Non-demented Individuals Research Articles

What does the Dementia Rating Scale-2 measure? The relationship of neuropsychological measures to DRS-2 total and subscale scores in non-demented individuals with Parkinson’s disease

Objective The Dementia Rating Scale-2 (DRS-2) is recommended for assessing global cognition in Parkinson’s disease (PD) by the Movement Disorder Society. However, empirical evidence is limited regarding the degree to which the DRS-2 corresponds to traditional neurocognitive domains (i.e., construct validity) in PD. Thus, this study aims to determine the construct validity of the DRS-2 in a non-demented sample of PD patients. Method Patients with PD (n = 359; mean age = 64.50 ± 8.53, education = 14.97 ± 2.73, disease duration = 8.48 ± 4.87, UPDRS Part III motor scale scores = 25.23 ± 10.17) completed the DRS-2 as part of a comprehensive neuropsychological assessment consisting of attention/working memory, executive function, language, delayed recall, and visuoperceptual-spatial skills.Bootstrapped bias-corrected Spearman rho’s correlations andhierarchical linear regressions were performed to examine construct validity of DRS-2 total and subscale scores. Results Speeded measures of set-shifting, rapid word generation to letter and semantic cues, and simple visuoperceptual skills largely accounted for variance in DRS-2 total scores. Most DRS-2 subscale scores showed weak relationships with theoretically related neuropsychological measures. Conclusions DRS-2 total scores reflect impairment across a range of cognitive domains (i.e., executive, language, and visuoperception), while DRS-2 subscale scores have limited construct validity. Together, the DRS-2 does not appear to have utility beyond screening for global cognition in PD.

Dissecting the Crosstalk between Endothelial Mitochondrial Damage, Vascular Inflammation, and Neurodegeneration in Cerebral Amyloid Angiopathy and Alzheimer's Disease.

Alzheimer’s disease (AD) is the most prevalent cause of dementia and is pathologically characterized by the presence of parenchymal senile plaques composed of amyloid β (Aβ) and intraneuronal neurofibrillary tangles of hyperphosphorylated tau protein. The accumulation of Aβ also occurs within the cerebral vasculature in over 80% of AD patients and in non-demented individuals, a condition called cerebral amyloid angiopathy (CAA). The development of CAA is associated with neurovascular dysfunction, blood–brain barrier (BBB) leakage, and persistent vascular- and neuro-inflammation, eventually leading to neurodegeneration. Although pathologically AD and CAA are well characterized diseases, the chronology of molecular changes that lead to their development is still unclear. Substantial evidence demonstrates defects in mitochondrial function in various cells of the neurovascular unit as well as in the brain parenchyma during the early stages of AD and CAA. Dysfunctional mitochondria release danger-associated molecular patterns (DAMPs) that activate a wide range of inflammatory pathways. In this review, we gather evidence to postulate a crucial role of the mitochondria, specifically of cerebral endothelial cells, as sensors and initiators of Aβ-induced vascular inflammation. The activated vasculature recruits circulating immune cells into the brain parenchyma, leading to the development of neuroinflammation and neurodegeneration in AD and CAA.

The relationship between plasma free fatty acids, cognitive function and structural integrity of the brain in middle-aged healthy humans

Background: The cerebral composition of ω-3 and ω-6 polyunsaturated fatty acids (PUFAs) is believed to influence cognitive function and structural damage of the aging brain. However, existing data is inconsistent.Materials and Methods: This retrospective study explored the association between free plasma PUFA concentrations, cognitive function and brain structure atrophy in a well-characterized community-dwelling cohort of elderly individuals without stroke and dementia. Ten different fatty acids were analyzed in stored plasma samples from 391 non-demented elderly individuals by gas chromatography mass spectrometry. Neuropsychiatric tests capturing memory, executive function and visuopractical skills were performed in all participants. Brain atrophy was assessed by MRI in a subset of 167 individuals.Results: Higher plasma concentrations of free ω-6 PUFAs (p = 0.042), and, in particular, linoleic acid (p = 0.01), were significantly associated with lower executive function. No significant association existed between ω-3 PUFA concentrations and cognitive functioning. The volume of the frontal lobes was inversely associated with ω-6 PUFAs, whereas ω-3 PUFAs were positively related with temporal lobe volumes. All associations did not withstand correction for multiple comparisons.Conclusions: Our study suggests subtle effects of PUFA imbalances on cognition and brain structure. Yet the observed associations are weak and unlikely to be of clinical relevance. The brain regions that seem to be most sensitive to imbalances of ω-3 and ω-6 PUFAs are the frontal and temporal lobes.

