Hippocampal Sclerosis and Amnesia Not Due to Alzheimer's Disease (ShaTau7)

Hippocampal Sclerosis (HS) leads to anterograde amnesia mimicking early Alzheimer's disease (AD) (so called HSA-nonAD). Recent studies showed that (a) the deficit of episodic memory as well as the level of hippocampal atrophy in bvFTD may be of similar severity to that observed in AD, even at initial presentation, leading to misdiagnosis in 22% of cases with post mortem diagnosis; (b) amnesia with HS due to microvascular lesion and microinfarcts can also cause impairment of episodic memory mimicking AD, without subcortical cognitive profile. Because these diseases involve distinct pathophysiological processes, they require different specific care and treatment. In consequence, it is very important to improve our knowledge about HS in order to identify its mechanism and improve the diagnosis.

Study Overview

• Status: Unknown
• Conditions: Patients With Cognitive Disturbances
• Intervention / Treatment: Other: Neurological examinations; Other: Neuropsychological examinations; Other: Clinical examinations; Radiation: MRI 3T; Radiation: MRI 7T

Detailed Description

Hippocampal sclerosis (HS) refers to neuronal cell loss and astrocytosis in subiculum and cornu ammonis subfields of the hippocampal formation unrelated to Alzheimer's disease pathology. In contrast to HS that affects younger adults with epilepsy, older individuals with HS have significant ante-mortem cognitive dysfunction but no epilepsy. Neuropathological studies demonstrated three main types of HS associated with aging: (a) HS-Ageing to refer to the disease with HS pathology in ageing individuals, observed in more than 10% of subjects aged over 85 years; (b) HS observed in the behavioural variant of frontotemporal dementia (bvFTD), HS being more frequent in tau-negative pathology, especially in FTLD-TDP. bvFTD patients may manifest severe episodic memory impairment and hippocampal atrophy; (c) HS associated with cortical or subcortical cerebral microinfarcts, which are invisible on conventional MRI. Cerebral microinfarcts are observed in 33% of elderly over 85 years in post-mortem studies.

HS leads to anterograde amnesia mimicking early Alzheimer's disease (AD) (so called HSA-nonAD). Recent studies showed that (a) the deficit of episodic memory as well as the level of hippocampal atrophy in bvFTD may be of similar severity to that observed in AD, even at initial presentation, leading to misdiagnosis in 22% of cases with post mortem diagnosis; (b) amnesia with HS due to microvascular lesion and microinfarcts can also cause impairment of episodic memory mimicking AD, without subcortical cognitive profile. Because these diseases involve distinct pathophysiological processes, they require different specific care and treatment. In consequence, it is very important to improve our knowledge about HS in order to identify its mechanism and improve the diagnosis.

• Study Type: Interventional
• Enrollment (Anticipated): 140
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Marie SARAZIN, MD, PhD; Phone Number: 00 33 1 45 65 61 72; Email: m.sarazin@ch-sainte-anne.fr
• Study Contact Backup: Name: Marie GODARD; Phone Number: 00 33 1 45 65 77 28; Email: m.godard@ch-sainte-anne.fr

Study Locations

• France
  • Paris, France, 75014
    • Recruiting
    • Neurologie de la mémoire et du langage, Service de Neurologie, Centre Hospitalier Sainte-Anne
    • Contact: Marie SARAZIN, MD, PhD; Phone Number: 00 33 1 45 65 61 72; Email: m.sarazin@ch-sainte-anne.fr
    • Contact: Marie GODARD; Phone Number: 00 33 1 45 65 77 28; Email: m.godard@ch-sainte-anne.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

General inclusion criteria

• Be older than18 years old.
• Consulting in one of the centers (patients only)
• Sufficient cognitive capacities for the realization of the clinical and neuropsychological evaluations, left to the judgement by the investigator.
• Women old enough to procreate under effective contraception
• Signed consent
• Absence of general or systemic disorders that may interfere with cognition.
• If available before inclusion, absence of brain lesions as determined by MRI that may account for even part of the clinical presentation.

Patients with Hippocampal sclerosis non AD (n=40)

Clinical criteria :

• CDR (Clinical Dementia Rating Scale) = 0.5 or 1
• Progressive amnestic syndrome of the hippocampal type, defined by a free recall score ≤ 17/48 and a total recall score ≤ 40/48 on the FCSRT.

Biological criteria : Absence of Profile suggestive of AD on the study of the biomarkers of the CSF (IATI ratio > 0.8)

Patients with Alheimer's Disase (n=40)

Clinical criteria :

• CDR (Clinical Dementia Rating Scale) = 0.5 or 1
• Typical amnesic AD : Progressive amnestic syndrome of the hippocampal type, defined by a free recall score ≤ 17/48 and a total recall score ≤ 40/48 on the FCSRT, associated or not with others cognitive impairment
• Posterior Cortical Atrophy : initial presentation of progressive visual or visuospatial impairment; absence of ophthalmologic impairment with evidence of complex visual and/or visuospatial disorder on examination; a relatively preserved episodic memory
• Logopenic progressive aphasia : word retrieval deficits in spontaneous speech and confrontation naming, impaired repetition of sentences, errors in spontaneous speech and naming (eg, phonological errors), and relative sparing of word and object knowledge and motor speech.

Biological criteria : CSF biomarkers suggestive of AD defined on CSF.

