Relative neuron loss in hippocampal sclerosis of aging and Alzheimer's disease

Abstract

Objective: To characterize the pattern of neuron loss in hippocampal sclerosis of aging (HS-Aging) and age-related diseases and to evaluate its contribution to cognitive impairment in the elderly. Methods: Participants (n = 1,361) came from longitudinal observational studies of aging at the Knight Alzheimer Disease Research Center, Washington University, Saint Louis, Missouri, USA. Relative neuron loss in the hippocampus of HS-Aging was measured using unbiased stereological methods. Transactive response DNA-binding protein of 43 kDa (TDP-43) proteinopathy, a putative marker of HS-Aging, was assessed. Clinical and cognitive data were analyzed using parametric statistical methods. Results: Ninety-three cases had HS-Aging (6.8%), eight cases had ‘pure’ HS-Aging, and 37 cases had comorbid intermediate or high Alzheimer disease neuropathologic change (i/h ADNC). Relative neuron loss (ratio of neuron number in hippocampal subfield CA1 to the neuron number in parahippocampal gyrus) was 0.15 for HS-Aging; this was significantly lower than 0.64 for i/h ADNC and 0.66 for control cases (Kruskal-Wallis test, p <0.0001, p = 0.0003, respectively). TDP-43 proteinopathy was present in 92.4% of HS-Aging cases, higher than that in i/h ADNC (52%) and control (25%) cases. Pure HS-Aging cases were more likely to have cognitive impairment in the memory domain. Interpretation: Relative neuron loss in the hippocampus compared to the PHG may be useful in distinguishing HS-Aging in the context of comorbid ADNC. HS-Aging contributes to cognitive impairment which phenotypically resembles AD dementia. TDP proteinopathy is a frequent comorbidity in HS-Aging and may contribute to cognitive impairment to a modest degree.

Neuropathologic features associated with basal forebrain atrophy in Alzheimer disease

“…11 In the current cohort, TDP-43 pathology was present at least to a mild extent in 37% of cases, which agrees with the prevalence of TDP-43 in previous studies, ranging between 33% and 52% in cases with AD pathology. 40,[42][43][44] Also consistent with these previous studies, the regional distribution of TDP-43 inclusions in the current sample was almost exclusively focused on MTL regions, including hippocampus, entorhinal cortex, and amygdala, and only 6 patients had neocortical TDP-43 inclusions in addition to MTL involvement. These data underscore the strong association of regional distribution of TDP-43 inclusions with the regional pattern of brain atrophy, consistent with previous reports on amygdala and hippocampal involvement with TDP-43 pathology 45 and the current discussion on limbic predominant TDP-43 pathology in older individuals that has recently been termed limbic-predominant age-related TDP-43 encephalopathy (LATE).…”

Brain atrophy in primary age‐related tauopathy is linked to transactive response DNA‐binding protein of 43 kDa

“…With that said, in our experience, the frequency of TDP-43 in PART is significantly lower than the frequency in Alzheimer's disease. In Alzheimer's disease, we and others have found frequencies of TDP-43 deposition in the range of 50%-70%, when the amygdala is screened [11,42,47,48]. In fact, one study reported a frequency even greater than 70% in Alzheimer's disease [49].…”

Sodium Dichloroacetate Stimulates Angiogenesis by Improving Endothelial Precursor Cell Function in an AKT/GSK-3β/Nrf2 Dependent Pathway in Vascular Dementia Rats

“…The hippocampal lesions in the CA1 area more likely cause dementia with deficits in memory. Reducing lesions in this area of the brain is conducive to improving cognitive function (Ihara et al, 2018). Thus, improved cognitive function following DCA treatment can be partly attributed to reduced hippocampal damage.…”