Dementia In Cohort Research Articles

Individualised prognostic models using plasma biomarkers for clinical progression to Alzheimer’s disease dementia in non‐demented elderly

AbstractBackgroundBlood‐based biomarkers can provide a low‐invasive and accessible way to identify neurodegenerative diseases before the clinical onset of dementia. We aimed to construct prognostic models for personalized risk of developing Alzheimer’s disease (AD) dementia in a memory clinic population of individuals with either subjective cognitive decline (SCD) or mild cognitive impairment (MCI), using plasma phosphorylated‐tau‐181 (pTau181), amyloid beta1‐42/1‐40 (Aβ42/40), glial fibrillary acidic protein (GFAP) and/or neurofilament light (NfL).MethodFrom the Amsterdam Dementia Cohort and SCIENCe project we included 303 individuals with SCD (age 61±9 years, n = 126(42%) female, MMSE 28±1) and 250 with MCI (age 65±7 years, n = 89(36%) female, MMSE 27±2), who had annual follow‐up visits for re‐evaluation of diagnosis (average follow‐up duration: 2.7±1.7 years.) Our outcome measure was progression to AD dementia. Plasma biomarkers were measured at baseline using SiMoa. Concentrations were then Z‐transformed for the statistical analysis and split into tertiles for risk chart visualisation. We evaluated adding the biomarkers individually, or as a panel, to a basic prognostic model including age, sex and baseline diagnosis. We selected a final model by its discrimination (Harrell’s C‐index, a value above 0.7 indicates a good model) and accuracy (Brier score, a value below 0.2 indicates a good model) and used it to calculate 5‐year risk scores for progression to AD dementia.ResultDuring follow‐up, 86 individuals developed AD dementia (8 with SCD, 78 with MCI at baseline, average time to progression: 2.8±1.7 years). Adding any of the biomarkers to the basic model improved the model discrimination (Table 1). The prognostic model with all four plasma biomarkers had the best discrimination and accuracy, followed by the model with GFAP only, and the model with pTau181 only (Table 1). Using the model with all four biomarkers, 5‐year individual progression risks to AD dementia varied from 1.9% (lowest tertiles for GFAP, pTau181 and NfL, highest tertile for Aβ42/40 ratio) to 40.6% (highest tertiles for GFAP, pTau181 and NfL, lowest tertile for Aβ42/40 ratio) (Figure 1).ConclusionPlasma biomarkers, particularly plasma GFAP, can be utilized to provide prognostic risk information about progression to AD dementia for individuals presenting at a memory clinic.

Neuropsychiatric Symptoms and Microglial Activation in Patients with Alzheimer Disease

Neuropsychiatric symptoms are commonly encountered and are highly debilitating in patients with Alzheimer disease. Understanding their underpinnings has implications for identifying biomarkers and treatment for these symptoms. To evaluate whether glial markers are associated with neuropsychiatric symptoms in individuals across the Alzheimer disease continuum. This cross-sectional study was conducted from January to June 2023, leveraging data from the Translational Biomarkers in Aging and Dementia cohort at McGill University, Canada. Recruitment was based on referrals of individuals from the community or from outpatient clinics. Exclusion criteria included active substance abuse, major surgery, recent head trauma, safety contraindications for positron emission tomography (PET) or magnetic resonance imaging, being currently enrolled in other studies, and having inadequately treated systemic conditions. All individuals underwent assessment for neuropsychiatric symptoms (Neuropsychiatry Inventory Questionnaire [NPI-Q]), and imaging for microglial activation ([11C]PBR28 PET), amyloid-β ([18F]AZD4694 PET), and tau tangles ([18F]MK6240 PET). Of the 109 participants, 72 (66%) were women and 37 (34%) were men; the median age was 71.8 years (range, 38.0-86.5 years). Overall, 70 had no cognitive impairment and 39 had cognitive impairment (25 mild; 14 Alzheimer disease dementia). Amyloid-β PET positivity was present in 21 cognitively unimpaired individuals (30%) and in 31 cognitively impaired individuals (79%). The NPI-Q severity score was associated with microglial activation in the frontal, temporal, and parietal cortices (β = 7.37; 95% CI, 1.34-13.41; P = .01). A leave-one-out approach revealed that irritability was the NPI-Q domain most closely associated with the presence of brain microglial activation (β = 6.86; 95% CI, 1.77-11.95; P = .008). Furthermore, we found that microglia-associated irritability was associated with study partner burden measured by NPI-Q distress score (β = 5.72; 95% CI, 0.33-11.10; P = .03). In this cross-sectional study of 109 individuals across the AD continuum, microglial activation was associated with and a potential biomarker of neuropsychiatric symptoms in Alzheimer disease. Moreover, our findings suggest that the combination of amyloid-β- and microglia-targeted therapies could have an impact on relieving these symptoms.