Longitudinal assessment of amyloid-beta deposition in initially amyloid-negative non-demented individuals with [11C]-PIB PET imaging.

This study aimed to assess the longitudinal changes in amyloid beta (Aβ) deposition in cortical regions with [11C]-PIB PET in initially amyloid-negative non-demented subjects and evaluate whether amyloid-negative subjects convert to amyloid-positive.Sixteen cognitively normal (CN) and 7 mild cognitive impairment (MCI) subjects (aged 60–75 years), who were amyloid-negative at baseline, underwent 60-minute dynamic [11C]-PIB PET and cognitive assessment over 5.0 to 9.4 years of a long follow-up, and the apolipoprotein-E (APOE) genotype was assessed. Regions of interest were defined in the bilateral cortex on coregistered MRI. Quantitative analysis of [11C]-PIB was performed using the distribution value ratio (DVR). Longitudinal changes in global and regional PIB DVRs were evaluated in the same regions, and the annual rate of change in the PIB DVR was calculated.Seven (30.4%) of 23 initially amyloid-negative non-demented subjects converted to globally amyloid-positive (global PIB DVR ≥1.40) over a follow-up of 6.5 ± 1.4 years (converter). The global PIB DVR in converters increased from 1.22 ± 0.07 at baseline to 1.63 ± 0.15 (n = 7, P < .01) at last follow-up, and an annual increase of global PIB DVR was 0.057 ± 0.019/year (n = 7, P < .01). In contrast, the global PIB DVR in the remaining 16 subjects was 1.15 ± 0.07 at baseline and did not change over a follow-up period (stable). The APOE ε4 allele was present in 4 (57.1%) of the 7 converters, differing from 2 (12.5%) of 16 stable subjects (Fisher's exact test, P < .05). Three amyloid-negative MCI subjects had an annual increase in global PIB DVR above 0.061/year and became positive at 2.8 ± 0.5 years of follow-up, which was faster than 5.0 ± 2.0 years in 4 CN subjects. The regional PIB DVR that increased early above the regional positivity threshold was most frequently found in the right lateral temporal cortex (71.4%), followed by the left frontal cortex (41.8%).Our results suggest that the initially amyloid-negative CN and MCI subjects, especially with APOE ε4, can become globally amyloid-positive over a longer time, based on early regional Aβ deposition in the lateral temporal cortex and/or frontal cortex.

How Well Does Subjective Cognitive Decline Correspond to Objectively Measured Cognitive Decline? Assessment of 10-12 Year Change.

Although not strongly correlated with current objective cognitive ability, subjective cognitive decline (SCD) is a risk factor for Alzheimer's disease. Most studies focus on SCD in relation to future decline rather than objective prior decline that it purportedly measures. We evaluated whether self-report of cognitive decline-as a continuous measure-corresponds to objectively-assessed episodic memory and executive function decline across the same period. 1,170 men completed the Everyday Cognition Questionnaire (ECog) at mean age 68 assessing subjective changes in cognitive ability relative to 10 years prior. A subset had mild cognitive impairment (MCI), but MCI was diagnosed without regard to subjective decline. Participants completed up to 3 objective assessments of memory and executive function (M = 56, 62, and 68 years). Informant-reported ECogs were completed for 1,045 individuals. Analyses controlled for depression and anxiety symptoms assessed at mean age 68. Participant-reported ECog scores were modestly associated with objective decline for memory (β= -0.23, 95%CI [-0.37, -0.10]) and executive function (β= -0.19, 95%CI [-0.33, -0.05]) over the same time period. However, these associations were nonsignificant after excluding MCI cases. Results were similar for informant ratings. Participant-rated ECog scores were more strongly associated with concurrent depression and anxiety symptoms, (β= 0.44, 95%CI [0.36,0.53]). Continuous SCD scores are correlated with prior objective cognitive changes in non-demented individuals, though this association appears driven by individuals with current MCI. However, participants' current depression and anxiety ratings tend to be strongly associated with their SCD ratings. Thus, what primarily drives SCD ratings remains unclear.

