Clinical Dementia Rating Scale Score Research Articles

Assessment of Behavioral and Psychological Symptoms in Dementia, Associated Risk Factors and Clinical Correlates

Background: The presence of behavioral and psychological symptoms in dementia (BPSD) are associated with hospitalization, rapid cognitive decline, poor quality of life and higher caregiver burden. Thus, we aim to characterize the BPSD symptoms, its relationship to dementia-related risk factors and their predictive value, if any.Methodology: In 48 adults (mean age: 70.27 ± 10.08) with major neurocognitive disorder (MNCD) as per diagnostic and statistical manual of mental disorders, 5th edition and with Hindi mental status examination scores less than or equal to 23 were recruited. Patients were assessed for cognition by hindi Montreal cognitive assessment (HMOCA) and the clinical dementia rating scale (CDR). BPSD and caregiver burden were assessed using the neuropsychiatric inventory (NPI) and burden assessment schedule (BAS). The correlation of NPI scores with socio-demographic variables and clinical variables was assessed. A forward stepwise linear regression (using p-value < .05) was used to identify possible predictors of the NPI scores.Results: The majority of participants were predominantly males, 25 (52.1%), from urban regions, belonged to middle-class socio-economic status and had severe grading (HMOCA (< 10) of MNCD (25 (52.2%) but had moderate caregiver burden (25 (52.2%)). The most common MNCD type was due to Alzheimer’s disease (22 (45.8%)). Cortical atrophy and ischemic infarcts were the most common neuroimaging abnormalities reported (7 (14.9%)). Mean HMOCA, clinical dementia rating scale (CDR), NPI and BAS scores were 9.13 ± 6.96, 1.50 ± 1.05, 41.79 ± 27.06 and 68.65 ± 22.84, respectively. The most common BPSD domains were sleep disturbance (60.4%) and hallucinations (56.25%). Among the established risk factors, hypertension was present in the highest proportion (21 (43.8%)). As per the stepwise logistic regression model CDR scores, smoking status and HTN were predicted risk factors (R²: 0.452; p = 0.045).Conclusion: Irritability/agitation is most prevalent BPSD. The severity of MNCD, smoking and hypertension may help in the prediction of BPSD and their role may have to be explored in further studies.

Choroid Plexus Volume, Amyloid Burden, and Cognition in the Alzheimer's Disease Continuum.

As a part of the glymphatic system, the choroid plexus (CP) is involved in the clearance of harmful metabolites from the brain. We investigated the association between CP volume (CPV), amyloid-β (Aβ) burden, and cognition in patients on the Alzheimer's disease (AD) continuum. We retrospectively reviewed the records of 203 patients on the AD continuum and 82 healthy controls who underwent brain magnetic resonance imaging and 18F-florbetaben positron emission tomography. Automatic segmentation was performed, and the CPV was calculated. Cognitive function was assessed using detailed neuropsychological tests, and patients on the AD continuum were categorized into the non-dementia and dementia groups. The relationships between CPV, Aβ burden, and cognitive function were assessed using multivariate linear regression and linear mixed model. CPV was greater in the AD group than in the healthy control group (1.50 vs. 1.30, P < 0.001), but was comparable between the AD non-dementia and dementia groups (1.50 vs. 1.48, P = 0.585). After adjusting for age and sex, a larger CPV was significantly associated with greater global Aβ deposition (β = 0.20, P = 0.002). Larger CPV was also associated with worse general cognitive function assessed using the sum of boxes of the clinical dementia rating scale (β = 0.85, P = 0.034) and lower composite scores for memory (β = -0.68, P = 0.002) and frontal/executive function domains (β = -0.65, P < 0.001). In addition, a larger CPV was associated with a more rapid decline in Mini-Mental State Examination scores in the AD dementia group (β = -0.58, P = 0.004). The present study demonstrated that CP enlargement was associated with increased Aβ deposition and impaired memory and frontal/executive function in patients on the AD continuum.

Facial emotion recognition is associated with executive functions and depression scores, but not staging of dementia, in mild-to-moderate Alzheimer's disease.

Although deficits in facial emotion recognition (FER) significantly affect interpersonal communication and social functioning, there is no consensus on how FER affects Alzheimer's disease (AD). In this study, we aimed to investigate the clinical and neuropsychological factors affecting the possible deficits in the FER abilities of patients with AD. This cross-sectional study included 37 patients with mild [clinical dementia rating (CDR) scale score=1] or moderate (CDR=2) AD, in whom vascular dementia and depression were excluded, and 24 cognitively normal (CDR=0) subjects. FER ability was determined using the facial emotion identification test (FEIT) and facial emotion discrimination test (FEDT). All participants underwent mini-mental state examination (MMSE), frontal assessment battery (FAB), and geriatric depression scale (GDS). The neuropsychiatric inventory-clinician rating scale (NPI-C), Katz index of independence in activities of daily living, and Lawton instrumental activities of daily living were also administered to patients with AD. The FEIT and FEDT total scores showed that patients with mild and moderate AD had significant FER deficits compared to healthy controls. However, no significant difference was observed between patients with mild and moderate AD in the FEIT and FEDT total scores. FEIT and FEDT scores were not correlated with the MMSE and NPI-C total and subscales scores in patients with AD. Linear regression indicated that FEIT and FEDT total scores were significantly related to age and FAB scores. The GDS score negatively moderated the relationship between FAB and FEDT. This study demonstrated a decreased FER ability in patients with AD. The critical point in FER deficits is the presence of dementia, not the dementia stage, in AD. It has been determined that executive functions and depression (even at a subsyndromal level), which have limited knowledge, are associated with FER abilities.

