ADDIA Proof-of-Performance Clinical Study

Inclusion Criteria:

For all groups:

• Female and male subjects aged 40 to 85 years.

• Dated and signed informed consent by the subject (or its legal representative if applicable in accordance with the local regulations).

• AD, NAD patients and control subjects will be age-matched and mean age similar in the three groups.

• Able to comply with all study procedures.

For AD group:

• Diagnosis of AD: typical and atypical AD.

• MMSE score (measured in the last 3 months): < 21 for patients with moderate to severe AD. MMSE score > 21 in subjects with mild AD with sporadic or a familial form of AD due to mutation in APP or PSEN1 or PSEN2 genes.

• FCSRT, MoCA tests (MoCA measured in the last 3 months).

• Neuroimaging compatible with a diagnosis of AD:

• At least quantitative volumetric structural MRI: volumes of hippocampus and cortical areas.

• Visual semi-quantitative MRI if practiced shall show medial temporal lobe atrophy (MTA) and parietal atrophy with visual rating (semi-quantitative) on the MTA-score (e.g. Scheltens' scores 0-4). MTA score must be ≥ 2 in patients aged 40-75 years and ≥ 3 in patients aged above 75 years. For patients younger than 60 years, and with familial form of AD, who may have normal MTA-scores, Koedam score (0-3) for Parietal Atrophy showing atrophy of the precuneus characteristic of AD may be used with a Koedam score from 1 to 3.

Other neuroimaging data (retrospectively available) including PET Amyloid scan and FDG PET are desired if practiced by clinical centres and if available.

• Cerebrospinal fluid biomarker data (retrospectively available) showing positive levels of at least 2 out of 3 biomarkers: i.e. Aβ1-42 and tau (phosphorylated-Tau and/or total-Tau). Note: If retrospective CSF data are not available, retrospective Aβ PET and Tau PET data can be used.

For NAD group:

For all patients of the group NAD, except PSP subgroup (when PSP has a clear-cut typical phenotype, sometimes called Steele-Richardson phenotype), the CSF biomarker data must show levels for CSF biomarkers Aβ1-42, phosphorylated-Tau and total-Tau, compatible with the respective NAD subgroup. If retrospective CSF data are not available, retrospective Aβ PET and Tau PET data can be used.

Fronto-temporal dementia (FTD)

• Diagnosis of probable behavioural FTD (bvFTD) for all subjects of this FTD subgroup, whether with familial or non-familial forms. If with familial form, the subject must be a member of family with a known mutation in one of the FTD related genes: MAPT, PGRN. The predominant phenotype in the kindred must be cognitive/behavioural (i.e. kindred in whom Parkinsonism or Amyotrophic Lateral Sclerosis is the predominant clinical phenotype among affected relatives is excluded).

• Centrally rated frontal and/or anterior temporal atrophy score of 2 or greater on brain MRI.

• MMSE score compatible. If currently taking an acetylcholinesterase inhibitor and/or memantine, the subject must have been taking such medication(s) for ≥3 months.

Dementia Lewy body (DLB)

• DLB should be diagnosed when dementia occurs before or concurrently with Parkinsonism.

• Patients diagnosed with probable DLB. Probable DLB can be made with the presence of two core features out of the following:

• Fluctuating cognition with pronounced variations in attention and alertness,

• Recurrent visual hallucinations that are typically well formed and detailed,

• Spontaneous features of Parkinsonism.

Probable DLB is diagnosed with the presence of one or more of the above core features and one or more of the following suggestive features. Probable DLB should not be diagnosed on the basis of suggestive features alone:

• REM sleep behaviour disorder,

• Severe neuroleptic sensitivity,

• Low dopamine transporter uptake in basal ganglia demonstrated by SPECT or PET imaging (if data retrospectively available).

Supportive diagnosis:

• Generalized low uptake on SPECT/PET perfusion scan with reduced occipital activity (if data retrospectively available),

• Abnormal (low uptake) MIBG myocardial scintigraphy,

• Prominent slow wave activity on EEG with temporal lobe transient sharp waves.

• MRI: Relative preservation of medial temporal lobe structures on CT/MRI scan.

• Clinical Dementia Rating (CDR) score is greater than or equal to 0.5.

• MMSE score compatible.

• Patients with familial forms caused by mutation in genes SNCA, SNCB.

Parkinson's disease dementia (PDD)

• Subjects with Parkinson's Disease Dementia (PDD) must have dementia after (not before) developing Parkinson's disease (PD).

• PD is diagnosed by the 3 typical PD symptomatic findings:

• tremor,

• rigidity, and

• slowed movement (bradykinesia).

• Subjects with dementia and with LRRK2 gene mutation (or with mutation in one of the following genes: PARK2 or SNCA, VPS35, PINK1, DJ1, ATP13A2, FBX07, SLC6A3, TAF1 are also included.

• L-DOPA responsive (a good response to levodopa as practiced by clinical investigator, retrospectively to the study).

• MMSE score < 21 for moderate to severe PDD and > 21 for mild PDD.

