bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of lower dementia risk with improved air quality in older women
Authors: Wang Xinhui , Younan Diana , Millstein Joshua , Petkus Andrew J , Garcia Erika , Beavers Daniel P , Espeland Mark A , Chui Helena C , Resnick Susan M , Gatz Margaret , Kaufman Joel D , Wellenius Gregory , Whitsel Eric A , Manson JoAnn E , Rapp Stephen R , Chen Jiu‐Chiuan
Published: December 2021

Background

Late‐life ambient air pollution is a novel risk factor for brain aging. Air quality improvement has been associated with improved cardiopulmonary health and reduced mortality; however, whether it is associated with reduced dementia risk is unknown.

Method

We studied a geographically‐diverse cohort from the Women’s Health Initiative Memory Study‐Epidemiology of Cognitive Health Outcomes (WHIMS‐ECHO). Participants included 2239 older women (aged 74‐92) without dementia at WHIMS‐ECHO enrollment in 2008‐12. Incident dementia cases, based on DSM‐IV criteria, were centrally‐adjudicated annually (2008‐18). Yearly mean concentrations of ambient PM2.5 (fine particulate matter) and NO2 at residential locations were estimated using validated regionalized universal kriging models. These annual estimates were then averaged over 3‐year periods at both immediately preceding (recent exposure) and 10 years prior to (remote exposure) WHIMS‐ECHO enrollment. Individual‐level improved air quality was defined as reduction from remote to recent exposures. We used Cox proportional hazard models to estimate the hazard ratios (HR) for dementia risk associated with air quality measures, adjusting for sociodemographic, lifestyle, and clinical characteristics. We incorporated inverse‐probability weighting to account for differential attrition during the follow up. Models were replicated using multiple imputation to include those with missing air pollution and covariate data as sensitivity analyses.

Results

We identified 398 incident dementia cases during median 6.1 years of follow up (interquartile range [IQR]=5.2 years). PM2.5 and NO2 reduced significantly over the 10 years before WHIMS‐ECHO enrollment. Greater improvement in air quality was significantly associated with reduced dementia risks (HRPM2.5=0.80 per IQR=1.78µg/m3, 95% confidence interval [CI]=[0.71, 0.91]; HRNO2=0.80 per IQR=3.91ppb, 95%CI=[0.71, 0.90]), equivalent to the lower risk observed in women 2.4 years younger at baseline. There was some evidence that recent PM2.5 exposure was associated with higher dementia risk (HRPM2.5=1.16 per IQR=2.90µg/m3, 95%CI=[0.98, 1.38]), but the lower dementia risk associated with improved air quality remained after further adjusting for the recent exposure effects. The observed associations did not substantially differ by age, education, geographic region, APOE e4 genotypes, or cardiovascular risk factors. Similar results were found in the sensitivity analyses using multiple imputation.

Conclusions

Long‐term air quality improvement in late‐life was associated with lower dementia risk in older women.
Inflammatory biomarkers are associated with cerebral large artery thickening and dilatation in older adults
Authors: Cambronero Francis E. , Liu Dandan , Bown Corey W. , Kresge Hailey A. , Pechman Kimberly R. , Khan Omair A. , Davis L. Taylor , Gifford Katherine A. , Hohman Timothy J. , Donahue Manus J. , Blennow Kaj , Zetterberg Henrik , Jefferson Angela L.
Published: December 2021

Background

Age‐associated changes in intracranial large arteries, including hypertrophic and dilatative remodeling, contribute to worse systemic and brain health in older adults. Vessel wall imaging (VWI) is a novel neuroimaging technique that offers the critical ability to quantify thickness and lumen diameter across arterial segments of the circle of Willis (CoW). Research suggests inflammation, a well‐known feature of aging, cerebrovascular disease, and Alzheimer’s disease, may be a central driver of age‐related changes in CoW morphology. We investigate if fluid biomarkers of inflammation predict key features of intracranial arterial aging, including CoW thickening and dilatation visible on VWI MRI.

Methods

Vanderbilt Memory & Aging Project participants free of clinical stroke and dementia were studied (n=117, 74±7 years, 73% male). Systemic inflammatory biomarkers (TNF‐α, IL‐6) were quantified from blood plasma samples and neuroinflammatory biomarkers (sTREM2, YKL‐40) were quantified from cerebrospinal fluid samples. Intracranial artery lumen diameter and thickness were manually measured across the basilar artery (BA) and bilateral segments of the internal carotid artery (ICA), anterior cerebral artery (ACA), and middle cerebral artery (MCA) using VWI MRI. Linear regressions related each inflammatory biomarker to intracranial artery lumen diameter and thickness in separate cross‐sectional models, adjusting for age, sex, race/ethnicity, education, Framingham Stroke Risk Profile, diagnosis, apolipoprotein ε4 status, and T1‐weighted intracranial volume.

Results

TNF‐α was related to right ICA thickness (b=0.01, p=0.03), left ICA thickness (b=0.01, p<0.05), and left ACA thickness (b=‐0.01, p=0.04); TNF‐α was unrelated to lumen diameters (p>0.51). IL‐6 was related to right ICA thickness (b=0.01, p=0.003) and was unrelated to lumen diameters (p>0.18). sTREM2 was related to left MCA lumen diameter (b=0.0001, p=0.03), right ACA lumen diameter (b=0.0001; p=0.001), and right ACA thickness (b=0.00003, p=0.03). YKL‐40 was unrelated to intracranial artery thickness (p>0.27) and lumen diameter (p>0.05).

