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Background: Negative impacts of the COVID-19 pandemic on people with dementia have been widely-documented, but most studies have relied on carer reports and few have compared responses to information collected before the pandemic., Objective: We aimed to explore the impact of the pandemic on community-dwelling individuals with mild-to-moderate dementia and compare responses with pre-pandemic data., Methods: During the second wave of the pandemic, we conducted structured telephone interviews with 173 people with dementia and 242 carers acting as informants, all of whom had previously participated in the IDEAL cohort. Where possible, we benchmarked responses against pre-pandemic data., Results: Significant perceived negative impacts were identified in cognitive and functional skills and ability to engage in self-care and manage everyday activities, along with increased levels of loneliness and discontinuity in sense of self and a decline in perceived capability to 'live well'. Compared to pre-pandemic data, there were lower levels of pain, depression, and anxiety, higher levels of optimism, and better satisfaction with family support. There was little impact on physical health, mood, social connections and relationships, or perceptions of neighborhood characteristics., Conclusion: Efforts to mitigate negative impacts of pandemic-related restrictions and restore quality of life could focus on reablement to address the effects on participation in everyday activities, creating opportunities for social contact to reduce loneliness, and personalized planning to reconnect people with their pre-COVID selves. Such efforts may build on the resilience demonstrated by people with dementia and carers in coping with the pandemic.

The actual role of SARS-CoV-2 in brain damage remains controversial due to lack of matched controls. We aim to highlight to what extent is neuropathology determined by SARS-CoV-2 or by pre-existing conditions. Findings of 9 Coronavirus disease 2019 (COVID-19) cases and 6 matched non-COVID controls (mean age 79 y/o) were compared. Brains were analyzed through immunohistochemistry to detect SARS-CoV-2, lymphocytes, astrocytes, endothelium, and microglia. A semi-quantitative scoring was applied to grade microglial activation. Thal-Braak stages and the presence of small vessel disease were determined in all cases. COVID-19 cases had a relatively short clinical course (0-32 days; mean: 10 days), and did not undergo mechanical ventilation. Five patients with neurocognitive disorder had delirium. All COVID-19 cases showed non-SARS-CoV-2-specific changes including hypoxic-agonal alterations, and a variable degree of neurodegeneration and/or pre-existent SVD. The neuroinflammatory picture was dominated by ameboid CD68 positive microglia, while only scant lymphocytic presence and very few traces of SARS-CoV-2 were detected. Microglial activation in the brainstem was significantly greater in COVID-19 cases (p = 0.046). Instead, microglial hyperactivation in the frontal cortex and hippocampus was clearly associated to AD pathology (p = 0.001), regardless of the SARS-CoV-2 infection. In COVID-19 cases complicated by delirium (all with neurocognitive disorders), there was a significant enhancement of microglia in the hippocampus (p = 0.048). Although higher in cases with both Alzheimer's pathology and COVID-19, cortical neuroinflammation is not related to COVID-19 per se but mostly to pre-existing neurodegeneration. COVID-19 brains seem to manifest a boosting of innate immunity with microglial reinforcement, and adaptive immunity suppression with low number of brain lymphocytes probably related to systemic lymphopenia. Thus, no neuropathological evidence of SARS-CoV-2-specific encephalitis is detectable. The microglial hyperactivation in the brainstem, and in the hippocampus of COVID-19 patients with delirium, appears as a specific topographical phenomenon, and probably represents the neuropathological basis of the "COVID-19 encephalopathic syndrome" in the elderly., (© 2021 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology.)

Introduction: The increasing evidence of SARS-CoV-2 impact on the central nervous system (CNS) raises key questions on its impact for risk of later life cognitive decline, Alzheimer's disease (AD), and other dementia., Methods: The Alzheimer's Association and representatives from more than 30 countries-with technical guidance from the World Health Organization-have formed an international consortium to study the short-and long-term consequences of SARS-CoV-2 on the CNS-including the underlying biology that may contribute to AD and other dementias. This consortium will link teams from around the world covering more than 22 million COVID-19 cases to enroll two groups of individuals including people with disease, to be evaluated for follow-up evaluations at 6, 9, and 18 months, and people who are already enrolled in existing international research studies to add additional measures and markers of their underlying biology., Conclusions: The increasing evidence and understanding of SARS-CoV-2's impact on the CNS raises key questions on the impact for risk of later life cognitive decline, AD, and other dementia. This program of studies aims to better understand the long-term consequences that may impact the brain, cognition, and functioning-including the underlying biology that may contribute to AD and other dementias., (© 2021 the Alzheimer's Association.)

