing” as used herein would be understood by one skilled in the art to refer to the process of attempting to determine or identify a possible disease or disorder, and to the opinion reached by this process.
  • predicts or “predicting” as used herein would be understood by one skilled in the art to refer to the process of anticipating, envisioning or foreseeing an outcome based on results obtained.
  • a “reference value” or “reference level” may be used interchangeably and may be selected from the group comprising an absolute value; a relative value; a value that has an upper and/or lower limit; a range of values; an average value; a median value, a mean value, a shrunken centroid value, or a value as compared to a particular control or baseline value.
  • a predetermined reference value obtained from a known sample prepared in parallel with the biological or test sample in question. It is to be understood that other statistical variables may be used in determining the reference value.
  • a reference value can be based on an individual sample value, such as for example, a value obtained from a sample from the individual with cognitive deterioration, but at an earlier point in time, or a value obtained from a sample from a patient or another patient with the disorder other than the individual being tested, or a "normal" or "healthy” individual, that is an individual not diagnosed with cognitive deterioration otherwise a CN individual.
  • the reference value can be based on a large number of reference samples, such as from AD patients or patients with cognitive deterioration, normal individuals or based on a pool of samples including or excluding the sample to be tested.
  • the "reference level” or “reference value” is typically a predetermined reference level, such as an average of levels obtained from a population that is or isn't afflicted with cognitive deterioration.
  • the predetermined reference level is derived from (e.g., is the mean or median of) levels obtained from an age-matched population.
  • the age-matched population comprises individuals with cognitive deterioration or neurodegenerative disease individuals.
  • a reference level may also be considered as generally a predetermined level considered "normal" for the particular diagnosis (e.g., an average level for age-matched individuals not diagnosed with cognitive deterioration or an average level for age-matched individuals diagnosed with cognitive deterioration other than AD and/or healthy age-matched individuals), although reference levels which are determined contemporaneously (e.g., a reference value that is derived from a pool of samples including the sample being tested) are also contemplated.
  • Patients who can be tested and/or treated according to any of the methods of the present invention include those who present with cognitive dysfunction with a history of treated depression, cognitive dysfunction with a history of depression, cognitive dysfunction with bipolar disease or schizoaffective disorders, cognitive dysfunction with generalized anxiety disorder, cognitive dysfunction with attention deficit, ADHD disorder or both attention deficit and ADHD disorder, dyslexia, developmental delay, school adjustment reaction, Alzheimer's Disease, amnesic mild cognitive impairment, non-amnesic mild cognitive impairment, cognitive impairment with white matter disease on neuroimaging or by clinical examination, frontotemporal dementia, cognitive disorders in those under 65 years of age, those with serum homocysteine levels of less than 10 nmol/l, and those with high serum transferrin levels (uppermost population quartile).
  • the patient must present with amyloid deposition in the brain.
  • the terms “individual,” “subject,” and “patient,” generally refer to a human subject, unless indicated otherwise, e.g., in the context of a non-human mammal useful in an in vivo model (e.g., for testing drug toxicity), which generally refers to murines, simians, canines, felines, ungulates and the like (e.g., mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, etc.).
  • a patient can also be confirmed as being positive for amyloid using imaging techniques including, PET and MRI, or with the assistance of diagnostic tools such as PiB when used with PET (otherwise referred to as PiB-PET).
  • the patient which is positive for amyloid is PiB positive.
  • the patient has a standard uptake value ratio (SUVR) which corresponds with high neocortical amyloid load (PiB positive).
  • SUVR standard uptake value ratio
  • a SUVR can reflect 1 .4 to 1 .5 as a high level in the brain and below 1 .4 to 1.5 may reflect low levels of amyloid load in the brain.
  • a skilled person would be able to determine what is considered a high or low level of amyloid load.
  • a patient can also be confirmed as being positive for a neurological disease by measuring amyloid beta and tau from the CSF.
  • a positive diagnosis of cognitive deterioration in a patient can be validated or confirmed if warranted, such as determining the amyloid load or amyloid level or amyloid deposition to confirm the presence of high neocortical amyloid.
  • amyloid load or amyloid level often used interchangeably, or presence of amyloid and amyloid fragments, refers to the concentration or level of cerebral amyloid beta ( ⁇ or amyloid- ⁇ ) deposited in the brain, amyloid-beta peptide being the major constituent of (senile) plaques.
  • the present invention relates to predicting cognitive decline in patients with amyloid deposition in the brain.
  • the patients may already show signs of cognitive deterioration correlating with amyloid levels.