Conclusions

Results suggest TNF‐α, IL‐6, and sTREM2 are related to intracranial large artery thickening, and sTREM2 may further relate to large artery dilatation. Given the increased reliability of ICA and BA manual measurements on VWI MRI, these findings may be most robust. Proinflammatory cytokines and microglia‐mediated immune responses may be key pathophysiological mechanisms underlying age‐related arterial remodeling within the brain.
How often is EEG used as part of routine dementia evaluation in community practice?
Authors: Pippenger Mark A
Published: December 2021

Background

Recommendations for evaluation of patients with dementia have changed little in the last thirty years. The guideline for diagnosis of dementia published by the American Academy of Neurology (AAN) in 1984 recommended against routine use of EEG for evaluation of dementia, and in the updated guideline from 2001 EEG is not specifically mentioned. Some authors continue to argue for use of EEG in dementia research, though mostly this focuses on specialized EEG techniques like quantitative EEG. There are few reports, however, on the frequency of EEG use in community neurological evaluations for dementia.

Method

All new patient referrals to the Novant Health Memory Clinic in Charlotte, NC, for 2020 were reviewed. Information was tabulated for those patients who had been previously evaluated by a neurologist in the community, specifically to determine how often EEG was included as part of the routine evaluation. Results of the EEG as taken from the clinician’s report were tabulated, though there was no opportunity to examined the EEG tracing itself. The author made a judgement as to whether the results of the EEG affected the clinical diagnosis or provided useful information for management of the patient in each case, and these data were tabulated.

Result

During the year of observation, there were a total of 845 new patient evaluations in the Memory Clinic. Of those, 274 patients met clinical criteria for “Probable” Alzheimer Disease, 237 met criteria for Mild Cognitive Impairment, and 207 for Subjective Cognitive Decline. Out of these patients, 89 had been previously evaluated by a community neurologist. In 63 of the evaluations, EEG was obtained as part of the routine evaluation. Of these, 16 were read as “normal,” and 47 were read as “abnormal” due to slowing of background rhythm. In 2 of the 47, the reader also reported finding “sharp waves” in temporal leads, and these 2 patients were treated by the reading neurologist with anticonvulsants, later discontinued in both cases. In no case did the EEG provide useful information for either diagnosis of management of dementia.

Conclusion

These data support the AAN guideline’s recommendation against routine use of EEG for dementia evaluation.
Urine dicarboxylic acids are metabolic biomarkers of early Alzheimer’s disease
Authors: Harrington Michael G. , Maldonado Salvador , Sagare Abhay P. , Zlokovic Berislav V. , Chui Helena C. , Fonteh Alfred N.
Published: December 2021

Background

We previously identified urine dicarboxylic acids (DCA) of carbon length 4‐9 as candidate biomarkers of probable Alzheimer’s disease (AD) and energy dysregulation, and found their levels correlated with hippocampal volume. Our aim was to evaluate these initial findings in a second cohort.

Method

Study participants (> 65 years) were classified clinically as cognitively healthy (CH, n=188) or with probable AD (n=66) based on Uniform Data System‐3 of the National Alzheimer’s Coordinating Center criteria. Cerebrospinal fluid (CSF) amyloid ß42 (A) and phospho‐ tau (T) levels were measured by validated immunoassay. Urine was collected in a “spot” sample after a 12 h overnight fast; target DCAs were detected using gas chromatography coupled with negative ion chemical ionization mass spectrometry and each DCA was normalized to deuterated internal standards and to a percent of total fatty acids.

Result

The mean of short‐chain DCA’s (C4‐C5) were higher in CH (44.38% ±17.79) compared to AD individuals (34.79% ±12.39) (p=0.0002), while the long‐chain DCA’s (C7‐C9) were lower for CH (34.70% ±16.88) when compared to AD individuals (45.22% ±15.11) (p<0.0001). DCA levels in the subset of CH participants with A+/T+ were in a transition to the levels of the AD group and C4‐C5 and C7‐C9 differed from those with A‐/T‐ biomarkers (p=0.0001). Combining results into a ratio of short‐ to long‐chain DCAs distinguished the A‐/T‐ (2.330 ±2.144) from the A+/T+ group (1.178 ±0.946); p<0.0001. ROC curve of the DCA ratio between CH‐NAT and AD is 82%. Study participant clinical and DCA groups were not significantly correlated with the common confounders of age, sex, education or ApoE genotype.

Conclusion

Our data extends our initial finding that urine DCA measures have potential as biomarkers of AD pathology, including for cognitively healthy individuals who are positive for CSF AT biomarkers. We propose that measurement of urine DCAs provides a new approach to screen for metabolic fluctuations in early AD and to monitor the effect of novel therapies in clinical trials. While studies are needed, including with other populations, varied clinical classifications, simplified chemistry, this data supports DCA biomarkers for widespread screening since the necessary urine sample is available from everyone.
Verbal fluency associated with tau accumulation and not amyloid deposition in the Alzheimer’s disease spectrum
Authors: Rahmouni Nesrine , Stevenson Alyssa , Stevenson Jenna , Tissot Cécile , Lussier Firoza Z , Bezgin Gleb , Therriault Joseph , Chamoun Mira , Kang Min Su , Pascoal Tharick A. , Gauthier Serge , Benedet Andréa Lessa , Rosa‐Neto Pedro
Published: December 2021

Background

Recent studies have shown that pathological amyloid deposition and tau accumulation, hallmarks of the Alzheimer's disease, are closely related to cognitive deficits in older individuals. The present study evaluates the associations between the Alzheimer's disease hallmarks and verbal fluency and lexical speed access impairment.