Predicting sojourn times across dementia disease stages, institutionalization, and mortality.

Inferring the timeline from mild cognitive impairment (MCI) to severe dementia is pivotal for patients, clinicians, and researchers. Literature is sparse and often contains few patients. We aim to determine the time spent in MCI, mild-, moderate-, severe dementia, and institutionalization until death. Multistate modeling with Cox regression was used to obtain the sojourn time. Covariates were age at baseline, sex, amyloid status, and Alzheimer's disease (AD) or other dementia diagnosis. The sample included a register (SveDem) and memory clinics (Amsterdam Dementia Cohort and Memento). Using 80,543 patients, the sojourn time from clinically identified MCI to death across all patient groups ranged from 6.20 (95% confidence interval [CI]: 5.57-6.98) to 10.08 (8.94-12.18) years. Generally, sojourn time was inversely associated with older age at baseline, males, and AD diagnosis. The results provide key estimates for researchers and clinicians to estimate prognosis.

Association of dementia with clinical and financial outcomes following lobectomy for lung cancer

ObjectiveThe number of adults with dementia is rising worldwide. Although dementia has been linked with inferior outcomes following various operations, this phenomenon has not been fully elucidated among patients undergoing elective lung resection. Using a national cohort, we evaluated the association of dementia with clinical and financial outcomes following lobectomy for cancer. MethodsAdults undergoing lobectomy for lung cancer were identified within the 2010-2020 Nationwide Readmissions Database. Patients with a comorbid diagnosis of dementia were considered the Dementia cohort (others: Non-Dementia). Multivariable regressions were developed to evaluate the association between dementia and key outcomes. ResultsOf ∼314,436 patients, 2863 (0.9%) comprised the Dementia cohort. Compared with Non-Dementia, the Dementia cohort was older (75 vs 68 years, P < .001), less commonly female (49.4 vs 53.9%, P = .01), and had a greater burden of comorbid conditions. After adjustment, dementia remained associated with similar odds of in-hospital mortality (adjusted odds ratio [aOR], 0.86; 95% confidence interval [CI], 0.54-1.38) but greater likelihood of pneumonia (aOR, 1.31; CI, 1.04-1.65) and infectious complications (aOR, 1.37; CI, 1.01-1.87). Further, dementia was associated with longer length of stay (β +0.96 days; CI, 0.51-1.41), but no difference in hospitalization cost (β $1528; CI, −92 to 3148). ConclusionsPatients with dementia faced similar odds of mortality, but greater complications and resource use following lobectomy for lung cancer. Novel interventions are needed to improve care coordination and develop standardized recovery pathways for this growing cohort.

Automating Rey Complex Figure Test scoring using a deep learning-based approach: a potential large-scale screening tool for cognitive decline

BackgroundThe Rey Complex Figure Test (RCFT) has been widely used to evaluate the neurocognitive functions in various clinical groups with a broad range of ages. However, despite its usefulness, the scoring method is as complex as the figure. Such a complicated scoring system can lead to the risk of reducing the extent of agreement among raters. Although several attempts have been made to use RCFT in clinical settings in a digitalized format, little attention has been given to develop direct automatic scoring that is comparable to experienced psychologists. Therefore, we aimed to develop an artificial intelligence (AI) scoring system for RCFT using a deep learning (DL) algorithm and confirmed its validity.MethodsA total of 6680 subjects were enrolled in the Gwangju Alzheimer’s and Related Dementia cohort registry, Korea, from January 2015 to June 2021. We obtained 20,040 scanned images using three images per subject (copy, immediate recall, and delayed recall) and scores rated by 32 experienced psychologists. We trained the automated scoring system using the DenseNet architecture. To increase the model performance, we improved the quality of training data by re-examining some images with poor results (mean absolute error (MAE) ge 5 [points]) and re-trained our model. Finally, we conducted an external validation with 150 images scored by five experienced psychologists.ResultsFor fivefold cross-validation, our first model obtained MAE = 1.24 [points] and R-squared ({R}^{2}) = 0.977. However, after evaluating and updating the model, the performance of the final model was improved (MAE = 0.95 [points], {R}^{2} = 0.986). Predicted scores among cognitively normal, mild cognitive impairment, and dementia were significantly different. For the 150 independent test sets, the MAE and {R}^{2} between AI and average scores by five human experts were 0.64 [points] and 0.994, respectively.ConclusionWe concluded that there was no fundamental difference between the rating scores of experienced psychologists and those of our AI scoring system. We expect that our AI psychologist will be able to contribute to screen the early stages of Alzheimer’s disease pathology in medical checkup centers or large-scale community-based research institutes in a faster and cost-effective way.

