bluuebunny/crossref_metadata_2025 huggingface dataset:
Cardiometabolic multimorbidity accelerates cognitive decline and progression to dementia in older adults
Authors: Dove Abigail , Marseglia Anna , Shang Ying , Vetrano Davide Liborio , Grande Giulia , Laukka Erika J , Fratiglioni Laura , Xu Weili
Published: December 2021

Background

Though cardiometabolic disorders (CMDs; including type 2 diabetes, heart disease, and stroke) have been individually associated with cognitive decline, their combined effect on the prodromal phase of dementia is unknown. We aimed to examine the extent to which CMD multimorbidity is associated with cognitive decline and the risk of cognitive impairment–no dementia (CIND) and its progression to dementia.

Method

Within the Swedish National Study on Aging and Care–Kungsholmen, 2934 dementia‐free adults aged ≥60—consisting of a cognitively intact (n=1821) and a CIND (n= 685) cohort—were followed over 12 years. At baseline and each follow‐up (every 3 or 6 years), participants were administered the Mini‐Mental State Examination (MMSE) and a neuropsychological test battery. CIND was defined as having no dementia and performance ≥1.5 SDs below age group‐specific means in at least one cognitive domain (episodic memory, processing speed, executive function, verbal fluency, or visuospatial ability). Dementia was diagnosed according to DSM‐IV criteria. CMDs were ascertained based on clinical examination, medication use, national patient registry data, and laboratory and instrumental tests. CMD multimorbidity was defined as the presence of ≥2 CMDs. Data were analyzed using multi‐adjusted linear mixed models, Cox regression, and Laplace regression, with adjustment for sociodemographic and vascular risk factors.

Result

Of all participants, 813 (27.7%) had one, 221 had two (7.5%), and 23 (0.8%) had three CMDs at baseline. Compared to no CMDs, the presence of one (β= ‐0.22, 95% CI: ‐0.28 to ‐0.15), two (β= ‐0.28, 95% CI: ‐0.40 to ‐0.16), and three (β= ‐0.40, 95% CI: ‐0.77 to ‐0.03) CMDs was related to accelerated MMSE decline in a dose‐dependent fashion (p<0.001). In Cox models, CMD multimorbidity was associated with nearly double the risk of both CIND (hazard ratio [HR] 1.71, 95% CI 1.22‐2.41) and the progression of CIND to dementia (1.89, 95% CI 1.17‐3.04). Furthermore, CMD multimorbidity anticipated the onset of CIND by 2.5 years and its progression to dementia by 2.2 years.

Conclusion

Cardiometabolic multimorbidity accelerates cognitive decline and increases the risk of CIND and dementia, anticipating the occurrence of both CIND and dementia by more than two years.
Retinal parameters, cortical microinfarcts and functional cognitive impairment
Authors: Hilal Saima , Cheung Carol Y. , Wong Tien Yin , Cheng Ching Yu , Schmetterer Leopold , Chen Christopher
Published: December 2021

Background

Quantitative changes in retinal vessels and thinning of optic nerves have been associated with subclinical and clinical age‐related brain pathologies. However, data on the association between both retinal vascular and neuronal parameters with cortical cerebral microinfarcts and how these factors jointly contribute to functional cognitive impairment is lacking. We investigate the association of retinal vascular and neuronal changes with cortical CMIs on 3T MRI and to explore their interaction in relation to functional cognitive impairment in a memory‐clinic population.

Method

A total of 538 participants (mean age:72.6±7.8 years) were included. Retinal vascular parameters (caliber, tortuosity, fractal dimension) were measured from retinal fundus photographs using a semi‐automated computer‐assisted program. Retinal nerve fiber layer (RNFL) and ganglion cell‐inner plexiform layer (GC‐IPL) thicknesses were obtained from spectral domain‐optical coherence tomography. Cortical CMIs were defined as hypointense lesions on T1‐weighted images, <5mm in diameter, restricted to the cortex, and perpendicular to the cortical surface. Functional cognitive impairment was assessed on Clinical Dementia Rating Sum‐of‐Boxes (CDR‐SoB) score.

Result

Larger venular caliber (Rate ratios (RR):1.21, 95%CI:1.03‐1.42), increased venular fractal dimension (RR:1.25, 95%CI:1.07‐1.46), increased venular tortuosity (RR:1.08, 95%CI:1.02‐1.15) and thinner GC‐IPL (RR:1.22, 95%CI:1.12‐1.32) were associated with increasing CMI counts. A significant interaction term was found between venular fractals, venular tortuosity, thinner GC‐IPL and RNFL and cortical CMIs (p<0.05) on CDR‐SoB scores. Among individuals in highest tertile of retinal parameters, a significant interaction was observed between venular tortuosity (RR:1.14, 95%CI:1.09‐1.19, p‐interaction<0.001), GC‐IPL (RR:1.23, 95%CI:1.13‐1.34, p‐interaction<0.001) and RNFL (RR:1.48, 95%CI:1.31‐1.68, p‐interaction=0.002) with CMIs on CDR‐SoB scores.

