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Background: Individuals with Down syndrome (DS) are at high risk of early-onset Alzheimer's disease (AD); yet, some 20 percent do not develop any signs of dementia until after 65 years or in their lifetime. Mosaicism could contribute to this phenotypic variation, where some disomic cells could lead to lower levels of gene products from chromosome 21., Methods: We examined longitudinal neuropsychological and biomarker data from two large studies of DS: the Alzheimer Biomarker Consortium-Down syndrome study (ABC-DS) (n = 357); and a legacy study (n = 468). We assessed mosaicism using karyotyping or GWAS data. Participants had data on plasma AD biomarkers (Aβ 40 , Aβ 42 , tau, and NfL) and longitudinal cognitive measures. A subset had cerebrospinal fluid biomarkers (Aβ 40 , Aβ 42 , tau, ptau181, and NfL) and amyloid and tau PET data., Findings: For both cohorts, the prevalence of mosaicism was <10% (ABC-DS: 7.3%; Legacy: 9.6%), and those with mosaicism had lower plasma Aβ 40 and Aβ 42 concentrations. For the older legacy cohort, when compared to those with full trisomy, those with mosaicism had significantly smaller decline in total and annualized neurocognitive scores, and lower incidence and prevalence of dementia., Interpretation: Mosaicism in DS was associated with lower concentrations of plasma Aβ peptides, possibly leading to lower AD risk. However, its clinical impact was less clear in the younger ABC-DC cohort, and a follow-up study is warranted., Funding: National Institutes of Health (R01AG014673, P01HD035897, R56AG061837), NIA (U01AG051412, U19AG068054), NICHD, ADRC programs, the Eunice Kennedy Shriver Intellectual and Developmental Disabilities Research Centers Program, and NCATS (UL1TR001873)., Competing Interests: Declaration of interests BA is a member of VCID Advisory Board without payment. BH receives funding from National Institute of Child Health and Human Development, Autism Speaks, and Roche Pharmaceuticals. EH has consulted for Alzheon and Cyclotherapeutics and received royalties from Elsevier Press. JHL is part of the external advisory board for the Alzheimer's Disease Resource Center for Minority Aging Research, University of Texas, and for the Center of Life Science, Nazarbayev University, Astana, Kazakhstan. MM is an inventor on patents related to biomarkers of neurodegenerative diseases owned by Georgetown University and the University of Rochester. SH is the vice-chair of the ISTAART Down syndrome PIA. SKM is an employee for the New York State Office for People with Developmental Disabilities (OPWDD) and is a consultant for the NIH grant R01-HD098179. SZ is the chair of the scientific committee of the T21 Research Society receiving paid registration to the biannual meeting. The other authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Integrating antiretroviral therapy (ART) into HIV care dramatically extended the lifespan for people living with HIV (PWH). Improving the health span requires understanding aging, HIV, associated comorbid conditions, and concurrent treatments. The 14th annual International Workshop on HIV and Aging on October 26-27, 2023 included podium presentations on: Sarcopenia Biology, Pathophysiology, Prevention and Treatment; Long-acting ART; Central Nervous System (CNS) Complications; Asymptomatic Neurocognitive Impairment (ANI); Mental Health; Loneliness; and Resilience. Presentations highlighted persistent concerns for PWH including sarcopenia and frailty, mental health, loneliness, and cognition. Presenters encouraged prioritizing mental health treatment, reducing social isolation, and research on resiliency., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Objective: This study aimed to examine sex differences in factors associated with mood and anxiety in midlife men and women during the COVID-19 pandemic., Methods: During a remote visit, 312 adults aged 40-60 years (167 female; 23.6% perimenopausal) from the Human Connectome Project in Aging completed PROMIS measures of depression, anxiety and anger/irritability; perceived stress; and questions about social support, financial stress and menopause stage. Multivariate linear regression models assessed sex differences in mental health and the association of social support, financial stress and menopause stage with mental health., Results: Anxiety was higher in women than in men ( b  = 2.39, p  = 0.02). For women only, decreased social support was associated with increased anxiety ( b  = -2.26, p  = 0.002), anger/irritability ( b  = -1.89, p  = 0.02) and stress ( b  = -1.67, p  = 0.002). For women only, not having close family was associated with increased depressive symptoms ( b  = -6.60, p  = 0.01) and stress ( b  = -7.03, p  < 0.001). For both sexes, having children was associated with lower depressive symptoms ( b  = -3.08, p  = 0.002), anxiety ( b  = -1.93, p  = 0.07), anger/irritability ( b  = -2.73, p  = 0.02) and stress ( b  = -1.44, p  = 0.07). Menopause stage was unrelated to mental health., Conclusion: Social support, but not financial stress, influenced mental health during the COVID-19 pandemic at midlife, particularly for women.

Introduction: Previous studies have applied normative modeling on a single neuroimaging modality to investigate Alzheimer Disease (AD) heterogeneity. We employed a deep learning-based multimodal normative framework to analyze individual-level variation across ATN (amyloid-tau-neurodegeneration) imaging biomarkers., Methods: We selected cross-sectional discovery (n = 665) and replication cohorts (n = 430) with available T1-weighted MRI, amyloid and tau PET. Normative modeling estimated individual-level abnormal deviations in amyloid-positive individuals compared to amyloid-negative controls. Regional abnormality patterns were mapped at different clinical group levels to assess intra-group heterogeneity. An individual-level disease severity index (DSI) was calculated using both the spatial extent and magnitude of abnormal deviations across ATN., Results: Greater intra-group heterogeneity in ATN abnormality patterns was observed in more severe clinical stages of AD. Higher DSI was associated with worse cognitive function and increased risk of disease progression., Discussion: Subject-specific abnormality maps across ATN reveal the heterogeneous impact of AD on the brain., Competing Interests: Competing Interests Author AS has received personal compensation for serving as a grant reviewer for BrightFocus Foundation. The remaining authors have no conflicting interests to report.

Introduction: Previous studies have applied normative modeling on a single neuroimaging modality to investigate Alzheimer Disease (AD) heterogeneity. We employed a deep learning-based multimodal normative framework to analyze individual-level variation across ATN (amyloid-tau-neurodegeneration) imaging biomarkers., Methods: We selected cross-sectional discovery (n = 665) and replication cohorts (n = 430) with available T1-weighted MRI, amyloid and tau PET. Normative modeling estimated individual-level abnormal deviations in amyloid-positive individuals compared to amyloid-negative controls. Regional abnormality patterns were mapped at different clinical group levels to assess intra-group heterogeneity. An individual-level disease severity index (DSI) was calculated using both the spatial extent and magnitude of abnormal deviations across ATN., Results: Greater intra-group heterogeneity in ATN abnormality patterns was observed in more severe clinical stages of AD. Higher DSI was associated with worse cognitive function and increased risk of disease progression., Discussion: Subject-specific abnormality maps across ATN reveal the heterogeneous impact of AD on the brain., Competing Interests: Competing Interests Author AS has received personal compensation for serving as a grant reviewer for BrightFocus Foundation. The remaining authors have no conflicting interests to report.

Objective: We address the problem of finding brain connectivities that are associated with a clinical outcome or phenotype., Methods: The proposed framework regresses a (scalar) clinical outcome on matrix-variate predictors which arise in the form of brain connectivity matrices. For example, in a large cohort of subjects we estimate those regions of functional connectivities that are associated with neurocognitive scores. We approach this high-dimensional yet highly structured estimation problem by formulating a regularized estimation process that results in a low-rank coefficient matrix having a sparse set of nonzero entries which represent regions of biologically relevant connectivities. In contrast to the recent literature on estimating a sparse, low-rank matrix from a single noisy observation, our scalar-on-matrix regression framework produces a data-driven extraction of structures that are associated with a clinical response. The method, called Sparsity Inducing Nuclear-Norm Estimator (SpINNEr), simultaneously constrains the regression coefficient matrix in two ways: a nuclear norm penalty encourages low-rank structure while an l 1 norm encourages entry-wise sparsity., Results: Our simulations show that SpINNEr outperforms other methods in estimation accuracy when the response-related entries (representing the brain's functional connectivity) are arranged in well-connected communities. SpINNEr is applied to investigate associations between HIV-related outcomes and functional connectivity in the human brain., Conclusion and Significance: Overall, this work demonstrates the potential of SpINNEr to recover sparse and low-rank estimates under scalar-on-matrix regression framework.

