bluuebunny/crossref_metadata_2025 huggingface dataset:
Unfulfilled potential for secondary prevention of cognitive decline in individuals with covert brain infarcts: A population‐based study
Authors: Wolters Frank J , Ikram M Arfan , Bos Daniel , Raso Francesco Mattace , Vernooij Meike W
Published: December 2021

Background

Modifiable cardiometabolic risk factors account for about 25% of all dementia, including Alzheimer’s disease. Risk factor control is therefore pivotal, particularly in patients with high risk of dementia after stroke. However, 15‐20% of elderly individuals have brain infarcts on routine MRI that have not produced notable stroke symptoms (‘covert brain infarcts’ [CBI]), and in whom risk factors consequently may not be treated optimally.

Method

We included 5934 participants of the population‐based Rotterdam Study who underwent routine brain MRI and cognitive assessment between 2005‐2016 (mean age 65 years, 55% women). Clinical stroke symptoms were ascertained through interview and medical records review. In individuals with CBI, we determined the extent to which cardiometabolic risk factors (systolic blood pressure, LDL‐cholesterol, serum glucose) are managed according to AHA/ASA guidelines for secondary stroke prevention.

Result

Of 507 patients with brain infarction on MRI, 395 (78%) had not had prior clinical stroke. Prevalence of CBI increased steeply with age, from 2% at age 45‐49 to 20% after age 85, and was associated with worse performance on a cognitive assessment battery (β[95%CI]=‐0.19[‐0.32;‐0.06]). 34% of participants >60 years with CBI had one or more untreated, modifiable cardiometabolic risk factors, compared to 9% of participants with prior clinical stroke, and optimal risk factor control was twice as likely after clinical stroke than with covert brain infarcts (28 vs. 13%). Among individuals with CBI, those with suboptimal cardiometabolic risk management did worse on cognitive testing, notably in the memory domain (global cognition– β[95%CI]=‐0.27[‐0.65;0.12]; memory– β=‐0.40[‐0.73;‐0.08]). Similar differences were seen when additionally examining lifestyle factors (obesity and smoking). Of participants with CBI, less than half (45%) were using antithrombotic medication, compared to 88% after clinical stroke. The percentage of undertreated individuals was similar when comparing the earlier (2005‐2010) with the later years of the study (2011‐2016).

Conclusion

In one third of individuals with covert brain infarcts, cardiometabolic risk factor management does not align with secondary stroke prevention guidelines, potentially resulting in poorer cognitive function. These findings should prompt further study into the optimal secondary preventive strategies for this large group of elderly individuals with undiagnosed covert brain infarcts.
Baseline characteristics in Japan‐multimodal intervention trial for prevention of dementia (J‐MINT) Tamba study
Authors: Ono Rei , Kowa Hisatomo , Oki Yutaro , Osaki Tohmi , Murata Shunsuke , Kumagai Ryoko , Uchida Kazuaki , Yasuda Hisafumi , Kido Yoshiaki
Published: December 2021

Background

To prevent Alzheimer’s disease, a multimodal intervention has been tried in world wide. J‐MINT is a trial in Japan and is studied in three different areas. J‐MINT Tamba, one of substudies of J‐MINT, has begun in September, 2020 in a Japanese rural area (UMIN000041938). The aim of this study is to report the characteristics of participants at the baseline, especially focusing on APOE subtypes and their cognitive functions.

Method

This study was cross‐sectional design. The inclusion criteria in this study were as follows; 1) Tamba citizen aged 65‐85 at the time of enrollment, 2) 24 or higher in the Mini‐Mental State Examination, and 3) having at least 1 of the following vascular risks (Treating hypertension or having systolic BP >=140 mm Hg or diastolic BP >= 85 mm Hg and treating diabetes or HbA1c >=6.0%). Cognitive functions were evaluated by following tests; the Trail Making Test (TMT) part A and part B, forward digit span, backward digit span, the Digit Symbol Substitution Test (DSST), the logical memory test from WMS‐R (immediate and delayed recall), and the Free and Cued Selective Reminding Test (FCSRT). The APOE epsilon 4 carrier or noncarrier were identified by serum blood test. Additionally, life‐related factors and number of drug use and type were assessed by self‐reported questionnaire. We performed statistical analyses using multiple regression, with each cognitive function as the dependent variables, the APOE epsilon 4 carrier and the other factors (and interaction) as the independent variable, and age and sex as confounding variables.

Result

Total 203 elderly were registered (mean age: 73.9 ± 4.8 years, females: 71.4%). The number of participants of APOE epsilon 4 carrier were 18.6% and that of participants with polypharmacy were 35.8%. Although the cognitive functions were not related with the APOE epsilon 4 carrier, TMT part A and DSST were observed the interaction between the APOE epsilon 4 carrier and polypharmacy (coefficient: 16.2, p values < 0.01; ‐10.1, 0.03).

Conclusion

Coexistence of APOE epsilon 4 and polypharmacy showed lower cognitive functions in spite of the community‐dwelling elderly with normal cognition. These elderlies might develop cognitive decline in early phase.
Task‐free functional networks related to emotion processing in frontotemporal lobar degeneration
Authors: Canu Elisa , Calderaro Davide , Castelnovo Veronica , Leocadi Michela , Basaia Silvia , Filippi Massimo , Agosta Federica
Published: December 2021

Background

Nonverbal communication is a crucial aspect of interpersonal relationships, and defective emotion recognition can lead to altered social interactions. The aim of our study was to investigate the relationship between emotion processing and resting‐state functional connectivity (RS‐FC) in frontotemporal lobar degeneration (FTLD).

