bluuebunny/crossref_metadata_2025 huggingface dataset:
One in five community‐dwelling older adults will develop Alzheimer's dementia in five years
Authors: Ford Christopher N , Rajan Kumar B , Bennett David A
Published: December 2021

Background

Alzheimer's dementia (AD) is the most common form of dementia and a growing public health problem. By 2050, one in 85 adults globally will have the disease, for which there are few effective treatments. The objective of this study was to estimate the five‐year incidence rate of AD among predominantly White, community‐dwelling older adults.

Method

Data were included from 837 community‐dwelling older adults in the Rush Memory and Aging Project (MAP) with ≥2 cognitive assessments and clinical neurological exams, which were collected annually for up to 15 years (mean: 5.06; SE: 0.01). Enrollment for the current study began in 2004. Participants in MAP were community‐dwelling older adults recruited from >40 retirement communities in Chicago beginning in 1997 and followed until death, first diagnosis of probable AD, or until lost to follow‐up. A life table was used to estimate follow‐up time. Estimates of the incidence rate in this and prior MAP studies reporting incidence of AD based on cognitive testing (not autopsy) were pooled. Fixed and random effects models were used to estimate the pooled incidence rate using Episheet.

Result

In the current study, the mean age was 82.1 years (SE: 1.5 years) and respondents were predominantly non‐Hispanic White (n=776; 92.7%), 5.7% non‐Hispanic Black (n=48) and predominantly female (n=633, 75.6%). There were 200 cases of probable AD over 5,098 person‐years of follow‐up (incidence rate: 0.039; 95% CI: 0.034; 0.045 cases per year of follow‐up). Six studies, including an estimated total of 27,816 person‐years of follow‐up and 1,045 cases of probable AD, were included in the pooled analysis. The pooled incidence rate from fixed effects models was 0.038 cases/year (95% CI: 0.036; 0.040). The pooled incidence rate from random effects models was 0.037 cases/year (95% CI: 0.035, 0.041). The test of heterogeneity was p=0.128.

Conclusion

These findings suggest that one in five (19%) predominantly White, community‐dwelling older adults will develop AD over five years. The burden of AD is already high but expected to increase significantly as the average age of the US population increases. This points to an urgent and growing need to find an effective treatment for Alzheimer’s dementia.
Plasma p217+tau concordance with 18F‐NAV4694 beta‐amyloid and 18F‐MK6240 tau PET in mild Alzheimer’s disease and cognitively unimpaired participants in the AIBL/ADNeT cohort
Authors: Rowe Christopher C. , Doecke James D. , Saad Ziad S. , Triana‐Baltzer Gallen , Slemmon J. Randall , Krishnadas Natasha , Fowler Christopher J. , Rainey‐Smith Stephanie R. , Ward Larry , Robertson Joanne , Martins Ralph N. , Fripp Jurgen , Masters Colin L. , Villemagne Victor L. , Kolb Hartmuth C. , Dore Vincent
Published: December 2021

Background

Beta‐amyloid (Aß) PET assists diagnosis of Alzheimer’s disease (AD) and has an important role in selection for trials. Aß PET is costly. Reports suggest that plasma measures of phospho‐tau have high concordance with both Aß and tau PET. We compared a new assay, plasma p217+tau to Aß and tau PET.

Method

181 MCI/mild AD and 222 cognitively unimpaired (CU) participants in AIBL and the Australian Dementia Network (ADNeT) trial screening program were studied. Aß PET threshold was set at 25 centiloids (CL) as the standard for defining a positive scan and also at 50 CL which best correlates with NIA/AA AD neuropathologic change criteria. In CU we also evaluated a 20 CL PET threshold as this may be used in preclinical trial selection. Tau PET threshold was set at the SUVR (normalised to cerebellar cortex) for a meta‐temporal ROI (entorhinal cortex, amygdala, parahippocampus, and fusiform, inferior and middle temporal gyri) at the 95th percentile of Aß PET negative CU. Plasma p217+tau was measured with SIMOA using a Janssen in‐house assay. ROC area under the curve (AUC) was generated with Youden Index defined sensitivity (sens) and specificity (spec).

Result

Rank‐order correlation between p217+tau and Aß CL was significant in MCI/AD: ρ=0.65, p<10‐22 and CU: ρ=0.45, p<10‐12 and with tau SUVR for MCI/AD:ρ=0.68, p<10‐25 and CU:ρ=0.32, p<10‐7. In MCI/AD the AUC for p217+tau to predict Aß >25CL was 0.91 (sens 83%, spec 85%) and at >50CL was 0.90 (sens 73%, spec 93%). For tau+ PET the AUC was 0.86 (sens 73%, spec 90%). In the CU, the AUC vs Aß >25CL was 0.84 (sens 81%, spec 81%) dropping to 0.79 (sens 72%, spec 82%) for the 20CL PET threshold. The AUC vs tau+ PET in CU was 0.87 (sens 90%, spec 76%).

Conclusion

Plasma p217+tau showed good concordance with PET defined Aß and tau positivity in both MCI/AD and CU indicating potential to support the diagnosis of AD and to screen for preclinical AD trials. Early triage with p217+tau may reduce the number of screening Aß PET needed to identify Aß+ PET CU for preclinical trials by 50%.
Evaluating robustness of the Centiloid scale against variations in amyloid PET image resolution
Authors: Shekari Mahnaz , Salvadó Gemma , Battle Mark R , Collij Lyduine E. , Heeman Fiona , Alves Isadora Lopes , Palombit Alessandro , Buckley Chris J , Farrar Gill , Bullich Santiago , Visser Pieter Jelle , Scheltens Philip , Barkhof Frederik , Gispert Juan Domingo ,   AMYPAD consortium
Published: December 2021

Background

The Centiloid method enables direct quantitative comparison of amyloid‐PET scans acquired with different amyloid tracers. However, it does not explicitly model differences in image resolution which may have an impact on quantification, particularly in multicenter studies. This study evaluated the stability of the Centiloid scale with or without post‐processing smoothing to simulate distinct reconstruction settings. In addition, the effect of reference region selection was assessed.