Nerve Growth Factor Compromise in Down Syndrome.

The basal forebrain cholinergic system relies on trophic support by nerve growth factor (NGF) to maintain its phenotype and function. In Alzheimer’s disease (AD), basal forebrain cholinergic neurons (BFCNs) undergo progressive atrophy, suggesting a deficit in NGF trophic support. Within the central nervous system, NGF maturation and degradation are tightly regulated by an activity-dependent metabolic cascade. Here, we present a brief overview of the characteristics of Alzheimer’s pathology in Down syndrome (DS) with an emphasis on this NGF metabolic pathway’s disruption during the evolving Alzheimer’s pathology. Such NGF dysmetabolism is well-established in Alzheimer’s brains with advanced pathology and has been observed in mild cognitive impairment (MCI) and non-demented individuals with elevated brain amyloid levels. As individuals with DS inexorably develop AD, we then review findings that support the existence of a similar NGF dysmetabolism in DS coinciding with atrophy of the basal forebrain cholinergic system. Lastly, we discuss the potential of NGF-related biomarkers as indicators of an evolving Alzheimer’s pathology in DS.

Interaction Between APOE Genotype and Diabetes in Longevity.

While both apolipoprotein E (APOE) genotype and diabetes affect longevity as well as Alzheimer's disease, their relationship remains to be elucidated. The current study investigated the potential interaction between diabetes and APOE for lifespan and their relationship with cognitive status. We reviewed the National Alzheimer's Coordinating Center (NACC) dataset, which documents longitudinally clinical records of 24,967 individuals with APOE genotype and diabetic status. Diabetes was associated with shorter lifespan in APOE3 carriers (n = 12,415, HR = 1.29, 95%CI = 1.17-1.42, p < 0.001) and APOE2 carriers (n = 2,390, HR = 1.37, 95%CI = 1.10-1.69, p = 0.016), while such associations were weaker and not significant in APOE4 carriers (n = 9,490, HR = 1.11, 95%CI = 0.99-1.24, p = 0.162). As there is a significant interactive effect of cognitive status and diabetes on lifespan (p < 0.001), we stratified subjects by cognitive status and observed persistent APOE-dependent harmful effects of diabetes in nondemented individuals but not demented individuals. Notably, questionnaire-based activity status, with which we previously observed an association between APOE genotype and longevity, was also significantly affected by diabetes only in non-APOE4 carriers. The effects of diabetes on longevity vary among APOE genotype. These effects are observed in nondemented individuals and are potentially associated with activity status during their lifespan.

Global Cardiovascular Risk Profile and Cerebrovascular Abnormalities in Presymptomatic Individuals with CADASIL or Autosomal Dominant Alzheimer's Disease.

Cardiovascular risk factors increase the risk of developing dementia, including Alzheimer's disease and vascular dementia. Studying individuals with autosomal dominant mutations leading to the early onset of dementia, this study examines the effect of the global cardiovascular risk profile on early cognitive and neuroimaging features of Alzheimer's disease and vascular dementia. We studied 85 non-demented and stroke-free individuals, including 20 subjects with Presenilin1 (PSEN1) E280A mutation leading to the early onset of autosomal dominant Alzheimer's disease (ADAD), 20 subjects with NOTCH3 mutations leading to cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and to the early onset of vascular dementia, and 45 non-affected family members (non-carriers). All subjects underwent clinical and neuropsychological evaluations and an MRI. The global cardiovascular risk profile was estimated using the office-based Framingham Cardiovascular Risk Profile (FCRP) score. In individuals with CADASIL, a higher FCRP score was associated with a reduced hippocampal volume (B = -0.06, p < 0.05) and an increased severity of cerebral microbleeds (B = 0.13, p < 0.001), lacunes (B = 0.30, p < 0.001), and perivascular space enlargement in the basal ganglia (B = 0.50, p < 0.05). There was no significant association between the FCRP score and neuroimaging measures in ADAD or non-carrier subjects. While the FCRP score was related to performance in executive function in non-carrier subjects (B = 0.06, p < 0.05), it was not significantly associated with cognitive performance in individuals with CADASIL or ADAD. Our results suggest that individuals with CADASIL and other forms of vascular cognitive impairment might particularly benefit from early interventions aimed at controlling cardiovascular risks.

