Serious mini‐games for cognitive function assessment

Introduction: The prevalence of mild and major neurocognitive disorders (NCDs), also referred to as mild cognitive impairment and dementia, is rising globally. The prevention of NCDs is a major global public health interest. We sought to synthesize the literature on potentially modifiable risk factors for NCDs. Methods: We conducted an umbrella review using a systematic search across multiple databases to identify relevant systematic reviews and meta-analyses. Eligible reviews examined potentially modifiable risk factors for mild or major NCDs. We used a random-effects multi-level meta-analytic approach to synthesize risk ratios for each risk factor while accounting for overlap in the reviews. We further examined risk factors for major NCD due to two common etiologies: Alzheimer’s disease and vascular dementia. Results: A total of 45 reviews with 212 meta-analyses were synthesized. We identified fourteen broadly defined modifiable risk factors that were significantly associated with these disorders: alcohol consumption, body weight, depression, diabetes mellitus, diet, hypertension, less education, physical inactivity, sensory loss, sleep disturbance, smoking, social isolation, traumatic brain injury, and vitamin D deficiency. All 14 factors were associated with the risk of major NCD, and five were associated with mild NCD. We found considerably less research for vascular dementia and mild NCD. Conclusion: Our review quantifies the risk associated with 14 potentially modifiable risk factors for mild and major NCDs, including several factors infrequently included in dementia action plans. Prevention strategies should consider approaches that reduce the incidence and severity of these risk factors through health promotion, identification, and early management.

BackgroundSexual minority older adults (SMOAs) report subjective cognitive decline (SCD) more than heterosexual older adults (HOAs). Inconsistent findings have emerged about the risk of cognitive decline in SMOAs. This study aimed to compare the impact of multiple psycho‐social risk factors on both objectively assessed and subjectively reported cognitive decline between HOAs and SMOAs.MethodTwo samples of self‐identified HOAs (n = 4180) and SMOAs (n = 92) who completed Waves 8 and 9 of the English Longitudinal Study of Ageing were selected. Reliable change indices for episodic and semantic memory were created to assess longitudinal cognitive changes. SCD was self‐assessed for both memory and general cognition. Mental and cardiovascular health, marital status, loneliness, and socio‐economic status (SES) were investigated as risk factors for cognitive decline. The effect of each risk factor and their interaction effects with sexual orientation on memory changes and SCD were tested, respectively, with general linear and logistic regression models. Age, education, and sex were included as covariates. A sensitivity analysis was carried out in a sub‐sample (n = 92, per group) matched for demographics.ResultCognitive changes and rates of SCD were similar between SMOAs and HOAs. All risk factors, apart from marital status, were associated SCD risk, while only SES was associated with decline in episodic memory (β = .01, p = .038). A SES×sexual orientation interaction was found for semantic memory (β = ‐.06, p = .042); among those in the lowest quintile, SMOAs had better semantic memory preservation over time than HOAs. A sensitivity analysis found among those in the highest quintile, SMOAs had worse semantic memory decline than HOAs.ConclusionSCD was associated with a multitude of risk factors, in line with previous evidence of SCD as a heterogeneous construct. This was similar between SMOAs and HOAs. Longitudinal changes in semantic memory were, instead, differentially impacted by SES in the groups. Sensitivity analysis confirmed a potential lack of protective effect in SMOAs, although the groups did not differ for SES. These findings may be interpreted within the framework of material deprivation, which is more likely among SMOAs and may contribute to their cognitive decline more severely than in HOAs.