Conclusion

We showed that retinal vascular and neuronal parameters are associated with cortical CMIs independent of risk factors. Moreover, there was an interaction between retinal parameters and cortical CMIs on CDR‐SoB. Further studies may be warranted to evaluate the potential clinical utility of retinal parameters in risk prediction for CMIs.
Impairment of auditory integration in subjective cognitive decline, amnestic mild cognitive impairment, and Alzheimer’s disease
Authors: Wang Changming , Wang Zhibin , Liu Lei , Yang Pengcheng , Xie Beijia , Shi Xinrui , Jia Jianping , Li Liang , Tang Yi
Published: December 2021

Background

Localization of sound sources in a noisy environment or ‘auditory scene analysis’ depends on central auditory processing (CAP) that is vulnerable in cognitive impairment. Here, we investigated the behavioral and electrophysiological characteristics of auditory integration, as a particular function in CAP, in relation to neuropsychological functions in SCD, aMCI, and AD.

Method

We introduced a binaural integration paradigm to measure sound‐localization‐related features (identification and retention of acoustic signals) by detecting break in interaural correlation (BIC) and primitive auditory memory (PAM) in wideband noises. We used a 128‐channel EEG to record the event‐related‐potential (peak amplitude, peak latency, and inter‐trial phase coherence [ITPC]) for the paradigm.

Result

A total of 121 participants (mean age 65.9 years) were included. Significant differences in BIC detection and PAM were revealed between groups adjusting for age and gender (BIC: F = 20.2, P < 0.001; PAM: F = 24.6, P < 0.001). Post‐hoc analysis showed that BIC detection and PAM were significantly higher in NC or SCD groups compared with aMCI or AD groups. Further adjusting for neuropsychological scores, the significances were not changed, suggesting that auditory integration impairment was partially independent from top‐down cognitive functions. In EEG experiment, the most prominent differences in EEG metrics among the four groups included the ITPC of N1 at left parietooccipital region (F = 3.85, P = 0.012) and of P2 at left parietooccipital (F = 3.89, P = 0.011) and frontocentral regions (F = 8.09, P < 0.001). Notably, there was a linear decrease for the ITPC of N1 and a U‐shape‐curve change for the ITPC of P2 among the four groups, indicating that EEG patterns are differentially modulated depending on disease severity. For the discrimination of AD vs NC and MCI vs NC, the AUC was 0.92 and 0.85 for BIC detection; 0.94 and 0.90 for PAM, respectively.

Conclusion

Auditory integration, as a partially independent phenotype, is impaired in aMCI and AD populations. A U‐shape‐curve change of P2 with the increasing disease severity was found, indicating a compensation on auditory scene analysis. Results support binaural integration paradigm as a biomarker for screening cognitive decline and identifying auditory integration deficit.
Individualized diagnostic and prognostic blood‐based models for use in clinical practice and trials
Authors: Hansson Oskar
Published: December 2021

Background

Blood‐based biomarker’s for Alzheimer’s disease are likely to revolutionize the diagnostic work‐up in both specialized clinics and in primary care. Further, they might be used to identify suitable participants for preclinical and prodromal AD trials, i.e., individuals with AD pathology who will exhibit cognitive decline in the coming 2‐4 years.

Method

We evaluated the diagnostic and prognostic performance of plasma P‐tau181, P‐tau217, Ab42/40, and NfL in the prospective and longitudinal BioFINDER I and II studies. We compared the accuracy of plasma biomarkers with CSF AD biomarkers, amyloid‐PET and tau‐PET. Diagnostic and prognostic algorithms were typically validated in an independent cohort.

Result

Plasma P‐tau alone could with very high accuracy differentiate AD dementia from other neurodegenerative diseases, and a plasma P‐tau217 assay was shown to be non‐inferior to tau‐PET and CSF biomarkers in this setting. A combination of plasma P‐tau and NfL could be used for individualized prediction of cognitive decline and conversion to AD dementia within 2‐ 6 years in patients with mild cognitive impairment (MCI), and this combination performed equal to CSF AD biomarkers. Further, in a population including both patients with subjective cognitive decline (SCD) and MCI, as often seen in primary care settings, an optimal prognostic algorithm for prediction of AD dementia included plasma P‐tau and brief cognitive tests of memory and executive function. We have developed an online tool for individualized prediction of AD dementia in cases with SCD or MCI (https://brainapps.shinyapps.io/PredictionADdementia/), which was shown to outperform the clinical prediction by memory clinic physicians. In cognitively unimpaired (CU) individuals we showed that plasma Ab42/Ab40 and P‐tau together could detect cerebral Ab pathology, but a combination of plasma Ab42/Ab40, P‐tau and NfL was needed for accurate prediction of subsequent cognitive decline and to enrich pre‐clinical trials with suitable research participants. Finally, results will be presented on the use of fully automated assays for quantification of relevant plasma AD biomarkers.

Conclusion

Different combinations of easily accessible tests are optimal during different disease stages of AD, and they are likely to be useful in both clinical practice and trials after validation in multiple large‐scale, relevant and diverse cohorts.
Exposure of non‐steroidal anti inflammatory drugs and risk of dementia based on National Sample Cohort data
Authors: Chae Wonjeong
Published: December 2021

Background

One of the most significant health problems caused by aging is dementia. The aim of this study was to investigate the impact of exposure to non‐steroidal anti‐inflammatory drugs to the risk for dementia.

Method

Data (2003–2013) from the Korean National Health Insurance Service‐National Sample Cohort was used. The study's 5‐year landmark period began on January 01, 2003. The Cox proportional‐hazard model was employed to analyze the effects of non‐steroidal anti‐inflammatory drug exposure on all‐cause dementia, Alzheimer’s disease dementia, vascular dementia, early‐onset dementia, and late‐onset dementia. Further analyses of non‐steroidal anti‐inflammatory drug types and their defined daily doses were also conducted.

