Clinical and Neuropathological Characteristics of Hippocampal Sclerosis

Leverenz, James B.; Agustin, Christina M.; Tsuang, Debby W.; Peskind, Elaine R.; Edland, Steven D.; Nochlin, David; DiGiacomo, Lillian; Bowen, James D.; McCormick, Wayne C.; Teri, Linda; Raskind, Murray A.; Kukull, Walter A.; Larson, Eric B.

doi:10.1001/archneur.59.7.1099

Cited by 124 publications

(155 citation statements)

References 43 publications

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“…Although some studies on HS‐Aging explicitly state a sparing of CA2/3 in HS‐Aging diagnosis 16, 17, 24, 27, 31, 55, others include cases which present with neuron loss also in other hippocampal sectors than the CA1 and subiculum 15, 29, 43, 44, 57, 58. Frequently, the term “selective” is used for CA1 neuron loss and gliosis, but how potential lesions in other CA areas are considered is not further specified (for example 2, 7, 26, 35).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2017

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Hippocampal neuron loss is a common neuropathological feature in old age with various underlying etiologies. Hippocampal sclerosis of aging (HS‐Aging) is neuropathologically characterized by severe CA1 neuronal loss and frequent presence of transactive response DNA‐binding protein of 43 kDa (TDP‐43) aggregations. Its etiology is unclear and currently no standardized approaches to measure HS‐Aging exist. We developed a semi‐quantitative protocol, which captures various hippocampal neuron loss patterns, and compared their occurrence in the context of HS‐Aging, TDP‐43, vascular and tau pathology in 672 brains (TDP‐43 staining n = 642/672, 96%) donated for the population‐based Cambridge City over‐75s Cohort and the Cognitive Function and Ageing Study. HS‐Aging was first evaluated independently from the protocol using the most common criteria defined in literature, and then described in detail through examination of neuron loss patterns and associated pathologies. 34 (5%) cases were identified, with a maximum of five pyramidal neurons in each of over half CA1 fields‐of‐view (x200 magnification), no vascular damage, no neuron loss in CA2‐CA4, but consistent TDP‐43 neuronal solid inclusions and neurites. We also report focal CA1 neuron loss with vascular pathology to affect predominantly CA1 bordering CA2 (Fisher's exact, P = 0.009), whereas neuron loss in the subicular end of CA1 was associated with TDP‐43 inclusions (Fisher's exact, P < 0.001) and high Braak stage (Fisher's exact, P = 0.001). Hippocampal neuron loss in CA4‐CA2 was not associated with TDP‐43. We conclude that hippocampal neuron loss patterns are associated with different etiologies within CA1, and propose that these patterns can be used to form objective criteria for HS‐Aging diagnosis. Finally, based on our results we hypothesize that neuron loss leading to HS‐Aging starts from the subicular end of CA1 when it is associated with TDP‐43 pathology, and that this neurodegenerative process is likely to be significantly more common than “end‐stage” HS‐Aging only.

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Section: Discussionmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2017

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“…The ABCC9 SNP rs704180 was previously associated with risk for HS-Aging, 24,25 a hippocampal pathology seen in $10-25% of autopsied individuals beyond 80 years at death. 26,[73][74][75] Recently, we found an association between HS-Aging and B-ASC in three separate cohorts, including the NACC data set. 8 Using digital image methods for analysis of arteriolar morphology, we found that HS-Aging cases had larger vessel areas, vessel perimeters, vascular areas, and vessel wall thicknesses compared to non HS-Aging cases.…”

Section: Discussionmentioning

confidence: 99%

Risk factors and global cognitive status related to brain arteriolosclerosis in elderly individuals