Subjective cognitive decline (SCD) is an established predictor of neurocognitive disorders (NCD) (i.e. mild cognitive impairment and dementia). Yet, its construct remains contentious. Many individuals with SCD do not progress to NCD, leading to an alternative term in the literature - 'functional cognitive disorders' - to describe the SCD experience in these individuals. This study examined the distinct differences in trajectories of subjective cognitive decline (SCD), between those who did and did not eventually develop NCD. This case-control study included 5,167 participants aged ≥50 years, followed-up near-annually to evaluate for SCD and NCD (median follow-up=8.1 years; range=1.0-18.0). Cases were defined as those who developed incident NCD during follow-up; controls completed ≥10 years of follow-up and had normal cognition throughout follow-up period. SCD trajectories were modelled with mixed-effect logistic regression, using a backward timescale. Those who developed NCD (cases) had new onset of SCD within past 20 years, which became particularly noticeable 13-14 years before diagnosis, and became even more prominent in the last 4 years. Those who did not develop NCD (controls) reported SCD since younger age, with the probability of SCD remaining constant over time. The distinctive trajectories were consistent across Alzheimer's & non-Alzheimer's disease, and among those with higher baseline rates of SCD due to psychiatric conditions. SCD has distinctive trajectories among those who do and do not progress to NCD. The distinctive trajectories can inform NCD risk for early interventions, and guide public health messaging to distinguish high-risk SCD from normal ageing. Future SCD scales may possibly need to evaluate for symptom changes over a longer, 20-year horizon to better capture new onset of SCD within this longer timeframe.

BackgroundPopulation ageing is associated with an increase in the number of persons with dementia, which constitutes a significant public health issue. The Hong Kong Mental Morbidity Survey for Older People (HKMMSOP) was carried out to evaluate the local prevalence of dementia and the factors that modulated the disease development.MethodParticipants aged 60 or over, stratified with age groups, were recruited through random sampling of residential addresses in Hong Kong. They underwent an assessment of their cognitive function (Montreal Cognitive Assessment, MoCA; Clinical Dementia Rating, CDR), physical health (Cumulative Illness Rating Scale, CIRS) and mental health (Clinical Interview Schedule‐Revised, CIS‐R; Short Warwick‐Edinburgh Mental Wellbeing Scale, SWEMWBS). Associative factors of neurocognitive disorders were determined by multinomial regression, with neurocognitive disorders as dependent variables.ResultIn this interim analysis, 4369 participants of HKMMSOP were included. Their mean age was 69.6, and there was a slight female preponderance (56.3%). On average, they received 8.8 years of education, and their mean MoCA score was 23.8 (SD 4.9). Using CDR, 71.8% were evaluated as having normal cognition, 23.1% with a mild neurocognitive disorder (ND), and 5.2% with a major ND. Older or less educated participants had a higher risk of developing mild and major ND (p<0.001). But the relationships between cognition and physical and mental health differed in the mild and major ND groups. Among those with mild ND, a higher CIRS total score (p<0.001), a higher CIS‐R total score (p<0.001) and a lower SWEMWBS score (p = 0.002) were significantly associated with CDR. However, only CIRS total score (p = 0.004) and SWEMWBS score (p<0.001) remained significant in the major ND group.ConclusionPoorer physical and mental health and lower mental well‐being and life satisfaction were associated with an increased risk of mild ND. But as the disease progressed, lower mental well‐being and life satisfaction and poorer physical health remained significant factors. On the contrary, a higher level of mental symptoms, as exemplified by CIS‐R, was not significantly associated with major ND. It sheds some light on the factors that may modulate the course of the disease and appropriate preventive measures.

Subjective cognitive decline (SCD) is a known risk factor for Alzheimer's disease. However, little research has examined whether healthy older adults with SCD (SCD+) exhibit lower cognition and increased rates of cognitive decline compared to those without SCD (SCD-). The goal of this study was to examine if cognitive change over a 15-year period differs between SCD+ and SCD-. 3,019 cognitively normal older adults (831 SCD+) from 3 Rush Alzheimer's Disease Center cohort studies were followed annually for up to a maximum of 15years. Due to attrition, the average follow-up time was 5.7years. Cognition was measured using z-scores of global cognition, episodic memory, semantic memory, perceptual speed, visuospatial ability, and working memory. Linear mixed-effects models investigated whether SCD was associated with cognitive change. Both baseline cognition and cognitive change over time differed between SCD+ and SCD-. People with SCD+ exhibited lower baseline scores and a steeper decline in global cognition, episodic memory, semantic memory, and perceptual speed. People with SCD+ did not differ from SCD- in baseline visuospatial ability or working memory but exhibited increased change over time in those two domains compared to SCD-. The observed results reveal that older adults with SCD+ have lower baseline cognition and steeper declines in cognition over time compared to SCD-. Older adults with SCD may be aware of subtle cognitive declines that occur over time in global cognition, episodic memory, semantic memory, perceptual speed, visuospatial ability, and working memory compared to those without SCD.