Method

The study was conducted in a population of 262 individuals (162 cognitively unimpaired individuals (CU), 100 cognitively impaired individuals (CI; 61 MCI and 39 AD). The verbal Letter Fluency test was used to assess the vocabulary size and lexical speed access. Individuals underwent an MRI, a [18F]AZD4694 amyloid‐PET scan and a [18F]MK6240 tau‐PET scan. [18F]AZD4694 and [18F]MK6240 standardized uptake value ratio (SUVRs) were calculated between 40 to 70 min and 90 to 110 min post‐injection, respectively, using cerebellum grey matter as the reference region. A voxel‐based regression model evaluated the relationship between the cognitive scoring and the PET markers [18F]AZD4694 and [18F]MK6240, correcting for age, sex, education, APOE, diagnosis and RFT was used to account for multiple comparisons

Result

Negative correlations were found between Letter Fluency scores and tau accumulation. The associated regions were medial frontal, superior temporal, medial occipital lobes and precuneus area. No associations were found between the Letter Fluency scoring and amyloid deposition.

Conclusion

Our results suggest that tau accumulation is associated with lower vocabulary size and lexical speed access, whereas amyloid deposition does not influence this neuropsychological field.
Accumulation of depressive symptoms over time in cognitively impaired individuals
Authors: Bhattacharya Gogol , Tosun Duygu
Published: December 2021

Background

Depressive symptoms in elderly are common, but the persistence of depressive symptoms in older adults with and without cognitive impairment (CI) is less studied. Accumulation of depressive symptoms over time might be a sign of developing chronic depressive course and therefore increased risk for cognitive decline and dementia. The aim of the present study was to assess patterns of depressive symptom accumulation over time among older adults, and to explore the association between the course of depressive symptoms over time and demographic and clinical characteristics at baseline.

Method

A data‐driven approach was used to cluster ADNI participants based of their longitudinal Geriatric Depression Scores (GDS‐15). We leveraged modern time‐series analysis techniques including the Dynamic Time Warping and Dynamic Barycenter Averaging as the clustering generation technique. ADNI participants were clustered to data‐driven groups presenting with unique time course of depressive symptom accumulation.

Result

We ran a search for the optimal number of clusters using the silhouette score as the indicator of a strong clustering. This resulted in the generation of 3 unique profiles with differing patient demographics. Specifically, 1st group presented with the lowest baseline depressive symptoms (GDS=0.44±0.61) and stayed stable over the course of ADNI study (GDS=1.03±1.25). P2nd group presented with slightly elevated depressive symptoms at baseline (GDS=1.78±1.10) and accumulated depressive symptoms (GDS=2.74±2.05). In contrast, 3rd group presented with significant depressive symptoms (GDS=3.80±1.42) and accumulated more symptoms over time (GDS=4.50±2.56). Although groups did not different in age at the baseline or prevalence of females, patients that have CI, indicated by both the clinical diagnosis and the patient's Clinical Dementia Rating, are more likely to have higher GDS scores and are at higher risk of developing depressive symptoms (i.e., baseline CI prevalence of 40% in Group 1 compared to 74% and 75% in Groups 2 and 3, respectively).

Conclusion

The data shows that there are differences in the persistence of the depressive symptoms in elderly population with and without CI. Identifying individuals that are more susceptible to depressive symptom accumulation might significantly improved patient outcomes and higher quality of life.
Inflammation and innate immune system activation in neurodegeneration, Down syndrome, aging, and infection: Therapeutic target or partner?
Authors: Potter Huntington , Boyd Timothy D. , Ahmed Md. Mahiuddin , Kendall Lon V. , Sillau Stefan H , Coughlan Christina M , Clarke Penny , Stonedahl Sarah , Chial Heidi J
Published: December 2021

Background

Characteristic features/biomarkers of innate immune system activation and inflammation are associated with neurodegenerative diseases (e.g., Alzheimer’s disease [AD], Parkinson’s disease [PD]), Down syndrome [DS], normal aging, and many infectious diseases. Evidence also suggests that peripheral inflammation interacts with and mirrors inflammation in the central nervous system (CNS) and can yield useful biomarkers of the disease or disorder and potentially of the efficacy of therapies. These findings have led to the additional conclusion that developing methods to dampen inflammation would be an effective therapeutic approach. However, recent findings indicate that innate immune system activation, including inflammation, may, instead, be beneficial.

Method

We used the proinflammatory cytokine granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) to modulate the innate immune system and determine the effects on biomarker, clinical, and/or behavioral outcomes in mouse models of AD, DS, aging, and viral infection and in a clinical trial in AD.

Result

Recent published and unpublished results from our laboratory and others show that treatment with GM‐CSF increases inflammatory biomarkers and also effectively reduces cognitive decline, brain pathology, and disease‐associated peripheral blood biomarkers in mouse models of AD, PD, DS, and normal aging. Interestingly, GM‐CSF treatment also reduces viral titer and mortality in mouse models of West Nile Virus and SARS‐CoV‐2 infection. Our retrospective study of patients with cognitive deficits due to chemotherapy‐induced CNS inflammation showed that recombinant human GM‐CSF (sargramostim) treatment was associated with improved cognition. A sargramostim clinical trial in PD also showed promising results. Finally, our recently‐completed clinical trial in AD showed that sargramostim treatment increased inflammatory cytokines and improved toward normal both a measure of cognition (MMSE) and blood biomarkers of amyloid (A) and Tau (T) deposition and neurodegeneration (N). Sargramostim clinical trials in COVID‐19 are underway.