Cognitive and brain cytokine profile of non-demented individuals with cerebral amyloid-beta deposition

BackgroundBrain inflammation has been increasingly associated with early amyloid accumulation in Alzheimer’s disease models; however, evidence of its occurrence in humans remains scarce. To elucidate whether amyloid deposition is associated with neuroinflammation and cognitive deficits, we studied brain inflammatory cytokine expression and cognitive decline in non-demented elderly individuals with and without cerebral amyloid-beta deposition.MethodsGlobal cognition, episodic, working, and semantic memory, perceptual speed, visuospatial ability, and longitudinal decline (5.7 ± 3.6 years) in each cognitive domain were compared between elderly individuals (66–79 years) with and without cerebral amyloid-beta deposition. The expression of 20 inflammatory cytokines was analyzed in frozen temporal, parietal, and frontal cortices and compared between older individuals with and without amyloid-beta deposition in each brain region. Correlation analyses were performed to analyze associations between amyloid-beta load, cytokine expression, and cognitive decline.ResultsIndividuals with cortical amyloid-beta deposition displayed deficits and a faster rate of cognitive decline in perceptual speed as compared with those individuals without amyloid-beta. This decline was positively associated with cortical amyloid-beta levels. Elderly individuals with amyloid-beta deposition had higher levels of IL-1β, IL-6, and eotaxin-3 in the temporal cortex accompanied by an increase in MCP-1 and IL-1β in the parietal cortex and a trend towards higher levels of IL-1β and MCP-1 in the frontal cortex as compared with age-matched amyloid-free individuals. Brain IL-1β levels displayed a positive association with cortical amyloid burden in each brain region. Finally, differential cytokine expression in each cortical region was associated with cognitive decline.ConclusionsElderly individuals with amyloid-beta neuropathology but no symptomatic manifestation of dementia, exhibit cognitive decline and increased brain cytokine expression. Such observations suggest that increased cytokine expression might be an early event in the Alzheimer’s continuum.

LATE Neuropathologic Changes with Little or No Alzheimer Disease is Common and is Associated with Cognitive Impairment but Not Frontotemporal Dementia

Limbic-predominant age-related TDP-43 encephalopathy neuropathologic changes (LATE-NC) often occur in aged brains that also contain appreciable Alzheimer disease neuropathologic changes (ADNC). Question has arisen as to whether LATE-NC can occur independently of ADNC. We evaluated data from the University of Kentucky Alzheimer's Disease Research Center autopsy cohort (383 included subjects) to address 2 questions: (i) Is LATE-NC seen in the absence of ADNC, outside of persons who had the frontotemporal dementia (FTD) clinical syndrome? and (ii) is LATE-NC associated with cognitive impairment across the full spectrum of ADNC severity? In the present study, the pathologic combination of LATE-NC (Stage >1) and low/no ADNC was common: 8.9% (34/383) of all subjects (including demented and non-demented individuals) showed this combination. There were no FTLD-TDP cases to be included from the community-based cohort. Across a broad range of ADNC severity, the presence of LATE-NC was associated with impaired cognition but was never associated with a FTD clinical syndrome.

Effects of restriction of activities and social isolation on risk of dementia in the community.