Result

Of the 555,643 individuals in the cohort, 21,809 (3.9%) had dementia. Compared to the never‐used non‐steroidal anti‐inflammatory drug group, the ever‐used non‐steroidal anti‐inflammatory drug group had a decreased risk for all‐cause dementia (HR: 0.91, 95% CI: 0.78–0.84) for those individuals who did not have all‐cause dementia during the landmark periods. The risk for subtype dementias was significantly lower in the case group. For types of non‐steroidal anti‐inflammatory drugs, ketorolac was found to have a decreased risk for all‐cause dementia (HR: 0.69, 95% CI: 0.53–0.91). For non‐steroidal anti‐inflammatory drug dosages, higher defined daily doses had a lower risk for all‐cause dementia.

Conclusion

The data indicates that common non‐steroidal anti‐inflammatory medication use in the general population may contribute to a decreased risk for dementia, with the possibility of preventing dementia at a low cost so that the high cost and burden of treating dementia might be reduced.
Afternoon‐snack glycemic load is associated with plasma amyloid‐beta peptides in APOE4 carriers at risk of dementia
Authors: Gentreau Mélissa , Raymond Michel , Féart Catherine , Samieri Cécilia , Chuy Virginie , Berticat Claire , Artero Sylvaine
Published: December 2021

Background

Recent evidence suggests that a high refined‐carbohydrate diet is a risk factor for dementia, especially among APOE4 carriers. Thus, refined‐carbohydrate diet may modify biomarkers of dementia, such as amyloid‐β (Aβ) peptides according to APOE4 carrier status. Here, we focus on afternoon‐snack glycemic load (GL) because snacks are generally richer in refined carbohydrates. We investigated the relationship between plasma Aβ, afternoon‐snack GL, and APOE4 carrier status in participants with or without incident dementia.

Method

We followed 377 non‐demented participants from the Three‐City Study (Bordeaux and Montpellier center), aged over 65, with plasma Aβ peptide concentrations measured at baseline. At 2‐year (Bordeaux center) and 4‐year (Montpellier center), the participants completed a semi‐quantitative Food Frequency Questionnaire which was used to estimate GL (GL assesses both the carbohydrate quantity and quality, and reflects glycemic response). At each follow‐up (every 2‐3 years during 15 years), participants had clinical diagnosis of dementia. We used linear regressions to evaluate the associations between plasma Aβ40, Aβ42, Aβ42/Aβ40 ratio and GL, APOE4 carrier status, and the interaction GL x APOE4, among participants with or without incident dementia. Models were adjusted for center, age, sex, education level, total cholesterol, serum creatinine and adherence to the Mediterranean diet.

Result

The sample included 60.2% of women and mean age of the participants was 76.1 (± 5.2) years. During the follow‐up, 51 participants developed dementia. Among dementia‐free participants, GL tended to be associated with Aβ42/Aβ40 ratio (β = ‐0.006 [SE = 0.003], P = .055) but not with Aβ40 and Aβ42 concentrations. Among incident dementia participants, the interaction GL x APOE4 was associated with plasma Aβ40 concentration (β = 54.2 [SE = 25.6] pg/mL, P = .042). Regarding Aβ42, no interaction was found. Regarding Aβ42/Aβ40 ratio, GL x APOE4 was no longer significant after adjustment (β = ‐0.038 [SE = 0.024] P = .124).

Conclusion

In APOE4 carriers with incident dementia, a higher afternoon‐snack GL was associated with worse plasma Aβ peptide concentrations. These results highlight that rich refined‐carbohydrate diet is a modifiable risk factor for plasma Aβ peptide concentrations and subsequent dementia risk. Experimental studies are required to explain potential mechanism involved.
Population attributable fractions for modifiable risk factors of dementia in cognitively normal and MCI populations: Data from two countries
Authors: Wezeman Sandra , Uleman Jeroen F , Peeters Geeske , Margioti Eleni , Scarmeas Nikolaos , Olde‐Rikkert Marcel
Published: December 2021

Background

Previous studies have shown that population‐wide up to 40% of all dementia cases are related to twelve modifiable risk factors, which thus calls for preventive measures. To inform health promotion strategies, it is important to know whether the risk attributable to modifiable risk factors differs in cognitively healthy persons and persons with Mild Cognitive impairment (MCI). This study analyzed associations and population attributable fractions (PAFs) of twelve modifiable risk factors with dementia in cognitively healthy and declining (MCI) adults aged ≥65 years, in two cohort studies from the US and Greece.

Method

Data were from the National Alzheimer’s Coordinating Centre (NACC) (n=16,147, impaired‐not‐MCI n=1007, mean age 75.2 ±6.9, 54.8% female) and the Hellenic Longitudinal Investigation of Aging and Diet (HELIAD) (n=1141, mean age 72.9 ±5.0, 58.0% female). PAFs were calculated based on hazard ratios (HRs) for the risk of dementia and risk factor prevalence in the NACC (9 risk factors) and HELIAD (10 risk factors) data. Weighted PAFs were calculated to adjust for communality between risk factors. Analyses were performed for the total samples, as well as separately for cognitively healthy participants and those with MCI at baseline.