Background: Loneliness has been associated with several consequences, including increased risk of developing Alzheimer disease (AD). Loneliness may arise during the preclinical phase of AD, but little is known about the relationship between loneliness and amyloid accumulation consistent with preclinical AD. Therefore, the purpose of this study was to examine the relationship between amyloid accumulation and subjective experiences of loneliness among cognitively normal older adults during the COVID-19 pandemic., Methods: A global Clinical Dementia Rating ® Scale score of 0 was required for enrollment. Cortical amyloid burden was measured using [11C] Pittsburgh compound B or [18F]-Florbetapir PET tracers. Centiloids were used to synchronize measures. Demographic characteristics and measures of loneliness, anxiety, and depression were collected via self-report. Multiple linear regression was used to examine the relationship between loneliness and amyloid accumulation., Results: The 108 participants had a mean age of 75.0 and an average amyloid accumulation of 22.2 ± 31.9. Mean UCLA Loneliness Scale scores were 31.6 ± 10.8. A significant positive association was detected between loneliness and amyloid accumulation (β = 0.064, SE = 0.027, 95% CI = [0.011, 0.118], p = 0.018)., Conclusions: These findings highlight the relationship between higher amyloid accumulation and greater loneliness during the COVID-19 pandemic. Healthcare professionals should include routine assessments for characteristics of loneliness in routine clinical evaluations and integrate loneliness reduction and prevention treatments among older adults experiencing loneliness. Additional research is needed with a larger, more diverse sample to examine the relationship between loneliness and amyloid accumulation., Competing Interests: No competing interests were disclosed., (Copyright: © 2024 Kehrer-Dunlap A et al.)

Introduction: Down syndrome (DS) is a genetic cause of early-onset Alzheimer's disease (AD). The National Institute on Aging-Alzheimer's Association AT(N) Research Framework is a staging model for AD biomarkers but has not been assessed in DS., Method: Data are from the Alzheimer's Biomarker Consortium-Down Syndrome. Positron emission tomography (PET) amyloid beta (Aβ; 15 mCi of [ 11 C]Pittsburgh compound B) and tau (10 mCi of [ 18 F]AV-1451) were used to classify amyloid (A) -/+ and tau (T) +/-. Hippocampal volume classified neurodegeneration (N) -/+. The modified Cued Recall Test assessed episodic memory., Results: Analyses included 162 adults with DS (aged M = 38.84 years, standard deviation = 8.41). Overall, 69.8% of participants were classified as A-/T-/(N)-, 11.1% were A+/T-/(N)-, 5.6% were A+/T+/(N)-, and 9.3% were A+/T+/(N)+. Participants deemed cognitively stable were most likely to be A-T-(N)- and A+T-(N)-. Tau PET (T+) most closely aligning with memory impairment and AD clinical status., Discussion: Findings add to understanding of AT(N) biomarker profiles in DS., Highlights: Overall, 69.8% of adults with Down syndrome (DS) aged 25 to 61 years were classified as amyloid (A)-/tau (T)-/neurodegeneration (N)-, 11.1% were A+/T-/(N)-, 5.6% were A+/T+/(N)-, and 9.3% were A+/T+/(N)+. The AT(N) profiles were associated with clinical Alzheimer's disease (AD) status and with memory performance, with the presence of T+ aligned with AD clinical symptomology. Findings inform models for predicting the transition to the prodromal stage of AD in DS., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Carriers of mutations responsible for dominantly inherited Alzheimer disease provide a unique opportunity to study potential imaging biomarkers. Biomarkers based on routinely acquired clinical MR images, could supplement the extant invasive or logistically challenging) biomarker studies. We used 1104 longitudinal MR, 324 amyloid beta, and 87 tau positron emission tomography imaging sessions from 525 participants enrolled in the Dominantly Inherited Alzheimer Network Observational Study to extract novel imaging metrics representing the mean (μ) and standard deviation (σ) of standardized image intensities of T1-weighted and Fluid attenuated inversion recovery (FLAIR) MR scans. There was an exponential decrease in FLAIR-μ in mutation carriers and an increase in FLAIR and T1 signal heterogeneity (T1-σ and FLAIR-σ) as participants approached the symptom onset in both supramarginal, the right postcentral and right superior temporal gyri as well as both caudate nuclei, putamina, thalami, and amygdalae. After controlling for the effect of regional atrophy, FLAIR-μ decreased and T1-σ and FLAIR-σ increased with increasing amyloid beta and tau deposition in numerous cortical regions. In symptomatic mutation carriers and independent of the effect of regional atrophy, tau pathology demonstrated a stronger relationship with image intensity metrics, compared with amyloid pathology. We propose novel MR imaging intensity-based metrics using standard clinical T1 and FLAIR images which strongly associates with the progression of pathology in dominantly inherited Alzheimer disease. We suggest that tau pathology may be a key driver of the observed changes in this cohort of patients., (© 2023 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Genome-wide association studies (GWAS) of cerebrospinal fluid (CSF) Alzheimer's Disease (AD) biomarker levels have identified novel genes implicated in disease risk, onset and progression. However, lumbar punctures have limited availability and may be perceived as invasive. Blood collection is readily available and well accepted, but it is not clear whether plasma biomarkers will be informative for genetic studies. Here we perform genetic analyses on concentrations of plasma amyloid-β peptides Aβ40 (n = 1,467) and Aβ42 (n = 1,484), Aβ42/40 (n = 1467) total tau (n = 504), tau phosphorylated (p-tau181; n = 1079) and neurofilament light (NfL; n = 2,058). GWAS and gene-based analysis was used to identify single variant and genes associated with plasma levels. Finally, polygenic risk score and summary statistics were used to investigate overlapping genetic architecture between plasma biomarkers, CSF biomarkers and AD risk. We found a total of six genome-wide significant signals. APOE was associated with plasma Aβ42, Aβ42/40, tau, p-tau181 and NfL. We proposed 10 candidate functional genes on the basis of 12 single nucleotide polymorphism-biomarker pairs and brain differential gene expression analysis. We found a significant genetic overlap between CSF and plasma biomarkers. We also demonstrate that it is possible to improve the specificity and sensitivity of these biomarkers, when genetic variants regulating protein levels are included in the model. This current study using plasma biomarker levels as quantitative traits can be critical to identification of novel genes that impact AD and more accurate interpretation of plasma biomarker levels., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Current approaches to classifying cognitive impairment in people living with HIV can overestimate disease burden and lead to ambiguity around disease mechanisms. The 2007 criteria for HIV-associated neurocognitive disorders (HAND), sometimes called the Frascati criteria, can falsely classify over 20% of cognitively healthy individuals as having cognitive impairment. Minimum criteria for HAND are met on the basis of performance on cognitive tests alone, which might not be appropriate for populations with diverse educational and socioeconomic backgrounds. Imprecise phenotyping of cognitive impairment can limit mechanistic research, biomarker discovery and treatment trials. Importantly, overestimation of cognitive impairment carries the risk of creating fear among people living with HIV and worsening stigma and discrimination towards these individuals. To address this issue, we established the International HIV-Cognition Working Group, which is globally representative and involves the community of people living with HIV. We reached consensus on six recommendations towards a new approach for diagnosis and classification of cognitive impairment in people living with HIV, intended to focus discussion and debate going forward. We propose the conceptual separation of HIV-associated brain injury - including active or pretreatment legacy damage - from other causes of brain injury occurring in people living with HIV. We suggest moving away from a quantitative neuropsychological approach towards an emphasis on clinical context. Our recommendations are intended to better represent the changing profile of cognitive impairment in people living with HIV in diverse global settings and to provide a clearer framework of classification for clinical management and research studies., (© 2023. Springer Nature Limited.)