  • the patients may have amyloid deposits and be cognitively unimpaired.
  • the methods of the present invention are useful for predicting an outcome for cognitive deterioration and rate of decline.
  • the prognosis may be either deteriorating cognitive performance or stable cognitive performance or somewhere in between.
  • PiB positive and PiB negative There have been numerous studies that have correlated the PiB radio tracer signal or output with the level of amyloid-beta and this has led to the terminology of PiB positive and PiB negative.
  • the normalisation of the PiB output, or uptake of the tracer occurs to allow inter- and intra-subject comparisons to be made.
  • SVS standard uptake value
  • the normalisation also incorporates standardisation with the (usually) unaffected cerebellum to provide the standard uptake value ratio (SUVR). This has led to the determination of a threshold value to differentiate those with high neocortical load (PiB positive) from those with a low load (PiB negative).
  • amyloid deposition is determined using PET amyloid imaging.
  • any method available to the skilled addressee may be used to determine amyloid deposition.
  • the patient may be stratified as being amyloid positive or amyloid negative or PiB positive or PiB negative. More preferably, the patient has a standard uptake value ratio (SUVR) which corresponds with high amyloid load (PiB positive).
  • SUVR standard uptake value ratio
  • a skilled person would be able to determine what is considered a high or low level of amyloid load.
  • the patient with amyloid deposition is amyloid positive.
  • the patient has a SUVR of >1 .4— 1 .5 as measured using PET amyloid imaging in unit consistent with PiB.
  • the 1.4 to 1 .5 threshold can be adapted for other traces like AV-45 to provide the same Amyloid positivity classification.
  • the magnetic susceptibility or preferably QSM and/or transverse relaxation is determined from hippocampus of the brain.
  • magnetic susceptibility or preferably QSM and/or transverse relaxation in the hippocampus could be used to predict those amyloid positive subjects who are on the pathway toward disease progression, regardless of diagnosis.
  • the QSM is determined from MRI data. MRI detects the levels of iron through variation in the magnetic susceptibility of the tissue and iron is the strongest biological contributor to this signal.
  • the QSM and/or transverse relaxation is a measure of hippocampus iron.
  • the QSM and/or transverse relaxation correlates to hippocampus iron and may be an indicator of a level of hippocampus iron.
  • QSM and/or transverse relaxation does not measure iron directly.
  • QSM measures the magnetic susceptibility of the tissue in which iron is the strongest biological contributor to this signal whereas transverse relaxation measures the speed at which the excited molecules relax. Therefore, these measures merely suggest or correlate to a level of iron in the tissue.
  • hippocampus iron content relative to a reference level as measured by QSM values, translates to increased cognitive deterioration in patients with amyloid deposition
  • an increase in hippocampus iron would translate to a difference between the patient and a reference level. This difference assists in predicting or diagnosing cognitive deterioration or a rate of progression of cognitive deterioration in patients with amyloid deposition in the brain.
  • a diagnostic cut-off may be a value, level or range. The diagnostic cut-off should provide a value level or range that assists in the process of attempting to determine or identify cognitive deterioration or significant rate of cognitive deterioration that would signal a greater propensity for serious deterioration or progression to AD.
  • the amyloid positive subjects may be stratified into high and low QSM, based on a QSM value that optimally separates healthy control (HC) from diseased participants.
  • a nominal cut-off value for the QSM may be determined from relative values obtained from HC or from other diseased individuals.
  • a QSM value from an individual with low iron and/or showing no cognitive deterioration or being cognitively unimpaired may be used to define the cut- off points for QSM.
  • the level of a measure of magnetic susceptibility or preferably QSM value and/or transverse relaxation may be diagnostic for cognitive deterioration if the value is above the diagnostic cut-off.
  • the measure of magnetic susceptibility or preferably QSM value and/or transverse relaxation may be diagnostic for cognitive deterioration if the level is below the diagnostic cut-off.
  • the diagnostic cut-off for measure of magnetic susceptibility or preferably QSM values and/or transverse relaxation can be derived using a number of statistical analysis software programs known to those skilled in the art.
  • a measure of magnetic susceptibility or preferably QSM values and/or transverse relaxation in the hippocampus of the methods of the present invention could also be used in combination with other methods of clinical assessment of a neurological disease known in the art in providing a prognostic evaluation of the presence of a neurological disease.
  • assessments that include, but are not necessarily limited to, memory and/or psychological tests, assessment of language impairment and/or other focal cognitive deficits (such as apraxia, acalculia and left-right disorientation), assessment of impaired judgment and general problem-solving difficulties, assessment of personality changes ranging from progressive passivity to marked agitation.