Orthostatic hypotension and its association with cerebral small vessel disease in a memory clinic population.

Orthostatic hypotension (OH), an impaired blood pressure (BP) response to postural change, has been associated with cognitive decline and dementia, possibly through cerebral small vessel disease (CSVD). We hypothesized that longer duration of BP drop and a larger BP drop is associated with increased risk of CSVD. This cross-sectional study included 3971 memory clinic patients (mean age 68 years, 45% female, 42% subjective cognitive complaints, 17% mild cognitive impairment, 41% dementia) from the Amsterdam Ageing Cohort and Amsterdam Dementia Cohort. Early OH (EOH) was defined as a drop in BP of ±20 mmHg systolic and/or 10 mmHg diastolic only at 1 min after standing, and delayed/prolonged OH (DPOH) at 1 and/or 3 min after standing. Presence of CSVD [white matter hyperintensities (WMH), lacunes, microbleeds] was assessed with MRI ( n = 3584) or CT brain (n = 389). The prevalence of early OH was 9% and of delayed/prolonged OH 18%. Age- and sex-adjusted logistic regression analyses showed that delayed/prolonged OH, but not early OH, was significantly associated with a higher burden of WMH (OR, 95%CI: 1.21, 1.00-1.46) and lacunes (OR, 95%CI 1.34, 1.06-1.69), but not microbleeds (OR, 95%CI 1.22, 0.89-1.67). When adjusting for supine SBP, these associations attenuated (ORs, 95%CI for WMH 1.04, 0.85-1.27; for lacunes 1.21, 0.91-1.62; for microbleeds 0.95, 0.68-1.31). A larger drop in SBP was associated with increased risk of WMH and microbleeds, however, when adjusted for supine SBP, this effect diminished. Among memory clinic patients, DPOH is more common than EOH. While longer duration and larger magnitude of BP drop coincided with a higher burden of CSVD, these associations were largely explained by high supine BP.

The Mediterranean diet is associated with better cardiometabolic health for women in mid-life but not men: A PREVENT dementia cohort cross-sectional analysis

Background and aimsThe Mediterranean diet (MedDiet) has been associated with better cardiovascular health in a number of studies. This study aimed to explore cross-sectional associations between MedDiet adherence in the PREVENT Dementia (PREVENT) programme, stratified by sex. Methods and resultsThree MedDiet scores were calculated (MEDAS, MEDAS continuous and Pyramid) alongside a Western diet score. We used linear regression and linear mixed effects models to test for associations between the MEDAS score and cardiovascular health. Propensity scores were calculated to strengthen causality inferences from the data, and used as covariates along with total energy intake and Western diet scores. Exploratory analysis repeated the linear regression models for each individual food component. This study included 533 participants, with a mean age 51.25 (±5.40) years, and a majority of women (60.0%). Women had higher MedDiet scores across all three scoring methods, had a lower Western diet score and consumed fewer total calories. Higher MedDiet scores were associated with lower blood pressure, body mass index (BMI) and lower cardiovascular risk scores. When stratified by sex, women had significant positive associations between MedDiet scores and lower blood pressure, BMI and glycemia, whereas men only had a significant association with lower BMI. ConclusionThere were significant associations between higher MedDiet scores and a number of cardiovascular health outcome measures. These associations were seen more consistently for women compared to men, which may have implications for the development of personalised nutritional recommendations to improve cardiovascular health.

Assessment of cheese sign and its association with vascular risk factors: Data from PUMCH dementia cohort.

In the clinic, practitioners encounter many patients with an abnormal pattern of dense punctate magnetic resonance imaging (MRI) signal in the basal ganglia, a phenomenon known as "cheese sign". This sign is reported as common in cerebrovascular diseases, dementia, and old age. Recently, cheese sign has been speculated to consist of dense perivascular space (PVS). This study aimed to assess the lesion types of cheese sign and analyze the correlation between this sign and vascular disease risk factors. A total of 812 patients from Peking Union Medical College Hospital (PUMCH) dementia cohort were enrolled. We analyzed the relationship between cheese sign and vascular risk. For assessing cheese sign and defining its degree, the abnormal punctate signals were classified into basal ganglia hyperintensity (BGH), PVS, lacunae/infarctions and microbleeds, and counted separately. Each type of lesion was rated on a four-level scale, and then the sum was calculated; this total was defined as the cheese sign score. Fazekas and Age-Related White Matter Changes (ARWMC) scores were used to evaluate the paraventricular, deep, and subcortical gray/white matter hyperintensities. A total of 118 patients (14.5%) in this dementia cohort were found to have cheese sign. Age (odds ratio [OR]: 1.090, 95% confidence interval [CI]: 1.064-1.120, P <0.001), hypertension (OR: 1.828, 95% CI: 1.123-2.983, P = 0.014), and stroke (OR: 1.901, 95% CI: 1.092-3.259, P = 0.025) were risk factors for cheese sign. There was no significant relationship between diabetes, hyperlipidemia, and cheese sign. The main components of cheese sign were BGH, PVS, and lacunae/infarction. The proportion of PVS increased with cheese sign severity. The risk factors for cheese sign were hypertension, age, and stroke. Cheese sign consists of BGH, PVS, and lacunae/infarction.