The relationship of intraindividual variability on mobile cognitive testing with age and frontotemporal dementia disease severity

AbstractBackgroundThere has been a rise in remote cognitive testing for neurodegenerative diseases. The ALLFTD Mobile App is designed to capture clinical features of frontotemporal dementia (FTD) through repeated remote assessment on smartphones. This is a departure from traditional neuropsychological practice in which a single examiner‐led assessment occurs in a controlled setting. When participants complete tasks on their own, those with greater disease severity may be more variable in their performance for a variety of reasons (e.g. greater distractibility, less engagement). Here we study whether intraindividual cognitive variability (IIV) is associated with older age and increasing disease severity.MethodParticipants were 279 (mean age = 54.9) healthy controls and participants with sporadic FTD or from familial FTD kindreds with a range of disease severities based on FTLD Clinical Dementia Rating scale (CDR®+NACC‐FTLD Global) scores: 0 (n = 132), 0.5 (n = 54), and ≥1 (n = 47). Participants completed three cognitive tasks at least two times across twelve days. Measures included an adaptive memory task and gamified versions of Flanker and Go/no‐go tasks. IIV was operationalized as the standard deviation in performance on each task. Regression analyses investigated the relationship of IIV with CDR®+NACC‐FTLD group, and with age in those without symptoms. Education and gender were included as covariates in all analyses.ResultGreater disease severity (CDR®+NACC‐FTLD) was associated with greater variability on Flanker (p&lt;.001) and Go/No‐go (p = .02) tasks; a positive but non‐significant association was seen with memory testing (p = .16). Post‐hoc comparisons found that those with CDR®+NACC‐FTLD of 0.5 had significantly more IIV on the Flanker task (𝛃 = .39, p = .004) than those with CDR®+NACC‐FTLD’s of 0. Moreover, those with a CDR®+NACC‐FTLD ≥1 had significantly greater IIV on the Flanker (𝛃 = .85, p&lt;.001) and Go/No‐go tasks (𝛃 = .51, p = .007) than those with a CDR®+NACC‐FTLD of 0. In those without symptoms (CDR®+NACC‐FTLD = 0), age was associated with increased IIV on the Flanker (𝛃 = .27, p&lt;.001) and Go/no‐go (𝛃 = .23, p&lt;.001) tasks.ConclusionIncreased IIV, particularly on processing speed/executive functioning tasks, was associated with greater age and greater functional impairment, even in the mildest stages. Future investigations exploring predictors of IIV and the prognostic value of IIV are warranted.

Urban‐rural differences in the prevalence of Subjective Cognitive Decline in India: A comparative study

AbstractBackgroundSubjective Cognitive Decline (SCD), defined as a self‐experienced persistent cognitive decline with a normal performance in objective neuropsychological assessments is one of the first clinical manifestations of dementia. SCD has a strong association with depression, and more research is needed to understand the relationship between the two. When they co‐occur the risk of developing dementia increases. Despite the increased focus on the preclinical stages of dementia such as SCD there is limited research on its prevalence specifically in India. The present study aims to bridge this research gap by estimating the prevalence of SCD in India and assessing urban‐rural differences in its prevalence as well as sociodemographic factors.MethodThe study used data from two ongoing community‐based prospective cohort studies, namely the Tata Longitudinal Study of Ageing (TLSA) and Srinivaspura Aging, Neuro Senescence and COGnition (SANSCOG) in urban Bangalore and Srinivaspura respectively (Sundarakumar et al., 2020). Baseline data collected from 4429 participants aged 45 years and older were included in the analysis. The study used Clinical Dementia Rating Scale (CDR) scores and participants' responses to the questions pertaining to subjective cognitive impairment in Cognitive Function Instrument (CFI) and Geriatric Depression Scale (GDS) to estimate the prevalence of SCD.ResultOf 4429 participants recruited between 2015 and 2022, a total of 1010 (22.8%) participants [median (IQR) age, 60 (15)] were classified as having SCD. As shown in Tabe1, the prevalence was higher in the rural cohort than in the urban cohort (25.1% vs 14.0%, p&lt;0.001). The rural cohort was also found to be comparatively younger (57 (15) vs 63 (14)), and have fewer years of education (4 (9) vs 15(2)). Depression was found to have significant association with SCD in both the cohorts, with more depressive symptoms observed in the rural cohort. As shown in Table 2, the prevalence of SCD was higher in women than men in the urban cohort.ConclusionThe study’s findings indicate that despite being comparatively younger, the rural cohort had a higher prevalence of SCD, potentially due to the protective effect of higher years of education in the urban cohort.