Social isolation and emotional isolation, i.e. loneliness, have been associated with dementia or cognitive decline. In contrast, the relationship of restriction of physical and instrumental activities of daily living to cognitive decline and dementia has been less studied. We examined multiple quality of life (QoL) indicators, including isolation and restriction of activities, utilizing two validated scales in elders without dementia to determine their associations with cognitive decline and incident dementia that were followed longitudinally over 6 years. We comprehensively controlled for other symptom constellations, including depression and anergia. A large multi-ethnic prospective study was conducted in northern Manhattan, NYC. An ethnically diverse sample of 855 non-demented individuals at baseline participated. The following QoL scales were utilized: Restriction, Anergia, Isolation, Loneliness, and Affective Suffering. Both Restriction (HR = 2.22, 95% CI [1.42, 3.47], P < .001) and Isolation (HR = 1.78, 95% CI [1.17, 2.70], P = 0.007) were associated with episodic memory and incident dementia, controlling for age, sex, and education. Loneliness and Affective Suffering (depression) were not associated with these outcomes (P's > .1) with both Restriction and Isolation in the same model for the prediction of dementia, only Restriction remained significant (HR = 1.97, 95% CI [1.24, 3.14], P = 0.004). In cross-lagged panel analyses, Restriction and Isolation had reciprocal influences (P's < .001), indicating that Restriction at the previous time point influenced current Isolation. Importantly, Restriction (but not Isolation) and Selective Reminding total recall memory demonstrated highly significant direct and reciprocal influences over time (P's < .001). Restriction and Isolation were associated with incident dementia. Restriction played a more prominent role in its impact on memory decline. The development of these impairments in QoL, particularly Restriction, may provide warning signs of future cognitive decline and dementia and provide multiple and novel avenues for therapeutic interventions with the goal of delaying the development of cognitive decline and dementia.

Sex Differences in Cortical Morphometry and White Matter Microstructure During Brain Aging and Their Relationships to Cognition.

Changes in brain structure are associated with aging, and accompanied by the gradual deterioration of cognitive functions, which manifests differently in males and females. Here, we quantify the age-related spatial aging patterns of brain gray and white matter structures, their volume reduction rate, their relationships with specific cognitive functions, as well as differences between males and females in a cross-sectional nondementia dataset. We found that both males and females showed extensive age-related decreases in the volumes of most gray matter and white matter regions. Females have larger regions where the volume decreases with age and a greater slope (females: 0.199%, males: 0.183%) of volume decrease in gray matter. For white matter, no significant sex differences were found in age-related regions, and the slope of volume decrease. More significant associations were identified between brain structures and cognition in males during aging than females. This study explored the age-related regional variations in gray matter and white matter, as well as the sex differences in a nondemented elderly population. This study helps to further understand the aging of the brain structure and sex differences in the aging of brain structures and provides new evidence for the aging of nondemented individuals.

Association of plasma P-tau181 with memory decline in non-demented adults.

Alzheimer’s disease is the leading cause of dementia worldwide and is characterized by a long preclinical phase in which amyloid-β and tau accumulate in the absence of cognitive decline. In vivo biomarkers for Alzheimer’s disease are expensive, invasive and inaccessible, yet are critical for accurate disease diagnosis and patient management. Recent ultrasensitive methods to measure plasma phosphorylated tau 181 (p-tau181) display strong correlations with tau positron emission tomography, p-tau181 in CSF, and tau pathology at autopsy. The clinical utility of plasma-based p-tau181 biomarkers is unclear. In a longitudinal multicentre observational study, we assessed 1113 non-demented individuals (509 cognitively unimpaired elderly and 604 individuals with mild cognitive impairment) from the Alzheimer’s Disease Neuroimaging Initiative who underwent neuropsychological assessments and were evaluated for plasma p-tau181. The primary outcome was a memory composite z-score. Mixed-effect models assessed rates of memory decline in relation to baseline plasma p-tau181, and whether plasma p-tau181 significantly predicted memory decline beyond widely available clinical and genetic data (age, sex, years of education, cardiovascular and metabolic conditions, and APOEε4 status). Participants were followed for a median of 4.1 years. Baseline plasma p-tau181 was associated with lower baseline memory (β estimate: −0.49, standard error: 0.06, t-value: −7.97), as well as faster rates of memory decline (β estimate: −0.11, standard error: 0.01, t-value: −7.37). Moreover, the inclusion of plasma p-tau181 resulted in improved prediction of memory decline beyond clinical and genetic data (marginal R2 of 16.7–23%, χ2 = 100.81, P < 0.00001). Elevated baseline plasma p-tau181 was associated with higher rates of clinical progression to mild cognitive impairment (hazard ratio = 1.82, 95% confidence interval: 1.2–2.8) and from mild cognitive impairment to dementia (hazard ratio = 2.06, 95% confidence interval: 1.55–2.74). Our results suggest that in elderly individuals without dementia at baseline, plasma p-tau181 biomarkers were associated with greater memory decline and rates of clinical progression to dementia. Plasma p-tau181 improved prediction of memory decline above a model with currently available clinical and genetic data. While the clinical importance of this improvement in the prediction of memory decline is unknown, these results highlight the potential of plasma p-tau181 as a cost-effective and scalable Alzheimer’s disease biomarker.

