bluuebunny/crossref_metadata_2025 huggingface dataset:
Examination of the accuracy of Cogniciti’s self‐administered, online, Brain Health Assessment in detecting amnestic mild cognitive impairment
Authors: Paterson Theone S.E. , Sivajohan Brintha , Gardner Sandra , Binns Malcolm , Stokes Kathryn A. , Freedman Morris , Levine Brian , Troyer Angela
Published: December 2021

Background

Our need for easily administered online assessments sensitive to mild cognitive difficulties is increasing as our population ages. Our team has recently presented data indicating the accuracy of an online, publicly available, self‐administered screening measure, Cogniciti’s Brain Health Assessment (BHA), in the detection of amnestic mild cognitive impairment (aMCI) in a sample of community dwelling older adults. This current work extends those findings by further examining diagnostic accuracy of this measure.

Method

Using a cross‐sectional design, community‐dwelling older adults aged 60‐89 completed a gold standard neuropsychological assessment to determine a diagnosis of normal cognition (NC) or aMCI (by consensus of 3 staff neuropsychologists). Each participant also completed the BHA. Penalized logistic regression (PLR) analyses were used to examine which specific BHA tasks and measured demographic variables contributed to this test’s predictive utility in detecting aMCI. Diagnostic accuracy of the PLR model was compared with a logistic regression (LR) model examining BHA total score accuracy.

Result

91 participants met inclusion criteria (51 aMCI, 40 NC). PLR modelling for the BHA indicated that of the tasks and variables measured by the BHA, the Face‐Name Association and Spatial Working Memory tasks predicted aMCI, with age also accounted for in the model (ROC‐AUC = 0.76; 95%CI: 0.66, 0.86). Based on this model, optimal performance cut‐points were determined, which resulted in 21% of the sample being classified as aMCI (positive), 23% as negative, and 56% as inconclusive. Projected general population classification rates are also presented to provide an estimate of how the BHA may perform in the broader population.

Conclusion

Results support that validity of the BHA as a screening measure for aMCI, and provide indication of the tasks within this measure that contribute to its utility in screening for this specific type of cognitive decline. Given the BHA is an online, self‐administered task, this measure has the potential to not only decrease unnecessary referrals for comprehensive assessment to determine presence of aMCI, but also to save practitioners time over commonly used paper and pencil screeners.
Personal history of breast cancer, cognitive function, and conversion in women from the ADNI cohort
Authors: Eastman Jennifer Ann , Yaffe Kristine , Kerlikowske Karla , Brenowitz Willa D , Kornblith Erica S , Inslicht Sabra
Published: December 2021

Background

Some women with a personal history of breast cancer (PHBC) may experience higher rates of objective/subjective cancer‐related cognitive impairment (CRCI) shortly after treatment, while others have persistent CRCI as many as 20 years after. It is unclear how this impacts cognitive aging years after diagnosis. We explored whether remote PHBC is associated with a specific pattern of cognitive decline or increased dementia diagnosis rates in women.

Method

We performed secondary analysis of data from women enrolled in the Alzheimer Disease Neuroimaging Initiative (ADNI) from October, 2005 ‐ September, 2018. A review of records identified 33 cognitively normal (CN) and 20 mild cognitive impairment (MCI) participants with PHBC, and 268 CN and 270 MCI participants without PHBC. We compared overall rates of PHBC in the MCI/CN groups as well as rates of conversion to MCI (from CN) or Alzheimer’s dementia (AD). Baseline scores on cognitive tests were corrected for age, education, and sex and averaged into composite scores: Structured‐Verbal‐Memory (Logical Memory Learning/Delay) Unstructured‐Verbal‐Memory (RAVLT Learning/Delay/Recognition), Attention/Processing‐Speed (Trails A+B/Number‐Cancellation) and Language (Animal‐fluency/Boston Naming). One‐way ANOVA and χ2 examined differences in PHBC rates, cognitive performance, and dementia conversion.

Result

Rates of PHBC did not differ significantly between CN(11%) and MCI(7%), (p=0.08). Among women with MCI, those absent PHBC performed significantly worse than those with PHBC on Unstructured‐Verbal‐Memory (p=0.012). Follow‐up examination of individual RAVLT scores revealed intact recognition in the MCI+PHBC women. Women with MCI alone, converted to AD at significantly higher rates than MCI+PHBC (p=0.04). Cognitively normal women with/without PHBC did not differ in cognitive test performance or conversation rates.