Methods

A total of 318 [18F]flutemetamol PET scans from the ADC and EMIF‐AD Twin 60++ cohorts are included in this study (Table 1). Scans were reconstructed with LOR‐Ramla algorithm. Additionally, images were smoothed to get an effective resolution of 8mm. All images were quantified with a validated Centiloid (CL) pipeline using the GAAIN cortical composite and five different reference regions (whole cerebellum, cerebellum gray, pons, whole cerebellum+brainstem and eroded white‐matter). To assess the impact of reconstruction settings on CL values, we calculated the mean absolute difference between CL values of the original reconstructions vs the smoothed images. Differences above 5CL were considered as relevant. Finally, Bland‐Altman plots were used to assess whether any proportional bias was present between these outcome measures.

Results

Figure 1 displays image quality differences between local reconstruction settings and post‐smoothed images. CL values were not significantly affected by reconstruction methods using either whole cerebellum, whole cerebellum+brainstem, or white‐matter as reference region (Table 2). However, for the images with a higher level of amyloid, ΔCL was higher than 5 using whole cerebellum. On the contrary, the CL was highly affected by image resolution when using the pons as reference region, introducing constant bias for all ranges of amyloid burden. Using cerebellum gray, ΔCL has an inverse linear relationship with amyloid burden, though it was below 5CL for subjects with low to moderate amyloid burden, and differences above 5 were observed for images with CL above 80 (Figure 2).

Conclusion

Whole cerebellum and whole cerebellum+brainstem, the standard reference regions in CL quantification, are capable of providing stable CL values irrespective of image resolution for a wide range of amyloid burden. Other reference regions were less stable.
Evaluation of sensory gating efficiency in adults with Down syndrome
Authors: Le April
Published: December 2021

Background

In Down syndrome (DS), the amyloid precursor protein (APP) gene‐dosing effect drives a lifelong over‐production of amyloid‐beta (Aβ). The accumulation of Aβ begins to manifest as amyloid plaques as early as the teens and virtually in all by 40 years. The progression of Alzheimer’s Disease(AD)‐related neuropathology may underlie inhibitory disruption leading to over‐ or under‐sensitivity to auditory processing and cognitive deficits in DS. In positron electromagnetic tomography (PET) studies in DS, amyloid deposition has a defined temporal‐spatial profile that begins in the striatum and predictably progresses to the dorsolateral pre‐frontal cortex (DLPFC) and ventral pre‐frontal cortex (VPFC). Typically developing (TD) individuals with AD exhibit deficits of sensory gating, which can lead to sensory overload and disruption of higher cognitive processes. The auditory paired‐click paradigm has been used to evaluate sensory gating deficits in AD. We extend this inquiry to a cohort with DS to assess sensory gating in adults with DS by measuring the P50 and the N100 event‐related potential (ERP) components. The P50 component is elicited 50 ms post‐stimulus, involves the DLPFC and is sensitive to striatum‐dependent sensory gating. The N100 is elicited 100 ms post‐stimulus by auditory stimuli in absence of task demands.

Method

In this cross‐sectional study, data were collected using high‐density QEEG in 39 DS adults and 39 age‐matched TD controls. In this paradigm, two identical auditory stimuli (S1 and S2) were presented. For each stimuli, the response latency and amplitudes of the P50, and more salient N100 component were measured at the Cz and Fz electrode sites. General linear models examined the modulation of the ERP responses to S1 and S2 between the two groups.

Result

With P50 and N100 response amplitudes, an effect of stimulus was found. In the DS group, longer response latencies for the P50 and N100 corresponding to both S1 and S2 were observed.

Conclusion

In DS, the ability to gate‐out irrelevant sensory information is intact when compared to TD; however, there is an overall slower processing of auditory stimuli, which may be attributed to amyloidopathy. The EEG‐based paired‐click paradigm offers functional insight into potential biomarkers for pre‐clinical AD in DS.
Neighborhood racial/ethnic segregation and cognition in older adults
Authors: Meyer Oanh L , Besser Lilah M , Booker Michaela , Luu Elaine , Mitsova Diana , Tobias Michele , Whitmer Rachel A , Farias Sarah Tomaszewski , DeCarli Charles S , Mungas Dan M
Published: December 2021

Background

Social determinants of health, including neighborhood factors, play a key role in the health of diverse older adults. Yet few longitudinal studies have examined the role of neighborhood racial/ethnic segregation on cognitive function and cognitive decline in both Latinos and Blacks, two populations at greater risk for Alzheimer’s disease and related dementias. We examined how one measure of residential segregation is associated with cognitive outcomes in a diverse cohort.

Methods

We evaluated older non‐Hispanic White (NHW), Black, and Latino participants evaluated at the UC Davis Alzheimer’s Disease Research Center. Individual level addresses were geocoded at the initial visit and appended to U.S. Census 2010 data. Residential segregation was measured using the Getis‐Ord Gi* statistic; this spatial measure of clustering was created for Latino and Black clustering separately. Cognitive outcomes included validated measures of episodic memory, semantic memory, and executive function. We used mixed effects multivariate regression models to evaluate associations between segregation and cognitive function and decline, controlling for age, sex, education, cognitive status at initial visit, clinic versus community recruited, site, vascular risk score, number of visits, neighborhood SES, and population density.