Result

2,630 participants enrolled by the NACC developed MCI (25.1%) and 3,333 developed dementia (20.7%) during a mean follow‐up of 4.9 (±3.5) years. 131 participants developed MCI (11.2%) and 68 developed dementia (5.9%) during HELIAD follow‐up of on average 3.1 (±0.86) years. A relatively low weighted overall PAF of 21.4% was found in the total sample of the NACC study. The PAF was 20.8% in the cognitively normal subgroup and ‐6.17% in the MCI subgroup A relatively high weighted overall PAF of 60.7% was found for the total sample in HELIAD. The PAF was 78.4% in the cognitively normal subgroup and 80.6% in the MCI subgroup.

Conclusion

In general, translating valuable global meta‐analysis data on modifiable risk factors should be carefully carried out per population before starting preventive interventions. Within each cohort, the PAFs for cognitively healthy and cognitively declining participants were in the same range, suggesting that also in persons with MCI, elimination of risk factors continues to be important.
A possible novel mechanism for cognitive resistance to neurodegeneration: modulation of interneuron activity in the hippocampus after exposure to enriched environments
Authors: Khan Zuhayr M , Kageyama Glenn
Published: December 2021

Background

Exposure to an enriched environment has been shown in many studies to be beneficial to brain structure and cognition by preserving neuronal integrity and strengthening the functioning and plasticity of neural circuits. These benefits derive from the added spatial, social, and sensory complexities in an enriched environment. It has been well known for a few decades that an enriched environment stimulates neurogenesis and cell proliferation in the dentate gyrus of the hippocampus, leading to an increased number of dentate granule cells (DGCs). However, the changes to other populations of cell types, particularly interneurons, has remained elusive. Interneurons are integral regulators of neurotransmission in the hippocampus. Damage to hippocampal interneurons have serious implications and lead to a decline in cognitive health. Our study sought to elucidate possible changes in interneurons affected by exposure to an enriched environment (EE) and enriched changing (EC) environment.

Method

The topographic distribution of nicotinamide adenine dinucleotide phosphate‐diaphorase (NADPHd) positive neurons was studied in the dentate gyrus of the rat dorsal hippocampus.

Result

Environmental enrichment increased the number of NADPHd positive neurons found in both enrichment groups. The elevated level of neurons was represented uniformly across almost all six layers of the dentate gyrus and was most significant in the expected granular cell layer (GRCL) and subgranular zone (SGZ).

Conclusion

The overall preliminary results suggest that the brain has the ability to adapt to increased amounts of sensory stimulation. These changes highlight a possible new mechanism of physiological homeostasis and physical evidence of a cognitive reserve; with an increased demand for energy from new‐born DGCs and increased sensory input, the brain will regulate its energy expenditure via an increase in either the activity of existing interneurons, or the actual number of interneurons. Further research will involve running a restudy and observing the differences to the ventral hippocampus, CA1, and CA3 regions, and the effects on specific subpopulations of interneurons.
The gut microbiome and cognitive function in midlife: The CARDIA study
Authors: Meyer Katie A
Published: December 2021

Background

Based on experimental and clinical studies of specific patients, a gut‐brain axis has been hypothesized as mechanism connecting peripheral metabolic and immunologic activity to the brain, including cognitive functioning. Few studies have investigated the association of gut microbial composition to cognition in large community samples.

Method

Cross‐sectional data were from a subsample (n=597) of participants in the U.S.‐based bi‐racial Coronary Artery Risk Development in Young Adults (CARDIA) study (2015‐16). Participants were aged 48‐60 years, 45% male, and 45% Black (Table). V3‐V4 regions of 16S rRNA were sequenced from stool DNA with Illumina MiSeq technology and. microbial taxonomic measures generated from the sequenced data. After filtering out rare taxa, 107 genera (of 375 originally assigned) were included in the analysis. Participants completed six interviewer‐administered cognitive tests: Montreal Cognitive Assessment (MoCA), Digit Symbol Substitution Test (DSST), Rey‐Auditory Verbal Learning Test (RAVLT), timed Stroop test, and letter and category fluency tests. Higher scores on all tests reflect greater cognitive functioning, except for Stroop, for which faster (lower time) is better.

Result

Regression analysis of cognitive test scores on genera included adjustment for sequencing batch; and participant age, sex, race, BMI, and diabetes. Eleven genera were associated with two or more cognitive measures at FDR<0.10, and 31 genera were associated with two or more at FDR<0.20 (Figure): Barnesiella was positively associated with DSST and category fluency; Lachnospira was positively associated with DSST, RAVLT, MoCA, category fluency, and negatively associated with the timed Stroop test; Sutterella was negatively associated with MoCA, RAVLT, and DSST. Seven of the 11 genera with shared associations at FDR<0.10 (and 22 of the 31 at FDR<0.20) were from within the Clostridia class.

Conclusion

Tests of global cognition and psychomotor speed were associated with specific microbes in the gut. These microbes, particularly those stemming from Clostridia class, may be involved in short‐chain fatty acid production and inflammatory pathways. Our data contribute to a growing body of literature suggesting that the gut microbiota may relate to cognitive function. These signals must be replicated and further researched to identify relevant genetic, metabolic, and inflammatory pathways.
Social engagement and cognitive decline in older African‐Americans: The Minority Aging Research Study
Authors: James Bryan D , Lamar Melissa , Lange‐Maia Brittney S , Capuano Ana W , Barnes Lisa L
Published: December 2021

Background

Social engagement in later life is associated with lower rates of cognitive decline and dementia, but most research has been conducted in primarily White cohorts. Little is known about this relationship in older African Americans, and some promoters of cognitive reserve in Whites may not have the same benefits in African Americans.