The persistence of HIV-1 associated neurocognitive disorders (HAND) in the post-cART era, afflicting between 40 and 70% of HIV-1 seropositive individuals, supports a critical need for the development of adjunctive therapeutic treatments. Selective estrogen receptor β agonists, including S-Equol (SE), have been implicated as potential therapeutic targets for the treatment of neurocognitive disorders. In the present study, the therapeutic efficacy of 0.2 mg SE for the treatment of HAND was assessed to address two key questions in the HIV-1 transgenic (Tg) rat. First, does SE exhibit robust therapeutic efficacy when treatment is initiated relatively early (i.e., between 2 and 3 months of age) in the course of viral protein exposure? Second, does the therapeutic utility of SE generalize across multiple neurocognitive domains? Treatment with SE enhanced preattentive processes and stimulus-response learning to the level of controls in all (i.e., 100%) HIV-1 Tg animals. For sustained and selective attention, statistically significant effects were not observed in the overall analyses (Control: Placebo, n = 10, SE, n = 10; HIV-1 Tg: Placebo, n = 10, SE, n = 10). However, given our a priori hypothesis, subsequent analyses were conducted, revealing enhanced sustained and selective attention, approximating controls, in a subset (i.e., 50%, n = 5 and 80%, n = 8, respectively) of HIV-1 Tg animals treated with SE. Thus, the therapeutic efficacy of SE is greater when treatment is initiated relatively early in the course of viral protein exposure and generalizes across neurocognitive domains, supporting an adjunctive therapeutic for HAND in the post-cART era.Graphical HIV-1 transgenic (Tg) and control animals were treated with either 0.2 mg S-Equol (SE) or placebo between 2 and 3 months of age (Control: Placebo, n = 10, SE, n = 10; HIV-1 Tg: Placebo, n = 10, SE, n = 10). Neurocognitive assessments, tapping preattentive processes, stimulus response learning, sustained attention and selective attention, were conducted to evaluate the utility of SE as a therapeutic for HIV-1 associated neurocognitive disorders (HAND). Planned comparisons between HIV-1 Tg and control animals treated with placebo were utilized to establish a genotype effect, revealing prominent neurocognitive impairments (NCI) in the HIV-1 Tg rat across all domains. Furthermore, to establish the utility of SE, HIV-1 Tg animals treated with SE were compared to control animals treated with placebo. Treatment with 0.2 mg SE ameliorated NCI, to levels that were indistinguishable from controls, in at least a subset (i.e., 50–100%) of HIV-1 Tg animals. Thus, SE supports an efficacious, adjunctive therapeutic for HAND.

Diagnostic Utility of Montreal Cognitive Assessment in the Fifth Edition of Diagnostic and Statistical Manual of Mental Disorders: Major and Mild Neurocognitive Disorders

High-Impact Pain Predicts Subjective Cognitive Decline and Interacts with APOE4 Genotype in the Development of Objective Cognitive Impairment

Human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) are not routinely assessed due to the lack of an adequate screening strategy. We aimed to develop a clinically relevant screening procedure for symptomatic HAND, validated against a gold standard neuropsychological (NP) test battery. Representative HIV-infected (HIV+) and demographically matched HIV-uninfected (HIV-) participants in an observational study completed a standard evaluation for mood, drug and/or alcohol use, and activities of daily living and a newly designed 20-minute computerized CogState battery that assessed 5 cognitive domains. A subset completed standard NP assessment for 8 cognitive domains. HAND definition on screening and gold standard NP was determined using demographically corrected z scores and the global deficit score (≥ 0.5), applying the Frascati criteria. Participants were blinded to screening results, and the NP examiner was blinded to screening and HIV status. A total of 254 HIV+ participants were enrolled-mean age, 48.9 ± 10.2 years; median nadir CD4, 270 cells/mL; tertiary educated, 54%; and HIV- controls, 72. HIV+ HAND screening prevalence was 30.7% (HIV-associated dementia, 3.2%; mild neurocognitive disorder, 12.6%; and asymptomatic neurocognitive disorder, 15.0%; HIV- group: 13.9%; P = .004). Of the 75 participants who completed the NP battery, the HAND rate in the HIV+ group was 50.9% vs 43.4% by screening (P > .50). HAND screening vs gold standard NP sensitivity was 76% and specificity was 71%. Clinically relevant HIV-associated dementia and mild neurocognitive disorder sensitivity was 100% and specificity was 98% (positive predictive value 0.92). Symptomatic HAND warranting neurological review was accurately predicted using a CogState-based screening procedure.