Method

80 FTLD patients and 65 age‐matched healthy controls underwent brain 3.0 Tesla MRI [3DT1‐weighted and RS‐functional MRI (RS‐fMRI)] and neuropsychological assessment, including the Comprehensive Affect Testing System (CATS). FLAME models in FSL were performed between each emotion construct and RS‐FC changes within crucial networks.

Result

FTLD patients performed worse than controls in all CATS‐subtests. In controls, a high performance at the emotion naming and emotion matching constructs was related with increased RS‐FC within the cerebellar network, and a high performance at the emotion discrimination construct was related with increased RS‐FC of the right occipital face area (OFA) within the visuo‐associative network. In FTLD patients, high performances at the emotion naming construct were related with increased RS‐FC of the bilateral OFA within the visuo‐associative network and the bilateral frontal pole within the default‐mode‐network, whereas high performances at the emotion matching construct were related with increased RS‐FC of the left OFA within the visuo‐associative network. Finally, in FTLD patients, high performances at each emotional construct were related with decreased RS‐FC within the basal ganglia network.

Conclusion

In healthy controls and FTLD patients, the RS‐FC within crucial networks is related to different constructs of emotion processing. In FTLD, the RS‐FC associated with emotional performances involved a large number of brain regions, likely due to brain functional specificity loss and compensatory attempts. These findings offer potential markers for detecting functional vulnerability linked to social interactions.

Disclosures. Supported by the Italian Ministry of Health (GR‐2013‐02357415); European Research Council (StG‐2016_714388_NeuroTRACK).
Investigating the impact of scatter correction on Centiloid
Authors: Li Shenpeng , O'Keefe Graeme , Gillman Ashley , Burnham Samantha C , Masters Colin L , Williams Robert , Rowe Christopher C , Fripp Jurgen , Bourgeat Pierrick , Villemagne Victor L , Dore Vincent
Published: December 2021

Background

Centiloid (CL) is a semiquantitative measure of amyloid‐β burden based on the ratio between neo‐cortical target region and the whole cerebellum. Photon scatter is one of the major sources of noise in PET data. Scatter correction methods are very different across PET cameras. In this study, we investigate how scatter correction affects the CL for inter/intra‐cameras by comparing PET images with/without scatter correction.

Method

203 subjects (Siemens mCT Biography (N=109), Philips Gemini TF 64 (N=94)) from the AIBL study were scanned with 18F‐NAV6240. All PET images were reconstructed off‐line with scatter correction enabled and then disabled. All images were processed by CapAIBL to generate CL values. The ΔCL, which was calculated as the difference between the scatter corrected CL and non‐scatter corrected CL, was investigated to quantify the impact of scatter correction. For the intra‐camera comparison, all subjects were categorised in three groups based on the head tilt along anteroposterior axis compared to the MNI‐152 template. For inter‐camera comparison, the head tilt angle was included as covariate into an ANOVA. Hierarchical linear regressions that included head tilt and camera models were used as covariates to investigate their effect on CL.

Result

Figure 1 shows that scatter correction has a larger impact on the cerebellum cortex than in neocortex. Figure 2 shows that scatter correction depends on the head position, and it has more impact on subjects with higher CL for both cameras. Figure 3 presents that scatter corrections from two different cameras have different impact on CL values. Both head tilt and camera model had an impact on the scatter correction with (F=19.5, p=1.67e‐5) and (F=109.4, p=1.1e‐20), respectively. The b coefficients were 0.38CL/degree for head tilt and 8.2CL for the camera model, where more scatter is corrected on the Siemens CT than on the Philips Gemini TF.

Conclusion

Our results show that difference in scatter correction from different cameras have a significant impact on CL, it is yet to be known whether it is caused by hardware difference or software difference. Additional investigations using test‐retest data is needed to further characterize the real impact of scatter correction on Centiloid.
Developing a blood‐derived gene expression biomarker specific for Alzheimer’s disease
Authors: Korukonda Anuradha , Dutkowski Janusz , Ronen Roy , Sachdev Pallavi
Published: December 2021

Background

Early detection, monitoring, and treatment of Alzheimer’s disease (AD) will require measurement of easily accessible and reliable fluid biomarkers. We compared brain and blood gene and pathway expression analyses to identify core features for discriminating AD from controls. The brain gene expression profile was generated using a dataset (GSE33000) from post‐mortem dorsolateral prefrontal cortex isolated from 624 AD patients and genotype‐matched control samples, while blood gene expression profiles were generated using GSE63060 (n=329) and GSE63061 (n=388) datasets derived from peripheral blood samples of two case‐controlled studies of the AddNeuroMed consortium.

Method

The gene expression datasets were retrieved from the Gene Expression Omnibus (GEO). Limma linear models were used to compute moderated T‐statistics and identify differentially expressed genes (DEGs) in the AD condition. Gene Set Enrichment Analysis (GSEA, applying the Piano R package to moderated T‐statistics from DEG analysis) was employed to identify significantly differentially regulated REACTOME and KEGG pathways. Comparison of the brain and blood‐derived analyses provided a common set of pathways modulated in AD patients.

Result

DEG analysis revealed 680, 116, and 21 upregulated genes and 136, 160, and 45 downregulated genes in GSE33000 (Brain), GSE63060, and GSE63061 (Blood) datasets, respectively (FDR < 0.05; upregulated: FC > 1.15, downregulated: FC < 0.8). Differential pathway expression analysis using GSEA (FDR < 0.05) yielded 218, 196, and 202 REACTOME and 151, 69, and 125 KEGG pathways in GSE33000, GSE63060, and GSE63061 datasets, respectively.