Patients with DLFT (n=20) :

Clinical criteria :

• Modifications of the personality and the social conducts in the foreground
• Compatible brain imaging with the diagnosis : profile of atrophy and/or hypometabolism in TEP-FDG (or hypoerfusion in Spect) compatible with the diagnosis of DFT and/or absence of atypie Biological criteria : No AD profile on CSF biomarkers

Patients with CBD/PSP (n=20) (Armstrong et al., 2013)

1. Corticobasal syndrome :

   • at least one of the following signs : limb rigidity or akinesia, limb dystonia, limb myoclonusplus at least one of the following sign : orobuccal or limb apraxia, e) cortical sensory deficit, alien limb phenomena (more than simple levitation)
   • Nonfluent/agrammatic variant of primary progressive aphasia: Effortful, agrammatic speech plus at least one of: a) impaired grammar/sentence comprehension with relatively preserved, single word comprehension, or b) groping, distorted speech production (apraxia of speech)

2. Progressive supranuclear palsy syndrome :

   • Three of the following items present: 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

Normal controls (n=20):

Absence of known psychiatric disorder Score on the Folstein Mini Mental Status (MMSE > or = 27) Normal neuropsychological assessment for the age and the educational level

Exclusion Criteria:

• Subject with a psychiatric evolutionary and/or badly checked pathology (left to the judgement of the investigator).
• Subject with a grave, severe or unstable pathology (left to the judgement of the investigator) the nature of which can interfere with the variables of evaluation.
• Epileptics subjects, badly tolerant MRI (1.5T, 3T or 7T), Subject presenting contraindications to the MRI (if necessary, a blood pregnancy test will be performed before 7T MRI) (Pacemaker or stimulating neurosensory or implantable defibrillator, cochlear implants, eye or cerebral ferromagnetic foreign bodies close to nervous structures, metallic prostheses, agitation of the patient : not cooperative or agitated patients, very young children, claustrophobics subjects, pregnant women, neurosurgical ventriculoperitoneal shunt valves, brace)
• Known or supposed histories (< or = 5 years) of severe alcoholism or misuse of drugs
• Vascular, inflammatory or expansive, visible lesion in the MRI which can interfere on the criteria of diagnosis.
• No health insurance
• Pregnant, breast-feeding woman or planning a pregnancy in two years of follow-up.
• For controls : anomaly detected on the MRI in the appreciation of the investigator

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Patients with Hippocampal sclerosis non AD; Patients with Hippocampal sclerosis non AD (n=40)	Other: Neurological examinations; Other: Neuropsychological examinations; Other: Clinical examinations; Radiation: MRI 3T; Radiation: MRI 7T
Other: Patients with Alhzeimer's Disase; Patients with Alhzeimer's Disase (n=40)	Other: Neurological examinations; Other: Neuropsychological examinations; Other: Clinical examinations; Radiation: MRI 3T; Radiation: MRI 7T
Other: Patients with DLFT; Patients with DLFT (n=20)	Other: Neurological examinations; Other: Neuropsychological examinations; Other: Clinical examinations; Radiation: MRI 3T; Radiation: MRI 7T
Other: Patients with CBD/PSP; Patients with CBD/PSP (n=20)	Other: Neurological examinations; Other: Neuropsychological examinations; Other: Clinical examinations; Radiation: MRI 3T; Radiation: MRI 7T
Other: Normal controls; Normal controls (n=20)	Other: Neurological examinations; Other: Neuropsychological examinations; Other: Clinical examinations; Radiation: MRI 3T; Radiation: MRI 7T

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
7 tesla MRI.	Structural morphometric analysisze of hippocampal and Papez circuit sub-regions, and detection of microinfarcts/microbleeds by 7 tesla MRI.	up to Month 18

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
3T MRI	Morphometry of hippocampus by 3T MRI	Baseline
3T MRI	Morphometry of hippocampus by 3T MRI	Month 12
3T MRI	Morphometry of hippocampus by 3T MRI	Month 24
3T MRI	White matter intensities assessed by 3T MRI	Baseline
3T MRI	White matter intensities assessed by 3T MRI	Month 12
3T MRI	White matter intensities assessed by 3T MRI	Month 24
7T MRI	Volumetry of the cholinergic nucleus basalis by 7T MRI	up to Month 18
CSF	CSF biomarkers	Baseline
Neuropsychological assessment	Neuropsychological assessment	Baseline
Neuropsychological assessment	Neuropsychological assessment	Month 12
Neuropsychological assessment	Neuropsychological assessment	Month 24
Clinical assessment	Clinical assessment	M0
Clinical assessment	Clinical assessment	Month 12
Clinical assessment	Clinical assessment	Month 24
Genetic markers of bvFTD	Genetic markers of bvFTD	Baseline
Blood markers	Blood markers	Baseline
Plasmatic progranulin levels	Plasmatic progranulin levels	Baseline
Regional glucose hypometabolism	Regional glucose hypometabolism assessed by FDG-PET (if performed during clinical care).	Baseline

Collaborators and Investigators

• Sponsor: Centre Hospitalier St Anne
• Investigators: Principal Investigator: Marie SARAZIN, MD, PhD, Centre Hospitalier Sainte-Anne

Study record dates

Study Major Dates

• Study Start (Actual): January 27, 2016
• Primary Completion (Anticipated): January 1, 2020
• Study Completion (Anticipated): October 1, 2020

Study Registration Dates

• First Submitted: October 13, 2015
• First Submitted That Met QC Criteria: October 14, 2015
• First Posted (Estimate): October 15, 2015

Study Record Updates

• Last Update Posted (Actual): October 20, 2017
• Last Update Submitted That Met QC Criteria: October 18, 2017
• Last Verified: October 1, 2017

More Information

Terms related to this study

• Keywords: Amnesia, Alzheimer, hippocampal sclerosis, fronto-temporal lobar degeneration
• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Neurocognitive Disorders; Neurodegenerative Diseases; Dementia; Tauopathies; Cognition Disorders; Memory Disorders; Sclerosis; Alzheimer Disease; Cognitive Dysfunction; Amnesia
• Other Study ID Numbers: D14-P010