Conclusion

Results suggest no increased risk of MCI or AD in women with a PHBC. In fact, women with MCI+PHBC show lower rates of conversion to AD, a pattern of memory impairment less consistent with AD, and better overall cognition relative to those with MCI alone. This may indicate that the etiology of memory problems in women with PHBC may be related to persistent CRCI rather than a neurodegenerative process like AD, but further research is needed to understand specific factors that contribute to the development of CRCI and their impact on cognitive aging.
Map of Care: 10 smart tools for the evaluation of senior care facilities
Authors: Georgarakos Manos
Published: December 2021

Background

Many senior care facilities (assisted living, nursing homes, memory care) are of average quality. There is lack of reliable and impartial information on care facilities. Furthermore, most people do not have the specific knowledge to evaluate their various senior care options in order to make the right choice.

Method

An interdisciplinary team of medical doctors, neuropsychologists, senior care industry professionals and information technology/user experience specialists analyzed the needs of older adults and their relatives. These needs were mapped to characteristics of senior care facilities and online tools were developed to assess different aspects of all types of senior care facilities (assisted living, nursing homes, memory care). In addition to a general assessment tool for each facility type, specialized tools (tech tool, design for dementia tool, accessibility tool) were included and in total 10 online tools were developed. These online tools were integrated in the Map of Care online platform for senior living, which features facility locations on an interactive map along with facility reviews and ratings.

Result

Users have the opportunity, after an in‐person visit or a virtual tour of a facility, to assess, compare and finally select the most suitable facility for their needs and preferences using the available online tools. Data from users’ responses to the online tools are collected anonymously, populating the Map of Care database. Continuous processing of this data will allow for the provision of senior care analytics at facility, city, state and national level. Thus, apart from impartial rating of senior care facilities, the Map of Care ecosystem will allow for monitoring of trends, gaps and unmet needs in the field of senior care facilities.

Conclusion

Through a democratic participatory process of user‐generated evaluations, reviews and ratings, Map of Care aims to empower older adults and their relatives to make informed choices about care facilities while providing vital insights to the field of senior care facilities with the overall goal of continuously improving the quality of senior care.
Reaction times of correct and incorrect performances are highly correlated no matter age groups but older age affects accuracy and speed relationships in the Wisconsin Card Sorting Test
Authors: Rosales‐Lagarde Alejandra , Martínez‐Alcalá Claudia
Published: December 2021

Background

The detection of non‐amnestic Mild Cognitive Impairment with difficult tasks as the Wisconsin Card Sorting Test (WCST) is still under debate. Associations concerning performance and/or speed are not usually evaluated even though speed decreases with age and so, the WCST may be preferentially administered in a computerized format. Therefore, 3 types of relationships were looked for: 1) between reaction times (RT) of correct and incorrect answers; 2) between the percentage of correct responses and RT of correct responses; and lastly, 3) between the percentage of incorrect responses and RT of incorrect responses.

Method

Two age groups, one group of executives of the INEGI (National Institute of Statistics, Geography and Informatics) (n = 12, 46.71 ± 5) and another one of older adults (OAs) who attended a “Centro Gerontológico Integral” in the state of Hidalgo in Mexico (n = 17, 66.35 ± 6) were evaluated.

Result

The RT of correct and incorrect performances were highly correlated for both groups (INEGI group: r = 0.80, p = 0.01; OAs: r = 0.89, p = 0.01). Instead, the correlations between performance and speed were only negatively related for the percentage of correct responses and RT of correct responses in the group of the INEGI (r = ‐ 0.72, p = 0.02), while they had a tendency to be positive in OAs although not significant (r = 0.43, p = 0.10). The percentage of incorrect responses and RT of incorrect responses was positive and significant for the group of the INEGI (r = 0.84, p = 0.01) and tended to be negative and not significant for OAs (r = ‐ 0.48, p = 0.10).