Results

The sample included 452 participants (mean age=75, SD = 7), 64% female, and 46% NHW, 26% Black, and 21% Latino, in 309 census tracts/neighborhoods. In race‐stratified adjusted analyses, Blacks demonstrated worse episodic memory at baseline among those living in neighborhoods with a higher clustering of Blacks (ß = ‐0.046; 95% CI: ‐0.075, ‐0.016) and worse executive function at baseline among those living in neighborhoods with a higher clustering of Latinos (ß = ‐0.025; 95% CI: ‐0.042, ‐0.008). Latinos demonstrated slower annual declines on episodic memory when living in neighborhoods with a greater clustering of Blacks (ß = 0.008; 95% CI: 0.004, 0.011) and/or Latinos (ß = 0.003; 95% CI: 0.001, 0.005). NHWs had slower annual declines on semantic memory when living in neighborhoods with a greater clustering of Latinos (ß = 0.005; 95% CI: 0.001, 0.008).

Conclusions

There may be some benefit for Latinos and NHWs living in ethnically clustered neighborhoods. Future research is needed to further investigate these findings.
Sex and APOE genotype‐specific white matter changes in Alzheimer’s disease
Authors: Horgusluoglu‐Moloch Emrin , Wang Minghui , Zhou Xianxiao , Zeng Qi , Zhang Bin
Published: December 2021

Background

APOE ε4 genotype and sex difference represent strong risk factors for Alzheimer’s Disease (AD) that also lead to white matter (WM) microstructural changes. However, it is still not clear which brain regions have the strongest changes with APOE ε3 and ε4 allele carrier status and sex difference, and what are the key drivers and biological pathways underlying WM abnormality during disease progression. In this study, we present a new comprehensive framework to identify sex‐ and APOE genotype‐specific WM changes in specific brain regions with AD severity using the data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI‐GO/2).

Method

DTI‐derived features including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (L1), radial diffusivity (RD) were calculated from ADNIGO/2 (N = 232). ADNI participants were classified depending on their sex and APOE genotype status as female APOE ε3/3, male APOE ε3/3, female APOE ε4 positive, and male APOE ε4 positive. Through correlating DTI features with the clinical/cognitive traits, we systematically rank‐ordered 176 brain regions in relation to disease severity for each group. Multiscale Embedded Gene co‐Expression Network Analysis (MEGENA) was performed using processed expression data to identify clusters of highly correlated genes and DTI‐features as modules. Gene Set Enrichment Analysis (GSEA) was carried out to annotate each module with enriched pathways for each group.

Result

The parahippocampal gyrus (PHG)‐right, posterior thalamic radiation (PTR)‐left, hippocampus (HIPPO)‐left, and the superior temporal gyrus (STG)‐right were top‐ranked regions with sex and APOE ε3 and ε4 alleles carrier status (Figure 1A‐D). WM changes in PTR‐right are the only specific for the male APOE ε4+ group compared to the other groups. PHG‐right is highly associated with worse AD clinical outcomes in APOE ε4 allele carriers regardless of sex difference. DTI features in MTWM‐left is significantly correlated with only female APOE ε3 group. Besides, the immune system, mitochondrial regulation, and myeloid cell differentiation are among the pathways enriched with modules in different sex and APOE genotype groups in top brain regions (Table 1).

Conclusion

Enhanced understanding of the biological processes and key drivers related to sex‐ and APOE genotype‐specific WM microstructural changes could lead to novel therapeutic strategies for AD.
Comparison of UDSNB 3.0 normative data with those developed in a diverse community cohort of older adults: Results from the Einstein Aging Study
Authors: Wang Cuiling , Katz Mindy J. , Chang Katherine H , Derby Carol A. , Lipton Richard B. , Rabin Laura
Published: December 2021

Background

Normative data for the Uniform Data Set, Version 3 Neuropsychological Battery (UDSNB3.0), from the database of the University of Washington’s National Alzheimer’s Coordinating Center (NACC), are limited by an overrepresentation of white, female, and highly‐educated older adults. Original norms, based on >3000 cognitively normal participants from US Alzheimer’s Disease Centers (ADCs), did not divide the sample by race/ethnicity as the sample is 83% White (Weintraub et al., 2018). In the current study, we compare the originally reported UDS norms with those derived from a systematically‐recruited, community‐residing, racially/ethnically diverse cohort of older adults and provide expanded norms for Black‐Americans and Whites.

Methods

The Einstein Aging Study (EAS) is a longitudinal cohort of racially/ethnically diverse community‐dwelling individuals, ≥ age 70, who reside in the Bronx, NY. Analyses include data from 225 cognitively normal EAS participants and 1759 cognitively normal participants ≥ age 70 from the NACC database. Descriptive statistics are in Table 1. Linear regression models were used to examine the effects of demographic factors—including sex, age, education, and further including race—on UDSNB3.0 test performance in the two samples and to develop demographically adjusted z‐scores for the EAS cohort.

Results

In both EAS and NACC samples, higher scores were observed for those with more years of education. Both samples demonstrated lower scores for non‐Hispanic Blacks and other racial/ethnic groups compared to non‐Hispanic Whites (Table 2). After accounting for sex, age, education, and race, mean performance was lower in the EAS sample compared to that of NACC across neurocognitive domains, including memory, visuospatial skills, attention, language, processing speed, and executive function (Tables 3‐4).

