Synaptology of the mesial temporal cortex in Alzheimer’s disease

AbstractChronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disease, characterized by hyperphosphorylated tau, found in individuals with a history of exposure to repetitive head impacts. While the neuropathologic hallmark of CTE is found in the cortex, hippocampal tau has proven to be an important neuropathologic feature to examine the extent of disease severity. However, the hippocampus is also heavily affected in many other tauopathies, such as Alzheimer’s disease (AD). How CTE and AD differentially affect the hippocampus is unclear. Using immunofluorescent analysis, a detailed histologic characterization of 3R and 4R tau isoforms and their differential accumulation in the temporal cortex in CTE and AD was performed. CTE and AD were both observed to contain mixed 3R and 4R tau isoforms, with 4R predominating in mild disease and 3R increasing proportionally as pathological severity increased. CTE demonstrated high levels of tau in hippocampal subfields CA2 and CA3 compared to CA1. There were also low levels of tau in the subiculum compared to CA1 in CTE. In contrast, AD had higher levels of tau in CA1 and subiculum compared to CA2/3. Direct comparison of the tau burden between AD and CTE demonstrated that CTE had higher tau densities in CA4 and CA2/3, while AD had elevated tau in the subiculum. Amyloid beta pathology did not contribute to tau isoform levels. Finally, it was demonstrated that higher levels of 3R tau correlated to more severe extracellular tau (ghost tangles) pathology. These findings suggest that mixed 3R/4R tauopathies begin as 4R predominant then transition to 3R predominant as pathological severity increases and ghost tangles develop. Overall, this work demonstrates that the relative deposition of tau isoforms among hippocampal subfields can aid in differential diagnosis of AD and CTE, and might help improve specificity of biomarkers for in vivo diagnosis.

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Bayesian model reveals latent atrophy factors with dissociable cognitive trajectories in Alzheimer’s disease

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1611073113 ◽

2016 ◽

Vol 113 (42) ◽

pp. E6535-E6544 ◽

Cited By ~ 68

Author(s):

Xiuming Zhang ◽

Elizabeth C. Mormino ◽

Nanbo Sun ◽

Reisa A. Sperling ◽

Mert R. Sabuncu ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Executive Function ◽

Bayesian Model ◽

Late Onset ◽

Temporal Cortex ◽

Cortical Atrophy ◽

Future Research ◽

Dementia Patients ◽

With Memory

We used a data-driven Bayesian model to automatically identify distinct latent factors of overlapping atrophy patterns from voxelwise structural MRIs of late-onset Alzheimer’s disease (AD) dementia patients. Our approach estimated the extent to which multiple distinct atrophy patterns were expressed within each participant rather than assuming that each participant expressed a single atrophy factor. The model revealed a temporal atrophy factor (medial temporal cortex, hippocampus, and amygdala), a subcortical atrophy factor (striatum, thalamus, and cerebellum), and a cortical atrophy factor (frontal, parietal, lateral temporal, and lateral occipital cortices). To explore the influence of each factor in early AD, atrophy factor compositions were inferred in beta-amyloid–positive (Aβ+) mild cognitively impaired (MCI) and cognitively normal (CN) participants. All three factors were associated with memory decline across the entire clinical spectrum, whereas the cortical factor was associated with executive function decline in Aβ+ MCI participants and AD dementia patients. Direct comparison between factors revealed that the temporal factor showed the strongest association with memory, whereas the cortical factor showed the strongest association with executive function. The subcortical factor was associated with the slowest decline for both memory and executive function compared with temporal and cortical factors. These results suggest that distinct patterns of atrophy influence decline across different cognitive domains. Quantification of this heterogeneity may enable the computation of individual-level predictions relevant for disease monitoring and customized therapies. Factor compositions of participants and code used in this article are publicly available for future research.

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Relation between neuritic plaques and depressive state in Alzheimer's disease

Acta Neuropsychiatrica ◽

10.1111/j.1601-5215.2009.00423.x ◽

2010 ◽

Vol 22 (1) ◽

pp. 14-20 ◽

Cited By ~ 5

Author(s):

Gerben Meynen ◽

Heleen Van Stralen ◽

Jan H. Smit ◽

Wouter Kamphorst ◽

Dick F. Swaab ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Depressive Symptoms ◽