Prediction of Mild Cognitive Impairment Progression to Alzheimer’s Disease Based on Diffusion Tensor Imaging-Derived Diffusion Parameters: Construction and Validation of a Nomogram

Introduction: The aim of the study was to construct and validate a nomogram that combines diffusion tensor imaging (DTI) parameters and clinically relevant features for predicting the progression of mild cognitive impairment (MCI) to Alzheimer’s disease (AD). Method: A retrospective analysis was conducted on the MRI and clinical data of 121 MCI patients, of whom 32 progressed to AD during a 4-year follow-up period. The MCI patients were divided into training and validation sets at a ratio of 7:3. DTI features were extracted from MCI patient data in the training set, and their dimensionality was reduced to construct a radiomics signature (RS). Then, combining the RS with independent predictors of MCI disease progression, a joint model was constructed, and a nomogram was generated. Finally, the area under the receiver operating characteristic curve (AUC) and decision curve analysis (DCA) were used to evaluate the diagnostic and clinical efficacy of the nomogram based on the data from the validation set. Result: The AUCs of the RS in the training and validation sets were 0.81 and 0.84, with sensitivities of 0.87 and 0.78 and specificities of 0.71 and 0.81, respectively. Multiple logistic regression analysis showed that the RS, clinical dementia rating scale score, and Alzheimer's disease assessment scale score were the independent predictors of progression and were thus used to construct the nomogram. The AUCs of the nomogram in the training and validation sets were 0.89 and 0.91, respectively, with sensitivities of 0.78 and 0.89 and specificities of 0.90 and 0.88, respectively. DCA showed that the nomogram was the most valuable model for predicting the progression of MCI to AD and that it provided greater net benefits than other analysed models. Conclusion: Changes in white matter fibre bundles can serve as predictive imaging markers for MCI disease progression, and the combination of white matter DTI features and relevant clinical features can be used to construct a nomogram with important predictive value for MCI disease progression.

61 The Impact of Cognitive Reserve on Executive Function in Dementia

Objective:Cognitive reserve (CR) refers to how flexibly and efficiently the individual makes use of available brain resources. Early-life education, midlife social and occupational activities, and later-life cognitive and social interactions are associated with greater CR. Years of education, premorbid intellectual (IQ) functioning, linguistic ability, and occupational complexity are often used as proxies of CR. CR theory seeks to explain discrepancies between the extent of disease pathology and clinical presentation amongst individuals with dementia. In the presence of Alzheimer’s Disease (AD) pathology, higher CR is associated with slower declines in executive functioning (EF). The current study examined the correlation between CR and EF performance across various stages of dementia severity as measured by the total score on the Clinical Dementia Rating Scale (CDRS).Participants and Methods:The study cohort consisted of 269 individuals who had completed measures of EF and the CDRS from phase 1 of the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Individuals who scored less than 2 on the CDRS were included in the MCI group (n=197), while individuals that scored 2 or higher on the CDRS were included in the dementia group (n=73). A simple linear regression was utilized to compare the MCI group to dementia group across CR and EF performance.Results:There was significant correlation between CR and EF performance in the MCI group as quantified on total CDRS score (F (200) = .353, p = .0, p &lt; .05). CR was not observed to be predictive of EF in the dementia group (F (200) = .031, p = .666, p &gt; .05).Conclusions:Findings are consistent with prior research suggesting CR is protective during early stages of dementia, but not in the later disease stages. As prior research has shown the expression of dementia is based on a complex interaction between genetic and lifestyle factors that are unique to each person, future research exploring the potentially protective role of CR amongst pre-symptomatic adults with a genetic predisposition for developing dementia may expand our understanding of the potential role of CR on dementia prevention and progression.

