Limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) is independently associated with dementia and strongly associated with arteriolosclerosis in the oldest-old

Harrison, William T.; Lusk, Jay B; Liu, Beiyu; Ervin, John F.; Johnson, Kurt E.; Green, Cynthia L.; Wang, Shih‐Hsiu J.

doi:10.1007/s00401-021-02360-w

Cited by 22 publications

(16 citation statements)

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“…The finding of increased arteriolosclerosis has also been associated with comorbid LATE-NC and HS. 27,[36][37][38] These positive results increase confidence about using this dataset for the evaluation of other clinical and pathologic correlates of HS in the context of LATE-NC.…”

Section: Discussionmentioning

confidence: 62%

“…46 Third, ABCC9 variations have already been linked to cerebrovascular pathologies: ABCC9 gain-of-function variations cause Cantu syndrome, a multifaceted condition often accompanied by tortuous cerebral blood vessels, 48 whereas separate ABCC9 loss-of-function variations lead to ABCC9- related intellectual disability myopathy syndrome, another complex phenotype that includes white matter hyperintensities detected on MRI even in adolescents. 49 Thus, the HS/ ABCC9 link may be a clue to help explain why vascular pathologies are more severe in brains with HS pathology than in non-HS brains, 27,36–38.50 despite the lack of associations between HS pathology and traditional cardiovascular risk factors. It remains an unanswered question whether ABCC9 genotypes also help to explain differential vulnerability to HS pathology among persons without LATE-NC such as in patients with FTLD-TDP.…”

Section: Discussionmentioning

confidence: 99%

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Limbic-Predominant Age-Related TDP-43 Encephalopathy

et al. 2022

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Background and Objectives:Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is present in ∼25% of older persons’ brains and is strongly associated with cognitive impairment. Hippocampal sclerosis (HS) pathology is often comorbid with LATE-NC, but the clinical and pathological correlates of HS in LATE-NC are not well understood.Methods:In this retrospective autopsy cohort study, data derived from the National Alzheimer’s Coordinating Center (NACC) Neuropathology Data Set, which included neurological status, medical histories, and neuropathologic results. All autopsies were performed in 2014 or later. Among participants with LATE-NC, those who also had HS pathology were compared with those without HS with regard to candidate risk factors or common underlying diseases. Statistical significance was set at nominal p<0.05 in this exploratory study.Results:A total of 408 participants were included (n=221 were LATE+/HS-; n=145 were LATE+/HS+, and n=42 were LATE-/HS+). Most of the included LATE-NC+ participants were severely impaired cognitively (83.3% demented). Compared to HS- participants, LATE-NC+ participants with HS trended towards having worse cognitive status and scored lower on the “Personal Care” and “Orientation” domains (both p=0.03). Among LATE-NC+ participants with Braak NFT Stages 0-IV (n=88), HS+ participants were more impaired in the “Memory” and “Orientation” domains (both p=0.02). There were no differences (HS+ compared with HS-) in the proportion with clinical histories of seizures, stroke, cardiac bypass procedures, diabetes, or hypertension. The HS+ group lacking TDP-43 proteinopathy (n=42) were relatively likely to have had strokes (p=0.03). Comparing LATE-NC+ participants with or without HS, there were no differences in Alzheimer’s disease neuropathologies (Thal Aβ phases or Braak NFT stages) or Lewy body pathologies. However, the HS+ group was less likely to have amygdala-restricted TDP-43 proteinopathy (LATE-NC Stage 1) and more likely to have neocortical TDP-43 proteinopathy (LATE-NC Stage 3); p<0.001. LATE-NC+ brains with HS also tended to have more severe Circle of Willis atherosclerosis and arteriolosclerosis pathologies.Discussion:In this cohort skewed toward severely demented participants, LATE-NC+HS pathology was not associated with seizures or with Alzheimer’s-type pathologies. Rather, the presence of comorbid HS pathology was associated with more widespread TDP-43 proteinopathy, and with more severe non-Aβ vessel wall pathologies.