Notably, 21/115 and 56/103 up‐ and downregulated REACTOME pathways respectively, in the brain‐derived dataset were shared with the blood‐derived dataset (FDR < 0.05). Strikingly, 52.4% and 23.8% of the upregulated pathways were dominated by immune system and hemostasis, respectively. Meanwhile, 42.9% and 10.7% of the downregulated pathways included cell cycle and signal transduction pathways, respectively.

Conclusion

Systematic analysis of genes and pathways differentially expressed in AD samples across brain and blood identified common signatures reproducible across studies and showed potential for distinguishing between AD and control patients. Our results suggest the potential of employing a blood‐based gene expression panel for early diagnosis and disease monitoring of AD.
Multicenter reproducibility of quantitative susceptibility mapping of the entorhinal cortex and hippocampal subfields at 7T MRI
Authors: Adeyemi Oluwatobi F , Mougin Olivier , Bowtell Richard , Penny Gowland , Hosseini Akram A.
Published: December 2021

Background

T2*‐weighted MRI images can be processed to produce quantitative susceptibility maps (QSM). These reflect iron and myelin concentrations, which are disturbed in neurodegenerative cascade and Amyloidb/tau pathological states. Changes in susceptibility have been measured in various regions of the brain in association with ADRD disease severity [Kim, et al.NeuroImage: Clinical. 2017], particularly in the hippocampus, amygdala, precuneus and thalamus, but no study has focused on subfields of the hippocampus in ADRD. As part of the UK7T Network’s “Travelling Heads” study [Clarke, et al. NeuroImage 2020], our aim here was to assess the inter‐subject and inter‐site reproducibility of QSM mapping at 7T in the entorhinal cortex, hippocampal subfields, and dentate gyrus preparing for future multi‐site clinical studies of Alzheimer’s disease and Related Dementias (ADRD).

Method

Ten healthy volunteers (3 female, 7 males; age 32.0±5.9 years) were scanned using harmonized single‐echo T2*‐weighted gradient echo, T1‐weighted and T2‐weighted sequences, as described in [Clarke, et al. NeuroImage 2020]. Participants were scanned five times at their “home” site on one of the following 7T MRI scanners: 1xPhilips, 2xSiemens Magnetom, 2xSiemens Terra scanners.

ASHS [Yushkevich, et al. Human Brain Mapping. 2015] was used to segment the hippocampus from the combination of the high resolution T1 and T2 weighted data and a detailed atlas. The volume of each subfield was obtained from the segmentation using FSL (in CA2 and CA3 sub‐volumes were too small for these regions to be included in the susceptibility analysis.).QSM maps of the whole brain were produced using Multi‐Scale Dipole inversion (MSDI) [Acosta‐Cabronero, et al. NeuroImage. 2018] and the average and standard deviation of the susceptibility in each sub‐field in each scan was extracted.

Result

The median intraclass correlation coefficient (ICC) value for the susceptibility for each subfield was found to be 0.84, 0.48, 0.71, 0.83 and 0.78 for entorhinal cortex (ERC), subiculum (SUB), CA1, dentate gyrus (DG) and Tail, respectively.

Conclusion

Susceptibility can be measured with good reproducibility for the hippocampal subfields and entorhinal cortex in healthy subjects and this protocol can now be translated to clinical studies of ADRD.
A 13‐year longitudinal study of the impact of air pollution on cognition
Authors: Wu Jing , Grande Giulia , Stafoggia Massimo , Ljungman Petter , Laukka Erika J , Bellander Tom , Rizzuto Debora
Published: December 2021

Background

Accumulation of evidence has raised concern regarding the harmful effect of air pollution on cognitive function, but results are inconclusive. We aimed to investigate whether long‐term exposure to air pollutants may have an adverse effect on cognitive function in older adults residing in an urban area.

Method

Data for this study were obtained from the Swedish National Study on Aging and Care in Kungsholmen. Cognitive impairment, no dementia (CIND) was assessed by a comprehensive neuropsychological battery. We assessed long‐term residential concentrations of particulate matters (PM2.5 and PM10) and nitrogen oxides (NOx) with land use regression. Long‐term air pollution was included as a time‐varying variable. Hazard ratio (HR) and 95% confidence interval (CI) were estimated with Cox proportional hazards. Departures from linearity were presented by fitting models with cubic splines with 3 knots at fixed percentiles (10th, 50th, 90th) of its distribution. We further explored the effect of long‐term air pollution exposure on the progression of CIND cases assessed at baseline to dementia incidence, using Cox hazard models.

Result

Among 2499 participants, 351 individuals developed CIND during the follow‐up. A 1‐μg/m3 increment in PM2.5 exposure was associated with a 63% increased risk of CIND incidence (HR=1.63, 95%CI: 1.44‐1.86). Weaker associations were found for PM10 (HR=1.06, 95%CI: 1.01‐1.11) and NOx (HR=1.01, 95%CI: 1.00‐1.02). Among those CIND cases at baseline (N=607), 118 participants developed dementia during follow‐ups. We observed an increased hazard of dementia for a 1‐μg/m3 increment in PM2.5 exposure in individuals with prevalent CIND at baseline, although non‐statistically significant (HR=1.24, 95%CI: 0.88‐1.74).