Conclusion

A positive correlation between RT of correct and incorrect answers was found, suggesting a consistent speed within subjects no matter the performance. A negative correlation was found for the percentage of correct responses and RT of correct responses in the group of the INEGI. However, this late relationship and the one concerning wrong performance was not confirmed for OAs, indicating that speed when decision making and problem solving are assessed suffer from severe alterations with age.
Cognitive performance in former professional football (soccer) players is affected by estimated heading frequency
Authors: Bruno Davide , Rutherford Andrew
Published: December 2021

Background

The link between football (soccer) heading and/or head injury is a concern given the popularity of football worldwide. To assess this link, memory ability of former professional footballers (FPFs) was tested, and self‐reported data on positions played, previous head injuries, and frequency of headers were obtained.

Method

Data were collected by post from 60 male FPFs who had played for teams in England. Each individual received a questionnaire requiring them to self‐report: demographics data; information on playing career, including playing position; information on number of head injuries sustained in training and match play; and an estimate of how many headers they normally took in training and match play. Additionally, the Test Your Memory (TYM) self‐administered memory test also was included. FPFs mean age was 67.5 (9.5), ranging from 39 to 87.

Result

Bayesian and traditional (frequentist) regression analyses were carried out using the TYM score as outcome (continuous and binary). Age and estimated non‐football head injuries served as covariates (null model). Predictors were playing position, estimated career head injuries, and estimated career headers. As playing position influences likelihood of heading the ball, a rating score was co‐designed with FPFs ranging from 1 (not likely, e.g., goal‐keeper) to 5 (most likely, e.g., centre‐forward). The results of our analyses showed across all tests that estimated career headers, but not playing position or estimated career head injuries, were associated with the overall cognitive outcome. We calculated from our data that the TYM score declined by about 3 points for each 100,000 career headers reported.

Conclusion

This is the first study, to our knowledge, to provide evidence in former professional football players that heading the ball may impact cognitive ability.
Reviewing the development of national dementia plans: Implications for Vietnam
Authors: Nguyen Tuan Anh , Tran Kham , Esterman Adrian , Brodaty Henry , Hinton Ladson , Dang Thu Ha , Kurrle Sue , Hoang Phuong , Crotty Maria , Pham Thang , Kim Giang Bao , Le Pham Tuan , Roughead Elizabeth E
Published: December 2021

Background

Vietnam, a country with a rapidly ageing population, is a member of the World Health Organization (WHO) and agreed to develop a national dementia plan consistent with the WHO’s guidelines in 2018. Recently, steps towards this plan have been implemented with national workshops and the development of research activities related to dementia. This paper reviews 32 national dementia plans (NDPs), based on the WHO’s guideline and WHO’s Global Dementia Observatory’s indicators (GDO), to inform the Vietnamese plan.

Methods

Data were extracted from 32 NDPs identified from the Alzheimer’s Disease International’s website regarding the vision, mission, objectives, framework, principles, priorities, stakeholders, budget, implementation and evaluation. We compared the plans using the WHO’s guideline and GDO.

Results

Most NDPs were from high‐income countries with only two from middle‐income countries and one from a low‐income country. Overarching visions encompassed improving the quality of life for persons with dementia. Principles covered respect, dignity, accessibility and equity. All plans addressed the seven priority areas advocated by the WHO, but differences in priorities were aligned with national situational analyses. There were similarities across NDPs: to improve awareness of dementia, reduce stigma, develop support services, improve quality of care, improve training and education, and improve dementia research. The process of developing the NDPs involved stakeholders including persons with dementia and their carers, civil society, central government units, state or provincial representatives, older people, disability associations, and local non‐governmental and international organisations.

Conclusion

This review provides an important resource for countries yet to develop their national dementia plans, both on plan content, the process of development, implementation and evaluation.
Prediction of conversion to dementia in subjects with amnestic mild cognitive impairment with interpretable machine learning
Authors: Chun Min Young , Kim JongHyuk , Jang Hyemin , Kim Kyunga , Seo Sang Won
Published: December 2021

Background

Mild cognitive impairment (MCI), especially the amnestic form, is considered a transitional state between normal aging and Alzheimer's disease (AD). However, not all amnestic MCI (aMCI) patients progress to AD. Thus, developing a predictive model for AD progression in aMCI patients has been considered important. Prametric methods such as logistic regression have been developed, but it is difficult to reflect complex patterns such as nonlinear relationships and interactions between variables. This study aims to improve the predictive power of aMCI patients' conversion to dementia by using an interpretable machine learning (IML) model and to identify factors that increase the risk of individual dementia conversion in each patient.

