The Skin as a Window to the Central Nervous System in Frontotempolar Lombar Degeneration

Nantes University Hospital80 enrolled

Overview

Frontotemporal lobar degeneration (FTLD) is a clinically heterogeneous syndrome, characterized by progressive decline in behaviour and/or language. From a pathological standpoint, like the great majority of neurodegenerative disorders, FTLD are proteinopathies, which are characterized by the presence of specific protein deposits in the Central Nervous System (CNS). Accordingly, the two main deposits observed in FTLD are either made of Tau or transactive response DNA binding protein 43 (TDP-43). In pathological conditions such as FTLD, both proteins are aggregated and hyperphosphorylated. It is now well established that the pathological process in some proteinopathies such as synucleinopathies (of which Parkinson's disease is the main representative) is not limited to the brain but also widespread throughout the peripheral autonomic networks, including the autonomic innervation of the skin. In this context, many independent studies have shown that the pathological process in PD could be detected using routine punch skin biopsies opening the way for the development of original histopathological markers of the disease. Our hypothesis is that such a scenario could also occur in FTLDs and that the detection of the pathological tau or TDP-43 protein in the skin could help in diagnosing FTLD. This is especially relevant as, despite the recent progress in genetics, neurobiology and neuroimaging, there are no available biomarkers for FTLD.

Participant with Frontotemporal Lobar degeneration equally distributed into behavioral variant of frontotemporal dementia (bvFTD), language variant with primary progressive aphasia (PPA) and motor presentations with atypical parkinsonian disorders (corticobasal degeneration-CBD and progressive supranuclear palsy-PSP) and motoneuron disorder (amyotrophic lateral sclerosis -ALS) will be included at Nantes University Hospital during a period of 24 months. Healthy volunteers will be included as comparative group. A skin biopsy and venous blood samples will be collected for all participants.

Study Type

INTERVENTIONAL

Allocation

Purpose

OTHER

Masking

Eligibility

Sex: ALLMin age: 50 YearsMax age: 75 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion Criteria (patients): * Adressed or followed at memory clinic or ALS expert center at Nantes university hospital. * Aged 50-75 years * Fulfilling current diagnosis criteria for one of the disorder: vcfFTD, non-Alzheimer PPA (semantic or non fluent), DCB or PSP,ALS * MMSE ≥ 18 * Membership of social security scheme Inclusion Criteria (healthy volunteers): * No history of neurological disease, diabetes, or alteration/damage of peripheral nervous system * Aged 50-75 years Paired to at least one patient on age (less or more 5 years) * MOCA ≥ 26 * Membership of social security scheme Non inclusion Criteria (Patients and healthy volunteers): * Concomitting conditions affecting the peripheral nervous system such as but not limited to diabetes, renal failure, thyroid disorder, vitamin B12 deficiency, acute and chronic inflammatory diseases HIV, syphilis * Know allergy to local anesthetic * Known coagulopathy * Pregnant women or breastfeeding women * Person under court protection sous sauvegarde de justice * Person under guardianship * Inability to sign an informed consent Non inclusion criteria (Patients) • Patient with neurological disease other than FTLD Non inclusion criteria (Healthy volunteers) : • Evidence of neurological disorder at the inclusion including but not limted to FTLD, Parkinson disease, Alzheimer disease, lewy body dementia, Huntington disease, systemic lupus erythematosus multiple sclerosis; learning disabilities, mental retardation, severe hypoxic brain injuries, brain trauma with permanent cognitive impairments.

Outcomes

Primary Outcomes

Amount of TDP 43

assessed by Western blot and qPCR to determine level of expression of TDP-43 in the skin

Time frame: Day of inclusion

Amount of Tau assessed by Western blot and qPCR

assessed by Western blot and qPCR to determine level of expression of Tau in the skin

Time frame: Day of inclusion

Secondary Outcomes

Amount of Tau phosphorylation

phospho-tau/tau ratio in the skin will be measured by Western blot

Time frame: Day of inclusion

Amount of TDP 43 phosphorylation

phospho-TDP-43 /TDP43 ratio in the skin will be measured by Western blot

Time frame: Day of inclusion

Neuropsychological characterization

During their follow-up FTLD patients underwent a complete neuropsycological assessment define as: * mini-mental state examination (MMSE) * the 16-item Free Recall/Indicated Recall test (RL/RI-16 items) * Rey figure and recall * Trail Making Test (TMT A \& B) * Wechsler Adult Intelligence Scale * Literal (letter P) and categorical (animals) fluency * Rapid Frontal Efficiency Battery (BREF) * Wisconsin Card Sorting Test (WCST) * Zoo test of Behavioural Assessment of the Dysexecutive Syndrome (BADS) * Stroop test - 4 boards * Oral image naming test (DO 80) * Theory of mind (ToM-15) * ekman facial emotion recognition test

Time frame: day of inclusion for patients vFTD, PPA and corticobasal degeneration-CBD and progressive supranuclear palsy-PSP within 12 months of inclusion for patients ALS

Behaviour profile

The 10-items scale Daphne will be used to explore disinhibition (4 items), apathy(1 item), perseveration (1 item), hyperorality (2items), personal neglect (1 item) and loss of empathy (1 item)

Time frame: day of inclusion for patients vFTD, PPA and corticobasal degeneration-CBD and progressive supranuclear palsy-PSP within 12 months of inclusion for patients ALS

FTLD mutation

Mutation carrier patient will be identified among participant (not all the participant) who had a genetic screening had neen carried out during their follow up.

Time frame: before inclusion

The Skin as a Window to the Central Nervous System in Frontotempolar Lombar Degeneration

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts