New insights into the genetic etiology of Alzheimer's disease and related dementias.

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Non-AIDS defining cancers in the D:A:D Study-time trends and predictors of survival : a cohort study

BACKGROUND:Non-AIDS defining cancers (NADC) are an important cause of morbidity and mortality in HIV-positive individuals. Using data from a large international cohort of HIV-positive individuals, we described the incidence of NADC from 2004-2010, and described subsequent mortality and predictors of these.METHODS:Individuals were followed from 1st January 2004/enrolment in study, until the earliest of a new NADC, 1st February 2010, death or six months after the patient's last visit. Incidence rates were estimated for each year of follow-up, overall and stratified by gender, age and mode of HIV acquisition. Cumulative risk of mortality following NADC diagnosis was summarised using Kaplan-Meier methods, with follow-up for these analyses from the date of NADC diagnosis until the patient's death, 1st February 2010 or 6 months after the patient's last visit. Factors associated with mortality following NADC diagnosis were identified using multivariable Cox proportional hazards regression.RESULTS:Over 176,775 person-years (PY), 880 (2.1%) patients developed a new NADC (incidence: 4.98/1000PY [95% confidence interval 4.65, 5.31]). Over a third of these patients (327, 37.2%) had died by 1st February 2010. Time trends for lung cancer, anal cancer and Hodgkin's lymphoma were broadly consistent. Kaplan-Meier cumulative mortality estimates at 1, 3 and 5 years after NADC diagnosis were 28.2% [95% CI 25.1-31.2], 42.0% [38.2-45.8] and 47.3% [42.4-52.2], respectively. Significant predictors of poorer survival after diagnosis of NADC were lung cancer (compared to other cancer types), male gender, non-white ethnicity, and smoking status. Later year of diagnosis and higher CD4 count at NADC diagnosis were associated with improved survival. The incidence of NADC remained stable over the period 2004-2010 in this large observational cohort.CONCLUSIONS:The prognosis after diagnosis of NADC, in particular lung cancer and disseminated cancer, is poor but has improved somewhat over time. Modifiable risk factors, such as smoking and low CD4 counts, were associated with mortality following a diagnosis of NADC

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

The neuropsychological profile of parietal and occipital lobe epilepsy

Despite the extensive body of research in clinical neurology on the functional organization of posterior cortices, parietal and occipital lobe epilepsy (PLE and OLE) have not as yet received the attention afforded frontal and temporal lobe epilepsy (FLE and TLE), perhaps due to their low prevalence. Posterior epilepsies however, represent a challenge for epileptology in general and neuropsychological differential diagnosis in particular. Our main purpose was to examine the likely existence of a pattern of cognitive dysfunction characterizing patients suffering from seizures with a parietal and/or occipital ictal onset. We hypothesized that such patients would present difficulties in the visuospatial and visuoconstructive domains, since spatial analysis and synthesis is an inherent feature of posterior cortical systems. Participants were 14 patients with epilepsy and 14 healthy controls matched for demographic characteristics (gender, age, and education level). We used an extensive battery of neuropsychological tests to assess auditory-verbal memory and learning, episodic memory, attention and working memory, verbal abilities, haptic perception, arithmetic abilities, and executive functions. Special attention was given to visuospatial abilities. Depression and anxiety symptoms were assessed through a self-administered questionnaire. Nonparametric (Mann–Whitney U test) statistical tests were conducted. We found that patients with epilepsy performed significantly worse in visuoconstruction, verbal, and executive functions compared to their healthy matches. Finally, we interpret our findings from the perspective of Luria of mental functions organized into functional systems and the current trends in epileptology to view epilepsy as a system (network) problem. © 201

Cognitive Neurorehabilitation in Acquired Neurological Brain Injury

[No abstract available

The hellenic longitudinal investigation of aging and diet (HELIAD): Rationale, study design, and cohort description

Background: Accumulating epidemiological evidence from several populations supports the important role of the Mediterranean- type diet (MeDi) in reducing the risk for age-related diseases such as Alzheimer's disease (AD). However, the relevant literature is clearly deficient for most Mediterranean countries that more closely adhere to the originally described MeDi. Greece resides in the Mediterranean basin, and older generations traditionally adhere to a MeDi. Methods: We here present the design and the preliminary baseline characteristics of the Hellenic Longitudinal Investigation of Aging and Diet (HELIAD). The HELIAD is a population-based, multidisciplinary, collaborative study designed to estimate the prevalence and incidence of AD, other dementias, mild cognitive impairment, and other neuropsychiatric conditions of aging in the Greek population and to investigate associations between nutrition and cognitive dysfunction/age-related neuropsychiatric diseases in this Mediterranean population. The study also ascertains several demographic, medical, social, environmental, clinical, nutritional, and neuropsychological determinants and lifestyle activities. Results: In total, 1,050 participants of a random sample have already completed the initial evaluation. The subjects were, on average, 73.4 (SD = 6.0) years old, 60% of the sample were female, and most of the participants were poorly educated with an average of 5.41 (SD = 3.5) years of education. The performance on the neuropsychological tests was equivalent to the average scores of previous normative Greek samples. More than one third of the population under investigation was considered to be at high risk for malnutrition. Conclusions: The HELIAD may provide important data for expanding our knowledge regarding the prevalence, incidence, and risk factors of AD and several other neuropsychiatric diseases in the Mediterranean region. © 2014 S. Karger AG, Basel

Off-road assessment of cognitive fitness to drive

Road safety is a major issue in every society. The assessment of driving ability with a real vehicle is a lengthy and costly process; therefore, there is a growing need for the development of a neuropsychological battery that can provide a fast and reliable evaluation of a person’s cognitive fitness to drive. In the present study, we examined the relationship of an off-road lab-type test, namely, the Driving Scenes test, with performance on a driving simulator, as well as the influence of cognitive factors on driving ability as evaluated by Driving Scenes. Our results demonstrated a relationship between Driving Scenes and driving simulator performance. They also showed that some cognitive factors (namely, selective attention and verbal memory), were predictive of driving ability (as determined by the Driving Scenes test), but not others (namely visuospatial perception/memory, working memory, and visuospatial recognition). In addition, age strongly predicted performance on this test (younger age was associated with better performance). The conclusions derived from the present study highlight the need to identify off-road tools with high predictive value in assessing driving ability. © 2020 Taylor & Francis Group, LLC

Identifying Appropriate Neuropsychological Tests for Uneducated/Illiterate Older Individuals

Objectives: We investigated the utility of traditional neuropsychological tests in older uneducated/illiterate individuals without dementia to determine the possibility that they are likely not appropriate for this group. Methods: We assessed the neuropsychological performance of 1122 older adults [≥65 years old; mean age: 74.03 (SD = 5.46); mean education: 4.76 (SD = 2.5) years; women: n = 714], in the context of the Hellenic Longitudinal Investigation of Aging and Diet (HELIAD), a population-based study conducted in Greece. Results: We based our analyses on three groups: high-functioning/cognitively healthy (i.e., without dementia) uneducated/illiterate individuals (n = 80), high-functioning/cognitively healthy educated/literate individuals (n = 932), and low-functioning/cognitively impaired educated/literate individuals (presumably with dementia; n = 110). We used binary regression analyses with Bonferroni correction to investigate whether test performance differentiated uneducated/illiterate from educated/literate individuals. Models were adjusted for age and sex; raw test scores were the predictor variables. The uneducated/illiterate cohort was at a disadvantage relative to the healthy educated/literate group on all variables but verbal memory recognition and consolidation, congruent motor responses, and phonological fluency clustering (p >.002). Moreover, only word list learning immediate and delayed free recall and delayed cued recall differentiated the high-functioning/cognitively healthy uneducated/illiterate from the low-functioning/cognitively impaired educated/literate group, favoring the former (p's <.002). Conclusions: Our findings suggest that only particular verbal memory test variables are fair in determining whether older uneducated/illiterate individuals have functional/cognitive impairment suggestive of a neurodegenerative process. On all other neuropsychological variables, this cohort was at a disadvantage. Therefore, we highlight the need for identifying appropriate methods of assessment for older uneducated/illiterate individuals. Copyright © INS. Published by Cambridge University Press, 2021

Identifying Appropriate Neuropsychological Tests for Uneducated/Illiterate Older Individuals

Objectives: We investigated the utility of traditional neuropsychological tests in older uneducated/illiterate individuals without dementia to determine the possibility that they are likely not appropriate for this group. Methods: We assessed the neuropsychological performance of 1122 older adults [≥65 years old; mean age: 74.03 (SD = 5.46); mean education: 4.76 (SD = 2.5) years; women: n = 714], in the context of the Hellenic Longitudinal Investigation of Aging and Diet (HELIAD), a population-based study conducted in Greece. Results: We based our analyses on three groups: high-functioning/cognitively healthy (i.e., without dementia) uneducated/illiterate individuals (n = 80), high-functioning/cognitively healthy educated/literate individuals (n = 932), and low-functioning/cognitively impaired educated/literate individuals (presumably with dementia; n = 110). We used binary regression analyses with Bonferroni correction to investigate whether test performance differentiated uneducated/illiterate from educated/literate individuals. Models were adjusted for age and sex; raw test scores were the predictor variables. The uneducated/illiterate cohort was at a disadvantage relative to the healthy educated/literate group on all variables but verbal memory recognition and consolidation, congruent motor responses, and phonological fluency clustering (p &gt;.002). Moreover, only word list learning immediate and delayed free recall and delayed cued recall differentiated the high-functioning/cognitively healthy uneducated/illiterate from the low-functioning/cognitively impaired educated/literate group, favoring the former (p&apos;s &lt;.002). Conclusions: Our findings suggest that only particular verbal memory test variables are fair in determining whether older uneducated/illiterate individuals have functional/cognitive impairment suggestive of a neurodegenerative process. On all other neuropsychological variables, this cohort was at a disadvantage. Therefore, we highlight the need for identifying appropriate methods of assessment for older uneducated/illiterate individuals. Copyright © INS. Published by Cambridge University Press, 2021