HIV infection has become a chronic and manageable disease due to the effective use of antiretroviral therapies (ART); however, several chronic aging-related comorbidities, including cognitive impairment, remain a major public health issue. However, these mechanisms are unknown. Here, we identified that glial and myeloid viral reservoirs are associated with local myelin damage and the release of several myelin components, including the lipid sulfatide. Soluble sulfatide compromised gap junctional communication and calcium wave coordination, essential for proper cognition. We propose that soluble sulfatide could be a potential biomarker and contributor to white matter compromise observed in HIV-infected individuals even in the current ART era., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

This study investigates whether tau has (i) an independent effect from amyloid-β on changes in cognitive and functional performance and (ii) a synergistic relationship with amyloid-β in the exacerbation of decline in aging Down syndrome (DS). 105 participants with DS underwent baseline PET [ 18 F]-AV1451 and PET [ 11 C]PiB scans to quantify tau deposition in Braak regions II-VI and the Striatum and amyloid-β status respectively. Linear Mixed Effects models were implemented to assess how tau and amyloid-β deposition are related to change over three time points. Tau was a significant independent predictor of cognitive and functional change. The three-way interaction between time, [ 11 C]PiB status and tau was significant in the models of episodic memory and visuospatial cognition. Baseline tau is a significant predictor of cognitive and functional decline, over and above the effect of amyloid-β status. Results suggest a synergistic relationship between amyloid-β status and tau as predictors of change in memory and visuospatial cognition., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Individuals with Down syndrome (DS) are at an increased risk of developing Alzheimer's Disease (AD). One of the early underlying mechanisms in AD pathology is the accumulation of amyloid protein plaques, which are deposited in extracellular gray matter and signify the first stage in the cascade of neurodegenerative events. AD-related neurodegeneration is also evidenced as microstructural changes in white matter. In this work, we explored the correlation of white matter microstructure with amyloid load to assess amyloid-related neurodegeneration in a cohort of adults with DS., Methods: In this study of 96 adults with DS, the relation of white matter microstructure using diffusion tensor imaging (DTI) and amyloid plaque burden using [ 11 C]PiB PET were examined. The amyloid load (Aβ L ) derived from [ 11 C]PiB was used as a global measure of amyloid burden. Aβ L and DTI measures were compared using tract-based spatial statistics (TBSS) and corrected for imaging site and chronological age., Results: TBSS of the DTI maps showed widespread age-by-amyloid interaction with both fractional anisotropy (FA) and mean diffusivity (MD). Further, diffuse negative association of FA and positive association of MD with amyloid were observed., Discussion: These findings are consistent with the white matter microstructural changes associated with AD disease progression in late onset AD in non-DS populations., (Copyright © 2021. Published by Elsevier Inc.)

Purpose: Recent studies have shown that standard compartmental models using plasma input or the cerebellum reference tissue input are generally not reliable for quantifying tau burden in dynamic 18 F-flortaucipir PET studies of Alzheimer disease. So far, the optimal reference region for estimating 18 F-flortaucipir delivery and specific tau binding has yet to be determined. The objective of the study is to improve 18 F-flortaucipir brain tau PET quantification using a spatially constrained kinetic model with dual reference tissues., Methods: Participants were classified as either cognitively normal (CN) or cognitively impaired (CI) based on clinical assessment. T1-weighted structural MRI and 105-min dynamic 18 F-flortaucipir PET scans were acquired for each participant. Using both a simplified reference tissue model (SRTM2) and Logan plot with either cerebellum gray matter or centrum semiovale (CS) white matter as the reference tissue, we estimated distribution volume ratios (DVRs) and the relative transport rate constant R 1 for region of interest-based (ROI) and voxelwise-based analyses. Conventional linear regression (LR) and LR with spatially constrained (LRSC) parametric imaging algorithms were then evaluated. Noise-induced bias in the parametric images was compared to estimates from ROI time activity curve-based kinetic modeling. We finally evaluated standardized uptake value ratios at early phase (SUVR EP , 0.7-2.9 min) and late phase (SUVR LP , 80-105 min) to approximate R 1 and DVR, respectively., Results: The percent coefficients of variation of R 1 and DVR estimates from SRTM2 with spatially constrained modeling were comparable to those from the Logan plot and SUVRs. The SRTM2 using CS reference tissue with LRSC reduced noise-induced underestimation in the LR generated DVR images to negligible levels (< 1%). Inconsistent overestimation of DVR in the SUVR LP only occurred using the cerebellum reference tissue-based measurements. The CS reference tissue-based DVR and SUVR LP , and cerebellum-based SUVR EP and R 1 provided higher Cohen's effect size d to detect increased tau deposition and reduced relative tracer transport rate in CI individuals., Conclusion: Using a spatially constrained kinetic model with dual reference tissues significantly improved quantification of relative perfusion and tau binding. Cerebellum and CS are the suggested reference tissues to estimate R 1 and DVR, respectively, for dynamic 18 F-flortaucipir PET studies. Cerebellum-based SUVR EP and CS-based SUVR LP may be used to simplify 18 F-flortaucipir PET study., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)

The objective of this paper is to evaluate available evidence for each step in autoimmune encephalitis management and provide expert opinion when evidence is lacking. The paper approaches autoimmune encephalitis as a broad category rather than focusing on individual antibody syndromes. Core authors from the Autoimmune Encephalitis Alliance Clinicians Network reviewed literature and developed the first draft. Where evidence was lacking or controversial, an electronic survey was distributed to all members to solicit individual responses. Sixty-eight members from 17 countries answered the survey. Corticosteroids alone or combined with other agents (intravenous IG or plasmapheresis) were selected as a first-line therapy by 84% of responders for patients with a general presentation, 74% for patients presenting with faciobrachial dystonic seizures, 63% for NMDAR-IgG encephalitis and 48.5% for classical paraneoplastic encephalitis. Half the responders indicated they would add a second-line agent only if there was no response to more than one first-line agent, 32% indicated adding a second-line agent if there was no response to one first-line agent, while only 15% indicated using a second-line agent in all patients. As for the preferred second-line agent, 80% of responders chose rituximab while only 10% chose cyclophosphamide in a clinical scenario with unknown antibodies. Detailed survey results are presented in the manuscript and a summary of the diagnostic and therapeutic recommendations is presented at the conclusion., Competing Interests: Competing interests: HA is a consultant for Roche/Genentech, which manufactures rituximab and tocilizumab that were discussed in this paper. HA is a consultant for Bristol-Myers Squibb, which manufactures cyclophosphamide that is discussed in this paper. SI is a coapplicant and receives royalties on patent application WO/210/046716 (UK patent No. PCT/GB2009/051441) licensed to Euroimmun for the development of assays for leucine-rich glioma inactivated protein 1 and other voltage-gated potassium channel complex antibodies discussed in this paper. AG has a patent for MAP1B autoantibodies as biomarkers of neurological autoimmunity and small cell lung cancer. S-TL is a consultant for GC Pharma, which manufactures IVIg that was discussed in this paper and for Advanced Neural Technologies which operates several neuronal autoantibody panels. SV receives research support from Quest Laboratories Diagnostics, which offers several commercial neuronal autoantibody panels, and from Genentech (rituximab) and Grifols (IVIG). SJP has a patent Patent# 8 889 102 (Application#12-678350) - Neuromyelitis Optica Autoantibodies as a Marker for Neoplasia issued, and a patent Patent# 9 891 219B2 (Application#12-573942) - SJP has a patent pending for GFAP, Septin-5, Kelch11 and MAP1B autoantibodies as biomarkers of neurological autoimmunity. Some of these antibodies are discussed in this paper. MJT has filed a patent for methods for typing neurologic disorders and cancer, and devices for use therein, and has received an unrestricted research grant from Euroimmun AG., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Nearly all persons with Down syndrome will show pathology of Alzheimer's disease in their 40s. There is a critical need for studies to identify early biomarkers of these various pathological changes of Alzheimer's disease in the Down syndrome population and understand the relationship of these biomarkers to cognitive symptoms in order to inform clinical trials. Although Alzheimer's disease is often considered a disease of gray matter, white matter degeneration has been documented during the preclinical stage of Alzheimer's disease. The current study examined the association between diffusion tensor imaging (DTI) measures of white matter microstructure and episodic memory performance in 52 adults with Down syndrome., Methods: Seventy (N = 70) participants (M = 40.13, SD = 7.77 years) received baseline scans as part of the Neurodegeneration in Aging Down Syndrome (NiAD) study at two imaging facilities (36 at the University of Wisconsin-Madison [UW-Madison] and 34 at the University of Pittsburgh Medical Center [UPMC]). All participants had genetically confirmed trisomy 21. Fifty-two (N = 52) participants remained after QC. The DTI measures, fractional anisotropy (FA) and mean diffusivity (MD), were calculated for each participant. A combined measure of episodic memory was generated by summing the z-scores of (1) Free and Cued Recall test and (2) Rivermead Behavioural Memory Test for Children Picture Recognition. The DTI data were projected onto a population-derived FA skeleton and tract-based spatial statistics analysis was conducted using the FSL tool PALM to calculate Pearson's r values between FA and MD with episodic memory., Results: A positive correlation of episodic memory with FA and a negative correlation of episodic memory and MD in the major association white matter tracts were observed. Results were significant (p < 0.05) after correction for chronological age, imaging site, and premorbid cognitive ability., Conclusion: These findings suggest that white matter degeneration may be implicated in early episodic memory declines prior to the onset of dementia in adults with Down syndrome. Further, our findings suggest a coupling of episodic memory and white matter microstructure independent of chronological age.