Conclusion

Together, these results indicate that targeted enhancement of the innate immune system and of inflammatory cytokines, specifically in response to GM‐CSF, can effectively treat many disorders that exhibit characteristic inflammation and innate immune system activation. Thus, the long‐held belief that inflammation and innate immune system activation only play a negative role in neurodegenerative diseases, DS, viral infections, and normal aging should be reassessed.
Effects of gamma sensory stimulation on cognitive function in Alzheimer’s disease patients
Authors: Cimenser Aylin , Konisky Alexandra , Shukla Mohinish , Mrozak Holly , Cohen Jacob , Kolin Katharine , Martin Karen , Boasso Alyssa , Hempel Evan , Malchano Zach , Hajos Mihaly
Published: December 2021

Background

Alzheimer’s disease (AD) patients exhibit distorted excitatory‐inhibitory balance of neuronal activity, leading to accelerated worsening of functional and cognitive abilities. Improving abnormal neuronal synchrony by long‐term non‐invasive, gamma sensory stimulation at 40 Hz in transgenic mice carrying pathological AD human genes has been shown to beneficially affect neural activity and improve learning and memory. In the present translational clinical trial, the effects of gamma sensory stimulation on cognition and global function were evaluated in AD patients using an at‐home therapy device (Cognito Therapeutics, Cambridge, MA).

Method

The phase I/II randomized, controlled, single‐blinded multi‐center clinical trial (Overture study; NCT03556280) evaluated safety, adherence rates and efficacy of gamma sensory stimulation therapy in patients with mild to moderate Alzheimer’s disease (MMSE 14‐26, inclusive). The 6‐month trial included treatment and sham groups receiving daily, one‐hour sensory stimulation but only participants in the treatment group were exposed to 40Hz auditory and visual stimulations. During the trial, cognitive functions were measured by Alzheimer's Disease Assessment Scale (ADAS‐Cog), Mini‐Mental State Examination (MMSE), and Clinical Dementia Rating Sum of Boxes (CDR‐SB). In order to align assessment data in time to study events (therapy start and end) and account for variable study visit intervals at start and end of therapy period, cognitive measures were calculated on a per‐patient basis by a model of AD‐related cognitive decline derived from a large‐scale dataset. Finally, adjusted cognitive scores were compared between the two groups.

Result

The trial has been completed by 33 and 19 patients in the treatment and sham groups, respectively. Daily therapy of gamma sensory stimulation was well tolerated, confirming safety and high adherence. The three independent cognitive tests demonstrated a diminished cognitive decline in the treatment group compared to the sham group. Final analysis results from MMSE, ADAS‐Cog, CDR‐SB and Integrated Alzheimer's Disease Rating Scale (iADRS) will be presented at the meeting.

Conclusion

The present findings, together with the established safety profile, functional benefit, and improvement in sleep justify further evaluation of gamma sensory stimulation in AD patients.
Protective factors associated with normal cognition in persons age 80 years and older
Authors: Trammell Antoine R , Hajjar Ihab , Goldstein Felicia C , Parker Monica W
Published: December 2021

Background

Identifying cognitive protective factors with aging is critical to addressing the development and progression of Alzheimer’s Disease and Related Dementias (ADRD). Despite evidence of cognitive resilience in African Americans (AA), older AA are at increased risk for ADRD. Studies exploring cognitive resilience have been conducted in predominantly white samples. Using a biracial sample, this study explores for factors related to normal cognition in persons over age 80.

Method

Data from the NACC through the November 2020 data freeze was requested. White and AA persons over age 80 with normal cognition (NC) and mild cognitive impairment (MCI) were analyzed. Demographics, functioning, medical and vascular factors, and medications were evaluated. Comparisons of white vs. AA and NC vs. MCI using ANOVA or chi‐square were performed. Multinomial logistic regression further evaluated race‐cognitive groups and potential factors related to normal cognition.

Result

Data from 20,088 subjects was reviewed. Mean age of the same was 85.7 years,15.3 years of education, and MoCA score of 23.7. It was 85.9% white, 57.8% female, and 36.2% had NC. AA/NC had higher BMI than AA/MCI (27.2vs.26.6,p=0.3). Most AA/NC were female (80.6%vs.74.4%,p<0.0001). AA/NC were non‐diabetic (61.4%vs.58.3%,p<0.0001) and lacked heart disease (7.4%vs.3.62%,p<0.0001). AA/NC lived independently (8.25%vs.3.01%,p<0.0001), were married (4.95%vs.1.97%, p<0.0001), and had intact problem‐solving (7.31%vs.1.95%,p<0.0001). Most white/NC were female (60.1%vs.47.3%,p<0.0001). White/NC were non‐diabetic (59.5%vs.31.3%,p<0.0001) and had no stroke (59.4% vs. 29.3%,p<0.0001). White/NC lived independently (55.3%vs.21.4%,p<0.0001), were married (28.9%vs.11.5%,p<0.0001), and had intact problem‐solving (55.7%vs.15.3%,p<0.0001). AA over age 80 were more likely to have NC if they lacked diabetes (OR:5.1,95%CI:1.38‐18.7), depression (OR:5.3,95%CI:1.33‐21.1), had intact problem solving (OR:4.26,95%CI:1.29‐14), and didn’t take ACEI (OR:3.59,95%CI1.58‐8.13) or diuretics (OR:3.51,95%CI1.71‐7.22). Whites over age 80 were more likely to have NC if they were female (OR:1.72, 9%CI:1.41‐2.11), had no depression (OR 2.93, 2.06‐1.14 95% CI), intact problem solving (OR:10.8,95%CI:6.43‐18.2), live with a spouse (OR:11.9,95%CI:1.46‐95.1), and not take antidepressants (OR:1.73,95%CI:1.35‐2.23).