Hypohomocysteinemia may increases the risk of dementia and Alzheimer's disease: A nationwide population-based prospective cohort study

Hyperhomocysteinemia has been repeatedly found to increase the risk of dementia. However, the effects of hypohomocysteinemia on the risk of dementia have been barely investigated. If hypohomocysteinemia, like hyperhomocysteinemia, increases the risk of dementia, misuse or overuse of homocysteine-lowing agents such as vitamin supplements may increase the risk of dementia. To investigate whether hypohomocysteinemia, like hyperhomocysteinemia, could increase the risk of dementia and Alzheimer's disease (AD) in a large population-based cohort of older adults. This prospective cohort study followed 2655 randomly sampled, community-dwelling, non-demented individuals aged 60 years or older from 2010 to 2018. We measured baseline serum total homocysteine (tHcy) levels and examined the effect of serum tHcy on the risks of dementia and AD using Cox proportional hazards models. During the follow-up period (mean=5.4 years, SD=0.9), dementia and AD developed in 85 and 64 participants, respectively. Not only the participants with high serum tHcy (≥10.6μmol/L) but also those with low serum tHcy (≤8.9μmol/L) were 4-5 times more likely to develop dementia and AD compared to those with serum tHcy levels between 9.0 and 10.5μmol/L. With the increase in serum tHcy concentration, the use of vitamin supplements decreased, and 41.2% of the participants with low serum tHcy (≤8.9μmol/L) were taking vitamin supplements. Not only hyperhomocysteinemia but also hypohomocysteinemia considerably increased the risk of dementia and AD in older adults. The risk of dementia that results from overuse or misuse of vitamin supplements should be acknowledged and homocysteine-lowering health policies should be tailored to consider dementia risks that are associated with hypohomocysteinemia.

The Effect of CAG Repeats within the Non-Pathological Range in the HTT Gene on Cognitive Functions in Patients with Subjective Cognitive Decline and Mild Cognitive Impairment

The Huntingtin gene (HTT) is within a class of genes containing a key region of CAG repeats. When expanded beyond 39 repeats, Huntington disease (HD) develops. Individuals with less than 35 repeats are not associated with HD. Increasing evidence has suggested that CAG repeats play a role in modulating brain development and brain function. However, very few studies have investigated the effect of CAG repeats in the non-pathological range on cognitive performances in non-demented individuals. In this study, we aimed to test how CAG repeats’ length influences neuropsychological scores in patients with subjective cognitive decline (SCD) and mild cognitive impairment (MCI). We included 75 patients (46 SCD and 29 MCI). All patients underwent an extensive neuropsychological battery and analysis of HTT alleles to quantify the number of CAG repeats. Results: CAG repeat number was positively correlated with scores of tests assessing for executive function, visual–spatial ability, and memory in SCD patients, while in MCI patients, it was inversely correlated with scores of visual–spatial ability and premorbid intelligence. When we performed a multiple regression analysis, we found that these relationships still remained, also when adjusting for possible confounding factors. Interestingly, logarithmic models better described the associations between CAG repeats and neuropsychological scores. CAG repeats in the HTT gene within the non-pathological range influenced neuropsychological performances depending on global cognitive status. The logarithmic model suggested that the positive effect of CAG repeats in SCD patients decreases as the number of repeats grows.