Methods

We used data from the Minority Aging Research Study (MARS), a study of community‐dwelling African American older adults in Chicago. Social activity was measured using an 8‐item scale assessing frequency of participation in activities involving social interaction (mean=2.5, SD=0.5). Social network size was assessed as the number of children, family, and friends seen at least once a month (mean=6.4, SD=6.0). Loneliness was measured with a 5‐item Likert scale assessing perceived emotional isolation (mean=2.1, SD=0.6). Life space is a measure of spatial movement through 6 zones of the environment from bedroom (smallest) to out of town (largest) (mean=5.5, SD=0.9). Global cognitive function was the average of z‐scores for 19 standard cognitive tests. Linear mixed models were used to test for associations with level and rate of change in cognitive function, with terms for each social engagement variable at baseline, age at baseline, sex, education, time since baseline, and interactions with time.

Results

Participants (n=768; mean age=73.5, SD=6.3) were followed for an average of 6.3 years (SD=4.6). Higher social activity was related to slower cognitive decline (est=0.021, SE=0.008, p=0.011), but not to level of cognitive function (est=0.052, SE=0.036, p=0.15). Alternately, loneliness and a larger life space were not related to cognitive decline (est=0.003, SE=0.007, p=0.64; and est=0.001, SE=0.005, p=0.82, respectively), but were related to level of cognitive function (est=‐0.104, SE=0.029, p<0.001; and est=0.062, SE=0.020, p=0.002, respectively). Social network size was not related to level or rate of change in cognition.

Conclusions

In older African Americans, social activity was related to less cognitive decline, while other measures of social engagement were related to level but not rate of change in cognitive function.
Generation of the AD Informer Set: Chemical tools to facilitate Alzheimer’s disease drug discovery
Authors: Potjewyd Frances M. , Annor‐Gyamfi Joel K. , Guduru Shiva K. R. , Nwogbo Felix , Rogers David A. , Hopkins Meghan D. , Conlon Ivie , Wells Carrow , Stashko Michael , Hardy Brian P. , Wang Xiaodong , Frankowski Kevin , Kireev Dmitri B. , Pearce Kenneth H. , Willson Tim , Aubé Jeff , Frye Stephen V. , Richardson Timothy , Young Jessica E. , Axtman Alison D.
Published: December 2021

Background

Currently, treatments for Alzheimer’s disease (AD) predominantly include acetylcholinesterase inhibitors, which address the symptomatic effects of the disease. The discovery of disease modifying interventions in the development and progression of AD are critical as there are currently no drugs or biologics which can elicit disease modifying effects. Promisingly there is an increase in the number of novel therapeutic strategies targeting AD that have progressed to clinical trials, and interrogation of targets implicated in AD pathology remains an area of extensive research.

Method

To assist the discovery of novel strategies that slow or halt AD pathology we have generated the AD Informer Set, the first iteration of which contains more than 150 chemical tools. We will make solutions of the physical set as well as all associated data available to the scientific community in 2021. Further data is being collected on compound kinetic solubility, pharmacokinetic properties, potential off‐target liabilities, and AD‐specific readouts, including mitochondrial metabolism, oxidative stress and glycolysis, and effects on p‐Tau and Aβ expression levels.

Result

The AD Informer Set includes compounds for targets that have AD implicated biology, either well validated or recently suggested, and contains relevant information about the gene, compound structure and activity, and associated AD phenotypes. 1, 2

Conclusion

The AD Informer Set will be shared with the scientific community at large to qualify assays, interrogate target validity in AD models, and to provide positive controls to aid in the discovery of new chemical entities. References: (1) Hodes RJ, Buckholtz N. Accelerating Medicines Partnership: Alzheimer's Disease (AMP‐AD) Knowledge Portal Aids Alzheimer's Drug Discovery through Open Data Sharing. Expert Opin Ther Targets. 2016, 20, 389‐91. PMID: 26853544. (2) Mullard A. NIH launches open science Alzheimer initiative. Nat Rev Drug Discov. 2019, 18, 895. PMID: 31780852.
Clinical diagnosis of Alzheimer’s disease: Recommendations of the International Working Group (IWG)
Authors: Villain Nicolas , Dubois Bruno , Frisoni Giovanni B. , Rabinovici Gil D. , Sabbagh Marwan Noel , Cappa Stefano , Bejanin Alexandre , Bombois Stéphanie , Epelbaum Stéphane , Teichmann Marc , Habert Marie‐Odile , Nordberg Agneta K. , Blennow Kaj , Galasko Doug R. , Stern Yaakov , Rowe Christopher C. , Salloway Stephen P. , Schneider Lon S. , Cummings Jeffrey L. , Feldman Howard H.
Published: December 2021

