Clinical trial: ADDIA Proof-of-Performance Clinical Study (NCT03030586)

Eligibility criteria:
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.
No condition on gender to be admitted to the trial.
Accepts Healthy Volunteers
Subject must be at least 40 Years old.
Subject must be at most 85 Years

Patient description (medical language): A 70-year-old man comes to the office accompanied by his wife.  The patient has experienced progressive memory loss over the last years.  He needs help with some of his routine activities, such as paying bills.  The patient's wife says, "He used to be such an independent person, but now he needs help with many things, even finding direction to home!"  Medical history includes hypertension, hyperlipidemia, and type 2 diabetes mellitus.  Family history includes Alzheimer disease in his father.  MRI reveals diffuse cortical and hippocampal atrophy. The diagnosis of AD is made using the National Institute on Aging and the Alzheimer's Association (NIA-AA) criteria.

Patient description (patient's own words): I am a 70-year-old man, and I paid a visit to the doctor with my wife the other day. I noticed that I tend to forget small things and that my memory has decreased over the past few years. I even ask my wife to help me out with my daily routine. I used to be the one paying the bills, but now she has to give me a hand. My wife mentioned to the doctor that I used to be independent and that I tend to forget where we live. I suffer from hypertension, high cholesterol, and type 2 diabetes. My poor dad was suffering from Alzheimer disease, so I hope I'm not going to end the same way! I did an MRI and they found out that some part of my brain was decreasing. I also did an Alzheimer test.

Does the patient match the trial criteria? Entailment