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

Resende, Elisa de Paula França; Nolan, Amber; Petersen, Cathrine; Ehrenberg, Alexander J.; Spina, Salvatore; Allen, Isabel Elaine; Rosen, Howard J.; Kramer, Joel H.; Miller, Bruce L.; Seeley, William W.; Gorno-Tempini, Maria Luiza; Miller, Zachary A.; Grinberg, Lea T.

doi:10.1212/wnl.0000000000008937

Cited by 26 publications

(23 citation statements)

References 53 publications

(57 reference statements)

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Section: Discussionsupporting

confidence: 61%

“…These findings may have implications regarding the atypical, non-amnestic clinical presentations of AD, which are more common in EOAD than in LOAD (Resende et al, 2020).…”

Section: Discussionmentioning

confidence: 93%

“…ARTAG was more commonly seen in LOAD cases compared to EOAD, as expected (Kovacs et al, 2016). ATAC pathology has been associated with worse performance on neuropsychological scores in domains corresponding to the function of the anatomical area affected by this type of pathology (Resende et al, 2020). These findings may have implications regarding the atypical, non-amnestic clinical presentations of AD, which are more common in EOAD than in LOAD (Resende et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

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Comorbid neuropathological diagnoses in early vs late-onset Alzheimer’s disease

Spina

Joie

Petersen

et al. 2020

Preprint

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Copathologies play an important role in the expression of the AD clinical phenotype and may influence treatment efficacy. Early-onset AD (EOAD), defined as manifesting before age 65, has been viewed as a relatively pure form of AD with a more homogenous neuropathological substrate. We sought to compare the frequency of common neuropathological diagnoses in a consecutive autopsy series of 96 patients with EOAD (median age of onset = 55 years, 44 females) and 48 with late-onset AD (LOAD) (median age of onset = 73 years, 14 females). The UCSF Neurodegenerative Disease Brain Bank database was reviewed to identify patients with a primary pathological diagnosis of AD. Prevalence and stage of Lewy body disease (LBD), limbic age-related TDP-43 encephalopathy (LATE), argyrophilic grain disease (AGD), hippocampal sclerosis (HS), cerebral amyloid angiopathy (CAA), vascular brain injury (VBI) and aging-related tau astrogliopathy (ARTAG) were compared between the two cohorts. We found at least one non-AD pathological diagnosis in 98% of patients with EOAD (versus 100% of LOAD), and the number of comorbid diagnoses per patient was lower in EOAD than in LOAD (median=2 versus 3, Mann-Whitney Z=3.00, p=0.002). LBD and CAA were common in both EOAD and LOAD (CAA: 86% versus 79%, Fisher exact p=0.33; LBD: 49% versus 42%, p=0.48, respectively), although amygdala-predominant LBD was more commonly found in EOAD than LOAD (22% versus 6%, p=0.02). In contrast, LATE (35% versus 8%, p<0.001), HS (15% versus 3%, p=0.02), AGD (58% versus 41%, p=0.052), and VBI (65% versus 39%, p=0.004) were more common in LOAD than EOAD, respectively. The number of copathologies predicted worse cognitive performance at the time of death on MMSE (1.4 points/pathology (95%CI [-2.5, -0.2]) and Clinical Dementia Rating Sum of Boxes (1.15 point/pathology, 95%CI [0.45, 1.84]), across the EOAD and the LOAD cohorts. Prevalence of at least one ApoE e4 allele was similar across the two cohorts (52%) and was associated with a greater number of copathologies (+0.42, 95%CI [0.01, 0.82], p=0.04), independent of age of symptom onset. Our findings suggest that non-AD pathological diagnoses play an important role in the clinical phenotype of EOAD with potentially significant implications for clinical practice and clinical trials design.

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Section: Discussionsupporting

confidence: 61%

“…These findings may have implications regarding the atypical, non-amnestic clinical presentations of AD, which are more common in EOAD than in LOAD (Resende et al, 2020).…”

Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

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Comorbid neuropathological diagnoses in early vs late-onset Alzheimer’s disease

Spina

Joie

Petersen

et al. 2020

Preprint

Self Cite

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“…A further interesting aspect of WM ARTAG in AD has been recently highlighted. Accordingly, irrespective of the regional NFT burden worsening language and visuospatial functions were correlated with higher TSA density in language-related and visuospatial-related regions, respectively (Resende et al, 2020).…”

Section: Clinical Relevance Of Artagmentioning

confidence: 93%

Astroglia and Tau: New Perspectives

Kovács

2020

Front. Aging Neurosci.