Conclusion

Differences in demographic and vascular factors, medications, and functioning are associated with normal cognition in advancing age. The factors can vary with race. Studies of prospective studies are needed to further study these differences.
Modified Mediterranean ketogenic diet resolves default mode network connectivity differences between adults with normal and impaired cognition
Authors: Kawas Mohammad I , Lockhart Samuel N. , Kim Jeongchul , Neth Bryan J. , Barcus Richard A. , Hughes Tim M. , Solingapuram Sai Kiran K , Craft Suzanne , Whitlow Christopher T.
Published: December 2021

Background

In the absence of disease modifying/preventative therapy for Alzheimer’s disease (AD), there has been increased focus on alternate therapeutic approaches, including the ketogenic diet, which supplies auxiliary metabolic fuel to brain and has potential neuroprotective effects. Our goal was to examine the modified Mediterranean‐ketogenic diet (MMKD) and an American Heart Association Diet (AHAD) in older adults at risk for AD with respect to cognitive performance and associated brain functional connectivity within the default mode network (DMN), which has been implicated in cognitive processes directed toward the self, such as introspection and autobiographic memory.

Method

Eighteen participants with normal cognition and subjective memory complaints (SMC) (n = 10, mean age = 65 ± 7) or Mild Cognitive Impairment (MCI) (n = 8, mean age = 64 ± 4) completed six weeks on both diets in a randomized crossover design. Before and after each diet, participants underwent 3T brain MRI and cognitive testing. MRI included T1‐weighted imaging for gray/white matter segmentation, and blood oxygen level dependent (BOLD) imaging for resting‐state functional connectivity. Cognitive function was evaluated using two memory tests, the Free and Cued Selective Reminding Test (FCSRT) and story recall, which were composited into a single memory score. BOLD data were pre‐processed and de‐noised using standard techniques, and normalized to the Mayo Clinic Adult Lifespan Template (MCALT). Connectivity analyses were performed using CONN functional connectivity toolbox. Briefly, functional connectivity of the DMN was analyzed utilizing the PCC for a seed to voxel connectivity analysis.

Result

At baseline, there were statistically significant differences in DMN connectivity between MCI and cognitively normal participants with SMC (Figure‐1), with connectivity increases between DMN and superior frontal gyrus, and decreases between DMN and superior parietal gyrus, which were significantly correlated with baseline memory scores (Figure‐2). After both diets, there were no detectable differences in DMN connectivity between the two groups. However, MMKD had a more pronounced effect on reducing DMN hyper‐connectivity among MCI participants than AHAD (Figure‐3).

Conclusion

Our results suggest that a ketogenic intervention may augment aberrant DMN network connectivity patterns in adults at risk for AD and lessen cognitive decline.
Using Bayesian hierarchical analysis to combine evidence across outcomes and trials
Authors: Dickson Samuel P , Nicodemus‐Johnson Jessie , Knowlton Newman , Syndergaard Tess , Neff Jacob , Earnshaw Madison , Hennessey Sean , Hendrix Suzanne B.
Published: December 2021

Background

The FDA’s statistical review for the recent aducanumab advisory committee included a Bayesian hierarchical analysis (BHA) combining CDR‐SB evidence across the ENGAGE and EMERGE studies resulting in a 62% probability of the treatment being efficacious. BHA can combine evidence across outcomes, trials within a drug development program, and trials for a specific mechanism of action, and provides an elegant solution to interpreting the totality of evidence. BHA is a comparable approach to composite scores and global statistical tests, but key differences exist.

Method

Using summary results from the aducanumab ENGAGE and EMERGE studies, solanezumab Expedition 1, 2, and 3 and the BAN2401 PRIME study, we combined evidence from ADAS‐Cog, ADCS‐ADL, and CDR‐SB using a BHA with hierarchies at the study, program, and three program level to assess the amyloid hypothesis, using the pre‐specified primary analysis populations. We compared these results to GSTs.

Results

The aducanumab program combined across EMERGE and ENGAGE with all 3 outcomes has a 0.92 probability (>99.9% with GST), the solanezumab program combined across Expedition 1, Expedition 2 and Expedition 3 has a 0.92 probability (>99.9% with GST), and the BAN2401 program has a 0.95 probability (99.2% with GST) of treatment efficacy. We present BHA and GST results for individual studies compared to the original results. We also compare the study‐level BHA results to the global statistical test (GST) approach. We combine evidence across all 3 programs to get an overall probability of efficacy for the amyloid hypothesis with these 3 programs using BHA and GST.

