Genetic risk factors of old-age hippocampal sclerosis.
Research type
Research Study
Full title
Genetic risk factors of old-age hippocampal sclerosis.
IRAS ID
152811
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 over-75s Cohort study (CC75C); Study ID 4288 , UKCRN: CC75C - brain donation for neuropathology; 05-Q0108-308, NRES: CC75C; Ref: 99/5/22, 05/MRE05/37, MREC: CFAS
Research summary
Dementia is a concern for our time, one consequence of the success in extending average human lifespans. An important cause of dementia among the older elderly may be 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. How this neuron loss develops, what it relates to, and how common HScl is, remain unclear.
HScl is often associated with accumulations of the protein TDP-43 in brain cells, a feature which is also characteristic for the most common form of frontotemporal lobar degeneration dementia (FTLD-TDP). Up to half of the familial FTLD-TDP cases are caused by mutations in the progranulin gene (GRN). GRN mutations result in low expression of progranulin, a protein which protects nerve cells. FTLD-TDP cases with a GRN mutation show similar nerve cell loss and TDP-43 accumulation pattern to HScl.
GRN mutations are rare, but there is a common gene variation (GRN rs5848), which affects the production of progranulin. This polymorphism has been associated with HScl in two selected US brain bank collections. However, this finding has not been confirmed in population-based studies. In a Finish population-based pathological study HScl was associated with an other genetic variation, the MAPT tau haplotype.
We aim to determine if HScl is associated with the progranulin gene polymorphism and/ or the MAPT haplotype in the English population-based clinicopathological studies CC75C and CFAS. This study will give deeper insight into potential etiological causes of hippocampal nerve cell loss. The acquired genetic data could also be used within CC75C and CFAS to define the risk of progranulin and MAPT variations on other diseases. Very recently, a further genetic variation in the ABCC9 gene has been suggested to be associated with HScl.
REC name
East of Scotland Research Ethics Service REC 2
REC reference
14/ES/1055
Date of REC Opinion
21 Aug 2014
REC opinion
Favourable Opinion