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Astrocytes contribute to the pathogenesis of neurodegenerative proteinopathies as influencing neuronal degeneration or neuroprotection, and also act as potential mediators of the propagation or elimination of disease-associated proteins. Protein astrogliopathies can be observed in different forms of neurodegenerative conditions. Morphological characterization of astrogliopathy is used only for the classification of tauopathies. Currently, at least six types of astrocytic tau pathologies are distinguished. Astrocytic plaques (AP), tufted astrocytes (TAs), ramified astrocytes (RA), and globular astroglial inclusions are seen predominantly in primary tauopathies, while thorn-shaped astrocytes (TSA) and granular/fuzzy astrocytes (GFA) are evaluated in aging-related tau astrogliopathy (ARTAG). ARTAG can be seen in the white and gray matter and subpial, subependymal, and perivascular locations. Some of these overlap with the features of tau pathology seen in Chronic traumatic encephalopathy (CTE). Furthermore, gray matter ARTAG shares features with primary tauopathy-related astrocytic tau pathology. Sequential distribution patterns have been described for tau astrogliopathies. Importantly, astrocytic tau pathology in primary tauopathies can be observed in brain areas without neuronal tau deposition. The various morphologies of tau astrogliopathy might reflect a role in the propagation of pathological tau protein, an early response to a yet unidentified neurodegeneration-inducing event, or, particularly for ARTAG, a response to a repeated or prolonged pathogenic process such as blood-brain barrier dysfunction or local mechanical impact. The concept of tau astrogliopathies and ARTAG facilitated communication among research disciplines and triggered the investigation of the significance of astrocytic lesions in neurodegenerative conditions.

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“…ARTAG seems to be present in cases of AD with both atypical and typical clinical presentation 22 . Following the description of clusters of argyrophilic thorn‐shaped astrocytes in combination with AD pathology and with the clinical manifestation of primary progressive aphasia, 23 a recent study suggested a negative impact of white matter ARTAG pathology to language and possibly visuospatial networks 24 . Recently, astroglial transactivation response DNA‐binding protein of 43 kDs (RDP‐43) proteinopathy has been also identified in atypical tau astrogliopathy 25,26 .…”

Section: Introductionmentioning

confidence: 99%

Multiple system aging‐related tau astrogliopathy with complex proteinopathy in an oligosymptomatic octogenarian

Klotz

Fischer²,

Hinterberger³

et al. 2020

Neuropathology

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The combination of multiple neurodegenerative proteinopathies is increasingly recognized. Together they can potentiate neuronal dysfunction and contribute to complex neurological symptoms. We report an octogenarian female case of multiple extraneural metastases of a rectal carcinoma. She attempted suicide, which ultimately led to cardiorespiratory failure nine days after hospital admission. Apart from the suicide attempt and late‐onset depression, other psychiatric or neurological symptoms were not reported. Unexpectedly, histopathologic examination revealed prominent aging‐related tau astrogliopathy (ARTAG) of all five types (subpial, subependymal, grey and white matter, and perivascular) affecting cortical and subcortical brain regions. This pathology was associated with intermediate Alzheimer's disease neuropathologic change (A2B2C2 score), cerebral amyloid angiopathy, Lewy body‐type α‐synuclein proteinopathy (Braak stage 4), and a multiple system transactivation response DNA‐binding protein of 43 kDa (TDP‐43) proteinopathy also involving the astroglia. In summary, we report a complex and extensive combination of multiple proteinopathies with widespread ARTAG of all five types in a patient who had attempted suicide. Although longitudinal psychometric tests and neuropsychological evaluations were not performed, this report poses the question of thresholds of cognition and pathology load, describes ARTAG affecting unusually widespread brain regions, and supports the notion that complex proteinopathies should be regarded as a frequent condition in the elderly.

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

Cited by 26 publications

References 53 publications

Comorbid neuropathological diagnoses in early vs late-onset Alzheimer’s disease

Comorbid neuropathological diagnoses in early vs late-onset Alzheimer’s disease

Astroglia and Tau: New Perspectives

Multiple system aging‐related tau astrogliopathy with complex proteinopathy in an oligosymptomatic octogenarian

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