Conclusion

We found suggestive evidence of an association between ambient air pollutants and incidence of CIND and its progression to dementia in older adults. Further research should focus more on the underlying mechanisms.
Self, insula and dementia with Lewy bodies
Authors: Tisserand Alice , Philippi Nathalie , Botzung Anne , Blanc Frédéric
Published: December 2021

Background

The objective is to review in the literature evidence of the relationship between the Self, the insular cortex, and Dementia with Lewy bodies (DLB). The notion of “Self” encompasses a subjective part that integrates the most internal bodily phenomena of self‐awareness, and an objective part that sustains autobiographical memory and its most specific details. Modifications of the Self, such as anosognosia and personal identity, or autobiographical memory deterioration, are frequently reported by relatives and noticed by clinicians, jointly with insular atrophy, which occurs early in the course of the disease.

Method

We performed research on PubMed and Google Scholar, using MeSH subheadings and keywords, limited to papers in English; 226 publications contributed to the review. The terms “Lewy bodies”, “Insula”, “Self” and different aspects related to the self, such as “subjective sense of self”, “self‐concept” and “autobiographical memory” were used to denote the themes of interest.

Result

The evidence suggest that insula is a multiconnected brain region involved in processing varied aspects of the self. On the one hand, insula’s posterior part integrates primary interoceptive representations through sensorimotor processes, and on the other hand insula’s anterior part sustains and integrates viscerosensory responses, socio‐emotional processing and cognitive functions, allowing the emergence of self‐awareness. In addition, changes in personal tastes resulting from insular atrophy have been highlighted in DLB. However, there is, to date, little work exploring the different components of the self (i.e. subjective sense of self; self‐concept; autobiographical memory) in DLB.

Conclusion

Based on our literature review, it seems that no experimental work have ever been performed on the Self in DLB. Numerous aspects related to the Self, from the most primitive to more elaborated ones are worthy of being studied in this affection, whose anatomic peculiarity sets in early insular damage. We intend to investigate these questionings in DLB, compared to Alzheimer disease – which is characterized by an early deterioration of episodic autobiographical memory – and healthy elderly population, by combining behavioral measures and multimodal neuroimaging, with a particular interest for the insular cortex.
Late‐life depression, allostatic load, and risk of dementia: The AGES‐Reykjavik study
Authors: Twait Emma L , Basten Maartje , Gerritsen Lotte , Gudnason Vilmundur , Launer Lenore J , Geerlings Mirjam I
Published: December 2021

Background

The biological underpinnings of the relationship between depression and dementia are currently not completely understood. Previous research has highlighted the role of vascular, metabolic, inflammatory, and stress markers in the role of both depression and dementia. Allostatic load has been an all‐encompassing term to describe these biological factors when investigating subgroups in individuals based on health characteristics. The current study aimed to elucidate if depression subtypes exist based on modifiable allostatic load factors using latent class analysis (LCA), and whether these subtypes have differing risk on incident all‐cause dementia, Alzheimer’s disease (AD), and non‐AD diagnosis using Cox regression analyses.

Method

The study included 5343 individuals without dementia at baseline from the AGES‐Reykjavik Study. Vascular factors (systolic blood pressure and pulse pressure), cholesterol (high‐density lipoprotein and low‐density lipoprotein), metabolic factors (abdominal circumference, fasting glucose, and triglycerides), inflammation (c‐reactive protein), and stress factors (salivary morning and evening cortisol) were used to indicate allostatic load. Both allostatic load indicators and depressive symptoms (Geriatric Depression Scale‐15) were assessed at baseline. Incident dementia was assessed after 12‐years follow‐up. Allostatic load indicators as well as each item on the GDS‐15 were used in the LCA.

Result

LCA revealed that allostatic load factors, more than the depression questionnaire, grouped the individuals in this cohort. We identified six classes, named based on their most identifying characteristics: ‘Average’ (34% prevalence), ‘Cardiovascular + metabolic risk’ (27% prevalence), ‘Slim’ (16% prevalence), ‘Depressed’ (10% prevalence), ‘Hypertension’ (10% prevalence), and ‘Diabetic’ (4% prevalence). Cox regression analyses found an increased risk for incident all‐cause dementia in the ‘Slim’, ‘Depressed’, and ‘Diabetic’ groups. The ‘Slim’ group had a specific risk for AD, and the ‘Depressed’ group for non‐AD dementias.

Conclusion

The findings suggest subgroups exist in older individuals based on allostatic load factors, with differing risk for incident dementia. This highlights the importance of early interventions in diabetes and depression and in monitoring for dementia symptoms.
Resting‐state alpha electroencephalographic rhythms are differently related to gender in cognitively unimpaired seniors and in patients with amnestic mild cognitive impairment due to Alzheimer’s disease
Authors: Lorenzo Ivan , Babiloni Claudio , Noce Giuseppe , Ferri Raffaele , Lizio Roberta , Lopez Susanna , Tucci Federico , Soricelli Andrea , Nobili Flavio Mariano , Arnaldi Dario , Famà Francesco , Giubilei Franco , Marizzoni Moira , Güntekin Bahar , Yener Gorsev , Stocchi Fabrizio , Frisoni Giovanni , Del Percio Claudio
Published: December 2021

Background

Here we tested the hypothesis that gender may diversely affect resting state eyes‐closed electroencephalographic (rsEEG) alpha (8‐12 Hz) rhythms recorded in normal elderly (Nold) seniors and patients with Alzheimer’s disease and mild cognitive impairment (ADMCI).