Combination antiretroviral therapies have revolutionized the treatment of HIV infection, and many patients now enjoy a lifespan equal to that of the general population. However, HIV-associated neurocognitive disorders (HAND) remain a major health concern, with between 30% and 70% of all HIV-infected patients developing cognitive impairments during their life time. One important feature of HAND is visuo-perceptual deficits, but the systems-level neural dynamics underlying these impairments are poorly understood. In the current study, we use magnetoencephalography and advanced time series analyses to examine these neural dynamics during a visuospatial processing task in a group of HIV-infected patients without HAND (n = 25), patients with HAND (n = 18), and a group of demographically-matched uninfected controls (n = 24). All participants completed a thorough neuropsychological assessment, and underwent magnetoencephalography and structural MRI protocols. In agreement with previous studies, patients with HAND performed significantly worse than HIV-infected patients without HAND and controls on the cognitive task, in terms of increased reaction time and decreased accuracy. Our magnetoencephalography results demonstrated that both spontaneous and neural oscillatory activity within the occipital cortices were affected by HIV infection, and that these patterns predicted behavioural performance (i.e. accuracy) on the task. Specifically, spontaneous neural activity in the alpha (8-16 Hz) and gamma (52-70 Hz) bands during the prestimulus baseline period, as well as oscillatory theta responses (4-8 Hz) during task performance were aberrant in HIV-infected patients, with both spontaneous alpha and oscillatory theta activity significantly predicting accuracy on the task and neuropsychological performance outside of the magnetoencephalography scanner. Importantly, these rhythmic patterns of population-level neural activity also distinguished patients by HAND status, such that spontaneous alpha activity in patients with HAND was elevated relative to HIV-infected patients without HAND and controls. In contrast, HIV-infected patients with and without HAND had increased spontaneous gamma compared to controls. Finally, there was a stepwise decrease in oscillatory theta activity as a function of disease severity, such that the response diminished from controls to patients without HAND to patients with HAND. Interestingly, the strength of the relationship between this theta response and accuracy also dissociated patient groups in a similar manner (controls > HIV with no HAND > HIV with HAND), indicating a reduced coupling between neurophysiology and behaviour in HIV-infected patients. This study provides the first neuroimaging evidence of a dissociation between HIV-infected patients with and without HAND, and these findings shed new light on the neural bases of cognitive impairment in HIV infection.

HIV-associated neurocognitive disorder (HAND) remains a common cause of cognitive impairment and persists in 15-55% of HIV+ individuals in the combination antiretroviral therapy (CART) era. CART is now the primary treatment for HAND, but it is effective in only a subset of patients. In the pre-CART era, HIV-associated dementia was the most common form of HAND. However, in CART-treated patients, the prevalence of HIV-associated dementia has declined substantially, and milder stages of HAND, i.e., ANI and MND predominate. HIV+ patients with mild neurocognitive disorder (MND) can still have significant functional impairment in some activities of daily living. There have been several other significant changes in the clinical features of HAND in the CART era. The mean survival for an individual diagnosed with HIV dementia has increased dramatically. In HIV+ individuals on CART with a suppressed systemic viral load, the majority of individuals with HAND remain stable, with a small proportion showing deterioration. Extrapyramidal signs are now less common in patients with HAND on CART. In the CART era, HAND may have a mixed pattern of both cortical and subcortical features with greater deficits in executive functioning and working memory. Despite the milder clinical phenotype, in the CART era, patients with HAND still have persistent laboratory and neuroimaging abnormalities in the central nervous system even with systemic viral suppression. As the HIV+ patient population ages, cerebrovascular disease risk factors such as hypertension, diabetes, and hypercholesterolemia are increasingly recognized as risk factors for cognitive impairment in HIV+ patients on CART. HAND remains a common neurological condition globally in the CART era, necessitating the need for new animal models to examine pathogenesis and potential treatments for HAND.