Donanemab in Early Symptomatic Alzheimer Disease

There are limited efficacious treatments for Alzheimer disease. To assess efficacy and adverse events of donanemab, an antibody designed to clear brain amyloid plaque. Multicenter (277 medical research centers/hospitals in 8 countries), randomized, double-blind, placebo-controlled, 18-month phase 3 trial that enrolled 1736 participants with early symptomatic Alzheimer disease (mild cognitive impairment/mild dementia) with amyloid and low/medium or high tau pathology based on positron emission tomography imaging from June 2020 to November 2021 (last patient visit for primary outcome in April 2023). Participants were randomized in a 1:1 ratio to receive donanemab (n = 860) or placebo (n = 876) intravenously every 4 weeks for 72 weeks. Participants in the donanemab group were switched to receive placebo in a blinded manner if dose completion criteria were met. The primary outcome was change in integrated Alzheimer Disease Rating Scale (iADRS) score from baseline to 76 weeks (range, 0-144; lower scores indicate greater impairment). There were 24 gated outcomes (primary, secondary, and exploratory), including the secondary outcome of change in the sum of boxes of the Clinical Dementia Rating Scale (CDR-SB) score (range, 0-18; higher scores indicate greater impairment). Statistical testing allocated α of .04 to testing low/medium tau population outcomes, with the remainder (.01) for combined population outcomes. Among 1736 randomized participants (mean age, 73.0 years; 996 [57.4%] women; 1182 [68.1%] with low/medium tau pathology and 552 [31.8%] with high tau pathology), 1320 (76%) completed the trial. Of the 24 gated outcomes, 23 were statistically significant. The least-squares mean (LSM) change in iADRS score at 76 weeks was -6.02 (95% CI, -7.01 to -5.03) in the donanemab group and -9.27 (95% CI, -10.23 to -8.31) in the placebo group (difference, 3.25 [95% CI, 1.88-4.62]; P < .001) in the low/medium tau population and -10.2 (95% CI, -11.22 to -9.16) with donanemab and -13.1 (95% CI, -14.10 to -12.13) with placebo (difference, 2.92 [95% CI, 1.51-4.33]; P < .001) in the combined population. LSM change in CDR-SB score at 76 weeks was 1.20 (95% CI, 1.00-1.41) with donanemab and 1.88 (95% CI, 1.68-2.08) with placebo (difference, -0.67 [95% CI, -0.95 to -0.40]; P < .001) in the low/medium tau population and 1.72 (95% CI, 1.53-1.91) with donanemab and 2.42 (95% CI, 2.24-2.60) with placebo (difference, -0.7 [95% CI, -0.95 to -0.45]; P < .001) in the combined population. Amyloid-related imaging abnormalities of edema or effusion occurred in 205 participants (24.0%; 52 symptomatic) in the donanemab group and 18 (2.1%; 0 symptomatic during study) in the placebo group and infusion-related reactions occurred in 74 participants (8.7%) with donanemab and 4 (0.5%) with placebo. Three deaths in the donanemab group and 1 in the placebo group were considered treatment related. Among participants with early symptomatic Alzheimer disease and amyloid and tau pathology, donanemab significantly slowed clinical progression at 76 weeks in those with low/medium tau and in the combined low/medium and high tau pathology population. ClinicalTrials.gov Identifier: NCT04437511.

Distinct and shared neuropsychiatric phenotypes in FTLD-tauopathies.

Frontotemporal lobar degeneration (FTLD) with tau pathology (FTLD-tau) commonly causes dementia syndromes that include primary progressive aphasia (PPA) and behavioral variant frontotemporal dementia (bvFTD). Cognitive decline in PPA and bvFTD is often accompanied by debilitating neuropsychiatric symptoms. In 44 participants with PPA or bvFTD due to autopsy-confirmed FTLD-tau, we characterized neuropsychiatric symptoms at early and late disease stages and determined whether the presence of certain symptoms predicted a specific underlying FTLD-tauopathy. Participants completed annual research visits at the Northwestern University Alzheimer's Disease Research Center. All participants had an initial Global Clinical Dementia Rating (CDR) Scale score ≤ 2, and neuropsychiatric symptoms were evaluated via the Neuropsychiatric Inventory-Questionnaire (NPI-Q). We assessed the frequency of neuropsychiatric symptoms across all participants at their initial and final visits and performed logistic regression to determine whether symptoms predicted a specific FTLD-tau pathologic diagnosis. Across the FTLD-tau cohort, irritability and apathy were most frequently endorsed at initial and final visits, respectively, whereas psychosis was highly uncommon at both timepoints. Irritability at initial visit predicted greater odds of a 4-repeat compared to a 3-repeat tauopathy (OR = 3.95, 95% CI = 1.10-15.83, p < 0.05). Initial sleep disturbance predicted greater odds of progressive supranuclear palsy (PSP) compared to other FTLD-tau subtypes (OR = 10.68, 95% CI = 2.05-72.40, p < 0.01). Appetite disturbance at final evaluation predicted lower odds of PSP (OR = 0.15, 95% CI = 0.02-0.74, p < 0.05). Our findings suggest that characterization of neuropsychiatric symptoms can aid in the prediction of underlying FTLD-tauopathies. Given considerable pathologic heterogeneity underlying dementias, neuropsychiatric symptoms may be useful for differential diagnosis and treatment planning.

Progression of white matter signal abnormalities in predementia frontotemporal dementia mutation carriers