CSF proteomics in autosomal dominant Alzheimer's disease highlights parallels with sporadic disease.

Autosomal dominant Alzheimer's disease (ADAD) offers a unique opportunity to study pathophysiological changes in a relatively young population with few comorbidities. A comprehensive investigation of proteome changes occurring in ADAD could provide valuable insights into AD-related biological mechanisms and uncover novel biomarkers and therapeutic targets. Furthermore, ADAD might serve as a model for sporadic AD, but in-depth proteome comparisons are lacking. We aimed to identify dysregulated CSF proteins in ADAD and determine the degree of overlap with sporadic AD. We measured 1472 proteins in CSF of PSEN1 or APP mutation carriers (n = 22) and age- and sex-matched controls (n = 20) from the Amsterdam Dementia Cohort using proximity extension-based immunoassays (PEA). We compared protein abundance between groups with two-sided t-tests and identified enriched biological pathways. Using the same protein panels in paired plasma samples, we investigated correlations between CSF proteins and their plasma counterparts. Finally, we compared our results with recently published PEA data from an international cohort of sporadic AD (n = 230) and non-AD dementias (n = 301). All statistical analyses were false discovery rate-corrected. We detected 66 differentially abundant CSF proteins (65 increased, 1 decreased) in ADAD compared to controls (q < 0.05). The most strongly upregulated proteins (fold change >1.8) were related to immunity (CHIT1, ITGB2, SMOC2), cytoskeletal structure (MAPT, NEFL) and tissue remodelling (TMSB10, MMP-10). Significant CSF-plasma correlations were found for the upregulated proteins SMOC2 and LILR1B. Of the 66 differentially expressed proteins, 36 had been measured previously in the sporadic dementias cohort, 34 of which (94%) were also significantly upregulated in sporadic AD, with a strong correlation between the fold changes of these proteins in both cohorts (rs = 0.730, P < 0.001). Twenty-nine of the 36 proteins (81%) were also upregulated among non-AD patients with suspected AD co-pathology. This CSF proteomics study demonstrates substantial biochemical similarities between ADAD and sporadic AD, suggesting involvement of the same biological processes. Besides known AD-related proteins, we identified several relatively novel proteins, such as TMSB10, MMP-10 and SMOC2, which have potential as novel biomarkers. With shared pathophysiological CSF changes, ADAD study findings might be translatable to sporadic AD, which could greatly expedite therapy development.

Diabetes treatment deintensification in Australians with dementia compared to the general population: A national cohort study.

Diagnosis of dementia may change peoples' goals of care. In people with diabetes, this may lead to relaxing treatment targets and reducing the use of diabetes medications. The aim of this study was to examine changes in diabetes medication use before and after initiating medication for dementia. A national cohort of people aged 65-97 years, living with dementia and diabetes, and a general population cohort with diabetes matched for age, sex, and index date were extracted from the Australian national medication claims database. Trajectories of diabetes medication use, expressed as mean defined daily dose (DDD) each month for each individual from 24 months before to 24 months after the index date, were estimated using group-based trajectory modeling (GBTM). Cohorts were analyzed separately. People with dementia (N = 1884) and the matched general population (N = 7067) had a median age of 80 years (interquartile range 76-84) and 55% were female. In both models, people exhibited one of five diabetes medication trajectories, with 16.5% of people with dementia and 24.0% of the general population assigned to trajectories that represented deintensification. In the general population model, those on deintensifying trajectories were older than those on stable trajectories (median 83 vs. 79 years). In the dementia cohort model, those on high or low deintensifying trajectories were slightly older (median age 81 or 82, respectively, vs. 80 years) and had at least 1 more comorbidity (median 8 or 7, respectively, vs. 6) than those on stable trajectories. Initiating medication for dementia does not appear to be a trigger for deintensification of diabetes treatment regimens. Deintensification was more common in the general population; people living with dementia are potentially overtreated for diabetes.

