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

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.

Study Overview

• Status: Recruiting
• Conditions: Frontotemporal Lobar Degeneration
• Intervention / Treatment: Procedure: Skin biopsy

Detailed Description

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
• Enrollment (Estimated): 80
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Claire BOUTOLEAU-BRETONNIERE, MD; Phone Number: +33 02 40 16 54 22; Email: claire.boutoleaubretonnière@chu-nantes.fr
• Study Contact Backup: Name: pascal DERKINDEREN, Pr; Phone Number: +33 02 40 16 54 22; Email: derkinderenp@yahoo.fr

Study Locations

• France
  • Nantes, France, 44093
    • Recruiting
    • Nantes University Hospital
    • Principal Investigator: Claire BOUTOLEAU BRETONNIERE
    • Contact: Claire BOUTOLEAU BRETONNIERE, MD; Phone Number: +33 02 40 16 54 22

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Single arm study; A single 3 mm-diameter punch skin biopsy will be obtained from FTLD patients and healthy volunteers at the C8 paravertebral under local anesthesia to analyze cutaneous innervation	Procedure: Skin biopsy; A single 3 mm-diameter punch skin biopsy will be obtained from FTLD patients and healthy volunteers at the C8 paravertebral under local anesthesia to analyze cutaneous innervation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Amount of TDP 43	assessed by Western blot and qPCR to determine level of expression of TDP-43 in the skin	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	Day of inclusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Amount of Tau phosphorylation	phospho-tau/tau ratio in the skin will be measured by Western blot	Day of inclusion
Amount of TDP 43 phosphorylation	phospho-TDP-43 /TDP43 ratio in the skin will be measured by Western blot	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	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)	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.	before inclusion

Collaborators and Investigators

• Sponsor: Nantes University Hospital

Study record dates

Study Major Dates

• Study Start (Actual): December 17, 2024
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): July 1, 2027

Study Registration Dates

• First Submitted: June 25, 2024
• First Submitted That Met QC Criteria: July 1, 2024
• First Posted (Actual): July 8, 2024

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: December 17, 2024
• Last Verified: December 1, 2024

More Information

Terms related to this study

• Keywords: tau; skin biopsy; FTLD; TDP43
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Mental Disorders; Metabolic Diseases; Neurocognitive Disorders; Dementia; Neurodegenerative Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Frontotemporal Lobar Degeneration
• Other Study ID Numbers: RC23_0575

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No