Background

In 2018, the National Institute of Aging and the Alzheimer Association proposed a purely biological definition of Alzheimer’s disease (AD) relying on biomarkers. While the intended use of the framework was for research purposes, it has engendered debate and challenges regarding its application in everyday clinical practice. For instance, cognitively unimpaired individuals may have biomarker evidence of both amyloid and tau pathology, but may never develop clinical manifestations in their lifetime. Furthermore, a positive AD pattern may be observed in other brain diseases where AD pathology is present as co‐pathology. In this presentation, the international Working Group (IWG) presents what we consider to be the current limitations of biomarkers in the diagnosis of AD, and on the basis of this evidence we propose recommendations for how biomarkers should and should not be used for diagnosis of AD in a clinical setting. We recommend that AD diagnosis be restricted to the occurrence of positive biomarkers together with specific AD phenotypes, whereas biomarker positive cognitively unimpaired individuals should be considered only at‐risk for progression to AD.
Effects of a lifestyle intervention on daytime sleepiness and cognitive function
Authors: Hayden Kathleen M , Spira Adam P , St‐Onge Marie‐Pierre , Ding Jingzhong , Anderson Andrea , Molina‐Henry Doris P , Sanderlin Ashley H , Reboussin David M , Espeland Mark A , Bahnson Judy
Published: December 2021

Background

Daytime sleepiness is common in older adults and may result from poor nighttime sleep due to sleep disordered breathing, fragmented sleep, or other sleep disorders. Daytime sleepiness may signify disruption of circadian rhythms and disorder in neural circuitry arising from neurodegenerative disease. We investigated the association between self‐reported daytime sleepiness and cognitive function in Look AHEAD, a randomized clinical trial of an intensive lifestyle intervention (ILI) in a cohort of adults with type 2 diabetes (T2D) and overweight or obesity at baseline.

Method

Participants (aged 45‐76 years) were randomized to ILI or diabetes support and education (DSE) conditions. After ∼10 years, the trial was stopped; observation continued to year 18. We included participants who reported levels of daytime sleepiness at baseline and year 18 (n=2,825). Change in daytime sleepiness was defined as increasing, stayed the same, or decreasing levels of daytime sleepiness. Cognitive assessments at years 13 and 18 included measures of global function, memory, executive function, and attention; a cognitive composite was derived from z‐score averages. The relationship between change in daytime sleepiness from baseline to year 18, and cognitive function at year 18 was examined using analysis of covariance, adjusting for year 13 cognitive performance, baseline age, gender, race/ethnicity, education, APOE ε4 carrier status, baseline CVD history, and baseline daytime sleepiness.

Result

Participants who reported increased daytime sleepiness from baseline to year 18 (n=402), performed significantly worse on the cognitive composite than those who reported no change (n=1089) or decreased levels of daytime sleepiness (n=948), (Least Squares Mean [standard error]) ‐0.50 (0.04); ‐0.40 (0.03), and ‐0.39 (0.03), respectively; p‐value=0.004. Significant interactions between treatment arm and daytime sleepiness were found in executive function (p<0.10) and memory (p<0.001) such that relationships were stronger among ILI compared with DSE participants including poorer scores among those with increasing daytime sleepiness in the executive function (34.3 (0.72); p<0.02); and memory domains (6.5 (0.30); p<0.05).

Conclusion

Increasing daytime sleepiness over 18 years predicted poorer cognitive performance in older individuals at high risk for sleep disorders. ILI may exacerbate relationships between increasing daytime sleepiness and cognitive deficits in adults with T2D and overweight/obesity.
Seas the day: Co‐designing immersive virtual reality exergames with exercise professionals and people living with dementia
Authors: Mehrabi Samira , Muñoz John E , Basharat Aysha , Li Yiru , Middleton Laura E , Cao Shi , Barnett‐Cowan Michael , Boger Jennifer
Published: December 2021

Background

Physical activity (PA) is associated with physical and cognitive benefits among people living with dementia or mild cognitive impairment (PLWD/MCI) and is a meaningful activity that can improve their confidence in everyday life. Exercising in virtual reality environments (VR Exergame) is becoming an increasingly feasible and enjoyable way to promote PA and well‐being in PLWD/MCI. Although co‐design can significantly improve the design of technology, it is rarely done with PLWD/MCI. This study uses participatory design methods and collaborative approaches to involve key stakeholders to develop and test a VR Exergame "Seas the Day", a novel solution targeting PLWD/MCI well‐being.

Methods

A multi‐stage, user‐centered co‐design approach was used to custom‐build VR Exergames tailored to the unique needs and abilities of PLWD/MCI based on a first generation of the prototype that was previously developed and tested with PLWD/MCI. This paper describes the next iteration of the prototype. Processes included concept ideation and brainstorming activities, iterative prototyping, and playtesting/input/feedback sessions with key stakeholders (PLWD/MCI, exercise professionals, engineers, VR game designers, content developers).

Results

The multidisciplinary and collaborative design process occurred over 15 months (overlapping with COVID‐19 pandemic) with 7 PLWD/MCI (6 females; M=81.3 years) and 9 exercise professionals (7 females; M=38.1 years) to date. The game was designed to target movements identified by exercise professionals and researchers (aerobic exercises, range of motion, seated‐balance, quick response to stimuli) and is structured in three exercise stages (warm‐up, conditioning, cool‐down). To ensure safety of participants while using VR headsets, only seated upper‐limb exercises were targeted. Stakeholder feedback regarding game mechanics, aesthetics, and visual/auditory cues were gathered during brainstorming and playtesting sessions and implemented into specific game‐related scenarios (tai‐chi, rowing, fishing).