Conclusion

BHA and GST both assess the totality of evidence within a study or development program, providing a natural correction for multiplicity, but results differ. BHA penalizes for divergence of outcomes or studies, and GST does not. This may be appropriate in some settings, but not in others. It allows an assessment of convergence of evidence, weakening of evidence, or elimination of evidence when a negative study “cancels out” a positive study. On a larger scale, it sheds light on how much evidence might exist for theories like the amyloid hypothesis when combining evidence across programs.
Potential anti‐Alzheimer alkaloids of Peganum harmala
Authors: Nasibova Tohfa , Garaev Eldar
Published: December 2021

Background

Alzheimer's disease (AD) is an irreversible, progressive brain condition that steadily affects the ability to perform the simplest tasks, memory and reasoning skills, and ultimately. In 2018, the latest year for which data is available, it is officially reported 122,019 deaths from AD, which makes Alzheimer's the sixth leading cause of death and the fifth leading cause of death among people aged 65 and older in the United States. Deaths resulting from stroke, HIV, and heart disease decreased between 2000 and 2018, while recorded Alzheimer's deaths increased by 146,2 %.

Different types of drugs are used against Alzheimer's disease. One of the medicines used for the treatment of Alzheimer's disease is acetylcholinesterase inhibitors (AChEIs). Methanol extracts of the seeds of the Peganum genus were found to show the significant inhibitory activity for acetylcholinesterase enzyme (AChE). Due to the beneficial effects of Peganum harmala alkaloids (harmine, harmaline, etc.) on the nervous system, the positive effects on Alzheimer's disease have been identified in studies. Our study aims to obtain these alkaloids from plants individually.

Method

Dried and ground grains of P. harmala are extracted 3 times by 95% ethanol. Extracts are combined, evaporated until a concentrated mass is formed, mixed with 5% HCl and the obtained solution is filtered. The solution is alkalized by 25% ammonia solution and extracted by liquid/liquid extraction with chloroform 4 times. Fractions are combined, concentrated, and analyzed by TLC. On TLC plates, 4 orange spots with Rf 0.69, 0.31, 0.2 and 0.1 (stationary phase “Sorbfil” (Russia), mobile phase chloroform/methanol, 9/1, v/v; revelator Dragendorff solution) are observed. For the purification, preparative TLC plates were used (stationary phase “Machery ‐ Nagel” (Germany), mobile phase chloroform/methanol, 8.5/1.5, v/v). Lines corresponding to each compound were scraped, extracted by ethanol, and filtered.

Result

Based on UV, IR, and NMR spectroscopy data, these compounds were identified as harmaline, harmine, and vasicine.

Conclusion

The wide distribution area, high quantity of alkaloids, and the positive effects of this plant on Alzheimer's disease make it possible to evaluate it as a potential medicine for the treatment and prevention of the disease.
Aβ42/Aβ40 ratio in plasma predicts amyloid‐PET status in amnestic‐MCI patients
Authors: Pascual‐Lucas María , Sarasa Leticia , Molina Elisabet P. , Castillo Sergio , Pesini Pedro , Allué Jose A.
Published: December 2021

Background

We have completed the analytical validation of an antibody‐free, HPLC‐MS/MS method (ABtest‐MS), to quantitate specifically Aβ1‐40 and Aβ1‐42 in plasma with high precision (inter‐assay %CV 6.2‐7.0% for Aβ1‐40 and 6.1%‐11.0% for Aβ1‐42) and accuracy (%RE ‐0.6 to 0.3% for Aβ1‐40 and ‐1.5 to 1.3% for Aβ1‐42).

Previous studies have shown that the Aβ42/Aβ40 ratio in plasma predicts β‐amyloid status reliably, suggesting that the assessment of plasma Aβ levels could be a useful screening tool for Alzheimer’s Disease (AD) clinical trials, reducing the need for invasive or complex procedures.

In this work we explore the ability of Aβ42/Aβ40 plasma ratio to predict the Aβ‐PET status at baseline visit in the ABvac40 (an active vaccine against Aβ40) phase II clinical trial.

Method

Aβ40 and Aβ42 plasma levels from 73 amnestic‐MCI (a‐MCI) participants, who had previously given their consent, were quantitated with ABtest‐MS. Levels of p‐tau181 were assessed with Simoa® p‐tau181 V2 Advantage Kit (Quanterix). The ability of plasma Aβ42/Aβ40 ratio or p‐tau181 to detect Aβ‐PET positivity was assessed as the area under the ROC curve (AUC).

Result

Aβ42/Aβ40 plasma ratio values were significantly lower in the Aβ‐PET positive than in the Aβ‐PET negative group (p<0.001). The opposite trend was observed for p‐tau181 plasma levels, which were significantly higher in the Aβ‐PET positive than in the Aβ‐PET negative group (p<0.001). The Aβ42/Aβ40 plasma ratio discriminated Aβ‐PET positivity with an AUC value of 0.87, performing identically to p‐tau181 plasma levels.

A negligible increment in the AUC was observed after adjusting for ApoE genotype. However, inclusion of both biomarkers in the predictive model increased AUC value up to 0.94, outperforming each biomarker alone.

Conclusion

Among the a‐MCI participants in the ABvac40 phase II clinical trial who had previously consent, the Aβ42/Aβ40 plasma ratio discriminates Aβ‐PET positivity with a high AUC, performing as well as p‐tau181. These results demonstrate that the Aβ42/Aβ40 ratio in plasma could be used to predict cerebral Aβ burden.
Utility of extracellular vesicles and their MicroRNA cargo as biomarkers for Alzheimer's disease
Authors: Sandau Ursula S. , McFarland Trevor , Smith Sierra J. , Baker Sarah Catherine , Duggan Erika , Nolan John P. , Saugstad Julie A
Published: December 2021

Background

Alzheimer’s disease (AD) is the most common cause of dementia. Developing effective therapies is dependent on the availability of biomarkers that accurately diagnosis AD and track disease progression. MiRNAs, which can be sorted into extracellular vesicles (EVs), reflect the disease state of many neurological disorders and have the potential to serve as biomarkers.