  • a difference in a measure of magnetic susceptibility or preferably QSM value and/or transverse relaxation as measured in the hippocampus between the patient and the reference level would indicate a change in cognitive deterioration in patients with amyloid deposition.
  • the degree of change can provide an indication of whether there is an increased or decreased risk for cognitive deterioration or the severity of the cognitive deterioration.
  • a small elevation may indicate a small risk whereas a high elevation is likely to indicate greater cognitive deterioration and rate of deterioration or a greater trajectory for deteriorating cognitive performance.
  • An increasing elevation between the patient and the reference level will indicate an increased risk for cognitive deterioration.
  • the measure of magnetic susceptibility and/or transverse relaxation in hippocampus from the first and second time points optionally comparing the measure of magnetic susceptibility and/or transverse relaxation in hippocampus from the first and second time points to a reference level; determining a difference in the measure of magnetic susceptibility and/or transverse relaxation at each of the first and second time points;
  • the progression in cognitive deterioration is a change in trajectory of the cognitive deterioration.
  • the change may be a measure of an increased rate of deterioration or a greater propensity for cognitive deterioration.
  • the changes in the magnetic susceptibility or preferably QSM values and/or transverse relaxation can additionally be used in assessing for any changes in cognitive deterioration of a patient. Accordingly, in the monitoring of the magnetic susceptibility or preferably QSM values and/or transverse relaxation, it is possible to monitor for the presence of cognitive deterioration over a period of time, or to track cognitive deterioration progression in a patient. This may be a measure of the rate at which the deterioration may occur over time.
  • changes in the level of magnetic susceptibility or preferably QSM values and/or transverse relaxation from a patient can be used to assess cognitive function and cognitive deterioration, to diagnose or aid in the prognosis or diagnosis of cognitive deterioration and/or to monitor progression toward AD in a patient (e.g., tracking progression in a patient and/or tracking the effect of medical or surgical therapy in the patient). For instance if the magnetic susceptibility or preferably QSM value increases over time, the rate at which the cognitive deterioration will occur will increase in patients with amyloid deposition.
  • a reference level may be the level of magnetic susceptibility or preferably QSM value or transverse relaxation at an earlier time point from the same patient. It is contemplated that magnetic susceptibility or preferably QSM values and/or transverse relaxation can also be obtained from a patient at more than one time point. Such serial sampling would be considered feasible through the methods of the present invention related to monitoring progression of cognitive deterioration in a patient.
  • Serial sampling can be performed on any desired timeline, such as monthly, quarterly (i.e., every three months), semi-annually, annually, biennially, or less frequently.
  • the comparison between the measured levels and predetermined levels may be carried out each time a new sample is measured, or the data relating to levels may be held for less frequent analysis.
  • the difference in magnetic susceptibility or preferably QSM values in hippocampus is an elevation between the first and second time points such that the magnetic susceptibility or preferably QSM value in the second time point is higher than the first time point relative to the reference level thereby indicating an increased progression or trajectory for cognitive deterioration in patients with amyloid deposition in the brain.
  • Applicants have shown that patients with amyloid deposition and with comparatively low hippocampus QSM value will not deteriorate in the foreseeable future.
  • an increase in hippocampus QSM value predicts a more rapid deterioration. Little change in the hippocampus QSM value would indicate stability of the cognitive deterioration. This will also be relevant to changes in magnetic susceptibility of the patient where the measure of magnetic susceptibility changes in a positive or negative way.
  • the transverse relaxation is changed, such as if it were to decrease, this may indicate the presence of iron in the tissues.
  • the methods of the invention can additionally be used for monitoring the effect of therapy administered to a mammal, also called therapeutic monitoring, and patient management in individuals with amyloid deposition.
  • Changes in the magnetic susceptibility or preferably hippocampus QSM values and/or transverse relaxation in hippocampus can be used to evaluate the response of a patient to drug treatment.
  • new treatment regimens can also be developed by examining the magnetic susceptibility or preferably QSM values and/or transverse relaxation in a patient with amyloid deposition in the brain following commencement of treatment.
  • the method of the present invention can thus assist in monitoring a clinical study, for example, for evaluation of a certain therapy for a neurological disease.
  • a chemical compound can be tested for its ability to change the magnetic susceptibility or preferably QSM values and/or transverse relaxation in hippocampus in a patient having cognitive deterioration to levels found in controls or CN patients.