Herpes simplex virus 1 (HSV1) is a neuroinvasive virus capable of entering the brain which makes it a candidate pathogen for increasing risk of dementia. Previous studies are inconsistent in their findings regarding the link between HSV1 and dementia, therefore, we investigated how HSV1 relates to cognitive decline and dementia risk using data from a population-based study. We measured HSV1 immunoglobulin (IgG) antibodies in serum collected between 2002 and 2005 from participants of the Rotterdam Study. We used linear regression to determine HSV1 in relation to change in cognitive performance during 2 consecutive examination rounds on average 6.5 years apart. Next, we determined the association of HSV1 with risk of dementia (until 2016) using a Cox regression model. We repeated analyses for Alzheimer's disease. All models were adjusted for age, sex, cardiovascular risk factors, and apolipoprotein E genotype. Of 1915 non-demented participants (mean age 71.3 years, 56.7% women), with an average follow-up time of 9.1 years, 244 participants developed dementia (of whom 203 Alzheimer's disease). HSV1 seropositivity was associated with decline in global cognition (mean difference of HSV1 seropositive vs seronegative per standard deviation decrease in global cognition - 0.16; 95% confidence interval (95%CI), - 0.26; - 0.07), as well as separate cognitive domains, namely memory, information processing, and executive function, but not motor function. Finally, HSV1 seropositivity was not associated with risk of dementia (adjusted hazard ratio 1.18, 95% CI 0.83; 1.68), similar for Alzheimer's disease. HSV1 is associated with cognitive decline but not with incident dementia in the general population. These data suggest HSV1 to be associated only with subtle cognitive disturbances but not with greater cognitive disorders that result in dementia.

Background: There is limited evidence on the characteristics and outcome of patients with dementia hospitalised for novel coronavirus infection (COVID-19)., Method: We conducted a prospective study in 2 gerontologic COVID units in Paris, France, from March 14, 2020, to May 7, 2020. Patients with dementia hospitalised for confirmed COVID-19 infection were systematically enrolled. A binary logistic regression analysis was performed to identify factors associated with mortality at 21 days., Results: We included 125 patients. Median age was 86 (IQI 82-90); 59.4% were female. Most common causes of dementia were Alzheimer's disease, mixed dementia and vascular dementia. 67.2% had ≥ 2 comorbidities; 40.2% lived in a long-term care facility. The most common symptoms at COVID-19 onset were confusion and delirium (82.4%), asthenia (76.8%) and fever (72.8%) before polypnea (51.2%) and desaturation (50.4%). Falls were frequent at the initial phase of the disease (35.2%). The fatality rate at 21 days was 22.4%. Chronic kidney disease and CRP at admission were independent factors of death. Persisting confusion, mood and behavioural disorders were observed in survivors (19.2%)., Conclusion: COVID-19 in demented individuals is associated with severe outcome in SARS-CoV-2 infection and is characterised by specific clinical features and complications, with confusion and delirium at the forefront. COVID-19 testing should be considered in front of any significant change from baseline.

The COVID-19 pandemic has infected more than 22 million people worldwide. Although much has been learned about COVID-19, we do not know much about its neurological features and their outcome. This observational study was conducted on the patients of Imam Hossein Hospital, and 361 adult patients (214 males) with confirmed diagnosis of COVID-19 from March 5, 2020 to April 3, 2020, were enrolled. Data was gathered on age, sex, comorbidities, initial symptoms, symptoms during the disease course, neurological symptoms, and outcome. The mean age of the patients was 61.90 ± 16.76 years. The most common initial symptoms were cough, fever, and dyspnea. In 21 patients (5.8%), the initial symptom was neurological. History of dementia was associated with severe COVID-19 disease (odds ratio = 1.28). During the course of the disease, 186 patients (51.52%) had at least one neurological symptom, the most common being headache (109 [30.2%]), followed by anosmia/ageusia (69, [19.1%]), and dizziness (54, [15%]). Also, 31 patients had neurological complications (8.58%). Anosmia, ageusia, dizziness, and headache were associated with favorable outcome (P < 0.001), while altered mental status and hemiparesis were associated with poor outcome. The mortality rate of patients who had neurological complications was more than twice than that of patients without neurological complication (P = 0.008). Almost half of the patients experienced at least one neurological symptom, which may be the initial presentation of COVID-19. Dementia appears to be associated with severe COVID-19. Mortality was higher in patients with neurological complications, and these patients needed more intensive care.

As the SARS-COV-2 becomes a global pandemic, many researchers have a concern about the long COVID-19 complications. Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a persistent, debilitating, and unexplained fatigue disorder. We investigated psychological morbidities such as CFS and post-traumatic stress disorder (PTSD) among survivors of COVID-19 over 6 months. All COVID-19 survivors from the university-affiliated hospital of Tehran, Iran, were assessed 6 months after infection onset by a previously validated questionnaire based on the Fukuda guidelines for CFS/EM and DSM-5 Checklist for PTSD (The Post-traumatic Stress Disorder Checklist for DSM-5 or PCL-5) to determine the presence of stress disorder and chronic fatigue problems. A total of 120 patients were enrolled. The prevalence rate of fatigue symptoms was 17.5%. Twelve (10%) screened positive for chronic idiopathic fatigue (CIF), 6 (5%) for CFS-like with insufficient fatigue syndrome (CFSWIFS), and 3 (2.5%) for CFS. The mean total scores in PCL-5 were 9.27 ± 10.76 (range:0-44), and the prevalence rate of PTSD was 5.8%. There was no significant association after adjusting between CFS and PTSD, gender, comorbidities, and chloroquine phosphate administration. The obtained data revealed the prevalence of CFS among patients with COVID-19, which is almost similar to CFS prevalence in the general population. Moreover, PTSD in patients with COVID-19 is not associated with the increased risk of CFS. Our study suggested that medical institutions should pay attention to the psychological consequences of the COVID-19 outbreak.

Competing Interests: The authors have declared that no competing interests exist.

Objectives: Social distancing under the COVID-19 pandemic has restricted access to community services for older adults with neurocognitive disorder (NCD) and their caregivers. Telehealth is a viable alternative to face-to-face service delivery. Telephone calls alone, however, may be insufficient. Here, we evaluated whether supplementary telehealth via video-conferencing platforms could bring additional benefits to care-recipient with NCD and their spousal caregivers at home., Participants: Sixty older adults NCD-and-caregiver dyads were recruited through an activity center., Design, Intervention: The impact of additional services delivered to both care-recipient and caregiver through video conference (n = 30) was compared with telehealth targeted at caregivers by telephone only (n = 30), over 4 weeks in a pretest-post-test design. Interviews and questionnaires were conducted at baseline and study's end., Measurements, Results: Supplementary telemedicine had averted the deterioration in the Montreal Cognitive Assessment evident in the telephone-only group (η p 2  = 0.50). It also reversed the falling trend in quality of life observed in the telephone only group (QoL-AD, η p 2  = 0.23). Varying degrees of improvements in physical and mental health (Short-Form 36 v2), perceived burden (Zarit Burden Interview Scale) and self-efficacy (Revised Caregiving Self-Efficacy Scale) were observed among caregivers in the video-conferencing group, which were absent in the telephone-only group (η p 2  = 0.23-0.51)., Conclusion: Telemedicine by video conference was associated with improved resilience and wellbeing to both people with NCD and their caregivers at home. The benefits were visible already after 4 weeks and unmatched by telephone alone. Video conference as the modus operandi of telehmedicine beyond the context of pandemic-related social distancing should be considered., (Copyright © 2020 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: To describe the experiences and needs of caregivers of persons with dementia during the COVID-19 pandemic and lockdown in a city in India., Design: Qualitative study using a telephonic semistructured interview., Setting: A specialist geriatric outpatient mental health service based in a nongovernmental organization in Chennai, India., Participants: A purposive sampling of family members of persons with dementia registered in the database and seen within the previous 6 months., Results: Thirty-one caregivers participated. Thematic analysis of the data showed two sets of issues that the caregivers of persons with dementia faced in their experiences during the pandemic. The first set was unique to the caregivers that directly related to their caregiving role, while the second set did not relate directly to their caregiving role. These two sets also appeared to have a two-way interaction influencing each other. These issues generated needs, some of which required immediate support while others required longer-term support. The caregivers suggested several methods, such as use of video-consultations, telephone-based support and clinic-based in-person visits to meet their needs. They also wanted more services postpandemic., Conclusion: Caregivers of persons with dementia had multiple needs during the pandemic. Supporting them during these times require a pragmatic multilayered approach. Systemic changes, policies and frameworks, increased awareness, use of technology, and better access to health are necessary., (Copyright © 2020 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

The COVID-19 pandemic is causing global morbidity and mortality, straining health systems, and disrupting society, putting individuals with Alzheimer's disease and related dementias (ADRD) at risk of significant harm. In this Special Article, we examine the current and expected impact of the pandemic on individuals with ADRD. We discuss and propose mitigation strategies for: the risk of COVID-19 infection and its associated morbidity and mortality for individuals with ADRD; the impact of COVID-19 on the diagnosis and clinical management of ADRD; consequences of societal responses to COVID-19 in different ADRD care settings; the effect of COVID-19 on caregivers and physicians of individuals with ADRD; mental hygiene, trauma, and stigma in the time of COVID-19; and the potential impact of COVID-19 on ADRD research. Amid considerable uncertainty, we may be able to prevent or reduce the harm of the COVID-19 pandemic and its consequences for individuals with ADRD and their caregivers., (Copyright © 2020. Published by Elsevier Inc.)

Background: The association between cytomegalovirus (CMV) and dementia remains controversial. Previous studies have suggested that CMV serostatus, as assessed by serum immunoglobulin G, plays a role in neurodegeneration with cognitive impairment. We aimed to evaluate the association between CMV tissue-invasive end-organ diseases and moderate-to-severe dementia., Methods: The ICD 10th revision codes from the National Health Insurance Database covering the entire population of the Republic of Korea were used to classify patients into exposed (n = 687, age ≥ 40 years, with CMV disease) and unexposed (n = 3435, without CMV disease) groups, matched by age and sex at a 1:5 ratio of exposed: unexposed. All non-HIV-1-infected subjects selected during 2010-2014 with a washout period of the previous 4 years were followed up until December 2016 to identify newly diagnosed cases of moderate-to-severe dementia., Results: Multivariate regression model (M3) adjusted for age, sex, low income, body mass index, transplantation status, malignant neoplasms, end-stage renal disease on dialysis, type 2 diabetes mellitus, hypertension, and dyslipidaemia showed a significantly higher incidence of dementia (odds ratio: 1.9; 95% confidence interval: 1.2-2.8) in the exposed group than that in the unexposed group. The risk of vascular dementia (2.9, 1.1-7.5) was higher than that of Alzheimer's disease (1.6, 1.0-2.6) in the exposed group in M3. In M3, patients aged 40-59 years with CMV diseases had a significantly higher risk of all kinds of dementia than those aged 60-79 and ≥ 80 years (11.7, 2.5-49.4 vs. 1.8, 1.1-3.2 vs. 1.3, 0.5-2.8; P = 0.025)., Conclusions: CMV diseases may be associated with the risk of moderate-to-severe dementia.

By incorporating appropriate drug(s) into lipid (biobased) nanocarriers, one obtains a combination therapeutic for dementia treatment that targets certain cell-surface scavenger receptors (mainly class B type I, or "SR-BI") and thereby crosses the blood-brain barrier. The cardiovascular risk factors for dementia trigger widespread inflammation -- which lead to neurodegeneration, gradual cognitive/memory decline, and eventually (late-onset) dementia. Accordingly, one useful strategy to delay dementia could be based upon nanotargeting drug(s), using lipid nanocarriers, toward a major receptor class responsible for inflammation-associated (cytokine-mediated) cell signaling events. At the same time, the immune response and excessive inflammation, commonly observed in the very recent human coronavirus (COVID-19) pandemic, may accelerate the progression of brain inflammatory neurodegeneration-which increases the probability of post-infection memory impairment and accelerating progression of Alzheimer's disease. Hence, the proposed multitasking combination therapeutic, using a (biobased) lipid nanocarrier, may also display greater effectiveness at different stages of dementia.

Interest is growing in the role of infectious agents in the pathogenesis of dementia, but current evidence is limited. We conducted a systematic review and meta-analysis to investigate the effect of any of eight human herpesviruses on development of dementia or mild cognitive impairment (MCI). We searched the Cochrane Library, Embase, Global Health, Medline, PsycINFO, Scopus, Web of Science, clinical trials registers and grey literature sources from inception to December 2017 for observational studies with cohort, case control or self-controlled designs, or randomised controlled trials of interventions against herpesviruses. Pooled effect estimates and 95% confidence intervals (CIs) were generated through random effects meta-analyses across studies with the same design, outcome, and virus type, method and site of measurement. We included 57 studies across various geographic settings. Past infection with herpesviruses, measured by IgG seropositivity, was generally not associated with dementia risk. A single cohort study rated moderate quality showed an association between varicella zoster virus reactivation (ophthalmic zoster) and incident dementia (HR 2.97; 95%CI, 1.89 to 4.66). Recent infection with, or reactivation of, herpes simplex virus type 1 or type 1/2 unspecified, cytomegalovirus and human herpes virus-6 measured by serum IgM, high titre IgG or clinical disease may be associated with dementia or MCI, though results were inconsistent across studies and overall evidence rated very low quality. Longitudinal population studies with robust repeated virus measurements taken sufficiently proximal to dementia onset are needed to establish whether, when and among whom herpesviruses affect dementia risk.

This retrospective cohort study is to investigate the association between herpes simplex virus (HSV) infections and dementia, and the effects of anti-herpetic medications on the risk involved, using Taiwan's National Health Insurance Research Database (NHIRD). We enrolled a total of 33,448 subjects, and identified 8362 with newly diagnosed HSV infections and 25,086 randomly selected sex- and age-matched controls without HSV infections in a ratio of 1:3, selected from January 1, to December 31, 2000. A multivariable Cox proportional hazards regression model was used to evaluate the risk of developing dementia in the HSV cohort. This analysis revealed an adjusted hazard ratio of 2.564 (95% CI: 2.351-2.795, P < 0.001) for the development of dementia in the HSV-infected cohort relative to the non-HSV cohort. Thus, patients with HSV infections may have a 2.56-fold increased risk of developing dementia. A risk reduction of dementia development in patients affected by HSV infections was found upon treatment with anti-herpetic medications (adjusted HR = 0.092 [95% CI 0.079-0.108], P < 0.001). The usage of anti-herpetic medications in the treatment of HSV infections was associated with a decreased risk of dementia. These findings could be a signal to clinicians caring for patients with HSV infections. Further research is, therefore, necessary to explore the underlying mechanism(s) of these associations.

Background: Earlier studies have documented an association between cytomegalovirus and cognitive impairment, but results have been inconsistent. Few studies have investigated the association of cytomegalovirus and Epstein-Barr virus with cognitive decline longitudinally. Our aim was to examine whether cytomegalovirus and Epstein-Barr virus are associated with cognitive decline in adults., Method: The study sample is from the Finnish Health 2000 Survey (BRIF8901, n = 7112), which is representative of the Finnish adult population. The sample was followed up after 11 years in the Health 2011 Survey. In addition, persons with dementia were identified from healthcare registers., Results: In the Finnish population aged 30 and over, the seroprevalence of cytomegalovirus was estimated to be 84% and the seroprevalence of Epstein-Barr virus 98%. Seropositivity of the viruses and antibody levels were mostly not associated with cognitive performance. In the middle-aged adult group, cytomegalovirus serointensity was associated with impaired performance in verbal learning. However, the association disappeared when corrected for multiple testing. No interactions between infection and time or between the two infections were significant when corrected for multiple testing. Seropositivity did not predict dementia diagnosis., Conclusions: The results suggest that adult levels of antibodies to cytomegalovirus and Epstein-Barr virus may not be associated with a significant decline in cognitive function or with dementia at population level., (Copyright © 2018. Published by Elsevier Inc.)

Introduction: Persisting neurotropic viruses are proposed to increase the risk of dementia, but evidence of association from robust, adequately powered population studies is lacking. This is essential to inform clinical trials of targeted preventive interventions., Methods and Analysis: We will carry out a comprehensive systematic review of published and grey literature of the association between infection with, reactivation of, vaccination against or treatment of any of the eight human herpesviruses and dementia or mild cognitive impairment. We will search the Cochrane Library, Embase, Global Health, Medline, PsycINFO, Scopus, Web of Science, clinical trials registers, the New York Academy of Medicine Grey Literature Report, Electronic Theses Online Service through the British Library and the ISI Conference Proceedings Citation Index for randomised controlled trials, cohort, caseâ€"control, case crossover or self-controlled case series studies reported in any language up to January 2017. Titles, abstracts and full-text screening will be conducted by two researchers independently. Data will be extracted systematically from eligible studies using a piloted template. We will assess risk of bias of individual studies in line with the Cochrane Collaboration tool. We will conduct a narrative synthesis, grouping studies by exposure and outcome definitions, and will describe any differences by population subgroups and dementia subtypes. We will consider performing meta-analyses if there are adequate numbers of sufficiently homogeneous studies. The overall quality of cumulative evidence will be assessed using selected Grading of Recommendations, Assessment, Development and Evaluations criteria., Ethics and Dissemination: As this is a review of existing studies, no ethical approval is required. Results will be disseminated through a peer-reviewed publication and at national and international conferences. We anticipate the review will clarify the current extent and quality of evidence for a link between herpesviruses and dementia, identify gaps and inform the direction of future research., Prospero Registration Number: CRD42017054684., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Herpes simplex virus (HSV) type 1 affects a majority of the population and recent evidence suggests involvement in Alzheimer's disease aetiology. We investigated the prevalence of HSV type 1 and 2 in the Tampere Autopsy Study (TASTY) brain samples using PCR and sero-positivity in plasma, and associations with Alzheimer's disease neuropathology. HSV was shown to be present in human brain tissue in 11/584 (1.9%) of samples in the TASTY cohort, of which six had Alzheimer's disease neuropathological amyloid beta (Aβ) aggregations. Additionally, serological data revealed 86% of serum samples tested were IgG-positive for HSV. In conclusion, we report epidemiological evidence of the presence of HSV in brain tissue free from encephalitis symptoms in a cohort most closely representing the general population (a minimum prevalence of 1.9%). Whereas 6/11 samples with HSV DNA in the brain tissue had Aβ aggregations, most of those with Aβ aggregations did not have HSV present in the brain tissue., Competing Interests: The authors declare no competing or financial interests., (© 2016. Published by The Company of Biologists Ltd.)

Enterovirus in the nervous system can present with protean manifestations, including polio-like paralysis, movement disorders, and seizures. This is a report of a single case of a rapidly progressive dementing illness in a young woman with common variable immunodeficiency (CVID). Over the course of several months, she developed profound aphasia, apraxia, and cerebellar signs. She underwent brain biopsy which was suggestive of toxoplasmosis; despite an adequate course of treatment, she continued to decline and ultimately died. Autopsy and PCR testing revealed diffuse coxsackie B3 infiltration in the meninges and brain parenchyma. To our knowledge, this is the first description of enterovirus causing a dementing illness in a young immunosuppressed adult. We highlight the need for a broad differential diagnosis, especially for immunocompromised individuals, who may present in an atypical fashion.

Objectives: To determine the contribution of peripheral blood mononuclear cells' (PBMCs) HIV DNA levels to HIV-associated dementia (HAD) and non-demented HIV-associated neurocognitive disorders (HAND) in chronically HIV-infected adults with long-term viral suppression on combined antiretroviral treatment (cART)., Methods: Eighty adults with chronic HIV infection on cART (>97% with plasma and CSF HIV RNA <50 copies/mL) were enrolled into a prospective observational cohort and underwent assessments of neurocognition and pre-morbid cognitive ability at two visits 18 months apart. HIV DNA in PBMCs was measured by real-time PCR at the same time-points., Results: At baseline, 46% had non-demented HAND; 7.5% had HAD. Neurocognitive decline occurred in 14% and was more likely in those with HAD (p<.03). Low pre-morbid cognitive ability was uniquely associated with HAD (p<.05). Log10 HIV DNA copies were stable between study visits (2.26 vs. 2.22 per 106 PBMC). Baseline HIV DNA levels were higher in those with lower pre-morbid cognitive ability (p<.04), and higher in those with no ART treatment during HIV infection 1st year (p = .03). Baseline HIV DNA was not associated with overall neurocognition. However, % ln HIV DNA change was associated with decline in semantic fluency in unadjusted and adjusted analyses (p = .01-.03), and motor-coordination (p = .02-.12) to a lesser extent., Conclusions: PBMC HIV DNA plays a role in HAD pathogenesis, and this is moderated by pre-morbid cognitive ability in the context of long-term viral suppression. While the HIV DNA levels in PBMC are not associated with current non-demented HAND, increasing HIV DNA levels were associated with a decline in neurocognitive functions associated with HAND progression.