Method

Cerebrospinal fluid (CSF) from AD, Parkinson’s disease (PD), and control (n=10/group) participants was analyzed by vesicle flow cytometry for size, concentration, and subtypes of EVs. In matching CSF and isolated CSF‐EVs we measured the expression of 34 miRNAs (previously validated candidate AD biomarkers) and assessed magnitude of fold change and classification potential for AD.

Result

The EVs in CSF from AD and PD were significantly larger than control CSF and there were fewer microvesicles. CSF‐EVs had 25 detectable miRNAs out of 34 assayed; while 30 were detectable in total CSF. For the detectable miRNAs in CSF‐EVs, 52% had at least a 1.5 fold change in expression in AD, relative to control. In total CSF, 30% of the assayed miRNAs had a 1.5 fold change in AD versus control. Classification performance for AD from controls was improved for CSF‐EV miRNAs, compared to total CSF. Four of the CSF‐EV miRNAs also had an AUC > 0.7 for classifying AD from PD.

Conclusion

EV biogenesis in neurodegenerative diseases is disrupted compared to neurologically normal controls, which leads to an altered EV profile in CSF. Further, the miRNA expression profile of CSF‐EVs improves the performance of candidate AD biomarkers.
A study on the research trends of effectiveness of telehealth for the elderly through bibliographic analysis
Authors: Park SunHa
Published: December 2021

Background

Telemedicine is being proposed as an alternative to the problem of medical restrictions on elderly in an aging society. However in Korea, telemedicine for the elderly is not in full swing and the need for telemedicine is increasing. In order to obtain implications for the study of the effectiveness of telemedicine for the elderly in Korea, it was intended to analyze overseas research trends empirically through the bibliographic analysis.

Method

This study collected bibliographic information on the effectiveness of telehealth for the elderly published in international academia from January 2010 to December 2020 and analyzed and visualized relationships between information using VOS viewer software.

Result

First of all, research trend analysis shows 678% increase or decrease in the number of papers published over the past 10 years. The research field was the most conducted in 145(45.89%) health care science services, and the most papers were published in 39 Telemedicine and e‐Health journals(9.11%). Second, the network analysis showed that the total connectivity of Oxford University among countries and institutions in the U.S. was 65, respectively, indicating the strongest influence in international academic societies. Third, as a result of keyword analysis elderly(64 times), treatment(62 times), health(50 times), technology(40 times), and results (41 times) were used in the paper.

Conclusion

In this study, trends and topics of international academia on the effectiveness of telehealth for the elderly will be analyzed to gain implications for the research activation and institutional basis of telehealth for elderly in Korea.
Why would Canada have the longest wait times for an Alzheimer’s treatment among the G7 countries? A policy analysis
Authors: Mattke Soeren , Wang Mo
Published: December 2021

Background

The emerging disease‐modifying Alzheimer’s treatments present a health system challenge because of the combination of a large prevalent patient pool and a complex diagnostic process. Analyses of system preparedness have projected Canada to have by far the longest and most protracted wait times for access among G7 countries.

Method

Policy analysis study using comparative health system data and 17 semi‐structured interviews with experts in Canada.

Result

Compared to other G7 countries, Canada has a high number of family physicians, but low numbers of dementia specialists and imaging equipment per capita, leading to wait times even today. The capacity constraints result from limited investment in infrastructure and deliberate use of supply side restrictions for cost containment. Several options exist to alleviate those constraints in the short run, such as building on existing primary‐led memory care models, more flexible use of existing imaging devices, and utilization of novel diagnostic technology like digital and blood‐based biomarker tests.

Conclusion

Canada faces a unique challenge to make a disease‐modifying Alzheimer’s treatment accessible because of limited capacity for memory care. While opportunities exist to improve access, they are not likely to be realized fast enough in the absence of a deliberate planning effort.
Identifying preclinical Alzheimer disease from driving patterns: A machine learning approach
Authors: Bayat Sayeh , Babulal Ganesh M , Schindler Suzanne E. , Fagan Anne M , Morris John C. , Mihailidis Alex , Roe Catherine M
Published: December 2021

Background

Alzheimer disease (AD) is the most prevalent form of age‐related dementia. The clinical manifestation of AD is generally preceded by a silent preclinical phase during which early AD brain changes are present but dementia symptoms have not yet appeared. Molecular biomarkers have been used to ascertain the presence of AD brain changes, which are obtained via imaging and lumbar puncture. However, the widespread use of these methods is limited by cost and availability. Therefore, there is a need for a non‐invasive and low‐cost solution for identifying individuals who are likely to have preclinical AD. Since the preclinical phase of AD has been shown to impact driving, daily driving behaviours captured using Global Positioning System (GPS) devices can serve as a digital biomarker to detect preclinical AD. The objective of the present study is to use machine learning methods to evaluate the ability of in‐vehicle GPS devices to distinguish cognitively normal older drivers with preclinical AD from those without preclinical AD.

