Hippocampal sclerosis in advanced age: clinical and pathological features

Abstract

Hippocampal sclerosis is a relatively common neuropathological finding (∼10% of individuals over the age of 85 years) characterized by cell loss and gliosis in the hippocampus that is not explained by Alzheimer's disease. Hippocampal sclerosis pathology can be associated with different underlying causes, and we refer to hippocampal sclerosis in the aged brain as hippocampal sclerosis associated with ageing. Much remains unknown about hippocampal sclerosis associated with ageing. We combined three different large autopsy cohorts: University of Kentucky Alzheimer's Disease Centre, the Nun Study and the Georgia Centenarian Study to obtain a pool of 1110 patients, all of whom were evaluated neuropathologically at the University of Kentucky. We focused on the subset of cases with neuropathology-confirmed hippocampal sclerosis (n=106). For individuals aged≥95 years at death (n=179 in our sample), each year of life beyond the age of 95 years correlated with increased prevalence of hippocampal sclerosis pathology and decreased prevalence of 'definite' Alzheimer's disease pathology. Aberrant TAR DNA protein 43 immunohistochemistry was seen in 89.9% of hippocampal sclerosis positive patients compared with 9.7% of hippocampal sclerosis negative patients. TAR DNA protein 43 immunohistochemistry can be used to demonstrate that the disease is usually bilateral even when hippocampal sclerosis pathology is not obvious by haematoxylin and eosin stains. TAR DNA protein 43 immunohistochemistry was negative on brain sections from younger individuals (n=10) after hippocampectomy due to seizures, who had pathologically confirmed hippocampal sclerosis. There was no association between cases with hippocampal sclerosis associated with ageing and apolipoprotein E genotype. Age of death and clinical features of hippocampal sclerosis associated with ageing (with or without aberrant TAR DNA protein 43) were distinct from previously published cases of frontotemporal lobar degeneration TAR DNA protein 43. To help sharpen our ability to discriminate patients with hippocampal sclerosis associated with ageing clinically, the longitudinal cognitive profile of 43 patients with hippocampal sclerosis associated with ageing was compared with the profiles of 75 controls matched for age, gender, education level and apolipoprotein E genotype. These individuals were followed from intake assessment, with 8.2 (average) longitudinal cognitive assessments. A neuropsychological profile with relatively high-verbal fluency but low word list recall distinguished the hippocampal sclerosis associated with ageing group at intake (P<0.015) and also 5.5-6.5 years before death (P<0.005). This may provide a first step in clinical differentiation of hippocampal sclerosis associated with ageing versus pure Alzheimer's disease in their earliest stages. In summary, in the largest series of autopsy-verified patients with hippocampal sclerosis to date, we characterized the clinical and pathological features associated with hippocampal sclerosis associated with ageing.

Memory Dysfunction

“…Neuropathologic studies reveal the abnormal accumulation of TAR-DNA binding protein 43 (TDP-43) in a pattern distinct from frontotemporal lobar degeneration. 20 Of clinical relevance, patients with hippocampal sclerosis tend to have less significant functional impairment than patients with Alzheimer disease. 21 Effective evaluation of a patient with an episodic memory concern requires a collateral historian.…”

Hippocampal sclerosis, hippocampal neuron loss patterns and TDP‐43 in the aged population

“…In contrast, hippocampal sclerosis of aging (HS‐Aging) is considered as a distinct, dementia‐related pathology 18, 31, 35, 56, 58, neuropathologically characterized by severe neuron loss and gliosis in the CA1 area. The subiculum may be affected, but CA4, CA3 and are CA2 spared 16, 41, 43.…”

FUS regulates genes coding for RNA-binding proteins in neurons by binding to their highly conserved introns

“…TDP-43 associates with the mRNA splicing and translational machinery (Freibaum et al 2010). Dominant mutations of the TARDBP gene were later found in familial ALS cases (Kabashi et al 2008;Sreedharan et al 2008;Van Deerlin et al 2008), and aggregation of TDP-43 is found in most cases of hippocampal sclerosis associated with aging (Nelson et al 2011) and in many cases of FTLD (Sieben et al 2012). The role of RBPs in ALS solidified with the discovery that dominant mutations of FUS also cause familial ALS (Kwiatkowski et al 2009;Vance et al 2009).…”