In the absence of treatment, HIV-1 infection, usually starting with a single virion, leads inexorably to a catastrophic decline in the numbers of CD4(+) T cells and to AIDS, characterized by numerous opportunistic infections as well as other symptoms, including dementia and wasting. In the 30 years since the AIDS pandemic came to our attention, we have learned a remarkable amount about HIV-1, the responsible virus--the molecular details about how it functions and interacts with the host cell, its evolution within the host, and the countermeasures it has evolved to overcome host defenses against viral infection. Despite these advances, we remain remarkably ignorant about how HIV-1 infection leads to disease and the death of the human host. In this brief article, we introduce and discuss important lessons that we have learned by examining the dynamics of viral populations and infected cells. These studies have revealed important features of the virus-host interaction that now form the basis of our understanding of the importance and consequence of ongoing viral replication during HIV-1 infection.

Objectives: Despite the introduction of combined antiretroviral therapy (cART), the prevalence of HIV-associated neurocognitive disorders (HANDs) remains high. Aim of the study was to investigate the potential relationship between ophthalmic artery resistance index (OARI), a marker of subclinical cerebrovascular disease, and cognitive performance., Methods: We performed a cross-sectional cohort study by consecutively enrolling HIV-infected patients during routine outpatient visits. All subjects underwent a comprehensive neuropsycological battery and ultrasonographic assessment of OARI. Patients were classified as cognitively impaired if they showed decreased cognitive function involving at least two ability domains. OARI was considered abnormal if above 0.72 at left or right side. Factors associated with cognitive performance were evaluated by linear and logistic regression analysis., Results: A total of 116 patients [78.4% males, median age 44 years (IQR 37-49), 13.8% with past AIDS-defining events, median CD4 482 cells/μL (IQR 352-690), 79.3% with HIV RNA <20 copies/mL] were enrolled. A hundred-thirteen (97.4%) subjects were on cART of which 88.5% on current regimen from one year. Fifty-four (46.6%) patients were classified as cognitively impaired. ROC curves indicated that the most discriminant left and right OARI values for predicting a mild cognitive impairment were >0.72 (AUC = 0.73, sensitivity 61.8%, specificity 81.4%, p < 0.001) and >0.71 (AUC = 0.72, sensitivity 69.1%, specificity 71.2%, p < 0.001), respectively. Multivariate analysis showed that OARI >0.72 (OR 4.7, p = 0.001) was independently associated with increased risk of cognitive impairment. Moreover, education (β = -0.18, p = 0.005), Zung depression score (β = +0.05, p = 0.021) and an abnormal OARI (β = +1.46, p = 0.002) were independently associated with an increased number of pathological performances. Evaluating separately each cognitive domain, an abnormal OARI confirmed an independent association with lower performance in attention and executive functions (p = 0.003) and in psychomotor speed (p = 0.010)., Conclusions: Increased OARI was associated with lower cognitive performance in HIV-infected patients. These findings suggest a potential role of subclinical cerebrovascular disease in the pathogenesis of HAND., (Copyright © 2012 The British Infection Association. Published by Elsevier Ltd. All rights reserved.)

Platelet-derived growth factor-CC (PDGF-CC) is the third member of the PDGF family, and has been implicated both in embryogenesis and development of the CNS. The biological function of this isoform however, remains largely unexplored in the context of HIV-associated dementia (HAD). In the present study, we demonstrate that exposure of human neuroblastoma cells SH-SY5Y to HIV transactivator protein Tat resulted in decreased intrinsic expression of PDGF-CC as evidenced by RT-PCR and western blot assays. Reciprocally, pretreatment of SH-SY5Y cells with PDGF-CC abrogated Tat-mediated neurotoxicity by mitigating apoptosis and neurite & MAP-2 loss. Using pharmacological and loss of function approaches we identified the role of phosphatidylinositol 3-kinase (PI3K)/Akt signaling in PDGF-CC-mediated neuroprotection. We report herein a novel role about the involvement of transient receptor potential canonical (TRPC) channel 1 in modulation of calcium transients in PDGF-CC-mediated neuroprotection. Furthermore we also demonstrated PDGF-CC-mediated inactivation of the downstream mediator--glycogen synthase kinase 3β (GSK3β) evidenced by its phosphorylation at Ser-9. This was further validated by gain and loss of function studies using cells transfected with either the wild type or mutant GSK3β constructs. Intriguingly, pretreatment of cells with either the PI3K inhibitor or TRPC blocker resulted in failure of PDGF-CC to inactivate GSK3β, thereby suggesting the intersection of PI3K and TRPC signaling at GSK3β. Taken together our findings lead to the suggestion that PDGF-CC could be developed as a therapeutic target to reverse Tat-mediated neurotoxicity with implications for HAD.

The increased life expectancy of HIV-infected individuals due to improved treatment has revealed an unexpected increase in non-AIDS comorbidities that are typically associated with older age including cardiovascular disease, dementia and frailty. The majority of these diseases arise as the result of dysregulated systemic inflammation, and both the aged and HIV-infected individuals exhibit elevated basal levels of inflammation. In the elderly, increased inflammation and age-related diseases are associated with a state of impaired immunity called immunosenescence, which is thought to result from a lifetime of immune stimulation. It is now apparent that HIV induces premature immunosenescence within T-cells; however, the impact of HIV on aging of cells of the innate arm of the immune system is unknown. Innate immune cells play a central role in inflammation and are thus critical for the pathogenesis of inflammatory diseases. Limited evidence suggests HIV infection mimics age-related changes to innate immune cells; however, the extent of this effect and the mechanism underlying these changes remain to be defined. This review focuses on the impact of HIV infection on the function and aging of innate immune cells and discusses potential drivers of premature immunosenescence including chronic endotoxaemia, residual viraemia, telomere attrition and altered cellular signalling.

