Alzheimer’s disease clinical variants show distinct regional patterns of neurofibrillary tangle accumulation

Petersen, Cathrine; Nolan, Amber; Resende, Elisa de Paula França; Miller, Zachary A.; Ehrenberg, Alexander J.; Gorno‐Tempini, Maria Luisa; Rosen, Howard J.; Kramer, Joel H.; Spina, Salvatore; Rabinovici, Gil D.; Miller, Bruce L.; Seeley, William W.; Heinsen, Helmut; Grinberg, Lea T.

doi:10.1101/538496

Cited by 21 publications

(40 citation statements)

References 46 publications

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“…This confirms our previous findings within atypical AD, 38 and another study that found greater neocortical flortaucipir uptake in younger age participants 39 . It also explains why in one recent pathological study, higher neurofibrillary tangle burden was found in the Aty‐AD cases compared with Ty‐AD cases where the latter group was older 40 . This mismatch between flortaucipir uptake and volume in the relationship with age could be due to a number of different factors.…”

Section: Discussionsupporting

confidence: 89%

MRI and flortaucipir relationships in Alzheimer's phenotypes are heterogeneous

Josephs

Tosakulwong

Graff‐Radford

et al. 2020

Ann Clin Transl Neurol

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Objective: To assess the relationships between MRI volumetry and [ 18 F]flortaucipir PET of typical and atypical clinical phenotypes of Alzheimer's disease, by genarian (age by decade). Methods: Five-hundred and sixty-four participants including those with typical (n = 86) or atypical (n = 80) Alzheimer's dementia and normal controls (n = 398) underwent apolipoprotein E genotyping, MRI, flortaucipir, and 11 C-PiB; all 166 Alzheimer's participants were beta-amyloid positive and all controls were beta-amyloid negative. Grey matter volume and flortaucipir standard uptake value ratios were calculated for hippocampus, entorhinal cortex, and neocortex. Ratios of hippocampal-to-neocortical and entorhinal-to-neocortical volume and flortaucipir uptake were also calculated. Linear regression models assessed relationships among regional volume, flortaucipir uptake, and ratios and phenotypes, within three genarians (50-59, 60-69, and 70+). Voxel-level analyses were also performed. Results: For 50-59 greater medial temporal atrophy and flortaucipir uptake was observed in the typical compared with atypical phenotype. The typical phenotype also showed greater frontal neocortex uptake with the voxel-level analysis. For 60-69 and 70+ there was greater hippocampal volume loss in the typical compared with atypical phenotype while only the 60-69, but not the 70+ group, showed a difference in hippocampal flortaucipir uptake. We also observed a pattern for higher neocortical flortaucipir uptake to correlate with younger age decade for both phenotypes. Interpretation: MRI volumetry versus flortaucipir PET relationships differ across Alzheimer's clinical phenotypes, and also within phenotype across age decades. This suggests that there is potential risk of masked effects by not accounting for genarian in participants with beta-amyloid and tau-positive biomarker defined Alzheimer's disease.

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Section: Discussionsupporting

confidence: 89%

MRI and flortaucipir relationships in Alzheimer's phenotypes are heterogeneous

Josephs

Tosakulwong

Graff‐Radford

et al. 2020

Ann Clin Transl Neurol

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“…Individuals presenting with PPA caused by AD pathology, for instance, tend to have a younger age at onset and to show an asymmetric distribution of NFT, 36 a higher ratio of neocortical to entorhinal tangles, 37 and a smaller influence of the APOE e4 allele as a risk factor. 38 Regarding anatomic distribution of pathology, recent clinicopathologic studies found that a higher semiquantitative burden of neuronal tau pathology in the superior and middle temporal gyrus and middle frontal gyrus in AD manifesting as a PPA syndrome, 39,40 suggesting a distinct pattern of NFT distribution in atypical AD manifestation, may reflect a cortical proposed subtype of NFT deposition. 41 Other autopsies studies unveiled comorbid conditions in cases of lvPPA with Lewy body pathology or FTLD.…”