Ighodaro

Abner

Fardo

et al. 2016

J Cereb Blood Flow Metab

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Risk factors and cognitive sequelae of brain arteriolosclerosis pathology are not fully understood. To address this, we used multimodal data from the National Alzheimer's Coordinating Center and Alzheimer's Disease Neuroimaging Initiative data sets. Previous studies showed evidence of distinct neurodegenerative disease outcomes and clinicalpathological correlations in the ''oldest-old'' compared to younger cohorts. Therefore, using the National Alzheimer's Coordinating Center data set, we analyzed clinical and neuropathological data from two groups according to ages at death: < 80 years (n ¼ 1008) and !80 years (n ¼ 1382). In both age groups, severe brain arteriolosclerosis was associated with worse performances on global cognition tests. Hypertension (but not diabetes) was a brain arteriolosclerosis risk factor in the younger group. In the ! 80 years age at death group, an ABCC9 gene variant (rs704180), previously associated with aging-related hippocampal sclerosis, was also associated with brain arteriolosclerosis. A post-hoc arterial spin labeling neuroimaging experiment indicated that ABCC9 genotype is associated with cerebral blood flow impairment; in a convenience sample from Alzheimer's Disease Neuroimaging Initiative (n ¼ 15, homozygous individuals), non-risk genotype carriers showed higher global cerebral blood flow compared to risk genotype carriers. We conclude that brain arteriolosclerosis is associated with altered cognitive status and a novel vascular genetic risk factor.

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“…HS often goes unrecognized as a cause of amnesia and progressive dementia in late life, is often diagnosed as AD, 36,37 and has been reported in 12% of older adults with dementia drawn from a community-based autopsy series. 38 The pathogenesis of HS remains controversial; associations with both vascular and degenerative processes have been observed or suggested. 19,37-40 Our data indicate that in elderly adults with progressive amnesia and hippocampal atrophy, HS should be considered as a possible underlying causative factor, although diagnostic tests for HS are not available.…”

Section: Discussionmentioning

confidence: 99%

Neuropathological basis of magnetic resonance images in aging and dementia

Jagust

Zheng

Harvey

et al. 2007

Annals of Neurology

276

211

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Objective-Magnetic resonance (MR) imaging is used widely for assessment of patients with cognitive impairment, but the pathological correlates are unclear, especially when multiple pathologies are present.Methods-This report includes 93 subjects from a longitudinally followed cohort recruited for the study of Alzheimer's disease (AD) and subcortical cerebrovascular disease (CVD). MR images were analyzed to quantify cortical gray matter volume, hippocampal volume, white matter hyperintensities, and lacunes. Neuropathological examination quantified CVD parenchymal pathology, AD pathology (defined as Consortium to Establish a Registry for Alzheimer's Disease scores and Braak and Braak stage), and hippocampal sclerosis. Subjects were pathologically classified as 12 healthy control subjects, 46 AD, 14 CVD, 9 mixed AD/CVD, and 12 cognitively impaired patients without significant AD/CVD pathology. Multivariate models tested associations between magnetic resonance and pathological findings across the entire sample. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptResults-Pathological correlates of cortical gray matter volume were AD, subcortical vascular pathology, and arteriosclerosis. Hippocampal volume was related to AD pathology and hippocampal sclerosis, and the effects of hippocampal sclerosis were greater for subjects with low levels of AD pathology. White matter hyperintensities were related to age and to white matter pathology. Number of MRI lacunes was related to subcortical vascular pathology.Interpretation-In this clinical setting, the presence of lacunes and white matter changes provide a good signal for vascular disease. The neuropathological basis of MR defined cerebral cortical and hippocampal atrophy in aging and dementia is complex, with several pathological processes converging on similar brain structures that mediate cognitive decline.Alterations in brain structure are a profound concomitant of aging and dementia. From a clinical perspective, structural magnetic resonance imaging (MRI) has become a standard component of the dementia evaluation, 1 helping to rule out infarcts and other nonneurodegenerative causes of dementia. Research studies have linked brain atrophy, especially in the hippocampus and medial temporal lobe structures, to clinically diagnosed Alzheimer's disease (AD), 2-4 and prediction of AD in patients with mild cognitive impairment, 5,6 whereas epidemiological studies show convincing associations between white matter hyperintensities (WMH) and a host of vascular factors. 7,8 There are, however, few studies that examine relations between MRI and neuropathology, which is a serious limitation because the extent of AD pathology cannot be ascertained without neuropathological examination.Knowing the pathological phenomena that underlie changes in MR measures of brain structure may help to clarify the significance of neuroimaging in complex clinical situations and elucidate underlying mechanisms of disease. Because of the early and severe involvement of th...

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Clinical and Neuropathological Characteristics of Hippocampal Sclerosis

Cited by 124 publications

References 43 publications

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

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

Risk factors and global cognitive status related to brain arteriolosclerosis in elderly individuals

Neuropathological basis of magnetic resonance images in aging and dementia

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