Infections represent an uncommon but important to recognize cause of rapidly progressive dementia, as diagnosis and treatment may produce a favorable outcome in selected instances. This article reviews infectious causes of rapidly progressive dementia, including selected viruses, bacteria, fungi, parasites, and prion diseases. Epidemiology, clinical manifestations, imaging characteristics, laboratory diagnosis, and treatment options are discussed., (© Thieme Medical Publishers.)

The difference between regional rates of HIV-associated dementia (HAD) in patients infected with different subtypes of HIV suggests that genetic determinants exist within HIV that influence the ability of the virus to replicate in the central nervous system (in Uganda, Africa, subtype D HAD rate is 89%, while subtype A HAD rate is 24%). HIV-1 nef is a multifunctional protein with known toxic effects in the brain compartment. The goal of the current study was to identify if specific three-dimensional nef structures may be linked to patients who developed HAD. HIV-1 nef structures were computationally derived for consensus brain and non-brain sequences from a panel of patients infected with subtype B who died due to varied disease pathologies and consensus subtype A and subtype D sequences from Uganda. Site directed mutation analysis identified signatures in brain structures that appear to change binding potentials and could affect folding conformations of brain-associated structures. Despite the large sequence variation between HIV subtypes, structural alignments confirmed that viral structures derived from patients with HAD were more similar to subtype D structures than to structures derived from patient sequences without HAD. Furthermore, structures derived from brain sequences of patients with HAD were more similar to subtype D structures than they were to their own non-brain structures. The potential finding of a brain-specific nef structure indicates that HAD may result from genetic alterations that alter the folding or binding potential of the protein.

We studied the rare case of an older adult with dementia following herpes zoster encephalitis (HZE). This 71-year-old woman presented to us approximately 1 year following resolution of a rapid-onset episode of HZE, and subsequently underwent neuropsychological and neuroimaging examinations. Cognitive assessment revealed impairments in general cognitive functioning, verbal and nonverbal memory, executive functions, speed of information processing, attention/working memory, and motor skills. The patient's neuroimaging data, when compared to a demographically similar healthy control sample (n = 9), demonstrated moderate central and perisylvian brain volume loss, several subcortical lesions in the white matter, and resting state whole brain and hippocampal hypoperfusion. These findings highlight neuropsychological changes evident in a dementia syndrome of this type, and they suggest that early identification and treatment of HZE has implications for the preservation of long-term cognitive functioning.

Besides opportunistic infections, direct or indirect HIV-mediated lesions of cerebral vascular or neural cells can also occur during the natural course of HIV infection. The main non-infectious complications of HIV are cerebral lymphomas, cerebrovascular disorders, HIV dementia and myelitis.

Infection with the human immunodeficiency virus-1 (HIV-1) and acquired immunodeficiency syndrome (AIDS) are often associated with severe and debilitating neurological problems that include behavioral abnormalities, motor dysfunction and frank dementia. HIV-1-infected peripheral immune cells, in particular macrophages, appear to infiltrate the CNS, release neurotoxins and provoke a neuropathological response involving all cell types in the brain. In the CNS, HIV-1 and its components initiate activation of chemokine receptors, inflammatory mediators and glutamate receptor-mediated excitotoxicity, all of which can activate numerous downstream signaling pathways and disturb neuronal and glial function. Recent experimental evidence suggests that disturbance by HIV-1 results not only in neuronal injury and death but also in impairment of neurogenesis. This article will review recently identified pathological mechanisms which potentially contribute to the development of neurocognitive impairment and dementia in association with HIV-1 infection.

Many viruses cause encephalitis, but understanding the mechanisms by which viral infection leads to encephalopathy or dementia remain elusive. In many cases, inflammation generated by the host's attempt to combat the infection is itself implicated as a primary factor in causing neuronal dysfunction or degeneration. In this review, we outline the current state of knowledge regarding the pathophysiology of CNS (central nervous system) injury in viral infection. We focus our review on the neuropathogenesis of HIV type 1 (HIV-1)-associated dementia, because, within this class of infection, it is the best studied. We will also discuss the key similarities and differences in the pathological mechanisms of other important viral encephalitides. Understanding these mechanisms should ultimately enable development of immunomodulatory therapies for treating these infections, as well as other neuro-inflammatory conditions.