Introduction: A biphasic model for brain structural changes in preclinical Alzheimer's disease (AD) could reconcile some conflicting and paradoxical findings in observational studies and anti-amyloid clinical trials., Methods: In this study we tested this model fitting linear versus quadratic trajectories and computed the timing of the inflection points vertexwise of cortical thickness and cortical diffusivity-a novel marker of cortical microstructure-changes in 389 participants from the Dominantly Inherited Alzheimer Network., Results: In early preclinical AD, between 20 and 15 years before estimated symptom onset, we found increases in cortical thickness and decreases in cortical diffusivity followed by cortical thinning and cortical diffusivity increases in later preclinical and symptomatic stages. The inflection points 16 to 19 years before estimated symptom onset are in agreement with the start of tau biomarker alterations., Discussion: These findings confirm a biphasic trajectory for brain structural changes and have direct implications when interpreting magnetic resonance imaging measures in preventive AD clinical trials., (© 2020 the Alzheimer's Association.)

The objective of this paper is to evaluate available evidence for each step in autoimmune encephalitis management and provide expert opinion when evidence is lacking. The paper approaches autoimmune encephalitis as a broad category rather than focusing on individual antibody syndromes. Core authors from the Autoimmune Encephalitis Alliance Clinicians Network reviewed literature and developed the first draft. Where evidence was lacking or controversial, an electronic survey was distributed to all members to solicit individual responses. Sixty-eight members from 17 countries answered the survey. The most popular bridging therapy was oral prednisone taper chosen by 38% of responders while rituximab was the most popular maintenance therapy chosen by 46%. Most responders considered maintenance immunosuppression after a second relapse in patients with neuronal surface antibodies (70%) or seronegative autoimmune encephalitis (61%) as opposed to those with onconeuronal antibodies (29%). Most responders opted to cancer screening for 4 years in patients with neuronal surface antibodies (49%) or limbic encephalitis (46%) as opposed to non-limbic seronegative autoimmune encephalitis (36%). Detailed survey results are presented in the manuscript and a summary of the diagnostic and therapeutic recommendations is presented at the conclusion., Competing Interests: Competing interests: HA is a consultant for Roche/Genentech, which manufactures rituximab and tocilizumab that were discussed in this paper. HA is a consultant for Bristol-Myers Squibb, which manufactures cyclophosphamide that is discussed in this paper. SRI is a coapplicant and receives royalties on patent application WO/210/046716 (UK patent No. PCT/GB2009/051441) licensed to Euroimmun for the development of assays for leucine-rich glioma inactivated protein 1 and other voltage-gated potassium channel complex antibodies discussed in this paper. SRI is supported by the BMA Research Grants- Vera Down grant (2013) and Margaret Temple (2017), Epilepsy Research UK (P1201), the Fulbright UK-US commission (MS-Society research award) and by the NIHR Oxford Biomedical Research Centre. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. AG has a patent for MAP1B autoantibodies as biomarkers of neurological autoimmunity and small cell lung cancer. S-TL is a consultant for GC Pharma, which manufactures IVIg that was discussed in this paper and for Advanced Neural Technologies which operates several neuronal autoantibody panels. SV receives research support from Quest Laboratories Diagnostics, which offers several commercial neuronal autoantibody panels, and from Genentech (rituximab) and Grifols (IVIG). SJP has a patent Patent# 8,889,102 (Application#12-678350)—Neuromyelitis Optica Autoantibodies as a Marker for Neoplasia issued, and a patent Patent# 9891219B2 (Application#12-573942)—SJP has a patent pending for GFAP, Septin-5, Kelch11 and MAP1B autoantibodies as biomarkers of neurological autoimmunity. Some of these antibodies are discussed in this paper. MJT has filed a patent for methods for typing neurological disorders and cancer, and devices for use therein, and has received an unrestricted research grant from Euroimmun AG., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Importance: Adults with Down syndrome (DS) are at high-risk of revealing Alzheimer's disease (AD) pathology, in part due to the triplication of chromosome 21 encoding the amyloid precursor protein. Adults with DS are uniformly affected by AD pathology by their 30's and have a 70% to 80% chance of clinical dementia by their 60's. Our previous studies have assessed longitudinal changes in amyloid beta (Aβ) accumulation in DS., Objective: The goal of the present study was to assess the presence of brain tau using [ 18 F]AV-1451 positron emission tomography (PET) in DS and to assess the relationship of brain tau pathology to Aβ using Pittsburgh Compound B (PiB)-PET., Design: Cohort study., Setting: Multi-center study., Participants: Participants consisted of a sample of individuals with DS and sibling controls recruited from the community; exclusion criteria included contraindications for magnetic resonance imaging (MRI) and/or a medical or psychiatric condition that impaired cognitive functioning., Exposures: PET brain scans to assess Aβ ([ 11 C]PiB) and tau ([ 18 F]AV-1451) burden., Main Outcomes and Measures: Multiple linear regression models (adjusted for chronological age, sex and performance site) were used to examine associations between regional [ 18 F]AV-1451 standard uptake value ratio (SUVR) (based on regions associated with Braak stages 1-6) and global [ 11 C]PiB SUVR (as both a continuous and dichotomous variable)., Results: A cohort of 156 participants (mean age = 39.05, SD(8.4)) were examined. These results revealed a significant relationship between in vivo Aβ and tau pathology in DS. As a dichotomous variable, [ 18 F]AV-1451 retention was higher in each Braak region in PiB(+) participants. We also found, based on our statistical models, starting with the Braak 3 region of interest (ROI), an acceleration of [ 18 F]AV-1451 SUVR deposition with [ 11 C]PiB SUVR increases., (© 2020 The Authors. Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: Adults with Down syndrome (DS) are at exceptionally high risk for Alzheimer's disease (AD), with virtually all individuals developing key neuropathological features by age 40. Identifying biomarkers of AD progression in DS can provide valuable insights into pathogenesis and suggest targets for disease modifying treatments., Methods: We describe the development of a multi-center, longitudinal study of biomarkers of AD in DS. The protocol includes longitudinal examination of clinical, cognitive, blood and cerebrospinal fluid-based biomarkers, magnetic resonance imaging and positron emission tomography measures (at 16-month intervals), as well as genetic modifiers of AD risk and progression., Results: Approximately 400 individuals will be enrolled in the study (more than 370 to date). The methodological approach from the administrative, clinical, neuroimaging, omics, neuropathology, and statistical cores is provided., Discussion: This represents the largest U.S.-based, multi-site, biomarker initiative of AD in DS. Findings can inform other multidisciplinary networks studying AD in the general population., Competing Interests: The authors have no conflicts of interest to declare., (© 2020 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, Inc. on behalf of Alzheimer's Association.)