AbstractBackgroundWhite matter signal abnormalities (WMSA) are frequently observed on magnetic resonance imaging (MRI) scans of people with frontotemporal dementia (FTD). We hypothesized that carriers of mutations in progranulin (GRN+), chromosome 9 open reading frame 72 (C9orf72+) and microtubule associated protein tau (MAPT+) have increased rates of progression of WMSA compared to non‐carrier individuals prior to onset of dementia, and that different mutations may have different rates of WMSA accumulation.MethodParticipants were recruited through the ARTFL‐LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) Study. We selected participants with Clinical Dementia Rating scale (CDR) scores of 0 and 0.5. If a participant developed FTD during the follow‐up, we only analyzed observations collected before the conversion. WMSA were defined as hyperintensities on FLAIR MRI. Total WMSA volumes were normalized to the respective intracranial volumes. We used a linear mixed effects model, with random intercepts and slopes, to compare the baseline burden and the longitudinal progression of total WMSA volumes between mutation carriers and controls. The model was adjusted for baseline age, sex, education, baseline Montreal Cognitive Assessment (MoCA) scores, and MRI acquisition sites.ResultWe analyzed MRI data from 199 participants who had at least two MRI visits (46 C9orf72+, 17 GRN+, 35 MAPT+, 101 non‐carrier controls; up to five years of follow‐up). We did not find significant group differences in baseline demographic features, except that MAPT+ was younger than non‐carrier controls (average age: C9orf72+ = 47, GRN+ = 56, MAPT+ = 40, controls = 47). Baseline WMSA volumes were not significantly different between mutation carriers and controls. Longitudinally, the rates of WMSA volume increase in C9orf72+ and MAPT+ were comparable to controls; whereas, GRN+ had higher rates of WMSA volume increases compared to controls (p = 0.01).ConclusionWMSA may accumulate at higher rates in GRN+ prior to the onset of FTD, which is consistent with the frequent presence of white matter diseases observed in symptomatic FTD patients with GRN mutations. Future work is warranted to investigate the association between white matter structural changes and cognitive/psychiatric changes in FTD mutation carriers.

Projection of Care Partners’ Preferences in the Proxy Assessments of Everyday Preferences for Persons With Cognitive Impairment

Bias in surrogate decision-making can occur when proxy decision-makers overestimate the degree to which their preferences are shared by others, resulting in a projection of their beliefs onto others. The purpose of this study is to assess projection of care partners' preferences onto surrogate assessments of everyday preferences for persons with cognitive impairment (CI) and to address clinical and demographic factors as predictors of projection. The sample included 116 dyads of persons with CI (Clinical Dementia Rating Scale score ≥ 0.5) and their care partners. The Preferences for Everyday Living Inventory (PELI) was used to assess importance of preferences among persons with CI. Care partners completed two separate PELI assessments: one from the perspective of the persons with CI (i.e., acting as a surrogate decision-maker) and one from their own perspective. To assess for projection of care partners' preferences onto surrogate assessments of preferences for persons with CI, two-step regression with multivariable-adjusted general linear models was used. Significant projection was noted within the PELI domains of autonomous choice, personal growth, and keeping a routine (p < 0.005). More significant cognitive impairment was associated with increased projection within the PELI domains of autonomous choice and personal growth (p < 0.05). The results of this study suggest that projection of care partners' own preferences may be a significant source of bias in proxy decision-making regarding everyday preferences for persons with CI, particularly for those with more significant CI.

Projection in Proxy Assessments of Everyday Preferences for Persons with Cognitive Impairment

AbstractBackgroundA source of bias in surrogate decision‐making has been articulated alternatively as the false consensus effect, assumed similarity, and attributive/social projection by which proxies overestimate the degree that their values and preferences are shared by others, resulting in a projection of their own beliefs onto others in the process of surrogate decision‐making. The aims of this study are to assess for projection of proxies’ preferences onto surrogate assessments of everyday preferences for persons with cognitive impairment (CI) and to address cognitive and neuropsychiatric symptom burden as predictors of projection.MethodThe sample included 116 dyads of persons with CI (Clinical Dementia Rating Scale score ≥ 0.5) and their care partners. The Preferences for Everyday Living Inventory (PELI) was used to assess importance of preferences among persons with CI. Care partners completed two separate PELI assessments: one from the perspective of the persons with CI (i.e., acting as a surrogate decision‐maker) and one from their own perspective. To assess for projection of care partners’ preferences onto surrogate assessments of preferences for persons with CI, two‐step regression with multivariable‐adjusted general linear models was used.ResultSignificant projection effects were noted within the PELI domains of autonomous choice, personal growth, and keeping a routine (p &lt; 0.0005). More significant cognitive impairment was associated with increased projection effects within the PELI domains of autonomous choice and personal growth (p &lt; 0.01)ConclusionThe results of this study suggest that projection effects of care partners own preferences may be a significant source of bias in everyday proxy decision‐making for persons with CI, particularly for those with more significant CI.

Progression of white matter signal abnormalities in predementia frontotemporal dementia mutation carriers