Method

Clinical and rsEEG datasets in 69 ADMCI and 57 Nold individuals ‐ matched as demography, education, and gender ‐ were taken from an international archive. The rsEEG rhythms were investigated at individual delta, theta, and alpha frequency bands as well as fixed beta (14‐30 Hz) and gamma (30‐40 Hz) bands. Each group was stratified into two subgroups based on gender (i.e., female and male).

Result

As compared to the Nold female subgroup, the male one showed greater reductions in the rsEEG alpha rhythms topographically widespread. In relation to the ADMCI female subgroup, the male one showed greater reductions in the rsEEG alpha rhythms with major topographical effects in posterior regions. Notably, the ADMCI subgroups pointed to similar cerebrospinal fluid AD diagnostic biomarkers, gray and white matter brain lesions as revealed by neuroimaging, and clinical and neuropsychological scores.

Conclusion

The present results suggest that gender may represent a deranging factor for dominant rsEEG alpha rhythms topographically widespread in Nold seniors and topographically posterior in ADMCI patients.
Mild cognitive impairment and transitions in cognitive status in the Systolic Blood Pressure Intervention Trial (SPRINT)
Authors: Gaussoin Sarah A , Pajewski Nicholas M , Chelune Gordon , Cleveland Maryjo , Crowe Michael G , Launer Lenore J , Lerner Alan J , Martindale‐Adams Jennifer , Nichols Linda O , Ogrocki Paula K , Sachs Bonnie C , Sink Kaycee M , Supiano Mark A , Wadley Virginia G , Wilson Valerie M , Wright Clinton B , Williamson Jeff D , Reboussin David M , Rapp Stephen R
Published: December 2021

Background

The Systolic Blood Pressure Intervention Trial (SPRINT) demonstrated a significant reduction in the occurrence of mild cognitive impairment (MCI) for adults with hypertension randomly assigned to intensive systolic blood pressure (SBP) lowering and a similar but non‐significant effect on incidence of dementia.. Given that individuals with MCI are at greater risk of progressing to dementia, an open question from the trial is the frequency of progression in cognitive status subsequent to an adjudication of MCI, and whether this associates with intensive SBP lowering.

Method

Randomized trial of community‐dwelling adults (≥50 years) with hypertension. Participants were randomized to a SBP goal of <120 mm Hg (intensive treatment; n=4678) or <140 mm Hg (standard treatment; n=4683). Adjudication of MCI or dementia followed standardized procedures by a panel of expert clinicians. Multistate survival models were used to examine transitions in cognitive status between normal cognitive function, MCI, and dementia, accounting for the competing risk of death.

Result

Among 9361 randomized participants (mean age, 67.9 years; 3332 women [35.6%]), 91.5% completed at least 1 follow‐up cognitive assessment over a median follow‐up of 5.1 years. Based on multistate modeling, from a state of normal cognitive function, the risk of transitioning to dementia in the next 2 years was 1.1% [95% Confidence Interval (CI): 1.0% to 1.3%]), with 2.3% [95% CI: 2.1% to 2.5%] of participants dying over that same interval. Subsequent to an adjudication of MCI, the probability of progressing to dementia in the next 2 years increased to 6.4% [95% CI: 5.3% to 7.8%], with the risk of death increasing to 8.2% [95% CI: 6.9% to 9.7%]. We did not observe any significant associations between treatment groups and transition risk within the multistate model, though power for these analyses was likely limited given the focus on complex transitions between multiple outcomes.

Conclusion

An adjudication of MCI in SPRINT was associated with an increased risk of progression to dementia and death in the following 2 years, highlighting the relevance of MCI as an outcome both within SPRINT and for future prevention trials of cognitive impairment.
How common is concurrent neurological and mood/anxiety disorder comorbidity over time? A population‐based cohort study in Ontario, Canada
Authors: Maclagan Laura C , Maxwell Colleen J , Harris Daniel A , Wang Xuesong , Guan Jun , Marrie Ruth Ann , Hogan David B , Austin Peter C , Vigod Simone N , Swartz Richard H. , Bronskill Susan E
Published: December 2021

Background

Neurological disorders and mental health conditions, including mood/anxiety disorders, are a leading cause of disability and healthcare use. These disorders have shared risk factors and commonly co‐occur in older adults. Mood/anxiety disorders are often under‐diagnosed and under‐treated among those with neurological disorders, potentially leading to more rapid symptom progression, worse health outcomes and increased health care use. We estimated the relative and absolute rates of neurological and mood/anxiety disorder comorbidity among adults in Ontario, Canada.

Method

We identified adults aged 40‐85 years on April 1st, 2002 in Ontario, Canada using health administrative databases. These individuals were followed for up to 14 years until March 31st, 2016. We estimated the association between between having a prior neurological disorder (dementia, Parkinson’s disease (PD), and stroke) or mood/anxiety disorder and developing a different, incident neurological or mood/anxiety disorder using cause‐specific hazard models. Exposure to prior disorders was modeled as a time‐varying covariate and death was considered a competing risk. Individuals who were not at risk for the specific incident outcome disorder were excluded from that model.

