TDP-43 pathology in FTLD-TDP and old-age hippocampal sclerosis
Research type
Research Study
Full title
TDP-43 pathology in FTDL-TDP and old-age hippocampal sclerosis
IRAS ID
197896
Contact name
Suvi R. K. Hokkanen
Contact email
Sponsor organisation
Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge
Clinicaltrials.gov Identifier
Study ID 3026, UKCRN: Cambridge City over75s Cohort study (CC75C); Study ID 4288, UKCRN: CC75C brain donation for neuropathology; 05Q0108308, NRES: CC75C; Ref: 99/5/22, 05/MRE05/37, MREC: CFAS; Ref: 09/h0906/52+5, REC: Manchester Brain Bank
Duration of Study in the UK
0 years, 6 months, 17 days
Research summary
One important cause of dementia among the older old is hippocampal sclerosis (HScl) - a condition about which very little is known. It is characterized by severe nerve cell loss in the part of the brain controlling memory processing. It usually presents with abnormal accumulations protein TDP-43.
Another type of dementia, frontotemporal lobar degeneration (FTLD), also frequently shows TDP-43 accumulations (FTLD-TDP). However, FTLD affects much younger people than HScl. Up to half of familial FTLD-TDP cases are caused by mutations in the progranulin gene (GRN). FTLD-TDP cases with this mutation show TDP-43 accumulation and nerve cell loss very similar to HScl. GRN mutations are rare, but there is a common variation in the gene (GRN rs5848). Two studies based on a selected collection of autopsy brains have associated this genetic variation with HScl, and we have recently confirmed this finding in studies with population representation.
The similar pathology and proposed common genetic background between FTLD-TDP and HScl suggest that they might be linked. The aim of this project is to compare the morphology, quantity and location of TDP-43 aggregates between HScl and FTLD-TDP cases. We hypothesize that HScl and FTDL-TDP might be related disorders, where familial FTLD-TDP would represent an early-onset variant, and HScl a late-onset sporadic variant of a disease spectrum.
We have identified 36 HScl cases in the population-based studies CC75C and CFAS. TDP-43 has been evaluated in CC75C, and the assessment is ongoing in CFAS. The FTDL-TDP-cases would be obtained from Prof Mann’s collection, University of Manchester Brain Bank. Prof Mann has recently reported an analysis of 45 FTLD-TDP brains. Sections from the FTLD-TDP brains would be stained analogous to the HScl cases, and evaluated with the same protocols. TDP-43 pathology type, presentation and severity will be statistically compared between FTLD-TDP and HScl.
REC name
East of England - Cambridgeshire and Hertfordshire Research Ethics Committee
REC reference
16/EE/0125
Date of REC Opinion
16 Mar 2016
REC opinion
Favourable Opinion