Method

We used commercial in‐vehicle GPS devices to study the naturalistic driving behaviours of 144 cognitively normal older drivers (aged 65+) over one year. The cohort included 69 individuals with and 75 without preclinical AD, as determined by cerebrospinal fluid (CSF) biomarkers. Four Random Forest (RF) models were trained with three sets of variables: (1) driving features only, (2) driving features and age, and (3) driving features, age and APOE ε4 status. Finally, the strongest predictors of preclinical AD were identified using an RF‐based Recursive Feature Elimination technique.

Result

The F1 score of the RF models for identifying preclinical AD was 82% using GPS‐based driving indicators, 88% using age and driving indicators, and 91% using age, APOE ε4 status and driving. The area under the receiver operating curve for the final model was 0.96. APOE ε4 status and age were the two most important features for predicting preclinical AD, and the most important driving feature was the vehicle’s jerk, which is a measure of driving smoothness.

Conclusion

Driving behaviours captured with GPS can accurately distinguish cognitively normal older drivers with preclinical AD from those without preclinical AD.
Perceptions of and needs for e‐Health solutions for elderly people with cognitive impairment, their caregivers and health care providers: A qualitative exploration
Authors: Gagnon Marie‐Pierre , Boucher Mylene , Ndiaye Mame‐Awa , Dequanter Samantha , Buyl Ronald , Gorus Ellen , Fobelets Maaike , Sasseville Maxime , Barony Romina
Published: December 2021

Background

The prevalence of mild cognitive impairment (MCI) and mild neurocognitive disorder (mNCD) are steadily increasing in Canada. Information and communication technologies (ICTs) in health represent an innovation to promote home care and autonomy for people with various degrees of cognitive impairment. The objective of this study is to develop a web‐based multicriteria decision support tool adapted to older adults with MCI or mNCD, their informal caregivers, and health care providers (HCPs) to support the development and implementation of ICTs adapted to the needs and preferences of people with cognitive impairments and their caregivers.

Methods

We used a participatory research strategy to develop of a decision support tool for the use of ICTs focused on the needs of patients, their caregivers, and HCPs. Data collection consisted of semi‐structured interviews with elderly people with MCI (N = 10) and caregivers of people with mNCD (N= 7) to explore their current knowledge and perceptions of various ICTs as well as their needs and preferences for such interventions and a focus group with HCPs to understand their perceptions of the needs of seniors with MCI and caregivers of people with mNCD.

Results

ICTs are seen as a beneficial solution to promote home care and autonomy for people with cognitive disorders. ICTs provide a sense of security and peace of mind, especially for caregivers of people with mNCD. However, the complexity and high cost of ICTs as well as the lack of support appear to be major limits to their use. HCP recognize the value of e‐Health but claim to lack reliable information and were therefore highly unsure to recommend its use.

Conclusions

People suffering from cognitive disorders and their caregivers are generally open to technological developments and favour the use of ICTs. For health professionals, continuous training on ICTs would make them more comfortable to recommend them to patients and their families. Although the use of ICTs is promising for maintaining elderly people with cognitive disorders at home, our study shows that it will be necessary to find ways to make them accessible to promote their use.
Impact of concomitant acetylcholinesterase inhibitor use on the pharmacokinetic profile of pimavanserin in patients with dementia‐related psychosis: Modeling data from the phase 3 HARMONY study
Authors: Darwish Mona , Jaworowicz David , Owen Joel , Brandt Teresa , DeKarske Daryl , Stankovic Srdjan
Published: December 2021

Background

Pimavanserin is a selective serotonin modulator with inverse agonist/antagonist activity at the 5HT2A receptor, and to a lesser extent at the 5HT2C receptor. Pimavanserin efficacy and safety were evaluated in patients with dementia‐related psychosis (DRP) in the phase 3 HARMONY study. Many patients with DRP receive acetylcholinesterase inhibitors (AChEIs) to treat their dementia. This analysis evaluated the pharmacokinetic (PK) profile of pimavanserin in patients receiving concomitant AChEIs using data from HARMONY.

Methods

HARMONY was a randomized discontinuation study in patients with DRP. Patients received open‐label pimavanserin, 34 mg daily with flexible dosing (20 mg) based on tolerability, for 12 weeks, and those with sustained response were randomized into the 26‐week double‐blind period where they continued their pimavanserin or switched to placebo. PK samples were collected at baseline and weeks 12, 13, 22, and 38 (or end of treatment). Individual Bayesian estimates of pimavanserin apparent clearance (CL/F) and apparent volume of distribution (V/F) were obtained using a previously developed population PK model for patients with/without concomitant AChEIs. Steady‐state area under the plasma concentration‐time curve (AUC) and maximum drug concentration (Cmax) were computed for pimavanserin doses normalized to 34 mg daily.

Results

158/337 (46.9%) patients in HARMONY had concomitant AChEI use (donepezil, galantamine, rivastigmine). In patients with/without AChEI use, CL/F and V/F showed no apparent differences between groups. Covariate testing found no statistically significant effect (α = 0.05) of AChEI use on CL/F or V/F. Minimal differences in predicted steady‐state pimavanserin exposures were observed between patients with concomitant AChEI use and those without (Table 1); median Cmax was 8.4% higher (with AChEI: 57.9 ng/mL; without AChEI: 53.4 ng/mL) and median AUC was 9.2% higher (with AChEI: 1328.9 ng × h/mL; without AChEI: 1216.5 ng × h/mL).

Conclusions

Concomitant AChEIs had no significant effect on the PK parameters of pimavanserin. Differences in exposure measures (Cmax and AUC) between groups were negligible (<10%). These results suggest that concomitant AChEI use does not have a clinically relevant impact on the PK profile of pimavanserin.