Result

All prior disorders were associated with increased rates of dementia: PD (adjHR= 4.05, 95%CI, 3.99‐4.11), stroke (adjHR=2.49, 95%CI, 2.47‐2.52), and mood/anxiety disorder (adjHR=1.79, 95%CI, 1.78‐1.80). Increased rates of PD were associated with prior dementia (adjHR=2.23, 95%CI, 2.17‐2.30) and mood/anxiety disorder (adjHR=1.77, 95% CI 1.74‐1.81), but not stroke (adjHR=1.04, 95% CI, 0.99 to 1.10). Rates of stroke were highest in persons with prior dementia (adjHR=1.56, 95% CI, 1.53 to 1.58) and showed more modest associations with PD (adjHR=1.21, 95% CI, 1.16 to 1.25) and mood/anxiety disorder (adjHR=1.09, 95% CI, 1.08 to 1.11). The associations were generally strongest in the six months following the prior disorder diagnosis, lowest in the interim periods (>six months to 10 years) and elevated in the later periods (10+ years) following diagnosis.

Conclusion

We observed associations between pairs of prior and incident neurological disorders and mood/anxiety disorder among middle‐ and older‐aged adults. Neurological and mental health comorbidity is common. This should be considered in clinical practice guidelines for these conditions and may necessitate care across multiple providers.
The COVID‐19 pandemic, a respiratory disease with a hidden time bomb in the brain: Impact on reserve and resilience
Authors: Amouyel Philippe , Dumont Magali , Dauchet Luc , Meirhaeghe Aline , Boulanger Eric , Hirsch Emmanuel
Published: December 2021

Background

We present an overview on the potential impact of COVID19 infection on cognitive reserve and resilience capacity. The presence of RNA virus in the brain and a pathognomonic symptom, the loss of smell and taste, suggest a long‐term brain impact that could directly affect cognitive reserve. A wide range of neurological manifestations associated with SARS‐CoV‐2 have been described and the list is still increasing, consistent with multiple pathogenic pathways as post‐infectious and immunity reactions. It includes stroke, brain haemorrhage or memory loss.

Method

Such events have already been observed in the course of other viral diseases. In addition, preventive actions to stop the exponential progression of the virus have been adopted by most of countries (masks, physical distancing, lockdowns or curfews), with a common impact: the reduction of our social and physical relationships. Thus, this dramatic stop of human interactions, known as the most effective brain stimulation, may also severely impair cognitive reserve and resilience. The global spread of the pandemic suggests that tens of thousands of individuals may have had cerebral symptoms. Hence, we must take actions to predict the consequences of COVID19 on cognitive reserve and brain resilience.

Results

Aged and frail people are especially concerned: (1) due to their ages, they are at a very high risk of severe forms; (2) as the specific containment imposed to retirement home residents precluded any social relationships for long periods of time. This double punishment had tragic immediate and long‐term consequences on their cognitive reserve and survival. We now need to actively find ways to estimate and limit the brain health impact of the COVID19 pandemic by: (1) helping elderly to resist to social distancing by promoting public health tools as the COVID‐SCORE French experience; (2) setting long term international cohorts to follow‐up the largest numbers of COVID19 patients for their cognitive reserve evolution; (3) Improving cognitive reserve in COVID19 patients by launching prevention programs,

Conclusion

The implementation of such an action plan will allow reducing the third possible consequence of the virus and the lockdown, i.e. a decrease of the cognitive reserve and resilience in older adults.
Greater psychological resilience during the COVID‐19 pandemic is associated with lower tau burden in cognitively unimpaired individuals
Authors: Vannini Patrizia , Gagliardi Geoffroy , Kuppe Madeline K , Dossett Michelle , Donovan Nancy , Gatchel Jennifer R , Quiroz Yakeel T. , Premnath Pranitha Y , Amariglio Rebecca E. , Sperling Reisa A. , Marshall Gad A
Published: December 2021

Background

The outbreak of the 2019 novel coronavirus SARS‐CoV‐2, causing the COVID‐19 pandemic, along with the global measures used to control the spread of the disease, have been particularly stressful for older individuals. Robust evidence suggests that stress‐related physiological processes may play a significant role in the onset of age‐related cognitive decline and dementia, such as Alzheimer’s disease (AD). For example, previous animal and human research have shown that stress exacerbates tau pathology and subsequent cognitive impairment. One important factor determining a person’s level of stress is psychological resilience, which refers to a person’s ability to return to equilibrium when difficulties occur. As such, resilience may buffer and protect individuals against the deleterious effects of stress. The objectives of this study were to examine the relationship between psychological resilience and tau burden in cognitively unimpaired individuals, and to evaluate whether amyloid (Aß) pathology modifies this relationship.

Method

A total of 114 older adults (mean age=74.5;66 females (57.9%)) enrolled in the Harvard Aging Brain Study or the Instrumental Activities of Daily Living study completed an electronic survey online including measures of psychological resilience (Connor‐Davidson Resilience Scale‐10, where a higher score indicates greater resilience) during the COVID‐19 pandemic period (May 2020). We used previously collected (mean time from survey=1.75 year) PET imaging data to assess Aß and tau burden.

Results

Overall, participants demonstrated high levels of resilience (mean=29.5,range=9‐40). Multiple regression analyses (correcting for age, gender and time difference between survey and PET) demonstrated an interaction between resilience and amyloid on tau pathology (ß=‐0.01,p=0.015, Figure1). Specifically, in Aß+ individuals (SUVR>1.324), those with higher psychological resilience also had lower tau pathology. No relationship was seen in Aß‐ individuals.