Conclusion

Racial differences in UDSNB3.0 tests were observed in both EAS and NACC samples. These differences between the UDSNB 3.0 normative data and the EAS sample, after adjusting for age, sex, education, and race, suggest that normative data from samples of optimally healthy, well‐educated individuals are not generalizable to those in diverse, urban communities. Furthermore, results suggest a need for local norms for community‐dwelling, racially/ethnically diverse cohorts to improve diagnostic accuracy and the ability to distinguish cognitive impairment from healthy cognitive aging.
Metabolic and cerebrovascular effects of gemfibrozil treatment: A randomized, placebo‐controlled, double‐blind, phase II clinical trial for dementia prevention
Authors: Jicha Gregory A , Kryscio Richard J , Nelson Peter T
Published: December 2021

Background

“Fibrates” (PPAR‐alpha agonists) are lipid lowering agents that are widely known to improve metabolic parameters and potentially reduce cerebrovascular (CVD) disease burden. We conducted a parallel‐design, double‐blind, placebo‐controlled clinical trial of gemfibrozil targeting predementia AD (NCT02045056). An administrative supplement funded by the NIH/NIA allowed us to evaluate metabolic and CVD outcomes that may contribute to mixed AD‐CVD cognitive decline.

Method

Patients with prodromal AD (CDR 0‐0.5) were randomized to receive gemfibrozil (600 mg twice daily) or placebo for 48 weeks. Metabolic and CVD endpoints included: 1) metabolic parameters including plasma glucose, HgbA1c, cholesterol, triglyceride levels, and inflammatory plasma biomarker profiles and 2) MRI imaging biomarkers including white matter hyperintensity (WMH) volumes, DTI, and ASL measures.

Result

Primary outcomes of the study reported previously include an excellent safety profile, CNS penetration, as well as trends for reducing Ab42 levels (0=0.063), hippocampal atrophy (p=0.15), and decline on the CANS‐MCI cognitive battery (MMTM p<0.01). Metabolic and cerebrovascular effects of gemfibrozil treatment included significant improvements in plasma glucose (p<0.001), lipid levels (p<0.001), and trends in CVD imaging biomarkers including reductions in WMH volumes (p=0.33), accompanied by ASL perfusion increases in the dorsolateral prefrontal cortex (p=0.13), hippocampus (p=0.10) and posterior cingulate cortex (p=0.16). Attenuation of reductions in the anti‐inflammatory cytokine IL‐13 (p<0.05) and increases in proinflammatory TNFa (p=0.08) were evident in the treatment group.

Conclusion

The overlap in disease mechanisms and possible therapeutics for prevention of dementia caused by AD and or CVD is remarkable. These pathologies frequently coexist in the aging population and appear to act additively as well as synergistically, It is quite possible that the beneficial effects seen on cognitive outcome measures in this study might be more related to metabolic and CVD influences than on the direct effects influencing AD pathways that were the target of this clinical intervention. Strong consideration of incorporating metabolic and CVD outcomes in AD trials may help us disentangle the conundrum of risks and treatments for both CVD and AD that are the leading causes of dementia worldwide today.
TMS‐EEG as a measure of cortical hyperexcitability in motor and parietal cortex in Alzheimer’s disease: A pilot study
Authors: Buss Stephanie S. , Ross Jessica , Hagan Brenna , Press Daniel Z. , Shafi Mouhsin
Published: December 2021

Background

Patients with Alzheimer’s disease (AD) have abnormally high cortical excitability, with an increased risk of seizures and epileptiform discharges. Transcranial magnetic stimulation with electroencephalography (TMS‐EEG) can noninvasively measure cortical excitability in local brain regions, and has shown increased excitability in motor cortex in AD. However, practical applications of TMS‐EEG measures are currently limited by a dearth of data from brain regions involved early‐on in AD, such as the parietal cortex. This pilot study investigated the feasibility of using TMS‐EEG to compare "Excitability Gain" across multiple brain regions in AD.

Method

Three biomarker‐confirmed AD participants (mean age 71, 1 female) and 4 healthy control participants (HC, mean age 68, 2 female) enrolled in this pilot study. Single‐pulse TMS stimulation was applied to left primary motor cortex (M1) and inferior parietal cortex (IPL), with 120 pulses given at both 120% and 135% resting motor threshold (RMT). We assessed tolerability of this protocol. TMS‐evoked potentials (TEPs) were measured as the average EEG response after a TMS pulse. The percent change in TEP between the two stimulation intensities was calculated (TEP Excitability Gain, %change). A power calculation for two sample means was performed to determine the number of subjects needed to demonstrate a between‐group difference in IPL excitability.

Result

The procedure was well‐tolerated; one HC participant complained of a mild positional neck discomfort. In HCs, TEP Excitability Gain was 12 (±19 SD) percent in M1, and ‐5 (±12 SD) percent in IPL. In AD participants, TEP Excitability Gain was 39 (±50 SD) percent in M1, and 31 (±31 SD) percent in IPL (Figure 1). Assuming a SD of 31 for IPL stimulation, a sample size of 13 in each group would have a >80% power to detect a between‐group difference of 36% in TEP Excitability Gain with an alpha of 0.05.

Conclusion

TMS‐EEG measures of "Excitability Gain" are feasible in AD participants. A sample size of 13 in each group will be required to test for a between‐group difference of cortical excitability in the parietal lobe. TMS‐EEG may be a useful tool to measure cortical excitability across multiple brain regions in AD.
Brainwaves correlate with senior moments in preclinical older adults: Towards a cognitive screening protocol using a wireless device
Authors: Jiang Yang , Wang Baoxi , Borhani Soheil , Gottschalk Karah E. , Kelly Margaret , Zhao Xiaopeng , Jicha Gregory A.
Published: December 2021

Background

We recently reported longitudinal findings that specific frontal memory‐related signatures in cognitively intact older adults, who later (on average 5 years after baseline) were diagnosed as mild cognitively impaired (MCI), had already shown left‐frontal patterns of MCI patients. Older adults who did not show the MCI‐patterns remained normal ten years post baseline testing (Jiang et al. 2021). Here we test the hypothesis that left frontal MCI‐like brainwaves are associated with online poor and slowed memory retrievals (senior moments).