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Section: Discussionmentioning

confidence: 62%

Section: Discussionmentioning

confidence: 99%

Limbic-Predominant Age-Related TDP-43 Encephalopathy

et al. 2022

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“…What are the implications of LATE-NC staging results? Clinical–pathological studies demonstrated that LATE-NC is associated with cognitive impairment (often with amnestic features), independent of other disease processes [ 17 , 36 , 42 , 51 , 58 , 62 , 68 , 72 , 88 , 103 , 104 , 111 , 130 , 132 , 135 ]. For example, in an attributable risk analysis based on all observed pathologic changes that may contribute to cognitive impairment in a large community cohort, LATE-NC accounted for more than 15% of identified amnestic dementia risk [ 16 , 114 ].…”

Section: Guidance In Autopsy Reportsmentioning

confidence: 99%

LATE-NC staging in routine neuropathologic diagnosis: an update

et al. 2022

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An international consensus report in 2019 recommended a classification system for limbic-predominant age-related TDP-43 encephalopathy neuropathologic changes (LATE-NC). The suggested neuropathologic staging system and nomenclature have proven useful for autopsy practice and dementia research. However, some issues remain unresolved, such as cases with unusual features that do not fit with current diagnostic categories. The goal of this report is to update the neuropathologic criteria for the diagnosis and staging of LATE-NC, based primarily on published data. We provide practical suggestions about how to integrate available genetic information and comorbid pathologies [e.g., Alzheimer’s disease neuropathologic changes (ADNC) and Lewy body disease]. We also describe recent research findings that have enabled more precise guidance on how to differentiate LATE-NC from other subtypes of TDP-43 pathology [e.g., frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS)], and how to render diagnoses in unusual situations in which TDP-43 pathology does not follow the staging scheme proposed in 2019. Specific recommendations are also made on when not to apply this diagnostic term based on current knowledge. Neuroanatomical regions of interest in LATE-NC are described in detail and the implications for TDP-43 immunohistochemical results are specified more precisely. We also highlight questions that remain unresolved and areas needing additional study. In summary, the current work lays out a number of recommendations to improve the precision of LATE-NC staging based on published reports and diagnostic experience.

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“…Although AD is characterized by brain extracellular β‐amyloid (Aβ) plaques, and intracellular phosphorylated tau (p‐tau) protein, and may lead to neuronal loss (i.e., Aβ, tau, neurodegeneration: ATN framework 6 ), other pathologies are frequently present in those with AD dementia. These include amyloid angiopathy, 7 cerebrovascular disease (CVD) with or without ischemia/infarctions, 8 the Lewy body (α‐synuclein) inclusions of Parkinson's disease and Lewy body dementia, 9 limbic predominant age‐related TDP43 encephalopathy neuropathologic change, 10 hippocampal sclerosis of aging, 11 non‐AD tauopathies (e.g., argyrophilic grain disease), 12 aging‐related tau astrogliopathy, 13 and systemic diseases (e.g., diabetes, hypertension). In addition, considerable variability exists in AD risk in underrepresented populations (URPs); such as Black/African American, Latinx/Hispanic, Asian American, Native Hawaiian/Pacific Islander, and American Indian/Alaska Native individuals, and those from lower socioeconomic backgrounds.…”

Section: Introductionmentioning

confidence: 99%

Increasing participant diversity in AD research: Plans for digital screening, blood testing, and a community‐engaged approach in the Alzheimer's Disease Neuroimaging Initiative 4

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Veitch

Miller

et al. 2022

Alzheimer's & Dementia

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Introduction: The Alzheimer's Disease Neuroimaging Initiative (ADNI) aims to validate biomarkers for Alzheimer's disease (AD) clinical trials. To improve generalizability, ADNI4 aims to enroll 50-60% of its new participants from underrepresented populations (URPs) using new biofluid and digital technologies. ADNI4 has received funding from the National Institute on Aging beginning September 2022.Methods: ADNI4 will recruit URPs using community-engaged approaches. An online portal will screen 20,000 participants, 4000 of whom (50-60% URPs) will be tested for plasma biomarkers and APOE. From this, 500 new participants will undergo in-clinic assessment joining 500 ADNI3 rollover participants. Remaining participants (∼3500) will undergo longitudinal plasma and digital cognitive testing. ADNI4 will add MRI sequences and new PET tracers. Project 1 will optimize biomarkers in AD clinical trials.Results and Discussion: ADNI4 will improve generalizability of results, use remote digital and blood screening, and continue providing longitudinal clinical, biomarker, and autopsy data to investigators.

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Limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) is independently associated with dementia and strongly associated with arteriolosclerosis in the oldest-old

Cited by 22 publications

References 5 publications

Limbic-Predominant Age-Related TDP-43 Encephalopathy

Limbic-Predominant Age-Related TDP-43 Encephalopathy

LATE-NC staging in routine neuropathologic diagnosis: an update

Increasing participant diversity in AD research: Plans for digital screening, blood testing, and a community‐engaged approach in the Alzheimer's Disease Neuroimaging Initiative 4

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