Apathy and executive functioning among non-demented community-dwelling elderly individuals in an everyday environment: the mediating effect of impulsivity.

Apathy is common in normal ageing and widely recognized as a predictor of cognitive decline, especially in executive functions. Much less characterized than apathy in the elderly is impulsivity, which increases with ageing. It is also frequently described in comorbidity with apathy in various clinical populations, in whom it is associated with poorer executive functioning. In the present study, by capitalizing on a multidimensional approach, we explore the mediating role of facets of impulsivity on the bidirectional relationships between apathy dimensions and executive functioning in non-demented community-dwelling elderly individuals in daily life. A sample of non-demented community-dwelling older adults (n= 101) completed self-rated questionnaires. Apathy was measured by the Apathy Evaluation Scale; impulsivity was examined through the Urgency, Premeditation, Perseverance, Sensation Seeking, Positive Urgency (UPPS-P) Impulsive Behaviour Scale; and executive functioning in daily life was assessed by the Behaviour Rating Inventory of Executive Function-Adult (BRIEF-A). Two models positing mediation were tested using conditional process modelling. Hierarchical regressions controlling for depressive symptoms indicated that the cognitive apathy dimension was associated with the UPPS-P facets sensation seeking, lack of perseverance, and premeditation. Among the UPPS-P facets, lack of perseverance and negative urgency were found to contribute significantly to BRIEF-A Metacognitive index variance. Finally, in both models, lack of perseverance was found to totally mediate the relationship between cognitive apathy and the BRIEF-A Metacognitive index. These preliminary findings suggest that, in normal ageing, apathy may share an overlap with impulsivity, contradicting the notion they represent opposite ends of a single behavioural spectrum. Our results argue for bidirectional relationship between a specific apathy dimension (i.e. cognitive apathy) and executive functioning. Moreover, they shed new light on the underlying psychological process implicated (i.e. lack of perseverance) among older adults without dementia and represent an interesting prospect for psychological interventions.

Smartphone-Based Neuropsychological Assessment in Parkinson's Disease: Feasibility, Validity, and Contextually Driven Variability in Cognition.

The prevalence of neurodegenerative disorders demands methods of accessible assessment that reliably captures cognition in daily life contexts. We investigated the feasibility of smartphone cognitive assessment in people with Parkinson's disease (PD), who may have cognitive impairment in addition to motor-related problems that limit attending in-person clinics. We examined how daily-life factors predicted smartphone cognitive performance and examined the convergent validity of smartphone assessment with traditional neuropsychological tests. Twenty-seven nondemented individuals with mild-moderate PD attended one in-lab session and responded to smartphone notifications over 10 days. The smartphone app queried participants 5x/day about their location, mood, alertness, exercise, and medication state and administered mobile games of working memory and executive function. Response rate to prompts was high, demonstrating feasibility of the approach. Between-subject reliability was high on both cognitive games. Within-subject variability was higher for working memory than executive function. Strong convergent validity was seen between traditional tests and smartphone working memory but not executive function, reflecting the latter's ceiling effects. Participants performed better on mobile working memory tasks when at home and after recent exercise. Less self-reported daytime sleepiness and lower PD symptom burden predicted a stronger association between later time of day and higher smartphone test performance. These findings support feasibility and validity of repeat smartphone assessments of cognition and provide preliminary evidence of the effects of context on cognitive variability in PD. Further development of this accessible assessment method could increase sensitivity and specificity regarding daily cognitive dysfunction for PD and other clinical populations.

Analysis of C9orf72 Intermediate Alleles in a Retrospective Cohort of Neurological Patients: Risk Factors for Alzheimer's Disease?