Section: Discussionmentioning

confidence: 99%

Language and spatial dysfunction in Alzheimer disease with white matter thorn-shaped astrocytes

et al. 2020

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ObjectivesAlzheimer disease (AD) shows a broad array of clinical presentations, but the mechanisms underlying these phenotypic variants remain elusive. Aging-related astrogliopathy (ARTAG) is a relatively recent term encompassing a broad array of tau deposition in astroglia outside the range of traditional tauopathies. White matter thorn-shaped astrocyte (WM-TSA) clusters, a specific ARTAG subtype, has been associated with atypical language presentation of AD in a small study lacking replication. To interrogate the impact of WM-TSA in modifying clinical phenotype in AD, we investigated a clinicopathologic sample of 83 persons with pure cortical AD pathology and heterogeneous clinical presentations.MethodsWe mapped WM-TSA presence and density throughout cortical areas and interrogated whether WM-TSA correlated with atypical AD presentation or worse performance in neuropsychological testing.ResultsWM-TSA was present in nearly half of the cases and equally distributed in typical and atypical AD presentations. Worsening language and visuospatial functions were correlated with higher WM-TSA density in language-related and visuospatial-related regions, respectively. These findings were unrelated to regional neurofibrillary tangle burden. Next, unsupervised clustering divided the participants into 2 groups: a high–WM-TSA (n = 9) and low–WM-TSA (n = 74) pathology signature. The high–WM-TSA group scored significantly worse in language but not in other cognitive domains.ConclusionsThe negative impact of WM-TSA pathology to language and possibly visuospatial networks suggests that WM-TSA is not as benign as other ARTAG types and may be explored as a framework to understand the mechanisms and impact of astrocytic tau deposition in AD in humans.

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“…For example, Murray et al have reported that, when AD autopsy cases were divided into three distinct groups based on the regional pattern of the NFT pathology observed ("hippocampal-sparing," "typical," and "limbic predominant"), there was a trend towards fewer APOE4 carriers in the "hippocampal-sparing" AD group, and there were significantly more late-onset (greater than 65 years old at diagnosis) APOE4 carriers vs. non-carriers in the "limbic predominant" AD group [61]. Although a more recent study failed to replicate this finding in a set of AD autopsy cases enriched for atypical presentation (in which APOE4 carriers were underrepresented), there did appear to be a trend (p = 0.0992) towards more APOE4 carriers among "limbic predominant" AD cases and fewer APOE4 carriers among "hippocampal-sparing" AD cases [107]. Interestingly, a recent follow-up paper by Murray and colleagues also reported that APOE4+ "typical" AD patients, as compared to APOE4− "typical" AD patients, possess more NFT pathology in their nucleus basalis of Meynert (nbM), the major source of cholinergic innervation in the brain [110].…”

Section: Apoe4 Associated With Increased Nft Deposition In Other Braimentioning

confidence: 97%

APOE4 is associated with cognitive and pathological heterogeneity in patients with Alzheimer’s disease: a systematic review

et al. 2020

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Possession of the ε4 allele of apolipoprotein E (APOE) is the primary genetic risk factor for the sporadic form of Alzheimer’s disease (AD). While researchers have extensively characterized the impact that APOE ε4 (APOE4) has on the susceptibility of AD, far fewer studies have investigated the phenotypic differences of patients with AD who are APOE4 carriers vs. those who are non-carriers. In order to understand these differences, we performed a qualitative systematic literature review of the reported cognitive and pathological differences between APOE4-positive (APOE4+) vs. APOE4-negative (APOE4−) AD patients. The studies performed on this topic to date suggest that APOE4 is not only an important mediator of AD susceptibility, but that it likely confers specific phenotypic heterogeneity in AD presentation, as well. Specifically, APOE4+ AD patients appear to possess more tau accumulation and brain atrophy in the medial temporal lobe, resulting in greater memory impairment, compared to APOE4− AD patients. On the other hand, APOE4− AD patients appear to possess more tau accumulation and brain atrophy in the frontal and parietal lobes, resulting in greater impairment in executive function, visuospatial abilities, and language, compared to APOE4+ AD patients. Although more work is necessary to validate and interrogate these findings, these initial observations of pathological and cognitive heterogeneity between APOE4+ vs. APOE4− AD patients suggest that there is a fundamental divergence in AD manifestation related to APOE genotype, which may have important implications in regard to the therapeutic treatment of these two patient populations.

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Alzheimer’s disease clinical variants show distinct regional patterns of neurofibrillary tangle accumulation

Cited by 21 publications

References 46 publications

MRI and flortaucipir relationships in Alzheimer's phenotypes are heterogeneous

MRI and flortaucipir relationships in Alzheimer's phenotypes are heterogeneous

Language and spatial dysfunction in Alzheimer disease with white matter thorn-shaped astrocytes

APOE4 is associated with cognitive and pathological heterogeneity in patients with Alzheimer’s disease: a systematic review

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