Conclusion

Our findings suggest that greater resilience during the pandemic is associated with lower tau burden in individuals at higher risk of cognitive decline (i.e. preclinical AD). Future studies are needed to determine the impact of stress and psychological resilience on prospective pathological brain changes and subsequent cognitive decline. Furthermore, resilience may be an important target for interventions to support older adults navigating stressful situations and to lessen the influence of stressors on AD pathological processes.
Alzheimer’s disease risk prediction using automated machine learning
Authors: Gao Xiaoyi Raymond , Li Yi‐Ju , Martin Eden R.
Published: December 2021

Background

Alzheimer’s disease (AD) is the most common late‐onset neurodegenerative disease. About 5.4 million Americans are living with AD. Unfortunately, there is no cure for AD at present, which makes early prediction crucial. Identifying individuals at increased risk of AD provides a better chance of benefiting from treatments. Risk prediction models are typically based on a limited number of predictors possibly with sub‐optimal performance. Here, we explore a state‐of‐the‐art automated machine learning (AutoML) framework for AD risk prediction, which can handle hundreds of predictors, including non‐traditional variables, with automatic feature engineering and model selection.

Method

We developed an AutoML model that aggregates polygenic risk scores (PRSs) and baseline individual characteristics (e.g., non‐genetic factors) for predicting AD. The PRSs were derived using summary statistics of the genome‐wide association studies from the Alzheimer Disease Genetics Consortium (ADGC) dataset (n = 19,918). The model was applied to 455,233 participants in UKBB without AD at baseline to predict development of AD at the final observation (n=1,452 developed AD). Our model was based on the H2O AutoML, an intelligent algorithm that can automatically select hyperparameters, tune ensembles of ML models, and carry out model assessment.

Result

The area under the receiver operating characteristic curve (AUC) for AD risk prediction was over 0.86. Polygenic risk scores ranked only second to age in feature importance. Furthermore, our AutoML model identified predictors that are not typically considered in traditional prediction models, such as an individual’s overall health rating and usual walking pace.

Conclusion

Our AutoML model improves the accuracy of AD risk prediction by efficiently exploring numerous predictors and ensemble models while greatly reducing manual coding hours. Furthermore, AutoML uncovered novel predictors for AD.
Cost‐effectiveness of non‐pharmacological interventions for patients with dementia: A systematic review and meta‐analysis
Authors: Huo Zhaohua , Chan Joyce YC , Lin Jiaer , Bat Baker Kwok Kwan , Chan Tak Kit , Tsoi Kelvin KF , Yip Benjamin HK
Published: December 2021

Background

Non‐pharmacological interventions are widely used in the treatment of dementia, however, the cost‐effectiveness of them remains unclear. This study aimed to review and synthesize the economic evidence of non‐pharmacological interventions for patients with dementia (PwDs).

Method

Trial‐based studies evaluating both the costs and effects of non‐pharmaceutical interventions for PwDs were searched from PubMed, Web of Science, EconLit, NHS EED and other five relevant databases. Study quality was assessed using the Cochrane Risk of Bias Tool and the Consensus on Health Economic Criteria list. Cost data were standardized in 2020 US dollars and analyzed from the healthcare perspective. Random‐effects models were used to synthesize the incremental cost and effects of different interventions, based on mean differences (MDs) or standardized mean differences (SMDs).

Result

Thirty‐one eligible studies were identified from 40,587 records. The follow‐up periods ranged from post‐discharge to three years. Care coordination and case management programs brought significant savings of $314 (95%CI: $47 to $582) per person in total healthcare cost, alongside more quality‐adjusted life years (QALYs) gained for PwDs (SMD: 0.197; 95%CI: 0.050 to 0.344). Cognitive‐oriented therapy improved patients’ cognitive functions (SMD: 0.105; 95%CI: 0.006 to 0.204), whereas psychological intervention and behavioral management improved the neuropsychiatric symptoms (SMD: 0.109; 95%CI: 0.033 to 0.185). However, they were accompanied with significant increases in total healthcare cost, $490 (95%CI: $70 to $910) and $338 (95%CI: $238 to $438), respectively. Psychological intervention and behavioral management also deteriorated patients' activity functions (SMD: ‐0.195; 95%CI: ‐0.360, ‐0.030).

Conclusion

Care coordination and case management for PwDs are most likely to be cost‐effective with lower healthcare cost and better QALYs gained. The acceptance of cognitive‐oriented therapy, psychological intervention and behavioral management depends on the society’s willingness to pay for the improvements in patients’ health. More economic evidence is required on other types of interventions, such as physical exercise, occupational therapy, and day care program.
Saliva biomarkers for Alzheimer’s disease risk in a rat model of low and high intrinsic exercise capacity
Authors: Almarghalani Daniyah , Hardy Ana Maria Gregio , Hasan Syed Abdul‐Moiz , Shah Zahoor A. , Koch Lauren Gerard
Published: December 2021

Background

Identifying a natural‐occurring animal model for Alzheimer's Disease (AD) and a non‐invasive early AD diagnostic are significant AD research challenges. Previously, we developed rat models by selectively breeding for low and high intrinsic exercise capacity. We found that compared to High Capacity Runners (HCR), Low Capacity Runners (LCR) have a reduced lifespan and greater risk for cardiovascular disease, diabetes, and obesity.1 LCR exhibit neurodegeneration, impaired memory, and decreased hippocampal neurogenesis. Saliva is a relatively new AD‐associated research area, and as a bioanalytic,2 is an important extension of protein changes in the autonomic nervous system and immune response. Our goal is to determine whether salivary biomarkers link with exercise capacity and brain health in LCR and HCR rats.