  • a chemical compound can be tested for its ability to maintain the magnetic susceptibility or preferably QSM values and/or transverse relaxation in hippocampus at a level at or near the level seen in controls, HC or CN patients indicating a reduced trajectory to cognitive deterioration.
  • a method for stratifying a patient with amyloid deposition in the brain for cognitive deterioration comprising
  • the changes in the level of magnetic susceptibility or preferably QSM and/or transverse relaxation in hippocampus of a patient with amyloid deposition in the brain can accordingly be used to stratify a patient (i.e., sorting a patient with cognitive deterioration into different classes of the condition).
  • stratifying of a patient typically refers to sorting of a patient into a different class or strata based on the features characteristic of cognitive deterioration.
  • stratifying patients with cognitive deterioration involves assigning the mammals on the basis of the severity of the deterioration or rate of deterioration.
  • a high QSM will identify those patients with amyloid loading that will deteriorate faster than those that have a low QSM which may have a stable deterioration of cognitive deterioration.
  • the assessment in the change of the levels of magnetic susceptibility or preferably QSM and/or transverse relaxation can be used as a manner of identifying a patient that may be at risk of cognitive deterioration. It would be considered that should a patient be identified as being likely to show cognitive deterioration, they may be further considered for potential therapeutic intervention to assess if the predisposition of cognitive deterioration can be arrested or attenuated. The effectiveness of the intervention in the progression or development of cognitive deterioration may be made possible through the monitoring for the change in the magnetic susceptibility or preferably QSM values and/or transverse relaxation in hippocampus.
  • Example 1 Predicting amyloid-related cognitive decline from QSM measurements in hippocampus in patients with amyloid deposition
  • QSM Quantitative Susceptibility Mapping
  • the carbon-1 1 -labelled Pittsburgh compound B (1 1 C-PiB) PET scans were performed using a Phillips Allegro (Phillips Medical Systems, Eindhoven, The Netherlands) camera. Each subject received -370 MBq 1 1 C-PiB IV over 1 minute. A 30-minute acquisition in 3D mode consisting of 6 frames each of 5 minutes, starting 40 minutes after PiB infusion. A transmission scan was performed for attenuation correction. PET images were reconstructed using a 3D Ramla algorithm. iii. PET Processing
  • T1 -weighted MPRAGE 3D T2*-weighted gradient echo (GRE), and 3D fluid-attenuated inversion recovery (FLAIR), on a 3T Siemens TRIO scanner (12-channel head coil).
  • the magnitude and phase images were retrospectively reconstructed for each head coil channel from the k-space data.
  • T1W-structural MRI The low frequency intensity non-uniformity present in T1 - weighted and FLAIR images was corrected using the N4 bias field correction (Tustison et al., 2010). The MRI data were rigidly aligned to MNI space using the open source Mirorr tool (Rivest-Henault et al., 2015). T1 -weighted data were then parcellated into 45 grey-matter and 34 white-matter regions by segmentation propagation of an atlas database that was previously parcellated using Automated Anatomical Labeling (Tzourio-Mazoyer et al., 2002) and FreeSurfer (FS) white matter parcellations (Salat et al., 2009), respectively.
  • Automated Anatomical Labeling Tzourio-Mazoyer et al., 2002
  • FS FreeSurfer
  • WML White-matter lesions
  • QSM A brain mask was generated from the bias-field corrected magnitude image (after combining the coil data) using FSL's BET with the robust parameter set.
  • a Laplacian-based method was used to unwrap each coil phase image followed by background field elimination using vSHARP (Wu et al., 2012). The corrected phase images were then combined by weighting the magnitude of the corresponding channel.
  • STI Suite software (v2.2) (Li et al., 2014) was used for QSM reconstruction by performing dipole inversion using an iLSQR technique.
  • AIBL neuropsychological test battery was administered every 18 months using standard protocols by trained neuropsychologists (described in (Lim et al., 2014)).
  • Cognitive composite scores of episodic memory (CVLT-delayed, Logical Memory Test-delayed, RCFT-Long Delay), executive function (FAS, Category Fluency Switching), and language (Boston Naming Test, Category Fluency [animals + boys names]) were used as outcome variables, as previously described (Lim et al., 2014).
  • FAS Category Fluency Switching
  • Boston Naming Test Category Fluency [animals + boys names]
  • Benjamini-Hochberg correction for multiple comparisons was applied in mixed effects models of cognition in ⁇ -ve and ⁇ +ve subjects (42 tests, false discovery rate of 0.25) and in the multiple regression models of QSM in each brain region (7 tests, false discovery rate of 0.25). Significance was inferred when the p-values were less than both the Benjamini-Hochberg critical value and 0.05.