Objective: To examine the effect of race in driving performance and behavior prospectively among cognitively normal older adults., Methods: Cognitively normal participants (Clinical Dementia Rating 0), ≥ 65 years of age (n = 177) were selected from prospective, longitudinal studies at the Knight Alzheimer Disease Research Center at Washington University. Self-reported driving behavior (Driving Habits Questionnaire) and driving performance (road test) were annually assessed. Daily driving behavior data were collected using the Driving Real World In-Vehicle Evaluation System (DRIVES). Baseline differences between African Americans and Caucasians were tested using t tests and general linear models. Amyloid imaging and cerebrospinal fluid Alzheimer disease (AD) biomarkers were compared across groups. Linear mixed models examined change in daily driving behavior over time. Survival analyses tested time to a marginal or fail rating on the road test., Results: There were no differences between African Americans (n = 34) and Caucasians (n = 143) in age, sex, education, or vascular risk factors. Baseline self-reported driving behavior and road test performance were largely similar for both races. Longitudinal analyses using the DRIVES data aggregated monthly showed that African Americans had a greater reduction in number of trips made per month, miles driven per month, and trips with aggressive behavior compared to Caucasians. These effects remained after controlling for AD biomarkers, age, education, and sex., Conclusions: In this sample of cognitively normal older adults, African Americans had a greater reduction of daily driving behavior compared to Caucasians. Observed racial differences may reflect differences in environmental/social factors, changes in cognition, and/or physical functioning.

Background: Rare variants in PLCG2 (p.P522R), ABI3 (p.S209F), and TREM2 (p.R47H, p.R62H) have been associated with late onset Alzheimer's disease (LOAD) risk in Caucasians. After the initial report, several studies have found positive results in cohorts of different ethnic background and with different phenotype., Objective: In this study, we aim to evaluate the association of rare coding variants in PLCG2, ABI3, and TREM2 with LOAD risk and their effect at different time points of the disease., Methods: We used a European American cohort to assess the association of the variants prior onset (using CSF Aβ42, tau, and pTau levels, and amyloid imaging as endophenotypes) and after onset (measured as rate of memory decline)., Results: We confirm the association with LOAD risk of TREM2 p.R47H, p.R62H and ABI3 p.S209F variants, and the protective effect of PLCG2 p.P522R. In addition, ABI3 and TREM2 gene-sets showed significant association with LOAD risk. TREM2 p.R47H and PLCG2 p.P522R variants were also statistically associated with increase of amyloid imaging and AD progression, respectively. We did not observe any association of ABI3 p.S209F with any of the other AD endophenotypes., Conclusion: The results of this study highlight the importance of including biomarkers and alternative phenotypes to better understand the role of novel candidate genes with the disease.

Background and Purpose: AV-1451 ( 18 F-AV-1451, flortaucipir) positron emission tomography was performed in C9orf72 expansion carriers to assess tau accumulation and disease manifestation., Methods: Nine clinically characterized C9orf72 expansion carriers and 18 age- and gender- matched cognitively normal individuals were psychometrically evaluated and underwent tau positron emission tomography imaging. The regional AV-1451 standard uptake value ratios from multiple brain regions were analyzed. Spearman correlation was performed to relate the AV-1451 standard uptake value ratio to clinical, psychometric and cerebrospinal fluid measures., Results: C9orf72 expansion carriers had increased AV-1451 binding in the entorhinal cortex compared to controls. Primary age-related tauopathy was observed postmortem in one patient. AV-1451 uptake did not correlate with clinical severity, disease duration, psychometric performance or cerebrospinal fluid markers., Conclusion: C9orf72 expansion carriers exhibited increased AV-1451 uptake in entorhinal cortex compared to cognitively normal controls, suggesting a propensity for primary age-related tauopathy. However, AV-1451 accumulation was not associated with psychometric performance in our cohort., (© 2019 EAN.)

Background and Purpose: Sporadic Creutzfeldt-Jakob disease (sCJD) is a rapidly progressive neurodegenerative disease caused by an abnormal isoform of the human prion protein. Structural magnetic resonance imaging in patients with pathologically confirmed sCJD was compared with cognitively normal individuals to identify a cortical thickness signature of sCJD., Methods: This retrospective cross-sectional study compared patients with autopsy-confirmed sCJD with dementia (n = 11) with age- and sex-matched cognitively normal individuals (n = 22). We identified regions of interest (ROIs) in which cortical thickness was most affected by sCJD. Within patients with sCJD, the relationship between ROI cortical thickness and clinical measures (disease duration, cerebrospinal fluid tau and diffusion-weighted imaging abnormalities) was evaluated., Results: Compared with cognitively normal individuals, patients with sCJD had significantly reduced cortical thickness in multiple ROIs, including the fusiform gyrus, precentral gyrus, precuneus and superior temporal gyrus bilaterally; the caudal middle frontal gyrus, superior frontal gyrus, postcentral gyrus, inferior temporal gyrus and transverse temporal gyrus in the left hemisphere; and the superior parietal lobule in the right hemisphere. Only one patient with sCJD had co-pathology consistent with Alzheimer's disease. Reduced cortical thickness did not correlate with disease duration, presence of diffusion restriction or elevated cerebrospinal fluid tau., Conclusion: Cortical signature changes in sCJD may reflect brain changes not captured by standard clinical measures. This information may be used with clinical measures to inform the progression of sCJD and patterns of prion protein spread throughout the brain. These results may have implications for prediction of symptomatic progression and plausibly for development of therapeutic strategies., (© 2019 EAN.)

Immune-mediated disorders of the CNS in children are a complex group of demyelinating, inflammatory, parainfectious and postinfectious disorders with heterogeneous pathobiological mechanisms and clinical manifestations, often associated with fundamental derangement in immune regulation. In this Review, we aim to provide an update on our knowledge of neuroimmune disorders and highlight areas of research that are priorities for improving clinical management. We outline the clinical features of neuroimmune disorders, the current approaches to their treatment and new approaches in development. We then consider the pathological features, including biomarkers, pathological mechanisms and genetics, and discuss the value of immune assays in clinical investigation and basic research. On the basis of current knowledge and techniques, we propose four research priorities: rigorous and consistent collection of core clinical data, cooperative investigation of treatments, development of biological assays and genetic studies. These priorities should help us to achieve the shared goal of precision medicine for neuroimmune disorders. However, multicentre research and the creation of clinical consortia for these rare disorders will be necessary, and we hope that this Review serves as a call to action that is timely given current exciting advances in neuroimmune therapeutics.

Background: Human immunodeficiency virus (HIV)-infected (HIV+) young adults often engage in risk-taking behavior. However, the disruptive effects of HIV on the neurobiological underpinnings of risky decision making are not well understood., Methods: Risky decision making, measured via the Iowa Gambling Task (IGT), was compared voxel-wise to resting cerebral blood flow (rCBF) acquired via arterial spin labeling. Separate topographical maps were obtained for HIV-uninfected (HIV-; n = 62) and HIV+ (n = 41) young adults (18-24 years old) and were compared to the full cohort of participants. For the HIV+ group, rCBF was compared to recent and nadir CD4., Results: IGT performance was supported by rCBF in 3 distinct brain regions: regions I, II, and III. The relationship between IGT performance and rCBF in HIV+ individuals was most robust in region I, the ventromedial prefrontal and insular cortices. Region II contained strong relationships for both HIV- and HIV+. Region III, dorsolateral prefrontal and posterior cingulate cortices, contained relationships that were strongest for HIV- controls. IGT performance was intact among HIV+ participants with higher rCBF in either region I or region III. By contrast, performance was worse among HIV+ individuals with lower rCBF in both regions I and III when compared to HIV- controls (P = .01). rCBF in region III was reduced in HIV+ compared with HIV- individuals (P = .04), and positively associated with nadir CD4 cell count (P = .02)., Conclusions: Recruitment of executive systems (region III) mitigates risk-taking behavior in HIV+ and HIV- individuals. Recruitment of reward systems (region I) mitigates risk-taking behavior when region III is disrupted due to immunological compromise. Identifying individual recruitment patterns may aid anatomically directed therapeutics or psychosocial interventions.