Method

Traditional scalp electroencephalogram (EEG) headsets (64‐ or 32 channels), typically used in the research laboratory, are limited for large‐scale clinical and community screening. Using a clinical‐friendly protocol (15‐min) with a wireless headset (eMotiv), we recorded (EEG) during both resting state (eyes‐closed and eyes‐open) and during a working memory task in 43 healthy older adults (median age 68; 23 females) in a clinical setting in central Kentucky.

Result

“Senior moments” were time intervals of 1‐2 seconds, during which participants’ memory performance dipped, with slower reaction times and less accuracy. Even for trials with accurate memory retrieval, we found that longer reaction times were associated with MCI‐like signatures in left‐frontal sites, compared to trials for which retrieval was both accurate and fast. We divided the memory‐related brainwaves of individuals who were normal cognition (NC) into NC‐like and MCI‐like patterns. We found that trials with MCI‐like patterns were associated with moments of poorer memory performance.

Conclusion

Our results suggest that the "senior moments" are MCI‐like brain moments. MCI‐like brainwave patterns are mixed with normal brain patterns in a cognitively normal older individual. Our short protocol using a wearable and wireless headset during resting‐state and a working memory task is a real‐time, sensitive, noninvasive, quick, and affordable pre‐screening tool for predicting cognitive decline in a clinical setting.
Visuospatial impairment in logopenic progressive aphasia: Why do we not “see” it?
Authors: Pudumjee Shehroo , Martin Peter R , Bailey Kimberly , Caves Courtney , Sharp Blair , Graff‐Radford Jonathan , Duffy Joseph R , Clark Heather M , Botha Hugo , Josephs Keith A , Whitwell Jennifer L , Machulda Mary M.
Published: December 2021

Background

Logopenic progressive aphasia (LPA) and posterior cortical atrophy (PCA) have distinct patterns of hypometabolism and atrophy. However, these clinical syndromes overlap: visuospatial impairment has been documented in LPA and aphasia in PCA. Rey‐Osterrieth Complex Figure – Copy (Rey‐O Copy) performance is correlated with parietal‐occipital atrophy in LPA. We explore visuospatial impairment on the Rey‐O Copy in LPA and PCA with the Mayo Older Americans Normative Studies (MOANS; which uses Meyers & Meyers criteria) and the Boston Qualitative Scoring System (BQSS). We also examine the proportion of visuospatial impairment in LPA, an under‐appreciated phenomenon, compared to PCA wherein it is fundamental.

Method

Patients with LPA (n=25) or PCA (n=23) were recruited by the Neurodegenerative Research Group. Patients underwent comprehensive neuropsychological testing (including Rey‐O Copy) at baseline visit. Cut‐offs of T‐score=40 (BQSS) or scaled score=7 (MOANS) were used based on normative data. Proportions of patients with low performance were examined across LPA and PCA groups. Individual logistic regressions and AUROC analyses were then conducted to quantify differences in visuospatial impairment in LPA and PCA with both scoring systems. Identical analyses were conducted using raw scores corrected for age and sex, to avoid confounds of adjustments in normative data.

Result

LPA and PCA groups were comparable on age, sex, and disease duration (LPA Median = 2.7 years, IQR=1.9‐3.5; PCA Median = 3.6 years, IQR=1.5‐4.9); p=.823). Surprisingly, 52‐72% of LPA participants demonstrated impaired performance across scoring systems, relative to 96% of the PCA group identified by both scoring systems. Odds ratios (OR) for the Rey‐O Copy MOANS (OR = 1.59; p=.008) and BQSS Copy Presence and Accuracy index (CPA; OR = 1.13, p=.002) were significant, persisting for age‐ and sex‐ controlled raw scores, suggesting the odds of a PCA diagnosis increased with decrement on Rey‐O Copy. AUROC values ranged from 0.77 to 0.88 across these indices.

Conclusion

A substantial number of LPA participants showed visuospatial impairment, despite initial primary language complaints. Differentiation of diagnostic groups by the Rey‐O is likely underscored by relatively uniform, profound, visuospatial impairment in PCA with more variability in LPA. However, the degree of visuospatial impairment overlaps remarkably across diagnoses.
Characterizing the phenomenology of anxiety in older adults with subjective cognitive decline
Authors: Mah Linda , Murari Geetanjali , Vandermorris Susan , Verhoeff Nicolaas Paul L.G. , Herrmann Nathan
Published: December 2021

Background

Subjective cognitive decline (SCD), defined as perception of memory or other cognitive decline with normal test performance, is conceptualized as a preclinical stage of Alzheimer’s disease. Formulations of SCD typically include presence of worry or concern regarding the perceived cognitive decline. Accordingly, SCD is associated with anxiety, but its underlying etiology remains unclear. In the current study, we compared mood, anxiety, and personality amongst SCD, mild cognitive impairment (MCI), and cognitively unimpaired (CU) older adults to characterize anxiety in SCD.

Methods

146 older adults received psychiatric/medical assessments, self‐report measures of subjective memory, and neuropsychological (NP) tests to establish diagnosis. MCI [n=33,17F, age 72.3(SD6.7)] had subjective memory/other cognitive complaints, impaired NP performance, and functional independence. SCD [n=71,49F, age 71.1(SD6.3)] endorsed subjective memory decline with worry and normal NP performance. CU [n=42, 27F, age 70.6(SD6.8)] had normal NP performance and absence of subjective memory decline with worry. Participants were free of lifetime history of psychiatric illness and neurological conditions. They completed the State Trait Anxiety Inventory (STAI), NEO Five‐Factor Inventory (NEO‐FFI) which includes neuroticism, Health Anxiety Inventory (HAI), and Geriatric Depression Scale (GDS). Multivariate ANOVA was used to examine group differences, followed by post hoc comparisons with Sidak correction.