AbstractBackgroundWhite matter signal abnormalities (WMSA) are frequently observed on magnetic resonance imaging (MRI) scans of people with frontotemporal dementia (FTD). We hypothesized that carriers of mutations in progranulin (GRN+), chromosome 9 open reading frame 72 (C9orf72+) and microtubule associated protein tau (MAPT+) have increased rates of progression of WMSA compared to non‐carrier individuals prior to onset of dementia, and that different mutations may have different rates of WMSA accumulation.MethodParticipants were recruited through the ARTFL‐LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) Study. We selected participants with Clinical Dementia Rating scale (CDR) scores of 0 and 0.5. If a participant developed FTD during the follow‐up, we only analyzed observations collected before the conversion. WMSA were defined as hyperintensities on FLAIR MRI. Total WMSA volumes were normalized to the respective intracranial volumes. We used a linear mixed effects model, with random intercepts and slopes, to compare the baseline burden and the longitudinal progression of total WMSA volumes between mutation carriers and controls. The model was adjusted for baseline age, sex, education, baseline Montreal Cognitive Assessment (MoCA) scores, and MRI acquisition sites.ResultWe analyzed MRI data from 199 participants who had at least two MRI visits (46 C9orf72+, 17 GRN+, 35 MAPT+, 101 non‐carrier controls; up to five years of follow‐up). We did not find significant group differences in baseline demographic features, except that MAPT+ was younger than non‐carrier controls (average age: C9orf72+=47, GRN+=56, MAPT+=40, controls=47). Baseline WMSA volumes were not significantly different between mutation carriers and controls. Longitudinally, the rates of WMSA volume increase in C9orf72+ and MAPT+ were comparable to controls; whereas, GRN+ had higher rates of WMSA volume increases compared to controls (p=0.01).ConclusionWMSA may accumulate at higher rates in GRN+ prior to the onset of FTD, which is consistent with the frequent presence of white matter diseases observed in symptomatic FTD patients with GRN mutations. Future work is warranted to investigate the association between white matter structural changes and cognitive/psychiatric changes in FTD mutation carriers.

Differentiation of patients with mild cognitive impairment and healthy controls based on computer assisted hand movement analysis: a proof-of-concept study

Mild cognitive impairment (MCI) is the prodromal phase of dementia, and it is highly underdiagnosed in the community. We aimed to develop an automated, rapid (< 5 min), electronic screening tool for the recognition of MCI based on hand movement analysis. Sixty-eight individuals participated in our study, 46 healthy controls and 22 patients with clinically defined MCI. All participants underwent a detailed medical assessment including neuropsychology and brain MRI. Significant differences were found between controls and MCI groups in mouse movement characteristics. Patients showed higher level of entropy for both the left (F = 5.24; p = 0.001) and the right hand (F = 8.46; p < 0.001). Longer time was required in MCI to perform the fine motor task (p < 0.005). Furthermore, we also found significant correlations between mouse movement parameters and neuropsychological test scores. Correlation was the strongest between motor parameters and Clinical Dementia Rating scale (CDR) score (average r: − 0.36, all p’s < 0.001). Importantly, motor parameters were not influenced by age, gender, or anxiety effect (all p’s > 0.05). Our study draws attention to the utility of hand movement analysis, especially to the estimation of entropy in the early recognition of MCI. It also suggests that our system might provide a promising tool for the cognitive screening of large populations.

Randomized, sham-controlled, clinical trial of repetitive transcranial magnetic stimulation for patients with Alzheimer's dementia in Japan.

BackgroundSeveral medications have been applied to Alzheimer’s dementia patients (AD) but their efficacies have been insufficient. The efficacy and safety of 4 weeks of repetitive transcranial magnetic stimulation (rTMS) in Japanese AD were evaluated in this exploratory clinical trial.MethodsForty-two patients, aged 60–93 years (average, 76.4 years), who were taking medication (> 6 months) and had Mini-Mental State Examination (MMSE) scores ≤ 25 and Clinical Dementia Rating Scale scores (CDR-J) of 1 or 2, were enrolled in this single-center, prospective, randomized, three-arm study [i.e., 120% resting motor threshold (120% RMT), 90% RMT for the bilateral dorsolateral prefrontal cortex, and Sham]. Alzheimer’s Disease Assessment Scale-Japanese Cognitive (ADAS-J cog), Montreal Cognitive Assessment (MoCA-J), Clinical Global Impression of Change (CGIC), Neuropsychiatric inventory (NPI), and EuroQOL 5 Dimensions 5-Level (EQ-5D-5L) were administered. The primary endpoint was the mean change from baseline in the MMSE score (week 4). An active rTMS session involved applying 15 trains bilaterally (40 pulses/train at 10 Hz; intertrain interval, 26 s). Participants received ≥ 8 interventions within the first 2 weeks and at least one intervention weekly in the 3rd and 4th weeks. Full Analysis set (FAS) included 40 patients [120% RMT (n = 15), 90% RMT (n = 13), and Sham (n = 12)].ResultsIn the FAS, MMSE, ADAS-J cog, MoCA-J, CDR-J, CGIC, NPI, and EQ-5D-5L scores between the three groups were not significantly different. Two patients were erroneously switched between the 120% RMT and 90% RMT groups, therefore, “as treated” patients were mainly analyzed. Post hoc analysis revealed significant treatment efficacy in participants with MMSE scores ≥ 15, favoring the 120% RMT group over the Sham group. Responder analysis revealed 41.7% of the 120% RMT group had a ≥ 3-point improvement in the ADAS-J cog versus 0% in the Sham group (Fisher’s exact test, p = 0.045). The MoCA-J showed the same tendency but was not significant. Efficacy disappeared in week 20, based on the ADAS-cog and MoCA-J. No intervention-related serious adverse events occurred.ConclusionThis paper is the first report of using rTMS in Japanese AD patients. The treatment seems safe and moderate-mild stage AD should be target population of pivotal clinical trial with 120% RMT rTMS.