HIV-associated neurocognitive disorders (HAND) have emerged as a problem among HIV-infected individuals in the era of antiretroviral therapy. However, there are insufficient data on HAND regarding its prevalence and clinical features in Japan. A test battery composed of eight neuropsycological tests proposed by the Ministry of Health, Labour and Welfare (MHLW test battery) was applied to assess 30 subjects at Tokyo Metropolitan Komagome Hospital. Among them, 5 subjects were excluded due to central nervous system complications. The background of each patient along with the results of head magnetic resonance imaging (MRI), cerebrospinal fluid (CSF) analysis and neuropsychological tests were compared to each HAND category. In addition, the clinical utility of a combination of neuropsychological tests as an abbreviated test battery of HAND was evaluated. A total of 19 (76%) subjects were diagnosed as having a HAND. Among them, HIV-associated dementia, mild neurocognitive disorders and asymptomatic neurocognitive disorders were diagnosed in 7, 8, and 4 subjects, respectively. Neither the patient's background nor the results of the head MRI and CSF analysis showed relevance to disease severity. The conventional International HIV Dementia Scale with the Digit Symbol Substitute Test was capable of detecting 94.7% cases of HAND. Most HIV-infected subjects clinically suspected as having neurocognitive disorders were diagnosed as having a HAND. Neuropsychological tests of the MHLW test battery were in some part useful to diagnose HAND. However, more precise neuropsychological tests are warranted to screen and diagnose HAND, based on the current criteria.

Medication use is associated with cognitive deficits in people with multiple sclerosis.

First paragraph: Perceived decline in cognition in the absence of what is commonly termed ‘objective evidence’ is frequently referred to as subjective cognitive decline (SCD). While etiologically heterogeneous and therefore potentially responsive to intervention in some cases, SCD remains primarily associated with an increased risk of developing dementia. It is becoming clear however that, irrespective of cause, SCD can have a detrimental effect upon quality of life. Although there is increasing interest in SCD within both research and clinical arenas, it remains a topic that provokes substantial debate particularly with regard to its definition, diagnosis, and management.

BackgroundIt is increasing recognized that care for people with neurocognitive disorders (NCDs) is costly, and cost of NCDs can be highly context dependent.ObjectiveTo evaluate the healthcare utilization and economic costs of NCDs in Hong Kong, cross referencing with other Asian metropolitan cities.Methods461 older adults aged ≥60 (major NCD: 68, mild NCD: 264, normal cognition: 129) were recruited from a population-based cross-sectional survey, Hong Kong Mental Morbidity Survey for Older People. Healthcare utilization was collected by Resource Utilization of Dementia. Per person cost was estimated from a societal perspective and expressed in 2022 US dollars. Cost-associative factors were explored. Our findings were compared to cost-of-illness evidence in major Asian metropolitan cities by a systematic review.ResultsAnnual costs per community-living adult with mild and major NCD were US$5677 (95%CI: 4985-6465) and US$12,841 (9940-16,590) in Hong Kong. For those with major NCD, costs doubled in severer stages, and diagnosed cases incurred nearly 30% more costs than hidden cases. Dementia cost in Hong Kong was lower than other high-income Asian economies and mainland China, mainly due to methodological heterogeneities and lower utilization of social care services.ConclusionsThe great economic burden of NCDs in Hong Kong reflects a striking social and care needs, particularly in moderate and severe stages. Care planning should prepare for the blowout needs being revealed by hidden cases and the diversified needs by different stages and family caregivers. Region- and population-specific studies with rigor design are warranted to estimate cost-effectiveness of upcoming treatment strategies.