Results

Groups differed in STAI‐trait, NEO‐FFI neuroticism, HAI, and GDS [F(2,143)=5.26, P=.006; F(2,143)=3.26, P=.041; F(2,143)=4.61, P=.011; F(2,143)=7.66, P=.046, respectively]. Relative to CU, STAI‐trait and HAI scores were elevated in SCD and MCI (P’s<.05). NEO‐FFI neuroticism was higher in SCD compared to CU (P=.024). No differences between SCD and MCI were detected on any measure. Differences in GDS scores did not survive Sidak correction.

Conclusions

Anxiety symptoms in SCD without lifetime history of psychiatric illness are best conceptualized as neuroticism, a personality trait that increases proneness to negative affect. Based on non‐elevated levels of state anxiety and depression, anxiety in SCD does not appear to represent an emotional reaction to cognitive decline nor epiphenomena of subclinical depression. Health anxiety, or belief that one has a serious illness, was comparable in SCD and MCI. Future research is needed to clarify the role of neuroticism and its links with subjective and objective memory in SCD.
Towards a universal cortical tau sampling mask
Authors: Dore Vincent , Bohorquez Sandra Sanabria , Leuzy Antoine , Shimada Hitoshi , Bullich Santiago , Bourgeat Pierrick , Burnham Samantha C , Huang Kun , Krishnadas Natasha , Fripp Jurgen , Takado Yuhei , Stephens Andrew W , Weimer Robby , Rowe Christopher C , Higuchi Makoto , Hansson Oskar , Villemagne Victor L
Published: December 2021

Background

The introduction of the AT(N) framework raised several issues in regards to the definition of T+. What brain regions should be sampled? Based on one or on multiple tracers? In this work, we developed a “universal” cortical tau mask for the AD continuum derived from all the major tau ligands. This “universal” cortical mask will serve as the common tau area for all tracers over which several different regional sampling VOI or composites can be then applied. Guaranteeing sampling of the same common regions is the first step to develop a common scale for all tau tracers: the CenTauR.

Method

464 participants underwent tau scans with either 18F‐AV1451 (CN=54/AD=24), 18F‐MK6240 (CN=157/AD=22), 18F‐PI2620 (CN=10/AD=21), 18F‐PM‐PBB3 (CN=30/AD=28), 18F‐GTP1 (CN=15/AD=38) or 18F‐RO948 (CN=35/AD=30). All CN were Aß‐ and all AD were Aß+. The tau scans were spatially normalized using CapAIBL and the cerebellar cortex was used as reference region. For each tracer, a difference image between the means of the Aß‐ CN and Aß+ AD patients was generated. Difference images were subsequently thresholded at 1/3 of the difference between Aß‐ CN and Aß+ AD in the inferior temporal lobe. A single tau specific mask was then constructed from the intersection of all the specific tau tracer masks.

A MRI‐derived grey matter mask at PET resolution was applied to the composite mask only sampling grey matter regions. Finally, the mask was mirrored and fused to remove the hemispherical asymmetry of tau pathology. Agreement between masks was assessed by dice‐scores.

Result

Visually, all the tracer‐specific masks appeared very similar. None of the known off‐target binding regions were discernible in the resulting masks (Figure 1). There was good agreement between all masks, with dice‐scores of 0.60 and 0.66 for cortical regions.

Conclusion

We constructed an “universal” tau mask for the AD continuum based on all the commonly used tau tracers aiming at standardizing tau sampling and quantification across tracers and across centres. The “universal” tau mask demarcates a tau specific space that can then be sub‐segmented into smaller regions to focus on specific areas or composite regions that might better capture early tau deposition and spreading.
Longitudinal characterization of mild cognitive impairment and dementia in World Trade Center responders at midlife
Authors: Clouston Sean A.P. , Mann Frank P , Diminich Erica D , Kritikos Minos , Pellecchia Alison , Mejia‐Santiago Stephanie , Carr Melissa , Kotov Roman , Gandy Samuel , Sano Mary , Bromet Evelyn , Luft Benjamin J
Published: December 2021

Background

Though the Montreal Cognitive Assessment (MoCA) is validated for cross‐sectional assessment, there is limited guidance as to methods for reliably identifying incident cases of Mild Cognitive Impairment (MCI) and dementia. The goal of this study was to examine characteristics of individuals identified as having MCI and dementia using different diagnostic routines.

Methods

World Trade Center (WTC) responders are a unique population, not only because of the historic significance of the traumatic exposures many endured while onsite following the terrorist attacks in New York City on 9/11/2001 but also given responders participation in a long‐term monitoring program established by the Centers for Disease Control (CDC) in 2002 to monitor the long‐term effects of WTC exposures on health outcomes. Since 2014, we have administered the MoCA to responders over at least three assessments (n=2,370). The MoCA was administered by trained research staff; alternate versions were used to account for learning. Seven diagnostic routines were examined that variably examined adjusting for learning, objective evidence of functional limitations, and cognitive decline to identify one with the least variability in outcome. Stability of diagnostic outcome was the primary outcome. Follow‐up studies in subsets of the population included a detailed computer‐assisted neuropsychological examination, measures of physical functional limitations, a cross‐sectional sample of plasma based biomarkers measured using Simoa (e.g., b‐Amyloid1‐40, b‐Amyloid1‐42, Total‐Tau, Glial Fibrillary Acidic Protein, and Neurofilament‐Light), a cross‐sectional assessment of cortical thickness, and a self‐reported version of the Mild Behavioral Checklist.