Conclusion

We presented the process, outcomes, and challenges of adopting a participatory/collaborative approach with multiple stakeholder groups to co‐design VR Exergames tailored to PLWD/MCI. Next steps will include a mixed‐method evaluation of the VR Exergames among community‐dwelling older adults and PLWD/MCI in retirement communities and long‐term care to evaluate: i) feasibility and acceptability of use, ii) game user experience, iii) barriers/facilitators to uptake of VR Exergames; and iv) inform/validate VR Exergames gameplay metrics reflective of cognitive and motor performance.
Traumatic brain injury accelerates Parkinson’s disease onset without altering Parkinson’s neuropathology
Authors: Spiegel Jonathan , Sone Je Yeong , Butler Tracy , Pirraglia Elizabeth , de Leon Mony J
Published: December 2021

Background

Traumatic brain injury (TBI) is a well‐established risk factor for Parkinson’s disease (PD), though the nature of this relationship remains unclear. This study examines TBI’s relationship with the AAO of and survival following PD onset among participants with PD and examines TBI’s relation with PD neuropathology in an autopsy cohort.

Methods

This is a retrospective observational study using the National Alzheimer’s Coordinating Centers (NACC) database. TBI status was assessed based on self‐reported history. Clinicians estimate was used for determining age at onset (AAO) of cognitive decline and autopsy examination was used in assessing degree of substantia nigra neuropathology. The most recent assessment of participants was used as of June 2018, including participant visits which occurred between 2005 and 2018. The NACC dataset includes a 423 (53 TBI+) participants diagnosed with PD. Substantia nigra neuropathology was assessed in 1,133 (150 TBI+) participants, selected without regard to antemortem diagnoses.

Results

TBI was associated with a 4.9 (1.5‐8.2) year earlier AAO of PD and a 5.9 (3.0‐8.8) year longer survival with PD, but not with death age or severity of substantia nigra pathology.

Conclusions

TBI appears to accelerate PD onset without altering death age or PD‐related neuropathology. This relationship suggests that TBI lowers the threshold required for PD pathology to present as symptomatic PD.
Semi‐quantitative assay for neurogranin peptides using IP‐MALDI‐MS
Authors: Kaneko Naoki , Takahashi Ryota , Korenaga Akihito , Yoda Ritsuko , Sekiya Sadanori , Iwamoto Shinichi , Tanaka Koichi
Published: December 2021

Background

Neurogranin (Ng) is a cerebrospinal fluid (CSF) biomarker for synaptic dysfunction at early stage of Alzheimer’s disease (AD). It has been reported that a variety of truncated peptides from Ng is increased in AD brain tissue. However, the clinical significance of Ng peptides in plasma has remained unclear. We have developed a simultaneous detection method of a plurality of amyloid βpeptides in plasma by using immunoprecipitation combined with matrix‐assisted laser desorption ionization time‐of‐flight mass spectrometry (IP‐MALDI‐MS) (Kaneko et al., Proc Jpn Acad Ser B Phys Biol Sci. 2014). In this study, we applied the IP‐MALDI‐MS technique to Ng measurement.

Method

Ng peptides and proteins were immunoprecipitated from human plasma or standard sample spiked by stable isotope‐labeled (SIL) Ng50‐78 using magnetic beads coupled with anti‐Ng monoclonal antibody. After the IP was performed two times consecutively, Ng proteins and peptides eluted from antibody beads were applied on the MALDI plate. SIL‐Ng50‐78 was used as an internal standard for normalizing an intensity of each Ng peptide.

Result

We optimized the condition such as a kind of detergent and an amount of antibody beads in IP for enhancing Ng signal intensity in MS. In the examination of detergents, UDM showed the highest sensitivity among six tested detergents. Using IP‐MALDI‐MS, we tried to detect Ng peptides and proteins in human plasma. As a result, some peaks corresponding to a variety of Ng peptides (m/z m/z > 5000.0) were detected in a plasma sample. To evaluate our semi‐quantitative assay using the internal standard, we selected some Ng peptides with low and high mass (m/z 2331.5–4084.7) to examine a linearity of the normalized intensity of Ng peptides. The accuracy in linear regression model showed within 80‐120% over a range of 5–160 pM in Ng48‐75 and 10‐160 pM in Ng50–78 and Ng33–75. Intra assay precision of Ng peptides in plasma was less than 20%CV.

Conclusion

IP‐MALDI‐MS enable the highly sensitive and simultaneous semi‐quantitative measurement of multiple Ng peptides levels. It could be helpful in the analysis of plasma Ng peptides for AD biomarker.
Influence of lifespan cognitive reserve indicator on cognitive trajectories in different domains: role of brain pathologies
Authors: Li Xuerui , Song Ruixue , Xu Hui , Yang Wenzhe , Qi Xiuying , Kivipelto Miia , Bennett David A , Xu Weili
Published: December 2021

Background

Evidence on the association of the cognitive reserve (CR) with the cognitive trajectories is limited. We examined the influence of lifespan CR indicator on domain‐specific cognitive trajectories taking brain pathologies into account.

Method

Within the Rush Memory and Aging Project, 1,697 dementia‐free participants (mean age: 79.6 years) were followed up to 21 years. Lifespan CR indicator encompassing education, early‐life, mid‐life, and late‐life cognitive activities, and late‐life social activities was ascertained at baseline and categorized by tertiles (lowest, middle, and highest). Global cognition, episodic memory, semantic memory, working memory, visuospatial ability, and perceptual speed were assessed annually with 19 tests battery, from which composite scores were derived. During the follow‐up, 648 died and underwent autopsies, and brain pathologies were assessed. Data were analyzed using linear mixed‐effects models.