Examining the effect of dementia on hospitalization outcome for GI cancer: A nationwide retrospective analysis.

e16336 Background: Dementia is a debilitating condition affecting a significant fraction of the elderly, with far-reaching consequences. It is an active field of research, with current emphasis on modifiable risk factors as well as treatment. Considering the limitations that dementia imposes on the management of other medical conditions, we attempt to study its association with, and impact on hospitalizations for gastrointestinal (GI) cancers. Methods: We queried the National Inpatient Sample databases for the years 2016 through 2020, using International Classification of Diseases, tenth revision (ICD-10) codes to include all adult admissions with esophageal, gastric, colorectal, biliary Tract, liver, and pancreatic cancers. We further stratified this cohort based on the presence of a secondary diagnosis of dementia. STATA 17 was used to perform a multivariate regression analysis to compare outcomes in the two cohorts, while adjusting for potential confounders. Results: The study identified 280,180 patients with GI cancer, of whom 4.7% (13,135) had a secondary diagnosis of dementia. The cohort with dementia was found to have a higher proportion of females (47.0%) compared to the non-dementia cohort (40.8%) and a higher median age (77.9 years vs 66.9 years). Additionally, this cohort had a higher prevalence of other medical comorbidities, with 98.2% having a Charlson comorbidity index (CCI) greater than 3 compared to 87.8% in the non-dementia cohort. The primary outcome of the study was in-patient mortality, which was stratified by age groups. In the 41-65 years old group, the mortality rate was higher in the dementia cohort (16.3%) compared to the non-dementia cohort (8.6%), with an adjusted odds ratio (aOR) of 1.96 (95% CI: 1.10-3.48, P&lt;0.05). In the 65-75 years old subgroup, the mortality rate was also higher in the dementia cohort (13.1%) compared to the non-dementia cohort (8.6%), with an aOR of 1.48 (95%CI: 1.14-1.93, P&lt;0.05). In the above-75-year-old subgroup, the mortality was higher in the dementia cohort (11.7%) compared to the non-dementia cohort (8.5%) (aOR: 1.35; 95%CI: 1.16-1.58, P&lt;0.05). Conclusions: Hospitalizations with GI cancer, with a secondary diagnosis of dementia, have higher odds of in-patient mortality compared to those without dementia. This was observed across all age groups. The dementia cohort also had a higher proportion of females and a higher median age, along with a higher prevalence of multiple comorbidities. These findings suggest that individuals with gastrointestinal cancer and dementia face a higher risk of in-patient mortality, highlighting the importance of considering dementia as a part of care planning in patients with GI cancer. [Table: see text]

Association between social support and cognitive function

AbstractBackgroundObservational studies suggest social support is associated with vulnerability for cognitive decline in older adults. Because of racial/ethnic homogeneity in prior studies beings predominantly in White/European ancestry, less is known about the generalization of these putative psychosocial mechanisms. Thus, we evaluated whether better telecommunication social support systems were associated with better cognitive performance using a unique longitudinal cohort of rural South African older adults.MethodWe conducted a cross‐sectional study using 541 participants from the HAALSI (Health and Aging in Africa: A Longitudinal Study of an INDEPTH Community in South Africa) Dementia Cohort. Participants’ exposure to social support via telecommunication was measured using a standard assessment. Cognitive performance was measured using a neuropsychological battery validated in this population that assesses the domains consistent with the Alzheimer’s Disease Research Centers Uniform Data Set. Raw scores were converted into z scores and a composite global cognitive score was created as an additional indicator of global cognition. We examined cross‐sectional associations with multivariate robust regression analysis using robust S‐estimation. Telecommunication social support was modeled as the independent variable; cognitive measures were modeled as dependent variables.ResultHigher telecommunication social support was associated with better global cognitive function after adjustment for age, gender, and education (β:0.01, 95% CI: 0.006, 0.022). This association persisted after additional adjustments for depressive symptoms and vascular risk factors. Higher telecommunication social support was also associated with cognitive function assessed by mini mental status examination and tests of executive function and memory.ConclusionTelecommunication‐based social support was associated with higher levels of cognitive performance in a rural South African cohort of Black older adults. Although these findings and the potential of reverse causality need to be further validated, our results suggest that intervention studies might be specifically merited to understand whether promoting social support through telecommunication in similar samples of older adult populations lessen vulnerability for cognitive decline.

Risk of Adverse Events and Delirium after COVID-19 Vaccination in Patients Living with Dementia.

The aim of this study was to compare incidences of adverse events of special interest (AESI) and delirium in 3 cohorts: after COVID-19 vaccination, prepandemic, and SARS-CoV-2 polymerase chain reaction (PCR) test positive. This is a population-based cohort study using electronic medical records linked with vaccination records in Hong Kong. A total of 17,449 older people with dementia received at least 1 dose of CoronaVac (n= 14,719) or BNT162b2 (n= 2730) between February 23, 2021, and March 31, 2022. Moreover, 43,396 prepandemic and 3592 SARS-CoV-2 test positive patients were also included in this study. The incidences of AESI and delirium up to 28days after vaccination in the vaccinated dementia cohort were compared with the prepandemic and SARS-CoV-2 test positive dementia cohorts by calculating incidence rate ratios (IRRs). Patients who received multiple doses were followed up separately for each dose, up to the third dose. We did not detect an increased risk of delirium and most AESI following vaccination compared to the prepandemic period and those tested positive for SARS-CoV-2. No AESI group nor delirium incidence exceeded 10 per 1000 person-days in vaccinated individuals. The findings provide evidence for the safe use of COVID-19 vaccines in older patients with dementia. In the short run, benefit appears to outweigh the harm due to vaccine; however, longer follow-up should be continued to identify remote adverse events.