The purpose of the present study is to examine the integrity of white matter microstructure among individuals coinfected with HIV and HCV using diffusion tensor imaging (DTI). Twenty-five HIV+ patients, 21 HIV+/HCV+ patients, and 25 HIV- controls were included in this study. All HIV+ individuals were stable on combination antiretroviral therapy (cART; ≥3 months). All participants completed MRI and neuropsychological measures. Clinical variables including liver function, HIV-viral load, and CD4 count were collected from the patient groups. DTI metrics including mean diffusivity (MD), axial diffusivity (AD), radial diffusivity (RD), and fractional anisotropy (FA) from five subregions of the corpus callosum were compared across groups. The HIV+/HCV+ group and HIV+ group were similar in terms of HIV clinical variables. None of the participants met criteria for cirrhosis or fibrosis. Within the anterior corpus callosum, significant differences were observed between both HIV+ groups compared to HIV- controls on DTI measures. HIV+ and HIV+/HCV+ groups had significantly lower FA values and higher MD and RD values compared to HIV- controls; however, no differences were present between the HIV+ and HIV+/HCV+ groups. Duration of HIV infection was significantly related to DTI metrics in total corpus callosum FA only, but not other markers of HIV disease burden or neurocognitive function. Both HIV+ and HIV+/HCV+ individuals had significant alterations in white matter integrity within the corpus callosum; however, there was no evidence for an additive effect of HCV coinfection. The association between DTI metrics and duration of HIV infection suggests that HIV may continue to negatively impact white matter integrity even in well-controlled disease.

One of the major findings from multimodal neuroimaging studies in the past decade is that the human brain is anatomically and functionally organized into large-scale networks. In resting state fMRI (rs-fMRI), spatial patterns emerge when temporal correlations between various brain regions are tallied, evidencing networks of ongoing intercortical cooperation. However, the dynamic structure governing the brain's spontaneous activity is far less understood due to the short and noisy nature of the rs-fMRI signal. Here, we develop a wavelet-based regularity analysis based on noise estimation capabilities of the wavelet transform to measure recurrent temporal pattern stability within the rs-fMRI signal across multiple temporal scales. The method consists of performing a stationary wavelet transform to preserve signal structure, followed by construction of "lagged" subsequences to adjust for correlated features, and finally the calculation of sample entropy across wavelet scales based on an "objective" estimate of noise level at each scale. We found that the brain's default mode network (DMN) areas manifest a higher level of irregularity in rs-fMRI time series than rest of the brain. In 25 aged subjects with mild cognitive impairment and 25 matched healthy controls, wavelet-based regularity analysis showed improved sensitivity in detecting changes in the regularity of rs-fMRI signals between the two groups within the DMN and executive control networks, compared with standard multiscale entropy analysis. Wavelet-based regularity analysis based on noise estimation capabilities of the wavelet transform is a promising technique to characterize the dynamic structure of rs-fMRI as well as other biological signals., (© 2015 Wiley Periodicals, Inc.)

Previous animal studies have identified a C31S residue substitution in the C30C31 dicysteine motif of the Tat protein that is associated with reduced neurovirulence in clade C human immunodeficiency virus (HIV). However, clinical studies of patients infected with clade C HIV have reported significant levels of cognitive impairment. To date, no study has specifically examined cognitive function in clade C-infected patients as a function of the presence or absence of the Tat C31 substitution. The present study investigated the impact of the Tat C30C31S genetic substitution among individuals residing in South Africa infected with clade C HIV that either exhibited the C30C31 motif (n = 128) or the C31S motif (n = 46). A control group of seronegative individuals was included to examine the overall impact of HIV on cognitive performance. All individuals completed a comprehensive neuropsychological battery consisting of tests sensitive to HIV. Results revealed that clade C-infected individuals performed significantly worse across cognitive tests compared to seronegative controls. However, there were no significant differences in cognitive performances between individuals with the C31S motif versus those without the C31S substitution. Proximal CD4 cell count and plasma viral load were unrelated to cognitive performances for either group. Results confirm that the C31S dicysteine motif substitution of the Tat protein does not appreciably moderate neuropsychological outcomes in clade C. Further, these findings highlight the importance of clinical management of cognitive symptoms among individuals infected with this viral clade worldwide.

Obesity and other metabolic variables are associated with abnormal brain structural volumes and cognitive dysfunction in HIV-uninfected populations. Since individuals with HIV infection on combined antiretroviral therapy (CART) often have systemic metabolic abnormalities and changes in brain morphology and function, we examined associations among brain volumes and metabolic factors in the multisite CNS HIV AntiRetroviral Therapy Effects Research (CHARTER) cohort, cross-sectional study of 222 HIV-infected individuals. Metabolic variables included body mass index (BMI), total blood cholesterol (C), low- and high-density lipoprotein C (LDL-C and HDL-C), blood pressure, random blood glucose, and diabetes. MRI measured volumes of cerebral white matter, abnormal white matter, cortical and subcortical gray matter, and ventricular and sulcal CSF. Multiple linear regression models allowed us to examine metabolic variables separately and in combination to predict each regional volume. Greater BMI was associated with smaller cortical gray and larger white matter volumes. Higher total cholesterol (C) levels were associated with smaller cortex volumes; higher LDL-C was associated with larger cerebral white matter volumes, while higher HDL-C levels were associated with larger sulci. Higher blood glucose levels and diabetes were associated with more abnormal white matter. Multiple atherogenic metabolic factors contribute to regional brain volumes in HIV-infected, CART-treated patients, reflecting associations similar to those found in HIV-uninfected individuals. These risk factors may accelerate cerebral atherosclerosis and consequent brain alterations and cognitive dysfunction.

This study compared the neurology residency training experience for a single neurology resident at the University of Pennsylvania from the years 2002-2005. The prevalence of encounters seen during this residency was compared to the prevalence of neurological disorders typically observed by ambulatory neurologists in the United States (US). A total of 1,333 patients were evaluated during this residency. Ischemic stroke/transient ischemic accident, epilepsy, metabolic encephalopathy, peripheral neuropathy, and multiple sclerosis were the most common neurological disorders observed. The four most common reasons for an outpatient visit to a neurologist (i.e., headache/migraine, epilepsy, cerebrovascular disease, and peripheral neuropathy) typically account for approximately 49-55% of all appointments, but only contributed to approximately 40% of patient encounters during this neurology residency. While these results reflect the encounters of a single neurology resident, both the total number and distribution of neurological diagnoses were similar to previous experiences over two decades ago at US academic medical centers despite significant changes in health care delivery and policy. This case report demonstrates that neurology residency programs continue to overemphasize acute management of inpatient neurological disorders compared to outpatient care of more prevalent neurological complaints. Additional measures could be instituted to ensure a broader range of experiences during residency (i.e., online resident log). These methods could allow residency coordinators to identify certain areas of deficiency with regards to exposure to patients for a resident and ensure greater competency during residency.

Visual cortical surface area varies two- to threefold between human individuals, is highly heritable, and has been correlated with visual acuity and visual perception. However, it is still largely unknown what specific genetic and environmental factors contribute to normal variation in the area of visual cortex. To identify SNPs associated with the proportional surface area of visual cortex, we performed a genome-wide association study followed by replication in two independent cohorts. We identified one SNP (rs6116869) that replicated in both cohorts and had genome-wide significant association (P(combined) = 3.2 × 10(-8)). Furthermore, a metaanalysis of imputed SNPs in this genomic region identified a more significantly associated SNP (rs238295; P = 6.5 × 10(-9)) that was in strong linkage disequilibrium with rs6116869. These SNPs are located within 4 kb of the 5' UTR of GPCPD1, glycerophosphocholine phosphodiesterase GDE1 homolog (Saccharomyces cerevisiae), which in humans, is more highly expressed in occipital cortex compared with the remainder of cortex than 99.9% of genes genome-wide. Based on these findings, we conclude that this common genetic variation contributes to the proportional area of human visual cortex. We suggest that identifying genes that contribute to normal cortical architecture provides a first step to understanding genetic mechanisms that underlie visual perception.