Results

8.0% of responders were male, 4.3% were Black, and 7.7% were Hispanic. The mean age at initial MoCA assessment was 52.6 years old (SD=8.1). There was enormous variability in longitudinal stability in MCI and dementia diagnostic outcomes between different longitudinal diagnostic routines (Spearman’s r=0.22‐0.86). Though domain‐specific sub‐scales with high internal consistency (a=0.92‐0.97) were available, the most stable definition relied on MoCA scores adjusted for learning and expected within‐person test‐retest score distributions. MCI and dementia identified using all diagnostic routines were variably associated poorer cognitive functioning and with biomarkers.

Conclusion

This study gives guidance about differences between methods relying on the MoCA to longitudinally screen WTC responders for MCI and dementia at midlife.
Changes in wall thickness of retinal arterioles as a surrogate marker of intracranial vascular pathology
Authors: Abdelhak Ahmed , Solomon Isaac , Saias Alexandra , Montes Shivany Condor , Cordano Christian , Asken Breton , Fonseca Corrina , Oertel Frederike Cosima , Arfanakis Konstantinos , Staffaroni Adam M. , Geschwind Michael , Elahi Fanny M. , Green Ari J.
Published: December 2021

Background

Microvascular injury is a significant contributor to cognitive impairment. Conventional neuroimaging is inadequate for assessing microvascular changes in the brain. Intensity‐based Retinal Arteriolar Visualization in OCT (I‐bRAVO) is a novel method that enables rapid, direct and non‐invasive visualization of retinal arterioles using standard optical coherence tomography images. We aimed to assess retinal microvascular changes using I‐bRAVO and compare it to measures of arteriolosclerosis, white and grey matter damage, and cognitive function.

Method

We included 500 eyes from 250 subjects with sporadic (n=91) and genetic (i.e., Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy, n=21) cerebral small vessel diseases (CSVD), non‐vascular neurodegenerative diseases (NVND, n=113), and healthy controls (HC, n=25). Mean Wall Thickness (MWT) and Wall to Lumen Ratio (WLR) were analyzed in association with imaging and cognitive markers of vascular pathology, including novel imaging classifier of brain arteriolosclerosis (ARTS), MRI markers of white matter injury (Fazekas scale), and grey and white matter atrophy, as well as the Uniform Data Set (v3.0) executive function (UDS3‐EF) score. Linear mixed‐effect models with subject‐specific intercepts were fitted using restricted maximum likelihood estimation.

Result

ARTS score correlated with MWT (ρ =0.44, P<0.001) and WLR (ρ=0.48, P<0.001). MWT and WLR were higher in CSVD (MWT: 28.18µm, WLR: 0.30) compared with NVND (MWT: 26.72µm, WLR: 0.29) and HC (MWT: 25.17µm, WLR: 0.25) (P<0.001). MWT and WLR were positively associated with superficial white matter disease burden (B= 0.07, 95% CI [0.05 – 0.1], and 5.63 [4.03 – 7.22], respectively, P<0.0001). A similar association was observed between MWT, WLR and deep white matter lesion load. WLR correlated inversely with grey (ρ =0.40, P<0.05) and white matter volume (ρ =0.48, P<0.01) in subjects with vascular cognitive impairment. WLR differentiated cognitively healthy individuals with vascular white matter lesions from those without (AUC= 0.81, P<0.001) with 94% specificity (cutoff value: 0.275). In asymptomatic CSVD, higher WLR was associated with a lower age‐, sex‐ and education‐adjusted UDS3‐EF (β=‐3.1 [‐6.3 – ‐0.01], P<0.05).

Conclusion

We describe a rapid, inexpensive novel technique for assessing retinal arterioles as a surrogate marker for intracranial vascular pathology and as a tool for early recognition of presymptomatic CSVD.
Does inflammation explain the link between multiple sensory impairment and dementia?
Authors: Brenowitz Willa D , Eastman Jennifer Ann , Leng Yue , Yaffe Kristine
Published: December 2021

Background

Multiple sensory impairments are associated with increased risk of dementia, but the underlying mechanisms are unclear. One potential explanation is that the association is due to shared risk factors such as inflammation. Our objective was to evaluate whether multisensory impairment was associated with markers of inflammation (interleukin‐6, and C‐Reactive Protein (CRP) independent of other health conditions and test whether inflammation might explain the association between multisensory impairments and dementia risk.

Method

We studied 1,794 black and white older adults from the Health, Aging, and Body Composition Study, a prospective cohort study of older adults who were aged 70‐79 and dementia‐free at enrollment. Sensory abilities were assessed at study years 3‐5, vision was measured by log contrast sensitivity, hearing by pure tone average at 500, 1,000, 2,000, and 4,000 Hz; smell by the 12‐item Cross Cultural Smell Identification Test; and touch by vibration detection threshold of the big toe. A multisensory score (0‐12) was calculated based on sample quartiles and summed across each sensory domain. Interleukin‐6, and CRP were assayed based on blood sample near baseline and log transformed. Incident dementia over follow‐up was determined based on a combination of hospitalization records, dementia medications, or clinically significant cognitive decline. Using regression models, we investigated the associations between inflammation biomarkers, multisensory impairment, and dementia with adjustment for demographics, health conditions, and health behaviors.

Result

Both measures of inflammation were associated with higher multisensory impairment scores. 1‐log interleukin‐6 was associated with 0.25 points worse multisensory score (95%CI: 0.10, 0.40; p>0.001), 1‐log CRP levels was associated with 0.11 points worse multisensory score (95%CI: 0.01, 0.20; p=0.02). Higher level of interleukin‐6 (HR = 1.18; 95% CI: 1.02, 1.37; p=0.03) but not CRP (p=0.84) was associated increased dementia risk. In adjusted models, a 1‐point increase in the multisensory score was associated with a 14% higher risk of dementia (95% CI: 1.08; 1.20), estimates were similar even after including interleukin‐6 as an explanatory variable.

