Hippocampal Sclerosis of Aging Can Be Segmental

Ighodaro, Eseosa T.; Jicha, Gregory A.; Schmitt, Frederick A.; Neltner, Janna H.; Abner, Erin L.; Kryscio, Richard J.; Smith, Charles D.; Duplessis, Taylor; Anderson, Sonya; Patel, Ela; Bachstetter, Adam D.; Eldik, Linda J. Van; Nelson, Peter T.

doi:10.1097/nen.0000000000000204

Cited by 35 publications

(39 citation statements)

References 80 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%

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%

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

et al. 2017

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“…TDP-43 pathology is a key component of the pathologic phenotype [3, 66]. Although TDP-43 pathology in CARTS is conspicuous within neurons and neurites [2, 34, 65], astrocytes may play an active role in the pathogenesis. In Alexander disease, a disorder caused by toxic upregulation of glial fibrillary acidic protein (GFAP), hippocampal TDP-43 pathology is frequently comorbid with the stereotypical astrocytic pathology and leukodystrophy [96].…”

Section: Discussionmentioning

confidence: 99%

Genomics and CSF analyses implicate thyroid hormone in hippocampal sclerosis of aging

et al. 2016

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We report evidence of a novel pathogenetic mechanism in which thyroid hormone dysregulation contributes to dementia in elderly persons. Two single nucleotide polymorphisms (SNPs) on chromosome 12p12 were the initial foci of our study: rs704180 and rs73069071. These SNPs were identified by separate research groups as risk alleles for non-Alzheimer’s neurodegeneration. We found that the rs73069071 risk genotype was associated with hippocampal sclerosis (HS) pathology among people with the rs704180 risk genotype (National Alzheimer’s Coordinating Center/Alzheimer’s Disease Genetic Consortium data; n=2,113, including 241 autopsy-confirmed HS cases). Further, both rs704180 and rs73069071 risk genotypes were associated with widespread brain atrophy visualized by MRI (Alzheimer’s Disease Neuroimaging Initiative data; n=1,239). In human brain samples from the Braineac database, both rs704180 and rs73069071 risk genotypes were associated with variation in expression of ABCC9, a gene which encodes a metabolic sensor protein in astrocytes. The rs73069071 risk genotype was also associated with altered expression of a nearby astrocyte-expressed gene, SLCO1C1. Analyses of human brain gene expression databases indicated that the chromosome 12p12 locus may regulate particular astrocyte-expressed genes induced by the active form of thyroid hormone, triiodothyronine (T3). This is informative biologically because the SLCO1C1 protein transports thyroid hormone into astrocytes from blood. Guided by the genomic data, we tested the hypothesis that altered thyroid hormone levels could be detected in cerebrospinal fluid (CSF) obtained from persons with HS pathology. Total T3 levels in CSF were elevated in HS cases (p<0.04 in two separately analyzed groups), but not in Alzheimer’s disease cases, relative to controls. No change was detected in the serum levels of thyroid hormone (T3 or T4) in a subsample of HS cases prior to death. We conclude that brain thyroid hormone perturbation is a potential pathogenetic factor in HS that may also provide the basis for a novel CSF-based clinical biomarker.

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“…At the time of that prior study, only 939 participants were evaluated for entorhinal thickness whereas the current study included 1,239 participants. Notably, entorhinal cortical atrophy may be a strong proxy for HS-Aging in a MRI study since the entorhinal cortex appears involved even early in the disease process [50]. …”

Section: Discussionmentioning

confidence: 99%

“…We previously reported evidence for brain pathology outside the hippocampal formation (specifically in the frontal cortex) in patients with comorbid HS-Aging [31], and multiple lines of evidence point to a multi-domain cognitive deficit in patients affected by the disease [1, 16]. The hypothesis that HS-Aging is actually a diffuse or multifocal disease that is often comorbid with brain arteriolosclerosis pathology rather than one localized to medial temporal lobe structures, is quite credible given the prior reports [13, 16, 31, 33, 50–52]. We conclude that the present study adds additional evidence to support a role for genetic variation in brain pathologies, and to the appreciation that this is a multi-factorial condition that can impact brain areas well beyond the hippocampus.…”

Section: Discussionmentioning

confidence: 99%

Hippocampal Sclerosis of Aging, a Common Alzheimer’s Disease ‘Mimic’: Risk Genotypes are Associated with Brain Atrophy Outside the Temporal Lobe

Nho

Saykin

Nelson

2016

JAD

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Hippocampal sclerosis of aging (HS-Aging) is a common brain disease in older adults with a clinical course that is similar to Alzheimer’s disease. Four single-nucleotide polymorphisms (SNPs) have previously shown association with HS-Aging. The present study investigated structural brain changes associated with these SNPs using surface-based analysis. Participants from the Alzheimer’s Disease Neuroimaging Initiative cohort (ADNI; n = 1,239), with both MRI scans and genotype data, were used to assess the association between brain atrophy and previously identified HS-Aging risk SNPs in the following genes: GRN, TMEM106B, ABCC9, and KCNMB2 (minor allele frequency for each is >30%). A fifth SNP (near the ABCC9 gene) was evaluated in post-hoc analysis. The GRN risk SNP (rs5848_T) was associated with a pattern of atrophy in the dorsomedial frontal lobes bilaterally, remarkable since GRN is a risk factor for frontotemporal dementia. The ABCC9 risk SNP (rs704180_A) was associated with multifocal atrophy whereas a SNP (rs7488080_A) nearby (~50 kb upstream) ABCC9 was associated with atrophy in the right entorhinal cortex. Neither TMEM106B (rs1990622_T), KCNMB2 (rs9637454_A), nor any of the non-risk alleles were associated with brain atrophy. When all four previously identified HS-Aging risk SNPs were summed into a polygenic risk score, there was a pattern of associated multifocal brain atrophy in a predominately frontal pattern. We conclude that common SNPs previously linked to HS-Aging pathology were associated with a distinct pattern of anterior cortical atrophy. Genetic variation associated with HS-Aging pathology may represent a non-Alzheimer’s disease contribution to atrophy outside of the hippocampus in older adults.

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Hippocampal Sclerosis of Aging Can Be Segmental

Cited by 35 publications

References 80 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

Genomics and CSF analyses implicate thyroid hormone in hippocampal sclerosis of aging

Hippocampal Sclerosis of Aging, a Common Alzheimer’s Disease ‘Mimic’: Risk Genotypes are Associated with Brain Atrophy Outside the Temporal Lobe

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