Expression relationship and significance of NEAT1 and miR-27a-3p in serum and cerebrospinal fluid of patients with Alzheimer’s disease

ObjectiveTo explore the expression relationship and significance of long chain non-coding RNA nuclear-enriched abundant transcript 1 (LncRNA NEAT1) and miR-27a-3p in serum and cerebrospinal fluid of patients with Alzheimer’s disease (AD).MethodsSixty-six AD patients received by the Department of Neurology of our hospital from October 2019 to September 2021 were gathered, according to the Clinical Dementia Rating Scale (CDR) score, they were grouped into mild group (≤1 point, n = 41) and moderate-to-severe group (> 1 point, n = 25). Another 32 cases of serum and cerebrospinal fluid samples from outpatient physical examination personnel were regarded as the control group. The general materials on all subjects was recorded and cognition was assessed;real-time quantitative PCR was performed to measure the expression levels of miR-27a-3p and NEAT1 in serum and cerebrospinal fluid;enzyme-linked immunosorbent assay was performed to measure the protein levels of β-amyloid precursor protein cleaving enzyme 1 (BACE1), β-amyloid (Aβ) 40 and Aβ42 in cerebrospinal fluid;Spearman’s method was performed to analyze the correlation of serum miR-27a-3p and NEAT1 levels with MMSE and MoCA scores;Pearson method was performed to analyze the correlation between serum miR-27a-3p and NEAT1 levels and Aβ deposition standard uptake value ratio (SUVR) and cerebrospinal fluid miR-27a-3p, NEAT1, BACE1, Aβ42 and Aβ40 levels.ResultsThe MMSE score, MoCA score, serum miR-27a-3p level, cerebrospinal fluid miR-27a-3p, Aβ42 levels and Aβ42/Aβ40 ratio of AD patients in mild group and moderate-to-severe group were all lower than those in the control group, and the moderate-to-severe group were lower than the mild group (all P < 0.05);the serum NEAT1 level, SUVR, and cerebrospinal fluid NEAT1 and BACE1 levels were higher than those in the control group, and the moderate-to-severe group were higher than the mild group (all P < 0.05). Serum NEAT1 level in AD patients was positively correlated with SUVR, cerebrospinal fluid NEAT1 and BACE1 (r = 0.350, 0.606, 0.341, all P < 0.05);serum miR-27a-3p level was positively correlated with cerebrospinal fluid miR-27a-3p level (r = 0.695, P < 0.05), and negatively correlated with SUVR and cerebrospinal fluid BACE1 level (r = − 0.521, − 0.447, both P < 0.05).ConclusionsThe expression trends of NEAT1 and miR-27a-3p in the serum and cerebrospinal fluid of AD patients are consistent, the level of NEAT1 is increased, and the level of miR-27a-3p is decreased. The levels of the two are negatively correlated, which is related to the degree of Aβ deposition in the brain of AD patients and is involved in the progression of AD.

Effect of a combination of donepezil tablets and butylphthalide soft capsules on neurological function in dementia patients, and its effect on serum inflammatory factors

Purpose: To determine the effect of combined use of donepezil tablets and butylphthalide soft capsules in the treatment of patients with vascular dementia, and its effect on serum inflammatory factor levels and neurological functional recovery of patients.Methods: 120 patients with vascular dementia were selected and assigned to group A (n = 60) and group B (n = 60). All patients were treated with donepezil tablets, while patients in group A were, in addition, treated with butylphthalide soft capsules. Mini mental state examination (MMSE) scores, clinical dementia rating scale (CDRS) scores, activities of daily living (ADL) scores, incidence of adverse reactions, serum inflammatory factor levels and neurological functional recovery were determined.Results: There was significantly higher MMSE score in group A than in B, while CDRS score was lower in group A. The ADL scores and inflammatory factor levels were lower in group A than in B (p &lt; 0.001), while neurological functional recovery was markedly better in A (p &lt; 0.001). Incidents of unwanted events were comparable in groups A and B, and there were no serious complications in the patients.Conclusion: The combination therapy of donepezil tablets and butylphthalide soft capsules reduces inflammatory factor levels and improved cognitive level and quality of life of patients with vascular dementia. It also produces good neurological functional recovery and low incidence of adverse reactions. Therefore, this treatment strategy has potentials for the management of vascular dementia.

Longitudinal changes in neuropsychiatric symptoms: Impact of discrepancy in everyday preferences between people with cognitive impairment and their care partners