The effect of the lockdown during the COVID‐19 pandemic on the risk of developing dementia; A cohort study

AbstractBackgroundIncreased social activity, relationships and being cognitively active have been associated with decreased risk of dementia. The COVID‐19 pandemic has significantly influenced these and increased the feeling of loneliness throughout society. Protective measures against the virus, such as social distancing and isolation, were enforced to reduce contact between people. We hypothesised that this would lead to an increased risk of transition to dementia.MethodWe obtained data from the Brains for Dementia (BDR) cohort, which has been collecting roughly annual data on 3,726 older adults with and without dementia since 2008. Data continued to be collected during the lockdowns, although by telephone and /or video call instead of in person. Individuals diagnosed with dementia at study entry were excluded from this study as were individuals with only one visit. Cognitive status was classified using the CDR global score.Poisson regression with cubic splines to account for differences in age was used to compare the rate ratio of developing dementia before/after March 1st 2020.ResultOut of 2,242 individuals, 205 individuals developed dementia before and 40 developed dementia after 1/3/20. The rate ratio of developing dementia after 1/3/20 was 0.770 (95% CI 0.438 – 1.356, p = 0.366) but there was evidence that this differed with age.ConclusionThe chance of individuals developing dementia did not change significantly after the first lockdown, although power was low. We will now perform sensitivity analyses to assess whether the type of assessment or using the CDR sum of boxes/MMSE to define cognitive status alters this relationship.

Amyloid pathology is associated with semantic loss in patients with subjective cognitive decline

AbstractBackgroundEvidence is emerging that subtle language decline is an early indicator of Alzheimer’s disease (AD). This study assessed change in semantic and letter fluency in individuals with subjective cognitive decline (SCD), and examined whether trajectories differed between individuals with and without amyloid‐beta (Aβ)‐pathology.MethodLongitudinal data from 437 individuals of the memory clinic‐based Amsterdam Dementia Cohort were included (Age 61±8 years, 184(42%) Female, follow‐up time 5.3±3.7 years; Table 1). Participants were classified as SCD at baseline, had available baseline Aβ‐information and had at least 1 follow‐up on semantic or letter fluency. Baseline Aβ‐status was dichotomized as positive/negative based on local cut‐offs for Aβ1‐42 concentrations in cerebrospinal fluid, or visual inspection of amyloid positron emission tomography‐imaging (Florbetapir or PiB). Two linear mixed models (LMM) were used to investigate change on semantic and letter fluency. Models included time and time*Aβ‐status as predictors of interest, a random intercept for participant, and age, sex, education were adjusted for. LMMs were subsequently stratified for Aβ‐status.ResultAt baseline, the groups did not differ in semantic (p = 0.313) or letter fluency (p = 0.294). Over time Aβ‐positive individuals changed more rapidly on semantic fluency compared to Aβ‐negative individuals (β = ‐0.32,CI = ‐0.49 – ‐0.14;p&lt;.001). The Aβ‐positive group declined with 0.35 words per year (CI = ‐0.49 – ‐0.20;p&lt;.001), while Aβ‐negative individuals did not show change (β = 0.03;CI = ‐0.12 – 0.06;p = 0.496) (Figure 1). On letter fluency Aβ‐positive individuals changed differently compared to Aβ‐negative individuals (β = ‐0.38;CI = ‐0.72 – ‐0.04;p = 0.028), to the extent that the Aβ‐positive group did not progress (β = 0.10;CI = ‐0.21 – 0.41;p = 0.533), while Aβ‐negative individuals improved with 0.47 words per year (CI = 0.29 – 0.65;p&lt;.001) (Figure 2).ConclusionOur results indicate that Aβ‐positive individuals decreased on semantic fluency, but remained stable on letter fluency. In contrast, Aβ‐negative individuals remained stable on semantic fluency, while they improved on letter fluency over time, which might suggest a learning effect. These findings suggest that the presence of Aβ‐pathology is characterized by semantic loss, highlighting the potential of language based performance as a biomarker for Aβ‐pathology in SCD.