Method

We obtained 760 aMCI patients, who had been followed at least three years after baseline neuropsychological tests from Samsung Medical Center from 2007 to 2019. We used neuropsychological tests and apolipoprotein E (APOE) genotype data for developing predictive models. Model building and model validation data sets were composed of 565 and 140 patients, respectively. For global interpretation, four models of logistic regression, random forest, support vector machine, and extreme gradient boost were compared. For local interpretation, individual conditional expectations (ICE) and SHapley Additive exPlanations (SHAP) were used to analyze individual patients.

Result

Among 4 models, the extreme gradient boost model showed the best performance with an AUC of 0.83, an accuracy of 0.76, and an f1‐score of 0.65. The variables such as RCFT‐DR, CDR‐SOB, age, K‐MMSE, COWAT‐animal, education, SVLT‐DR, RCFT‐copy time, and APOE genotype were important features for creating the model. Through ICE and SHAP analysis, it was also possible to interpret which variables acted as strong factors for each patient.

Conclusion

The present study developed a model for predicting dementia conversion in aMCI patients using IML technique. This predictive IML model is expected to be useful in clinical practice and research field as it can suggest conversion with high accuracy and identify the degree of influence of risk factors for each patient.
The care ecosystem: Outcomes from an integrated healthcare system
Authors: Rosenbloom Michael H , Hanson Leah R , Diaz‐Ochoa Ana , Svitak Aleta , Brombach Ann , Finstad Jennifer , Karrmann Jan , Barclay Michelle , Dulaney Sarah , Possin Kate
Published: December 2021

Background

The Care Ecosystem (CE) is a model of dementia care consisting of a multidisciplinary team of nursing, care team navigators (CTNs), and social workers designed to support persons with dementia (PWD) and their caregivers. Developed and tested at the UCSF Memory and Aging Center, the CE has been shown to improve PWD quality of life, reduce emergency department visits, and decrease caregiver depression/burden compared to usual care. We present CE data from a high volume neurology clinic within an integrated healthcare system.

Method

A total of 435 patient‐caregiver dyads were enrolled in the CE over a 2.5 year period. Data relating to demographics, dementia severity, caregiver burden, and healthcare utilization were collected at baseline and after one year (n=116). Experience surveys were completed by dyads at 6 and 12 months (n=200). A retrospective review of data captured by RedCap and the electronic medical record was performed.

Result

There was worsening of dementia disease severity (DSRS) and functional impairment (FAQ) over a one year period (figure 1a/b). Both immediate/anticipated caregiver needs (figure 2) and safety concerns (figure 3) decreased over time. For safety, there were particular sizable reduction of caregiver safety concerns for driving (65%), falls (52%), problems getting lost (57%), weight and appetite changes (63%), and medication safety concern (61%) for the PWD. There was a reduction in the number of PWD using >10 medications with the CE (figure 4). The number of ED visits decreased over time whereas hospitalizations increased over the one year (figure 5a/5b). There was a reduction in caregiver depression, difficulty, and burden (6a/b/c). Dyads rated CTNs favorably ranging from 88‐92% of the time.

Conclusion

Our results suggest that the CE is feasible and effective in an integrated healthcare system setting. Despite worsening of disease state in the PWD, caregiver burden and distress decreased over the one year assessment period, suggesting a favorable impact on caregiver quality of life. PWD and caregivers rated the CTN experience positively. Although these preliminary results favor the CE, further studies are necessary to better understand the impact of the CE on healthcare utilization in integrated healthcare systems.
Differential impact of obstructive sleep apnea on hippocampal structure in late middle‐aged and older women and men
Authors: Martineau‐Dussault Marie‐Ève , André Claire , Daneault Véronique , Blais Hélène , Petit Dominique , Lorrain Dominique , Bastien Célyne , Hudon Carol , Descoteaux Maxime , Montplaisir Jacques , Boré Arnaud , Theaud Guillaume , Thompson Cynthia , Legault Julie , Martinez Guillermo E. , Gilbert Danielle , Carrier Julie , Gosselin Nadia
Published: December 2021

Background

Recent studies have suggested that obstructive sleep apnea (OSA) could be a modifiable risk factor for dementia. Consequently, efforts have been made to better understand the role of OSA on brain structure integrity, but results between studies are inconsistent. Discrepancies could be partly due to moderating factors (e.g., sex) or complex physiological mechanisms (e.g., oedema) that blur the association between OSA and brain structure. Here, we investigated the association between OSA severity and hippocampal grey matter volume in women and men. We also performed free‐water fraction analyses to understand how oedema could impact hippocampal volumes.

