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Transactive response DNA-binding protein 43 kDa (TDP-43) proteinopathy is the hallmark of limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC). LATE-NC is a common copathology with Alzheimer disease neuropathologic change (ADNC). Data from the National Alzheimer's Coordinating Center were analyzed to compare clinical features and copathologies of autopsy-confirmed ADNC with versus without comorbid LATE-NC. A total of 735 participants with ADNC alone and 365 with ADNC with LATE-NC were included. Consistent with prior work, brains with LATE-NC had more severe ADNC, more hippocampal sclerosis, and more brain arteriolosclerosis copathologies. Behavioral symptoms and cognitive performance on neuropsychological tests were compared, stratified by ADNC severity (low/intermediate vs high). Participants with ADNC and LATE-NC were older, had higher ADNC burden, and had worse cognitive performance than participants with ADNC alone. In the low/intermediate ADNC strata, participants with comorbid LATE-NC had higher prevalence of behavioral symptoms (apathy, disinhibition, agitation, personality change). They also had worsened performance in episodic memory and language/semantic memory. Differences narrowed in the high ADNC strata, with worsened performance in only episodic memory in the comorbid LATE-NC group. The co-occurrence of LATE-NC with ADNC is associated with a different pattern of behavioral and cognitive performance than ADNC alone, particularly in people with low/intermediate ADNC burden.

Background and ObjectivesLimbic-predominant age-related Tar DNA binding protein 43 (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 pathologic correlates of HS in LATE-NC are not well understood.MethodsThis retrospective autopsy cohort study used data derived from the National Alzheimer's Coordinating Center Neuropathology Data Set, which included neurologic 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.ResultsA total of 408 participants were included (n = 221 were LATE-NC+/HS−, n = 145 were LATE-NC+/HS+, and n = 42 were LATE-NC−/HS+). Most of the included LATE-NC+ participants were severely impaired cognitively (83.3% with dementia). Compared to HS− participants, LATE-NC+ participants with HS trended toward having worse cognitive status and scored lower on the Personal Care and Orientation domains (both p = 0.03). Among LATE-NC+ participants with Braak neurofibrillary tangle (NFT) stages 0 to 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) was relatively likely to have had strokes (p = 0.03). When LATE-NC+ participants with or without HS were compared, there were no differences in Alzheimer disease neuropathologies (Thal β-amyloid 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.DiscussionIn this cohort skewed toward participants with severe dementia, LATE-NC+ HS pathology was not associated with seizures or with Alzheimer-type pathologies. Rather, the presence of comorbid HS pathology was associated with more widespread TDP-43 proteinopathy and with more severe non–β-amyloid vessel wall pathologies.

Transactive response DNA-binding protein 43 kDa (TDP-43) is aberrantly aggregated and phosphorylated in frontotemporal lobar degeneration of the TDP-43 type (FTLD-TDP), and in limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC). We examined data from the National Alzheimer's Coordinating Center to compare clinical features of autopsy-confirmed LATE-NC and FTLD-TDP. A total of 265 LATE-NC and 92 FTLD-TDP participants were included. Cognitive and behavioral symptoms were compared, stratified by level of impairment based on global clinical dementia rating (CDR) score. LATE-NC participants were older at death, more likely to carry APOE ε4, more likely to have Alzheimer disease neuropathology, and had lower (i.e. less severe) final CDR global scores than those with FTLD-TDP. Participants with FTLD-TDP were more likely to present with primary progressive aphasia, or behavior problems such as apathy, disinhibition, and personality changes. Among participants with final CDR score of 2–3, those with LATE-NC were more likely to have visuospatial impairment, delusions, and/or visual hallucinations. These differences were robust after sensitivity analyses excluding older (≥80 years at death), LATE-NC stage 3, or severe Alzheimer cases. Overall, FTLD-TDP was more globally severe, and affected younger participants, whereas psychoses were more common in LATE-NC.

Background Despite high efficacy of oral antiretroviral therapy (ART), viral suppression among adolescents and young adults (AYA) living with HIV in sub-Saharan Africa (SSA) remains low. Compared to daily oral ART, bimonthly long-acting injectable ART (LA-ART) may simplify adherence, improve clinical outcomes, and decrease HIV transmission in this priority population. However, LA-ART will likely cost more than oral ART and the cost threshold at which LA-ART will be cost effective in SSA has not been evaluated. Methods We adapted a mathematical model of HIV transmission and progression in Kenya to include HIV acquisition and viral suppression among AYA (age 10–24). We projected the population-level health and economic impact of providing LA-ART to AYA over a 10-year time horizon assuming oral ART costs of US$233 annually and a two-month duration of viral suppression per LA-ART injection. We calculated the maximum cost at which switching from oral to LA-ART would be considered cost-effective, using thresholds of $500 and $1,508 per disability-adjusted life year averted (WHO's threshold of HIV treatment interventions and Kenya's gross domestic product per capita). Findings Assuming 85% of AYA switch from oral to injectable formulations, LA-ART is estimated to prevent 40,540 infections and 20,480 deaths over 10 years. The maximum increase in the annual per-person cost of receiving LA-ART is estimated to be $89 and $236 for LA-ART to be cost-effective under the thresholds of $500 and $1,508 per DALY averted, respectively. The cost threshold was lower when non-adherent oral ART AYA users were assumed to be less likely to switch to LA-ART. Interpretation Providing LA-ART to AYA can be cost-effective in Kenya if it is less than twice the cost of oral ART. Long-acting injectable ART for priority populations with low viral suppression has the potential to cost-effectively avert disability and death. Funding National Institutes of Health (R01 HD085807; PI: Kohler)