Result

Among all participants, the score of CR indicator ranged from ‐8.00 to 5.74 (mean: 0.00±2.23). In multi‐adjusted mixed‐effects models, compared to the lowest CR, the highest CR was related to slower decline in global cognition (β=0.028, 95% confidence interval [CI]: 0.012 to 0.043), episodic memory (β=0.028, 95% CI: 0.010 to 0.047) and working memory (β=0.019, 0.005 to 0.033) during the follow‐up. Moreover, the association of the highest CR with cognitive function changes remained significant among participants with high Alzheimer’s disease pathology or gross infarcts.

Conclusion

High lifespan CR indicator is associated with preserved global cognitive function, episodic memory, and working memory over time, even in the presence of brain pathologies.
Patient, disease, and study characteristics in contemporary dementia research: A systematic review on external validity
Authors: Mooldijk Sanne S , Licher Silvan , Wolters Frank J
Published: December 2021

Background

For informed decision making on diagnosis, prognosis and care of dementia, physicians and patients rely on the transportability and applicability of evidence from published studies into daily clinical practice. It is uncertain, however, whether routine clinical assessment of dementia is sufficiently captured in contemporary research.

Method

We systematically reviewed PubMed/Medline to characterise study populations in contemporary dementia research by capturing one calendar year of dementia research in humans. We included all studies with patients with dementia that were published in any language in the top 100 journals in the categories clinical neurology, neurosciences, geriatrics & gerontology, psychiatry, neuroimaging, or general & internal medicine between September 1, 2018 and August 31, 2019. Key study details were extracted by 2 reviewers, such as study setting, number of participants, age at dementia diagnosis, and use of imaging or biomarker modalities. Potential discrepancies were resolved by an independent, third reviewer.

Result

Among a total of 513 identified studies, 211 (41%) included <50 individuals with dementia. The remaining 302 studies included a median of 214 patients (interquartile range (IQR): 98‐628) with a mean age at diagnosis of 74.1 years (standard deviation (SD): ±8.0). Age differed substantially with study base, such that patients in clinical studies were on average 71.8 years (±6.4; n=180) at time of diagnosis, compared to 80.6 years (±4.7; n=79) in population‐based studies (mean difference: 8.8 years, 95% confidence interval: 7.3‐10.2; figure 1). Use of MRI, PET and CSF, but not blood biomarkers, was limited to clinical studies (80‐96%), and consequently applied to relatively young patients (mean age: 71.6 years). Studies mainly originated from North America and Western Europe (figure 2); in the 22% of all studies that reported on ethnicity, the vast majority of participants were of Caucasian descent (median: 90%, IQR: 79‐97). The three most studied cohorts represented 21% of all included study populations.

Conclusion

Contemporary dementia research is limited in terms of ethnic and geographic diversity, and draws largely from clinical populations with relatively young patients. Greater inclusivity as well as deeper phenotyping in unselected cohorts could benefit diagnosis and development of effective treatment for all patients with dementia.
Test‐retest variability of relative tracer delivery rate as measured by [11C]PiB
Authors: Heeman Fiona , Hendriks Janine , Alves Isadora Lopes , Tolboom Nelleke , Van Berckel Bart N.M. , Yaqub Maqsood , Lammertsma Adriaan A.
Published: December 2021

Background

In Alzheimer’s disease (AD), reductions in cerebral blood flow (CBF) have been reported and these may be used as proxy for measuring treatment efficacy or disease progression. The gold standard technique for measuring CBF is [15O]H2O positron emission tomography (PET). Recent studies, however, have reported high correlations between [11C]PiB PET derived relative tracer delivery rate R
1 and [15O]H2O derived relative CBF, suggesting that [11C]PiB R
1 may be a good proxy of relative CBF. As longitudinal PET studies become more common for measuring disease progression, it is important to know the intrinsic variability of R
1. The purpose of the present study was to determine R
1 test‐retest (TRT) variability.

Method

Previously, TRT variability of [11C]PiB binding potential has been reported for a group of twelve participants (five cognitively unimpaired (CU), one with mild cognitive impairment and six with AD dementia), in which all participants underwent two 90 min [11C]PiB PET scans using a Siemens ECAT EXACT HR+ scanner1. This dataset was reanalysed to also determine TRT variability of [11C]PiB R1. The voxel‐based implementation of the two‐step simplified reference tissue model with cerebellar grey matter as reference tissue was used to generate R1 images. Next, TRT variability was calculated both globally and regionally, and global R1 measures were compared between diagnostic groups using a non‐parametric Mann‐Whitney U test. Next, correlation analysis was used to assess the relationship between TRT variability and regional volume. Finally, regional test and retest R1 measures were compared using Linear Mixed Effect Models and Bland‐Altman analysis.

Result

Global relative tracer delivery (R1) was significantly lower in AD patients (test R1:0.82±0.04, retest R1:0.82±0.03) compared with CU participants (test R1:0.93±0.04 retest R1:0.91±0.03, p<0.01). TRT variability was low across regions (range:1.5‐5.8%), with a trend effect towards smaller TRT for larger regions (R2=0.14, p=0.09). Furthermore, test and retest measures showed high, significant correlations (R2=0.92, slope=0.98) and negligible bias (0.69±3.07%).

Conclusion

The high precision of [11C]PiB R1 suggests suitable applicability for cross‐sectional and longitudinal studies. This finding further demonstrates the utility of dynamic [11C]PiB PET scans for dual‐biomarker imaging in AD research. Reference: Tolboom et al.(2009) Eur J Nucl Med Mol Imaging 36:1629‐38.