AbstractBackgroundNeuropsychiatric symptoms (NPS) of major neurocognitive disorders are common and debilitating facets of the illness process. Yet, little is known about the impact on NPS of discrepancy in the importance of everyday preferences between persons with cognitive impairment (CI) and proxy ratings by their care partners.MethodThe sample included 48 dyads of persons with CI (Clinical Dementia Rating Scale score ≥ 0.5) and their care partners. NPS of the person with CI were measured using the Neuropsychiatric Inventory brief Questionnaire (NPI‐Q) and 15‐item Geriatric Depression Scale (GDS‐15) at baseline and follow‐up (mean 486 days). The Preferences for Everyday Living Inventory was used to assess importance of preferences for persons with CI at baseline; care partners separately completed concurrent proxy assessments at baseline. Mixed random and fixed effects longitudinal models were used to evaluate the impact of baseline discrepancy in everyday preferences assessment between persons with CI and their car partners on changes in NPS across time.ResultHigher levels of underestimation of the importance of “social engagement” preferences in the proxy ratings of care partners relative to the self‐ratings of persons with CI were associated with a higher degree of neuropsychiatric symptoms across time as a whole as measured by the NPI‐Q but not the GDS‐15.ConclusionThis study yields new insights into the relationship between discrepant importance ratings of “social engagement” preferences and neuropsychiatric manifestations of neurocognitive disorders, suggesting that a baseline level of discrepancy is associated with changes in neuropsychiatric symptoms over time. Resolving such discrepancies may then offer a therapeutic avenue to lessen NPS over time for persons with CI.

Associations between sleep and Alzheimer’s disease biomarkers within the EPAD cohort

AbstractBackgroundChanges in sleep quality are common in Alzheimer’s Disease (AD) and may even play a role in the onset and accumulation of disease. However, in preclinical stages, it is unclear whether sleep quality or sleep disturbance relate to disease pathology after controlling for known covariates and AD risk factors. This study aimed to determine if self‐reported sleep quality is associated with AD biomarkers after accounting for such factors.MethodData were obtained from the European Prevention of Alzheimer’s Disease (EPAD) Longitudinal Cohort Study (LCS) data set (v1500.0). Cerebrospinal fluid (CSF) samples were collected for measurement of b‐amyloid (Ab42) and phosphorylated tau (p‐tau). Self‐reported sleep quality was assessed by the Pittsburgh Sleep Quality Index (PSQI). Participants with Clinical Dementia Rating (CDR) scale scores greater than 0.5, indicative of dementia, were excluded. Linear regression models were used to determine whether the p‐tau/Ab42 ratio was associated with PSQI component scores when controlling for multiple potential confounders such as demographics, ApoE4 status, depressive symptoms, body mass index, vascular risks, smoking status, use of psychotropics, white matter lesions, and hippocampal volume. PSQI component scores of 2 or 3 were combined due to small numbers of participants with component scores of 3.ResultFrom the 1500 participants in the EPAD‐LCS v1500.0 data, a total of 1239 participants were included in the regression analysis (mean age=65.30 years, SD=7.11; mean PSQI total score=5.31, SD=3.38). After adjustment for all covariates, higher p‐tau/Ab42 ratio was found to be associated with longer self‐reported sleep latency (component score of 1: b=0.16, p=0.007; component score of 2/3: b=0.12, p=0.134; R2=0.22) and better self‐reported sleep efficiency (component score of 1: b=‐0.22, p=0.04; component score of 2/3: b=‐0.31, p=0.009; R2=0.22)ConclusionWithin the EPAD cohort, longer sleep latency and greater efficiency are associated with greater AD pathology after controlling for covariates. These findings contribute to growing evidence suggesting sleep is an important early marker of underlying neurodegeneration. Longitudinal assessment of EPAD‐LCS participants will allow for the evaluation of self‐reported sleep as a predictive marker of neurodegeneration.

Evaluating changes in gait and activity associated with cognitive impairment using a home‐based technology platform

AbstractBackgroundChanges in mobility are associated with cognitive decline in older adults. Mobility is frequently assessed in the clinic setting at episodic intervals. Passive sensors within a home‐based technology platform allow for unobtrusive collection of mobility and gait information over an extended time period. This method of high‐frequency data collection could be sensitive to early changes in mobility associated with cognitive decline.MethodWe present data for a cohort of 32 participants living alone and enrolled in the Collaborative Aging Research Using Technology (CART) Initiative aging study with a pervasive sensing and computing system deployed in their homes. Sixteen individuals with a Clinical Dementia Rating (CDR) scale score of 0.5 were matched by age, sex and education to 16 participants with a CDR of 0; 80% lived in low‐income senior apartments; 6% were non‐white. Mobility and gait data is derived from a gait line, consisting of four ceiling mounted, field‐of‐view restricted passive infrared motion sensors placed 61 cm apart in a line, in each home. The number of walking events, defined as all four sensors being triggered, was analyzed between the two groups.ResultParticipants with a CDR score of 0 had a mean age of 72.1 years and a mean MoCA score of 26.1 (range 21 – 30). Participants with a CDR score of 0.5 had a mean age of 72.2 and a mean MoCA score of 22.1 (range 15 – 27). Fifty‐six percent of participants in each group were female. Preliminary data from the gait line from a combined 1400 days for CDR 0 participants and a combined 1250 days for CDR 0.5 participants is presented here. The mean number of daily walking events detected by the gait line was significantly greater for CDR 0 participants (101.4) compared to CDR 0.5 participants (92.8, p=0.03).ConclusionAmbient sensors are able to collect longitudinal data on gait and activity levels in individuals with a technology platform deployed within their home. This unobtrusive remote mobility assessment methodology identifies individuals experiencing cognitive impairment. Further evaluation of other gait metrics and home‐based activity patterns is ongoing to explore their association with changes in cognition.