Objective: To evaluate relationships between HIV-associated neurocognitive disorder and metabolic variables in a subgroup of HIV+ participants examined in a prospective, observational, multicenter cohort study., Methods: In a cross-sectional substudy of the CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) cohort, 130 HIV+ participants provided fasting blood samples. Neurocognitive impairment (NCI) was defined by performance on neuropsychological tests adjusting for age, education, gender, and race/ethnicity. Global ratings and global deficit scores were determined. Demographics, biomarkers of HIV disease, metabolic variables, combination antiretroviral therapy (CART) history, other drug exposures, and self-reported diabetes were examined in multivariate models predicting NCI. Separate models were used for body mass index (BMI) alone (n = 90) and BMI and waist circumference (WC) together (n = 55)., Results: NCI (global impairment rating ≥5) was diagnosed in 40%. In univariate analyses, age, longer duration of HIV infection, obesity, and WC, but not BMI, were associated with NCI. Self-reported diabetes was associated with NCI in the substudy and in those >55 in the entire CHARTER cohort. Multivariate logistic regression analyses demonstrated that central obesity (as measured by WC) increased the risk of NCI and that greater body mass may be protective if the deleterious effect of central obesity is accounted for., Conclusions: As in HIV-uninfected persons, central obesity, but not more generalized increases in body mass (BMI), was associated with a higher prevalence of NCI in HIV+ persons. Diabetes appeared to be associated with NCI only in older patients. Avoidance of antiretroviral drugs that induce central obesity might protect from or help to reverse neurocognitive impairment in HIV-infected persons.

Objective: To describe the development of progressive multifocal leukoencephalopathy (PML) in patients with rheumatoid arthritis (RA) treated with rituximab., Design: Case study., Setting: Clinical care for patients with rheumatologic diseases. Most were referred to academic centers for care after diagnosis (Washington University, St Louis, Missouri; Karolinska Insitute, Stockholm, Sweden; and Royal Melbourne Hospital, Melbourne, Australia) while one was cared for in a neurology practice in Dallas, Texas, with consultation by an academic neurovirologist from the University of Colorado in Denver., Patients: Four patients developing PML in the setting of rituximab therapy for RA., Intervention: Rituximab therapy., Main Outcome Measures: Clinical and pathological observations., Results: Four patients from an estimated population of 129 000 exposed to rituximab therapy for RA are reported in whom PML developed after administration of this drug. All were women older than 50 years, commonly with Sjögren syndrome and a history of treatment for joint disease ranging from 3 to 14 years. One case had no prior biologic and minimal immunosuppressive therapy. Progressive multifocal leukoencephalopathy presented as a progressive neurological disorder, with diagnosis confirmed by detection of JC virus DNA in the cerebrospinal fluid or brain biopsy specimen. Two patients died in less than 1 year from PML diagnosis, while 2 remain alive after treatment withdrawal. Magnetic resonance scans and tissue evaluation confirmed the frequent development of inflammatory PML during the course of the disease., Conclusion: These cases suggest an increased risk, about 1 case per 25 000 individuals, of PML in patients with RA being treated with rituximab. Inflammatory PML may occur in this setting even while CD20 counts remain low.

HIV can infect the brain and impair central nervous system (CNS) function. Combination antiretroviral therapy (cART) has not eradicated CNS complications. HIV-associated neurocognitive disorders (HAND) remain common despite cART, although attenuated in severity. This may result from a combination of factors including inadequate treatment of HIV reservoirs such as circulating monocytes and glia, decreased effectiveness of cART in CNS, concurrent illnesses, stimulant use, and factors associated with prescribed drugs, including antiretrovirals. This review highlights recent investigations of HIV-related CNS injury with emphasis on cART-era neuropathological mechanisms in the context of both US and international settings.

Subject performance, scanner hardware, or biological factors can affect single session neuroimaging measures. Stability studies using calibrated blood oxygenation level-dependent functional magnetic resonance imaging (BOLD-fMRI) have been performed in health but not disease. We utilized calibrated BOLD-fMRI to determine the effects of HIV on neurovascular coupling. Six clinically stable HIV-infected patients (HIV+) and 10 seronegative controls (HIV-) were scanned at two separate sessions approximately 3 months apart. Both mild hypercapnia (5% CO(2)) exposure and a visual functional activation task were performed. Intraclass correlation coefficients (ICC) and inter-subject variance were determined for calibrated BOLD-fMRI measures (baseline cerebral blood flow (CBF), functional CBF, BOLD, and cerebral metabolic rate of oxygen consumption (CMRO(2)) changes) for HIV+ and HIV- subjects. The two groups did not differ in age, sex, or education. HIV+ subjects had lower mean baseline CBF (p<0.04, Cohen's d=-1.07) and functional BOLD responses (p<0.001, Cohen's d=-2.47) and a trend towards a decrease in mean functional CBF responses (p=0.07, Cohen's d=-0.92) despite similar mean functional CMRO(2) changes (p=0.71, Cohen's d=0.19). The stability of each calibrated BOLD-fMRI measure, as assessed by ICC, was significantly lower for HIV+ subjects. In addition, HIV+ participants had greater inter-subject variability for baseline CBF (p<0.02), functional BOLD (p<0.001), CBF (p<0.001), and CMRO(2) (p<0.002) responses. Our results demonstrate that calibrated BOLD-fMRI measures have excellent stability within healthy controls. In contrast, these values have greater variability in clinically stable HIV+ subjects and may reflect alterations in coupling between CBF and CMRO(2) with disease., (Copyright © 2010. Published by Elsevier Inc.)

Objectives: Diagnostic challenges exist for differentiating HIV dementia from Alzheimer disease (AD) in older HIV-infected (HIV+) individuals. Similar abnormalities in brain amyloid-beta42 (Alphabeta42) metabolism may be involved in HIV-associated neuropathology and AD. We evaluated the amyloid-binding agent (11)C-Pittsburgh compound B ((11)C-PiB), a biomarker for Alphabeta42 deposition, in cognitively unimpaired HIV+ (n = 10) participants and matched community controls without dementia (n = 20)., Methods: In this case-control study, all participants had an (11)C-PiB scan within 2 years of concomitant CSF studies and neuropsychometric testing. Statistical differences between HIV+ and community controls for demographic and clinical values were assessed by chi(2) tests. Participants were further divided into either low (<500 pg/mL) or normal (>or=500 pg/mL) CSF Alphabeta42 groups with Student t tests performed to determine if regional differences in fibrillar amyloid plaque deposition varied with CSF Alphabeta42., Results: Regardless of CSF Alphabeta42 level, none of the HIV+ participants had fibrillar amyloid plaques as assessed by increased (11)C-PiB mean cortical binding potential (MCBP) or binding potential within 4 cortical regions. In contrast, some community controls with low CSF Alphabeta42 (<500 pg/mL) had high (11)C-PiB MCBP with elevated binding potentials (>0.18 arbitrary units) within cortical regions., Conclusions: Cognitively unimpaired HIV+ participants, even with low CSF Alphabeta42 (<500 pg/mL), do not have (11)C-PiB parameters suggesting brain fibrillar amyloid deposition. The dissimilarity between unimpaired HIV+ and preclinical AD may reflect differences in Abeta42 production and/or formation of diffuse plaques. Future longitudinal studies of HIV+ participants with low CSF Abeta42 and normal (11)C-PiB are required.

Objective: To provide updated estimates of the prevalence and clinical impact of human immunodeficiency virus-associated sensory neuropathy (HIV-SN) and neuropathic pain due to HIV-SN in the combination antiretroviral therapy (CART) era., Design: Prospective, cross-sectional analysis. Clinical correlates for HIV-SN and neuropathic pain, including age, exposure to CART, CD4 levels, plasma viral load, hepatitis C virus infection, and alcohol use disorders, were evaluated in univariate and multivariate models., Setting: Six US academic medical centers., Patients: One thousand five hundred thirty-nine HIV-infected individuals enrolled in the CNS (Central Nervous System) HIV Anti-Retroviral Therapy Effects Research study., Main Outcome Measures: The presence of HIV-SN, defined by 1 or more clinical signs (diminished vibration or sharp sensation in the legs and feet; reduced ankle reflexes) in a distal, symmetrical pattern. Neuropathic pain was defined as aching, stabbing, or burning in a similar distribution. The effect on quality of life was assessed with the Medical Outcomes Study HIV Health Survey., Results: We found HIV-SN in 881 participants. Of these, 38.0% reported neuropathic pain. Neuropathic pain was significantly associated with disability in daily activities, unemployment, and reduced quality of life. Risk factors for HIV-SN after adjustment were advancing age (odds ratio, 2.1 [95% confidence interval, 1.8-2.5] per 10 years), lower CD4 nadir (1.2 [1.1-1.2] per 100-cell decrease), current CART use (1.6 [1.3-2.8]), and past "D-drug" use (specific dideoxynucleoside analogue antiretrovirals) (2.0 [1.3-2.6]). Risk factors for neuropathic pain were past D-drug use and higher CD4 nadir., Conclusions: Neuropathic pain and HIV-SN remain prevalent, causing substantial disability and reduced quality of life even with successful CART. The clinical correlates of HIV-SN have changed with the evolution of treatment. These findings argue for redoubled efforts to determine HIV-SN pathogenesis and the development of symptomatic and neuroregenerative therapies.