  • Beta coefficient values represent a one unit change in the explanatory variable associated with a one PPB change in QSM.
  • P-values for the QSM-SUVR comparisons are in bold text.
  • Hippocampus is the primary analysis, other regions are included for exploratory analysis.
  • QSM values in the other brain regions examined were not predictive of cognitive change.
  • QSM-MRI in tandem with ⁇ - ⁇ , could be used to stratify subjects at risk of cognitive decline.
  • Example 2 Assessing a risk of cognitive deterioration in a patient
  • a patient will be assessed for a level of cognitive ability. This level will set a base for determining whether they will over time deteriorate. They patient may already show signs of cognitive impairment after being initially assessed.
  • the patient is also assessed for amyloid loading before performing QSM in the hippocampus of the patient. If the patient is not amyloid positive as assessed using any method available to the skilled addressee such as but not limited to PET amyloid imaging, the patient is not progressed.
  • QSM amyloid positive
  • a high or low QSM predicts the trajectory for cognitive deterioration.
  • Example 3 Monitoring cognitive deterioration in a patient
  • a patient is tested according to Example 2 at a first time point.
  • a second test is conducted at another time point after the first time point.
  • the difference between the patient QSM is assessed.
  • the difference may then be compared to the difference from the first time point or with a reference level from a CN patient.
  • a degree of deterioration can be determined by assessing the cognitive function with the following cognitive composite scores: episodic memory (CVLT-delayed, Logical Memory Test-delayed, RCFT-Long Delay), executive function (FAS, Category Fluency Switching), and language (Boston Naming Test, Category Fluency [animals + boys names]) were used as outcome variables, as previously described (Lim YY, Maruff P, Pietrzak RH, Ames D, Ellis KA, Harrington K, et al. Effect of amyloid on memory and non-memory decline from preclinical to clinical Alzheimer's disease. Brain : a journal of neurology 2014; 137(Pt 1 ): 221 -31 .)
  • QSM Quantitative susceptibility mapping

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Abstract

La présente invention concerne l'évaluation, la prédiction ou le diagnostic de détérioration cognitive chez un patient présentant des dépôts amyloïdes dans le cerveau, telle que mesurée par susceptibilité magnétique et, de préférence, à l'aide de QSM et/ou de la relaxation transversale dans l'hippocampe comme indicateur du taux de déclin de la capacité cognitive. Les patients peuvent être stratifiés sur la base de la susceptibilité magnétique, de préférence, telle que mesurée à l'aide de QSM et/ou de la relaxation transversale dans l'hippocampe, qui prédit la trajectoire du déclin cognitif chez des sujets positifs aux amyloïdes.
PCT/AU2018/050226 2017-03-28 2018-03-13 Prédiction de progression de détérioration cognitive WO2018176082A1 (fr)

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US20230230233A1 (en) * 2020-08-14 2023-07-20 Splink, Inc. Recording Medium, Information Processing Device, Information Processing Method, Trained Model Generation Method, and Correlation Image Output Device
WO2023167157A1 (fr) * 2022-03-01 2023-09-07 株式会社Splink Programme informatique, dispositif de traitement d'informations et procédé de traitement d'informations
RU2819148C1 (ru) * 2023-10-19 2024-05-14 федеральное государственное автономное образовательное учреждение высшего образования "Пермский национальный исследовательский политехнический университет" Способ диагностики болезни альцгеймера

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020261608A1 (fr) * 2019-06-28 2020-12-30 株式会社島津製作所 PROCÉDÉ ET DISPOSITIF D'ÉVALUATION DE L'ÉTAT D'ACCUMULATION INTRACRÂNIENNE DE β-AMYLOÏDE
US20230230233A1 (en) * 2020-08-14 2023-07-20 Splink, Inc. Recording Medium, Information Processing Device, Information Processing Method, Trained Model Generation Method, and Correlation Image Output Device
US11972564B2 (en) * 2020-08-14 2024-04-30 Splink, Inc. Recording medium, information processing device, information processing method, trained model generation method, and correlation image output device
WO2023167157A1 (fr) * 2022-03-01 2023-09-07 株式会社Splink Programme informatique, dispositif de traitement d'informations et procédé de traitement d'informations
RU2819148C1 (ru) * 2023-10-19 2024-05-14 федеральное государственное автономное образовательное учреждение высшего образования "Пермский национальный исследовательский политехнический университет" Способ диагностики болезни альцгеймера

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