C9orf72 hexanucleotide GGGGCC (G4C2) large repeat expansions within the first intron of the gene are a major cause of familial frontotemporal dementia, but also of apparently sporadic cases. Alleles with > 30 repeats are often considered pathogenic, but the repeat length threshold is still undefined. It is also unclear if C9orf72 intermediate alleles (9-30 repeats) have clinically significant effects. We correlated the presence of C9orf72 intermediate alleles with clinical diagnoses in a perspective cohort referred to a secondary memory clinic. All samples were genotyped with AmplideXPCR/CE C9ORF72 Kit (Asuragen, Inc), an optimized C9orf72 PCR amplification reagent. We showed that in patients with Alzheimer's disease (AD) the frequency of the intermediate repeat alleles was significantly increased versus controls (34/54, 63%AD versus 16/39, 41%CTRLs, *p = 0.01, OR 2.91 CI 95%1.230-6.077), whereas no significant differences (p > 0.05) were observed when comparing all other dementias with non-demented individuals. Our findings suggest that C9orf72 intermediate repeat units may represent a genetic risk factor, contributing to the occurrence of AD. Nevertheless, further longitudinal studies, including larger cohort of subjects with intermediate alleles with long-term follow-up, would be needed to confirm these results.

The Proportion of APOE4 Carriers Among Non-Demented Individuals: A Pooled Analysis of 389,000 Community-Dwellers

The apolipoprotein E epsilon 4 (APOE4) is the strongest genetic risk factor for sporadic Alzheimer's disease (AD). Its carriage percentage in non-demented population varies across geographic regions and ethnic groups. To estimate the proportion of APOE4 (2/4, 3/4, or 4/4) carriers in non-demented community-dwellers. PubMed, EMBASE, and China National Knowledge Infrastructure were searched from inception to April 20, 2020. Community-based studies that reported APOE polymorphisms with a sample of≥500 non-demented participants were included. Random-effects models were used to pool the results. Meta-regression and subgroup analyses were performed to test the source of heterogeneity and stratified effects. Age-standardized pooled proportion estimates (ASPPE) were calculated by direct standardization method. A total of 121 studies were included, with a pooled sample of 389,000 community-dwellers from 38 countries. The global average proportion of APOE4 carriers was 23.9% (age-standardized proportion: 26.3%; 2.1% for APOE4/4, 20.6% for APOE3/4 and 2.3% for APOE2/4), and varied significantly with geographical regions (from 19.3% to 30.0%) and ethnic groups (from 19.1% to 37.5%). The proportion was highest in Africa, followed by Europe, North America, Oceania, and lowest in South America and Asia (p < 0.0001). With respect to ethnicity, it was highest in Africans, followed by Caucasians, and was lowest in Hispanics/Latinos and Chinese (p < 0.0001). APOE4 carriers are common in communities, especially in Africans and Caucasians. Developing precision medicine strategies in this specific high-risk population is highly warranted in the future.

Dementia-associated changes of immune cell composition within the cerebrospinal fluid

Inflammation and alterations in essential protein structures in the brain might also change the cellular distribution in the cerebrospinal fluid (CSF).Using flow cytometry, we analyzed cell populations of the innate and adaptive immune system associated with the most frequent forms of dementias. We included patients with mild cognitive impairment (MCI; N ​= ​33), Alzheimer’s disease (AD; N ​= ​90), vascular dementia (VD; N ​= ​35) and frontotemporal dementia (FTD; N ​= ​17) at the time of diagnosis, before onset of treatment and 11 elderly non-demented individuals. Dependent on the form of dementia, an increased frequency of CD14+ monocytes, NK cells and NKT cells was measured. Within the T cell population, a dementia-associated shift from central memory towards (late-stage) effector cells was detected. T cells and NKT cells were correlated with MMSE, NK and NKT cells were correlated with ptau, CD14+ monocytes and NK cells were correlated with Amyloid-β 1–40.Our data suggest that each investigated immune cell type is involved in dementia-associated alterations within the CSF, possibly having distinct functions in their pathogenesis.