Objective: HIV enters the brain soon after infection causing neuronal damage and microglial/astrocyte dysfunction leading to neuropsychological impairment. We examined the impact of HIV on resting cerebral blood flow (rCBF) within the lenticular nuclei (LN) and visual cortex (VC)., Methods: This cross-sectional study used arterial spin labeling MRI (ASL-MRI) to measure rCBF within 33 HIV+ and 26 HIV- subjects. Nonparametric Wilcoxon rank sum test assessed rCBF differences due to HIV serostatus. Classification and regression tree (CART) analysis determined optimal rCBF cutoffs for differentiating HIV serostatus. The effects of neuropsychological impairment and infection duration on rCBF were evaluated., Results: rCBF within the LN and VC were significantly reduced for HIV+ compared to HIV- subjects. A 2-tiered CART approach using either LN rCBF < or =50.09 mL/100 mL/min or LN rCBF >50.09 mL/100 mL/min but VC rCBF < or =37.05 mL/100 mL/min yielded an 88% (29/33) sensitivity and an 88% (23/26) specificity for differentiating by HIV serostatus. HIV+ subjects, including neuropsychologically unimpaired, had reduced rCBF within the LN (p = 0.02) and VC (p = 0.001) compared to HIV- controls. A temporal progression of brain involvement occurred with LN rCBF significantly reduced for both acute/early (<1 year of seroconversion) and chronic HIV-infected subjects, whereas rCBF in the VC was diminished for only chronic HIV-infected subjects., Conclusion: Resting cerebral blood flow (rCBF) using arterial spin labeling MRI has the potential to be a noninvasive neuroimaging biomarker for assessing HIV in the brain. rCBF reductions that occur soon after seroconversion possibly reflect neuronal or vascular injury among HIV+ individuals not yet expressing neuropsychological impairment.

Substantial work on the peripheral and central nervous system complications of HIV was presented at the 16th Conference on Retroviruses and Opportunistic Infections. Six studies of more than 4500 volunteers identified that distal sensory polyneuropathy remains common, ranging from 19% to 66%, with variation based on disease stage, type of antiretroviral therapy, age, and height. Eight studies of more than 2500 volunteers identified that neurocognitive disorders are also common, ranging from 25% to 69%, with variation based on stage of disease, antiretroviral use, diabetes mellitus, and coinfection with hepatitis viruses. Therapy-focused studies identified that resistance testing of cerebrospinal fluid (CSF)-derived HIV may improve management of people with HIV-associated neurologic complications, that poorly penetrating antiretroviral therapy is associated with persistent low-level HIV RNA in CSF, and that efavirenz concentrations in CSF are low but in the therapeutic range in most individuals. Neuroimaging reports identified that people living with HIV had abnormal findings on magnetic resonance imaging (gray matter atrophy, abnormal white matter), magnetic resonance spectroscopy (lower neuronal metabolites), and blood-oxygen-level dependent functional magnetic resonance imaging (lower cerebral blood flow). Other important findings on the basic neuroscience of HIV and diagnosis and management of neurologic opportunistic infections are discussed.

Data from the neurosurgical critical care arena demonstrate a correlation between cerebral oxygenation, survival, and cognitive function. Transfusion may increase and hemodilution decrease cerebral oxygenation. Both acute and chronic anemia have been associated with cognitive dysfunction. Aggressive blood conservation protocols have been instituted across all age groups without conclusive evidence for their impact upon outcome. Aged subjects are at the greatest risk of cognitive sequelae after major surgery associated with significant blood loss. We hypothesize that cerebral physiologic changes associated with "normal" aging may compromise cerebral oxygenation in the presence of severe anemia.Fischer 344 rats, the NIH National Institute of Aging normal aging rat model, underwent a stepwise isovolemic hemodilution protocol. Age groups (Age Grp) studied were as follows: Age Grp-A (3 months), n=14; Age Grp-B (9 to 12 months), n=14; and Age Grp-C (24 months), n=14. Brain oxygen tension (PBrO2), laser Doppler flow, and mean arterial pressure were measured. Final hemoglobin averaged 6.1+/-0.9 g/dL. PBrO2 levels decreased from a baseline of 18.1+/-4.1 to 17.5+/-6.8 mm Hg (P=0.49), and laser Doppler flow increased by 18+/-20% (P<0.0001) after hemodilution. Employing repeated measures multiple regression, Age Grp (P=0.30) was not a significant controlling covariate of PBrO2 in response to isovolemic hemodilution. PBrO2 levels were actually higher in Age Grp-C animals at all time points of the hemodilution protocol, although this was not statistically significant. Aged animals were also fully capable of mounting a robust local cerebral hyperemic response to the anemic challenge that was not separable from the response of younger animals.

Objective: To evaluate the effects of HIV-associated neurocognitive impairment on caudate blood flow and volume., Methods: The authors performed continuous arterial spin labeled MRI on 42 HIV+ patients (23 subsyndromic and 19 HIV neurosymptomatic) on highly active antiretroviral therapy and 17 seronegative controls. They compared caudate blood flow and volume among groups., Results: A stepwise decrease in both caudate blood flow and volume was observed with increasing HIV-associated neurocognitive impairment. Compared with seronegative controls, baseline caudate blood flow was reduced in HIV+ neurosymptomatic patients (p = 0.001) with a similar decreasing trend for subsyndromic HIV+ patients (p = 0.070). Differences in caudate volume were observed only for neurosymptomatic HIV+ patients compared with controls (p = 0.010). A Jonckheere-Terpstra test for trends was significant for both caudate blood flow and volume for each of the three subgroups. Pearson product moment correlation coefficients were not significant between caudate blood flow and volume for each group., Conclusions: Decreasing trends in caudate blood flow and volume were associated with significantly increasing HIV-associated neurocognitive impairment (HNCI), with the greatest decreases observed for more severely impaired patients. However, reductions in caudate blood flow and volume were poorly correlated. Changes in residual caudate blood flow may act as a surrogate biomarker for classifying the degree of HNCI.

We report four young women who developed acute psychiatric symptoms, seizures, memory deficits, decreased level of consciousness, and central hypoventilation associated with ovarian teratoma (OT) and cerebrospinal fluid (CSF) inflammatory abnormalities. Three patients recovered with treatment of the tumor or immunosuppression and one died of the disorder. Five other OT patients with a similar syndrome and response to treatment have been reported. Our patients' serum or CSF showed immunolabeling of antigens that were expressed at the cytoplasmic membrane of hippocampal neurons and processes and readily accessed by antibodies in live neurons. Immunoprobing of a hippocampal-expression library resulted in the isolation of EFA6A, a protein that interacts with a member of the two-pore-domain potassium channel family and is involved in the regulation of the dendritic development of hippocampal neurons. EFA6A-purified antibodies reproduced the hippocampal immunolabeling of all patients' antibodies and colocalized with them at the plasma membrane. These findings indicate that in a young woman with acute psychiatric symptoms, seizures, and central hypoventilation, a paraneoplastic immune-mediated syndrome should be considered. Recognition of this disorder is important because despite the severity of the symptoms, patients usually recover. The location and function of the isolated antigen suggest that the disorder is directly mediated by antibodies.