Conclusion

Inflammation was independently associated with worse multisensory impairment scores. Although inflammation is also associated with dementia, it did not explain the association between multisensory impairment and dementia.
Brief smell identification test performance in RBD, DLB and AD
Authors: Forsberg Leah K. , Syrjanen Jeremy A , Ferman Tanis J , Boeve Bradley F. , Miyagawa Toji , Graff‐Radford Neill R. , Knopman David S. , Graff‐Radford Jonathan , Savica Rodolfo , Savica Rodolfo , Jones David T. , Fields Julie A. , Lucas John A. , Allen Laura A , St. Louis Erik K , Silber Michael H , Petersen Ronald C.
Published: December 2021

Background

Impaired olfaction has been associated with neurodegenerative diseases and may be a useful tool to aid in diagnosis or track disease progression. We sought to compare olfaction in participants with the clinical diagnoses of idiopathic REM sleep behavior disorder (RBD), dementia with Lewy bodies (DLB), or Alzheimer’s disease dementia (AD).

Method

Participants from the Mayo Clinic Alzheimer’s Disease Research Center database who had a diagnosis of RBD (n=27, 56% male), DLB (n=51, 84% male), or AD (n=83, 47% male), and were given the Brief Smell Identification Test (B‐SIT) were included in this analysis. The B‐SIT score was calculated as the sum of correct responses (12 possible). Scores were categorized as reflecting anosmia (<6), hyposmia (6‐10), and normal olfactory function (>10). All participants underwent clinical and neuropsychological evaluations.

Result

Global cognition was lower in AD and DLB than RBD (MMSE 21.5 ±4.9 in AD, 23.3 ±4.3 in DLB, 28.8 ± 1.2 in RBD; p <0.001). The mean B‐SIT total score was significantly lower for DLB (4.5 ± 3.1) compared to RBD (7.5 ± 3.0) or AD (7.0 ± 2.7) (p<0.001) using an ANOVA F‐test. Anosmia was present in 76% of DLB, which compared to 32% in RBD, and 32% in AD (p=0.9). Hyposmia was present in 18% of DLB, 47% of RBD, and 52% of AD (p=ns). Of 22 patients with normal olfaction, X% were DLB, X% RBD, and X% AD (p=X). An item analysis illustrated that participants with DLB were less likely to identify Menthol, Clove, Strawberry, Smoke, and Soap than those with RBD and AD. On serial examination, 12 RBD (60%) patients’ B‐SIT score decreased by at least one point at their most recent visit compared to their baseline visit.

Conclusion

These findings suggest that impaired olfactory function is frequent in RBD, DLB and AD, with olfaction being worst in DLB in this cohort. Olfaction was declining in most of those with RBD who underwent serial evaluations. Further analyses are needed to determine if any scents are more sensitive to phenotype, progression, and degree of cognitive impairment. Supported by: NIH grants AG016574, NS100620, AG056639, AG015866
Evaluation of blood pressure and cognitive function using individual participant data meta‐analysis: The Life‐Course Blood Pressure Cognition (LCBP‐COG) study
Authors: Xu Ying , McFall G. Peggy , Rydén Lina , Skoog Johan , Tully Phillip J , Anderson Craig S , Anstey Kaarin J , Cherbuin Nicolas , Dixon Roger A , Skoog Ingmar , Peters Ruth
Published: December 2021

Background

The prognostic significance of various blood pressure (BP) indices (i.e. systolic BP [SBP], diastolic BP [DBP], pulse pressure [PP] and mean arterial pressure [MAP]) on cardio‐ and cerebrovascular health vary across age groups. We examined the association between baseline BP indices in mid‐ and late‐life and cognitive function over a 9‐15 year period.

Method

We performed pooled analyses of data from 3 longitudinal cohort studies. The Personality and Total Health (PATH) Through Life study of adults initially aged 40‐44 and 60‐64 years in Australia, and Victoria Longitudinal Study (VLS) of adults initially aged 55‐85 years in Canada, included four waves of data collection every 4‐5 years. The Gothenburg H70 Birth cohort study of adults initially aged 70 years included three waves of data collection every 4‐5 years. The association between baseline BP and cognitive decline on the Mini‐Mental State Examination (MMSE) was categorized using the reliable change index (Duff K. 2012) and analyzed using logistic regression adjusted for age, sex, and study. Additional analyses examined relationships between baseline BP and repeated cognitive measures of memory, attention and processing speed, and executive function, using linear mixed models (PATH and H70). Only participants with complete BP and cognitive measures were included.

Result

Data from 2912 participants (mean baseline age 54.3 years, range 40 to 83 years, 1395 (47.9%) male) were included. Examining baseline BP and age, we observed SBP increasing with age until a small decrease at around 80 years. DBP and MAP also showed an increase with age until early late‐life (around 60 years) and were lower at older ages, PP consistently increased (Figure 1). There were no relationships between baseline BP measures and MMSE. For PATH only, higher SBP (P=0.002), DBP (P=0.0007) and MAP (P=0.0006) at age 40 years, and higher DBP (P=0.004) at 60 years, were associated with greater annual deterioration in attention and processing speed (symbol‐digit‐modalities test) over the subsequent decade (Figure 2).

Conclusion

Higher BP in midlife and DBP in early late‐life, were associated with a greater decline in measures of attention and processing speed. We observed no associations between BP and MMSE decline.