Facilitating clinical use of the Amsterdam instrumental activities of daily living questionnaire: Dutch normative data and clinical cutoff values

AbstractBackgroundThe Amsterdam Instrumental Activities of Daily Living Questionnaire (A‐IADL‐Q) is a proxy‐based instrument aimed at measuring difficulties in daily functioning due to cognitive decline in the context of dementia. To facilitate its interpretation and clinical implementation, normative data from the general population are necessary. Here, we aimed to compose normative scores for the A‐IADL‐Q and provide clinical cutoff values for mild cognitive impairment (MCI) and dementia.MethodCross‐sectional data from three Dutch cohorts (i.e., Dutch Brain Research Registry, European Medial Information Framework‐Alzheimer’s Disease (EMIF‐AD) 90+, and Amsterdam Dementia Cohort (ADC)) were used, including 1127 cognitively healthy individuals and 380 individuals with MCI and/or dementia. Regression‐based norms were constructed in the healthy sample, using linear models including age, sex, education(high/low) and their interactions, and the optimal model was selected using backward elimination. Individual differences between observed and expected IADL t‐scores were divided by the residual standard error of the model. Optimal normative score cutoffs to distinguish healthy from MCI and/or dementia were based on bootstrap average estimates(500 repeats) of the Youden Index. Diagnostic accuracy was evaluated using receiver operating curves (ROC), area under the curve (AUC), sensitivity and specificity.ResultNormative data (mean age = 64±13year, 68.6%female, 67.8% highly educated) and memory clinic data (mean age = 66±8year, 43.9%female, 38.9% highly educated) were used (Table1). The best normative model (i.e., with the lowest Akaike information criterion) included age‐squared, sex, education and the interaction between age and education. The optimal normative score cutoffs to distinguish healthy from dementia and MCI/dementia were, respectively, 1.78SD and 1.79SD below the mean, with high AUCs of 0.96 [95%CI 0.95‐0.98] and 0.94 [95%CI 0.92,0.95]. The optimal cutoff to distinguish healthy from MCI was higher; 1.01SD below the mean, also with a high AUC‐score of 0.86 [95%C 0.81‐0.9])(Table2, Figure1).ConclusionWe composed normative scores with clinical cutoff values that can aid in the distinction between cognitively healthy from MCI and/or dementia with high diagnostic accuracy. These normative scores are accessible via an online tool to further facilitate and implement clinical use of the A‐IADL‐Q. Future studies should include participants from different countries, cultures and different socio‐economic background to facilitate world‐wide use.

Automated detection of lacunar infarcts from MRI images

AbstractBackgroundWhen MRI images of patients with memory problems are assessed, the presence of lacunar infarcts is evaluated. Lacunar infarcts, fluid‐filled cavities of 3‐15 mm in diameter, are one possible result of cerebral small vessel disease and therefore relevant in dementia diagnostics. In this study, we propose an automated tool for detecting lacunar infarcts on MRI images.MethodWe adapted our previous approach [1] in three ways: 1) post‐processing steps were added to the convolutional neural network segmentation pipeline, e.g., to exclude enlarged perivascular spaces and segmentations located inside sulci or ventricles, 2) memory clinic data from the Amsterdam Dementia Cohort and PredictND cohort were included in addition to the LADIS cohort data, and 3) the ground truth was defined by three experienced neuroradiologists (A, B, C) instead of one rater. T1 and T2‐FLAIR images were available for all cases and T2 for a subset in visual rating. The dataset was composed of 393 subjects and each expert rated 1156 potential lacunar infarcts as “1 = no”, “2 = probably no”, “3 = probably yes” or “4 = yes”. A consensus (CO) was created by calculating the average and using a cutoff at 2.5. The agreement was measured between individual raters (A‐B, B‐C, A‐C), between automatic rating and individual raters (AU‐A, AU‐B, AU‐C), and between the automatic rating and the consensus rating (AU‐CO) using Kappa. Correlation coefficient for the number of lacunar infarcts per subject was defined. Cross‐validation was used in training the algorithm.ResultOut of 1156 candidate regions evaluated, 540 were considered as lacunar infarcts based on consensus. The individual raters agreed with each other in 74% of cases whether the shown lesion was lacunar infarct (kappa = 0.48). Correspondingly, automatic rating agreed with the individual raters in 74% of cases (kappa = 0.47). When automatic rating was compared with consensus, agreement/accuracy was 78% (kappa = 0.55). The correlation coefficient for the number of lacunar infarcts detected automatically from the whole image and visually (consensus) was 0.85 (Figure 1).ConclusionThis study suggests that the agreement in detecting lacunar infarcts automatically is comparable to inter‐rater variability between experienced neuroradiologists. [1] Jokinen et al. Stroke 2020 Nov 9; 50(1)