• MRI: evidence of relevant structural abnormality (i.e. basal ganglia for Parkinsonism and potentially medio-temporal or cortical findings that may be related to dementia). Functional imaging techniques such as fluoro-dopa PET, FDG PET or SPECT to document the presence of dopaminergic dysfunction if retrospectively available.

Progressive Supranuclear Palsy (PSP)

• Diagnosis of probable or possible PSP as defined by the National Institute of Neurological Disorders and Stroke and Society for Progressive Supranuclear Palsy (NINDS-SPSP) diagnostic criteria, and as summarized by Armstrong et al. (2013) for the conclusions on CBD criteria from an international consortium of behavioural neurology, neuropsychology, and movement disorders specialists):

• Gradually progressive disorder,

• Onset at age 40 or later,

• Vertical (upward or downward gaze) supranuclear palsy and prominent postural instability with tendency to fall in the first year of disease onset,

• No evidence of other diseases that could explain the foregoing features, as indicated by mandatory exclusion criteria.

• Brain MRI at Screening consistent with PSP: neuroradiologic evidence of relevant structural abnormality in the midbrain and frontal lobes (i.e. basal ganglia, lobar atrophy).

• MMSE score compatible.

• Be able to ambulate and stand unassisted for 5 minutes.

• Be able to cooperate with gait and balance testing.

Corticobasal degeneration (CBD)

• Diagnosis of possible CBD. Inclusion clinical criteria for possible CBD, with features of Cortico-Basal Syndrome (CBS); familial forms related to MAPT included, Progressive Supranuclear Palsy Syndrome (PSPS) phenotype included.

• Features of CBS: a) limb rigidity or akinesia, b) limb dystonia, c) limb myoclonus plus 1 of: d) orobuccal or limb apraxia, e) cortical sensory deficit, f) alien limb phenomena (more than simple levitation).

• Features of PSPS: Three of: a) axial or symmetric limb rigidity or akinesia, b) postural instability or falls, c) urinary incontinence, d) behavioural changes, e) supranuclear vertical gaze palsy or decreased velocity of vertical saccades.

Note: subjects with probable sporadic CBD (no familial form) are excluded.

• MRI findings: parietal cortical atrophy (asymmetric).

• MMSE score compatible.

Controls

• Normal cognitive performance with normal scores of neuropsychological tests for their age.

• MMSE >26 (performed in less than 3 months).

• At least volumetric structural MRI with normal findings. Normal retrospective finding in β-amyloid PET scan, FDG PET scan if practiced by clinical centres.

• If retrospectively available, normal CSF biomarkers concentrations: negative levels for all three CSF biomarkers Aβ1-42, phosphorylated-Tau and total-Tau.

• If retrospectively available, Aβ PET and/or Tau PET scan(s) shall be negative.

• Able to comply with the study procedures.

EXCLUSION CRITERIA for all subjects:

The following exclusion criteria apply to all subjects:

• Neutropenia (Neutrophils: < 1,500/mm3 according to ethnic group).

• Thrombocytopenia (platelets: < 100,000/mm3, rule out EDTA-induced pseudo-thrombocytopenia).

• Subjects with less than an elementary education are excluded.

• Subject with no medical insurance are excluded in the countries where medical insurance is mandatory such as in France. In the countries where medical insurance is not mandatory, subjects with no medical insurance may not be excluded.

• Psychiatric history: schizophrenia, psychosis.

• Vascular dementia.

• Infection diseases, chronic inflammatory diseases that affect blood cells, patients with an active infection/ immunosuppressive disorders/ treatment with immunosuppressive or immunomodulatory medication.

• Current malignancy or past diagnosis of malignancy affecting blood cells under treatment or with treatment stopped only during last 3 months.

• Medication interfering with cognitive functions and ADDIA biomarkers (i.e. kinase inhibitors and beta-amyloid and tau passive and active immunizations).

• Major sensory deficits that could interfere with cognitive assessment (visual and auditory).

• Epilepsy.

• Patients with known contraindication for MRI imaging such as MRI-incompatible stent or MRI-incompatible endoprosthesis.

EXCLUSION CRITERIA for AD group

• Mixed dementia.

• Vascular dementia.

• Other dementia type.

• Other neurodegenerative disease.

• Absence of CSF biomarker data and/or amyloid PET data is an exclusive criterion for all subjects with sporadic forms of AD, but it is not an exclusive criterion for subjects with a familial form of AD that is due to a mutation of a gene among APP, PSEN1, PSEN2.

EXCLUSION CRITERIA for NAD group

• AD diagnosis.

• Mixed dementia.

• Vascular dementia.

• Absence of either CSF biomarker data or amyloid PET data is an exclusive criterion for all subjects in sporadic DLB, PDD, FTD and CBD (but not for subjects with PSP when PSP has a clear-cut typical phenotype, sometimes called Steele-Richardson phenotype). However, absence of CSF biomarker and/or amyloid PET data is not an exclusive criterion for subjects with a familial form of NAD that is due to a mutation of a gene among MAPT, PGRN, SNCA, SNCB, PARK2 or SNCA, VPS35, PINK1, DJ1, ATP13A2, FBX07, SLC6A3 or TAF1, TREM2.

EXCLUSION CRITERIA for Control group

• AD patients.

• Dementia patients.

• Cognitive impairments.