Temporal Cortex ◽

Clinical Severity ◽

Depressive State ◽

Neuritic Plaques ◽

Prospective Longitudinal Study ◽

Severity Of Dementia ◽

Prospective Longitudinal

Meynen G, Van Stralen H, Smit JH, Kamphorst W, Swaab DF, Hoogendijk WJG. Relation between neuritic plaques and depressive state in Alzheimer's disease.Background:To investigate for the first time in a prospective study the relationship between depressive state and the neuropathological hallmarks of Alzheimer's disease, using a scale for depressive symptoms in dementia, while controlling for clinical severity of dementia.Method:Within the framework of a prospective longitudinal study of depression in Alzheimer's disease, patients with dementia underwent a clinical evaluation every six months during the last years of their lives, using the Cornell scale for depression in dementia to assess depressive symptoms and using the Functional Assessment Staging scale to control for clinical severity of dementia. The brains of 43 Alzheimer patients were obtained. The last clinical evaluations prior to death together with post-mortem neuropathology measures were analysed.Results:We found a correlation between the Cornell scores and the sum score for the density of neuritic plaques in the entire cortex (p = 0.027), and even stronger in the temporal cortex (p = 0.012). The observed correlations were independent of sex, age of death, clinical dementia severity and duration of Alzheimer's disease.Conclusions:This study shows a positive relationship between depressive state at time of death and the presence of neuritic plaques in Alzheimer's disease, which is independent of the clinical severity of dementia.

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Decreased Protein Levels of Nicotinic Receptor Subunits in the Hippocampus and Temporal Cortex of Patients with Alzheimer’s Disease

Journal of Neurochemistry ◽

10.1046/j.1471-4159.2000.0740237.x ◽

2001 ◽

Vol 74 (1) ◽

pp. 237-243 ◽

Cited By ~ 203

Author(s):

Zhi-Zhong Guan ◽

Xiao Zhang ◽

Rivka Ravid ◽

Agneta Nordberg

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Nicotinic Receptor ◽

Temporal Cortex ◽

Protein Levels

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Diagnostic utility of sound naming in early Alzheimer’s disease

Journal of the International Neuropsychological Society ◽

10.1017/s135561770909033x ◽

2009 ◽

Vol 15 (2) ◽

pp. 231-238 ◽

Cited By ~ 4

Author(s):

HYEON-AE JEON ◽

KYOUNG-MIN LEE

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Picture Naming ◽

Temporal Cortex ◽

Cognitive Domain ◽

Diagnostic Utility ◽

Future Studies ◽

Early Alzheimer’S Disease

AbstractWhile it is well known that picture naming (PN) is impaired in Alzheimer’s disease (AD), sound naming (SN) has not been thoroughly investigated. We postulated that SN might be impaired more severely and earlier than PN, given the early involvement of the temporal cortex by AD-related pathology. SN and PN were assessed in 21 normal participants, 40 patients with mild cognitive impairment (MCI), and 27 patients in early stages of AD. Our results showed that SN accuracy and latency were more sensitive to advancing pathology in AD than PN accuracy and latency. SN was more useful and specific in distinguishing MCI patients from normal participants and therefore in potentially identifying the subset of MCI patients who already have impairment in more than one cognitive domain and may actually have incipient AD. These findings indicate a potential diagnostic utility of SN for early detection of the disease. Furthermore, even though most AD patients demonstrated more or less comparable impairment in both tasks, some were disproportionately impaired on SN and others were differentially impaired on PN. Future studies may be able to show that these discrepant groups correspond to patients with right and left hemisphere predominant AD, respectively. (JINS, 2009, 15, 231–238.)

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Distinct Transcriptome Expression of the Temporal Cortex of the Primate Microcebus murinus during Brain Aging versus Alzheimer's Disease-Like Pathology

PLoS ONE ◽

10.1371/journal.pone.0012770 ◽

2010 ◽

Vol 5 (9) ◽

pp. e12770 ◽

Cited By ~ 18

Author(s):

Ronza Abdel Rassoul ◽

Sabine Alves ◽

Véronique Pantesco ◽

John De Vos ◽

Bernard Michel ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Brain Aging ◽

Temporal Cortex ◽

Microcebus Murinus ◽

Transcriptome Expression

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Alternative Splicing Regulation of an Alzheimer’s Risk Variant in CLU

International Journal of Molecular Sciences ◽

10.3390/ijms21197079 ◽

2020 ◽

Vol 21 (19) ◽

pp. 7079

Author(s):

Seonggyun Han ◽

Kwangsik Nho ◽

Younghee Lee

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Alternative Splicing ◽

Genetic Variants ◽

Temporal Cortex ◽

Integrative Approach ◽

Splicing Regulation ◽

Rna Seq ◽

Risk Variant

Clusterin (CLU) is one of the risk genes most associated with late onset Alzheimer’s disease (AD), and several genetic variants in CLU are associated with AD risk. However, the functional role of known AD risk genetic variants in CLU has been little explored. We investigated the effect of an AD risk variant (rs7982) in the 5th exon of CLU on alternative splicing by using an integrative approach of brain-tissue-based RNA-Seq and whole genome sequencing data from Accelerating Medicines Partnership—Alzheimer’s Disease (AMP-AD). RNA-Seq data were generated from three regions in the temporal lobe of the brain—the temporal cortex, superior temporal gyrus, and parahippocampal gyrus. The rs7982 was significantly associated with intron retention (IR) of the 5th exon of CLU; as the number of alternative alleles (G) increased, the IR rates decreased more significantly in females than in males. Our results suggest a sex-dependent role of rs7982 in AD pathogenesis via splicing regulation.

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