Method

We studied three‐generations of female rats (6 months: 9 LCR, 10 HCR), (20 months: 8 LCR, and 8 HCR), and (26 months: 7 LCR, 6 HCR). We assessed exercise capacity using a treadmill running test and cognitive function using a Y‐maze. Salivary gland weight and salivary flow rate (SFR) of a submandibular gland (SMG) were measured and compared. The acinar cells proliferation of SMG was assessed by IHC using PCNA. Biomarkers for p‐tau ser610 and amyloid‐beta were investigated in hippocampus tissue, saliva, and plasma using ELISA.

Result

The LCR and HCR groups were significantly different for maximal treadmill running distance and time spent in novel arm of the Y‐Maze. The SFR and acinar cell proliferation were higher in HCR. The size and mass of SMG were bigger in LCR rats. Levels of p‐tau in saliva and plasma were markedly greater in LCR than HCR, but no differences in the hippocampus. There was no difference between the two groups in the hippocampus or saliva regarding amyloid‐beta levels. However, it was significantly increased in plasma in the LCR group compared with the HCR group.

Conclusion

Taken together, the findings of this study provide experimental evidence that saliva biomarkers are significantly increased in the LCR group compared with the HCR group. This is the first study using novel and unexplored preclinical rat models that combines exercise capacity with AD risk by utilizing saliva biomarkers.
Cardiorespiratory fitness mitigates brain atrophy and cognitive decline in preclinical Alzheimer’s disease
Authors: Dougherty Ryan J , Jonaitis Erin M , Johnson Sterling C , Okonkwo Ozioma C , Cook Dane B
Published: December 2021

Background

Cardiorespiratory fitness (CRF) may be a mitigating factor for Alzheimer’s Disease (AD) progression. The purpose of this study was to examine the longitudinal associations of CRF with brain atrophy and cognitive function in a late‐middle‐aged cohort of adults at risk for AD.

Method

One hundred and ten adults (mean age = 64.2 ± 5.7 years, 65% female) from the Wisconsin Registry for Alzheimer’s Prevention (WRAP) completed a baseline graded treadmill exercise test, two brain MRI scans (over 4.67 ± 1.17 years) and neurocognitive assessments (2.18 ± .78 neurocognitive tests over 3.26 ± 1.02 years) as part of their WRAP study involvement. The oxygen uptake efficiency slope (OUES) was calculated for each participant and served as the CRF measure. Total gray matter and hippocampal volumes and the preclinical Alzheimer’s cognitive composite (PACC) score were the primary outcome measures. Linear mixed effects models examined the longitudinal associations adjusted for covariates. The CRF x age (i.e., time) interaction was centered and was the term of interest as it would indicate whether longitudinal decline in volumetrics or cognition differed as a function of CRF.

Result

Baseline OUES values were 1.16 ± 0.28. Total gray matter and hippocampal volume declined at a rate of ‐0.73 ± 0.90% and ‐0.16 ± 1.30% per year, and cognitive trajectories decline ‐.047 points (standardized score) per year. The CRF × age interaction was significant for total gray matter volume (β=.26 SE .11; p=.020; Figure 1) and PACC score (β=.07 SE .03; p=.049; Figure 2), but not hippocampal volume (β=.002 SE .002; p=.347). These findings were most pronounced among APOE‐e4 carriers (p<.05).

Conclusion

CRF may be a modifiable physiological attribute to target during the preclinical stage of AD in effort to delay disease progression.
Association of retinal nerve fiber layer thickness with temporal lobe atrophy
Authors: Mathew Sunu , WuDunn Darrell , Mackay Devin , Vosmeier Aaron , Tallman Eileen F. , Garrett Makaylah N. , West John D. , Deardorff Rachael , Harris Alon , Farlow Martin R. , Brosch Jared R. , Gao Sujuan , Apostolova Liana G. , Saykin Andrew J. , Risacher Shannon L.
Published: December 2021

Background

The retinal nerve fiber layer (RNFL) is an extension of the brain that often reflects changes seen in the brain in neurodegenerative diseases. The purpose of this study was to examine the relationship of RNFL thickness measured using optical coherence tomography (OCT) with temporal lobe neurodegeneration in older adults along the Alzheimer’s disease (AD) continuum.

Method

Participants included 26 individuals with subjective cognitive decline (SCD), 21 mild cognitive impairment (MCI/{AD}) and 28 age‐matched cognitively normal (CN) from the Indiana Memory and Aging Study at the Indiana Alzheimer’s Disease Research Center. Participants were excluded from the study if they had significant eye disease determined to interfere with OCT and other ocular measures, non‐AD dementia, or exclusion for MRI. OCT scans were acquired from each eye to measure peripapillary RNFL among other metrics. Structural MRI scans were acquired and processed using Freesurfer version 6 to measure medial and lateral temporal lobe volumes. Finally, the association between the average RNFL thickness and bilateral mean hippocampus, amygdala, and lateral temporal lobe volumes was assessed using a partial Pearson correlation, covaried for age, sex, diagnosis, and total intracranial volume (ICV). A p‐value of p<0.05 was considered significant.

Result

Peripapillary RNFL thickness was generally decreased in patients with AD compared to all other groups. In addition, average RNFL thickness across the retina was significantly correlated with brain atrophy, including bilateral mean hippocampal, amygdala, and lateral temporal lobe volumes.

Conclusion

RNFL thinning measured using OCT is associated with regional atrophy in medial and lateral lobes. Imaging of the eye may represent a useful biomarker to screen patients at risk for AD prior to more invasive and prolonged testing.