Executive function may underlie cognitive reserve: A 3‐year follow‐up study

AbstractBackgroundThe hypothetical concept of cognitive reserve (CR) has been proposed to explain why someone can manage to function normally even in the presence of brain pathology. However, it still remains to be determined what components constitute such resilience against Alzheimer’s disease (AD) pathology. In the current study we investigated the characteristics of cognitively normal (CN) elders with high CR.MethodWe included CN participants from the Gwangju Alzheimer’s Disease and Related Dementia Cohort in Korea. We selected a group of CN individuals who showed a significant amyloid‐beta (aß) deposition at baseline and stayed CN over the follow‐up period. They were defined as high CR group. For comparison purpose, individuals with a significant aß deposition at baseline but converted to MCI at follow‐up were also included. In the final analysis, 94 high CR group and 24 control group were included. Group comparisons in socio‐demographic, clinical and cognitive variables were performed using χ2 tests and ANOVA controlling for age, education, gender, and follow‐up month.ResultMean follow‐up month were 43.37. There were no group differences in education, gender, socio‐economic status, family history of dementia or stroke, medical conditions, body mass index, subjective memory complaints, and instrumental activities of daily living. However, high CR group was younger and had shorter follow‐up period, therefore such variables were controlled when cognitive tests were compared. High CR group was more religious (p &lt; 0.001), showed higher complexity in former job (p = 0.009), and higher level of executive functoning (Digit Dpan Backward, p = 0.012; Fluency test, p = 0.008; Boston Naming Test, p = 0.014; Trail Making Test part B, p = 0.017) than control group. There were no group differences in episodic memory tests and visuospatial abilities.ConclusionIndividuals with high CR could cope better with AD pathology. Many factors have been suggested to be associated with CR. Regarding cognitive process involved, our findings suggest that executive function plays an important role in constituting high CR. Preserved executive function may, at least in part, underlie CR.

Oral health and risk of cognitive disorders in older adults: A biannual longitudinal follow-up cohort.

Oral health may be associated with cognitive disorders such as mild cognitive impairment or dementia. This study elucidates the effects of oral health conditions on the progression of cognitive disorders. Data were collected from 153 participants of the Korean Longitudinal Study on Cognitive Aging and Dementia cohort who completed the longitudinal dental examinations and cognitive function assessments using the three-wave biannual survey. We analysed the relationship between dental factors and the conversion of cognitive function. The ratio of maxillary removable partial denture use (p = .03) was high in the converter and mild cognitive impairment/dementia groups. The low-grade ratio of posterior masticatory performance increased in the converter and mild cognitive impairment/dementia groups (modified Eichner index 2, p = .04). The mild cognitive impairment/dementia group had a higher rate of complete mandibular denture use (p < .001). The converter and mild cognitive impairment/dementia groups had fewer remaining teeth (p < .05) or removable prostheses (p < .01) than the normal group. Masticatory performance is associated with the conversion of cognitive disorders. Our findings suggest that oral health management can help delay the progression of cognitive disorders.

Differentiation of Alzheimer's Disease from Frontotemporal Dementia and Mild Cognitive Impairment Based on Arterial Spin Labeling Magnetic Resonance Imaging: A Pilot Cross-Sectional Study from PUMCH Dementia Cohort.

Arterial spin labeling (ASL) is helpful in early diagnosis and differential diagnosis of Alzheimer's disease (AD), with advantages including no exposure to radioactivity, no injection of a contrast agent, more accessible, and relatively less expensive. To establish the perfusion pattern of different dementia in Chinese population and evaluate the effectiveness of ASL in differentiating AD from cognitive unimpaired (CU), mild cognitive impairment (MCI), and frontotemporal dementia (FTD). Four groups of participants were enrolled, including AD, FTD, MCI, and CU based on clinical diagnosis from PUMCH dementia cohort. ASL image was collected using 3D spiral fast spin echo-based pseudo-continuous ASL pulse sequence with background suppression and a high resolution T1-weighted scan covering the whole brain. Data processing was performed using Dr. Brain Platform to get cerebral blood flow (ml/100g/min) in every region of interest cortices. Participants included 66 AD, 26 FTD, 21 MCI, and 21 CU. Statistically, widespread hypoperfusion neocortices, most significantly in temporal-parietal-occipital cortices, but not hippocampus and subcortical nucleus were found in AD. Hypoperfusion in parietal lobe was most significantly associated with cognitive decline in AD. Hypoperfusion in parietal lobe was found in MCI and extended to adjacent temporal, occipital and posterior cingulate cortices in AD. Significant reduced perfusion in frontal and temporal cortices, including subcortical nucleus and anterior cingulate cortex were found in FTD. Hypoperfusion regions were relatively symmetrical in AD and left predominant especially in FTD. Specific patterns of ASL hypoperfusion were helpful in differentiating AD from CU, MCI, and FTD.