Introduction: Dementia is a decline of intellectual abilities. The etiology of dementia syndrome is diverse. The authors describe three patients with early-onset dementia., Case Reports: The first patient was a 44 years old male with mild gait, body ataxia, memory loss, slowness and apathy Investigations proved AIDS dementia syndrome. In the second case of a 37 years old female patient, herpes simplex encephalitis was suspected due to sudden onset of speech arrest and to brain MRI and CSF findings. Her symptoms improved during antiviral treatment but later progressive dementia developed. CSF serological tests proved the presence of neurolues-dementia paralytica. The third patient was a 38-years-old female. Neurological examination was performed because of progressive memory loss, changed behaviour and impaired attention. Neuropsychological test showed severe dementia. Metachromatic leukodystrophy was proven by decreased arylsulfatase activity., Conclusions: It is not easy to recognize the early symptoms of dementia. In these cases, besides detailed history, neurological examination and neuropsychological tests, brain MRI and cerebral spinal fluid serological tests were indispensable for a correct diagnosis, especially in the young patients.

The virus, herpes simplex virus type 1 (HSV1), when present in brain, acts together with the type 4 allele of the APOE gene, a known susceptibility factor in Alzheimer disease (AD), to confer a strong risk of AD; in carriers of the other two main alleles of the gene, the virus does not confer a risk. It also has been shown that the outcome of infection in the case of five diseases known to be caused by viruses is determined by APOE. It is hoped that the discovery of the involvement of HSV1 in AD will lead to future antiviral therapy and possibly to immunization against the virus in infancy.

TT virus (TTV) is a widespread infectious agent of humans identified in 1998. In infected individuals, TTV induces persistent viremia but its life cycle and pathogenic potential are still poorly understood. In the present study, the presence of TTV DNA in 32 consecutive paired serum and cerebrospinal fluid (CSF) samples from patients with neurological (mainly multiple sclerosis) disorders was investigated by means of a sensitive quantitative real-time PCR assay. Of the 24 patients who were found to carry TTV DNA in serum, 3 also had detectable TTV DNA in their CSF. Two TTV positive CSF samples had markers indicative of blood contamination or a disrupted blood-brain barrier and contained considerably lower TTV loads as compared with the corresponding serum samples, thus suggesting that the virus they contained was of plasma origin. These findings indicated that in general TTV does not permeate effectively an intact blood-brain barrier. Furthermore, the CNS does not represent a common site of TTV replication and persistence. However, at least one exception was observed: the third TTV positive CSF sample (obtained from a patient with subacute dementia of unknown origin) showed no markers suggestive of disrupted blood-brain barrier or blood contamination and had a TTV DNA concentration similar to that found in the patient's serum. In addition, the TTV isolates detected in the two body fluids were distinct genetically. The detection of TTV DNA in CSF is of considerable interest but the clinical significance remains unknown., (Copyright 2001 Wiley-Liss, Inc.)

In a well-defined population of adult AIDS patients from Oslo, we studied the correlation between clinical dementia and autopsy results. The study included 91% of all adult AIDS patients from Oslo who died between 1983 and 1996. The autopsy rate was 73% (167/229). Twenty-three percent of patients had definite dementia and 24% possible dementia. In more than half of the patients with definite dementia multinucleated giant cells were present in the brain tissue, suggesting that the dementia was due to HIV encephalitis. Diffuse damage of white matter also showed a significant association with clinical dementia. When found alone it tended to occur in symptomatic patients with a short survival time from onset of dementia until death. This indicates that diffuse damage of white matter may be an early stage of HIV encephalitis. CMV encephalitis was found in 28 cases (17%). Of these, 20 were classified as definitely or possibly demented. In 14 of these 20 cases we detected no multinucleated giant cells, suggesting that CMV caused or contributed to the dementia. Multiple logistic regression supported an association between CMV and conditions clinically classified as HIV dementia. We conclude that HIV encephalitis is the major cause of dementia in AIDS patients, but that CMV encephalitis as a cause of dementia has been underestimated.

Acute encephalitis is an inflammation of the brain parenchyma. In the United States, 20,000 cases occur yearly. A variety of cognitive deficits, often the sole cause of disability, may persist after the acute stage. Still, infectious diseases tend to be covered only briefly in neuropsychological handbooks. Recent literature demonstrates the heterogeneity of both amnestic disorders and the outcome following encephalitides. Herpes Simplex virus (HSV), the most common single etiology of sporadic encephalitis, usually causes the most severe symptoms. Modern antiviral medication, however, seems to improve the cognitive outcome. Much less is known about non-HSV encephalitides, where both mild and severe defects have been observed. This article summarizes the current knowledge and also calls upon a more active neuropsychological research in the area.

Rapidly progressive dementia in an adult with findings of bilateral, symmetric high signal intensity on T2-weighted sequences and normal findings on T1-weighted sequences predominantly in the deep grey matter is suggestive of Creutzfeldt-Jakob disease (CJD). The peripheral cortex may be involved, as it was in the present case. The absence of subcortical periventricular white matter high signal intensity suggests that symmetric high signal intensities within the basal ganglia and cortical grey matter are more likely to be due to a degenerative process rather than due to ischaemia, infection or tumour.

Five cases of irreversible mental disorders (dementia) are reported in patients with immunodeficiency as the consequence of HIV-infection. Such cases comprise 4.3% of the patients infected by HIV at the stage of AIDS. Among the patients with dementia a cytomegaloviral damage to the brain was diagnosed in 83.3% of the cases. Mean life span of the patients was 2 months from the moment of the rise of psychopathologic symptomatology. An early diagnosis of the disorders of mental activity in individuals infected by HIV is necessary for establishing etiology of the pathologic process and for prescribing a specific medicine early.