Method

Seventy‐three men (age: 65.47±7.22 years; apnea‐hypopnea index [AHI]: 15.52±16.14 events/h; 31 with mild cognitive impairments [MCI]) and 47 women (age: 71.11 ± 6.65; AHI: 11.56 ± 9.92; 22 with MCI) underwent an overnight polysomnography, a neuropsychological evaluation and a magnetic resonance imaging session. Using the hippocampal subfield module in Freesurfer 7.1, total bilateral hippocampal volumes were extracted and normalised to the total intracranial volume. Diffusion data was preprocessed using TractoFlow‐ABS, and Freewater‐Flow and the Sherbrooke Connectivity Imaging Lab scripts were used to extract bilateral hippocampal free‐water fraction. Controlling for age and cognitive status, sex‐stratified linear regressions were performed between (i) the bilateral hippocampal volume or (ii) Free‐water‐corrected bilateral hippocampal volume and log‐transformed AHI.

Result

In women, we observed a positive association between the AHI and bilateral hippocampal volumes (r=0.414; p=0.005), where more severe OSA was associated with higher volumes. This association was not observed in men (p=0.427). When using the free‐water corrected volumes, this association was no longer significant in women (p=0.481), suggesting that the increased hippocampal volume could be due to OSA‐related cytotoxic (intracellular) oedema.

Conclusion

In this cohort, while men’s hippocampal volume was unaffected by OSA, women with OSA presented hippocampal hypertrophy likely due to intracellular oedema. Cytotoxic oedema is a known precursor to vasogenic (extracellular) oedema and cell death, suggesting that women might be more vulnerable to the cerebral consequences of OSA than men. Since women have a higher lifetime risk of developing Alzheimer's disease, future studies on OSA should pay a particular attention to women.
Increased adiposity is related to reduced neurite complexity in the hippocampus, fornix, and uncinate fasciculus of cognitively unimpaired adults
Authors: Noughani Hanna M , Ennis Gilda E , Vogt Nicholas M , Johnson Sterling C , Asthana Sanjay , Alexander Andrew L , Beeri Michal Schnaider , Bendlin Barbara B
Published: December 2021

Background

Obesity is a risk factor for dementia. However, results from studies associating obesity to volume in the hippocampus and parahippocampal gyrus, regions underpinning memory, are inconsistent. Null findings could be due to the insensitivity of volumetric MRI to detect early neurodegenerative change. The neurite orientation dispersion and density imaging (NODDI) model provides unique information about neurite microstructure that may be relevant to the earliest stages of neurodegeneration. In cognitively healthy participants, we used NODDI to examine if body mass index (BMI) and waist circumference (WC) were related to the microstructure of the hippocampus and parahippocampal gyrus and white matter (WM) tracts linking these gray matter (GM) regions to the brain (i.e., hippocampal cingulum, uncinate fasciculus, and fornix).

Method

Participants were enrolled in the Wisconsin Alzheimer’s Disease Research Center (ADRC) Clinical Core, had T‐1 weighted and multi‐shell diffusion MRI, and lacked history of stroke and cognitive impairment (Table 1). Microstructure was assessed using neurite density (NDI) and orientation dispersion (ODI) indices obtained from the NODDI model. Higher NDI indicates higher neurite density; higher ODI reflects lower neurite coherence and greater neurite dispersion. N=383 had NODDI indices, height, weight and covariate data. Waist circumference (WC) (n=382) was dichotomized according to sex‐specific thresholds for cardiovascular/diabetes disease risk (females >88cm; males >102cm). Linear regression tested the relationship of BMI and WC to NDI and ODI in regions of interest controlling for age, sex, education, diabetes, hypertension, depression, and APOE4 carrier status.

Result

Individuals with higher BMI and in the higher‐risk WC category had significantly lower hippocampal ODI and fornix NDI when adjusting for covariates (Table 2, Figure 1). Higher BMI was also related to higher uncinate fasciculus ODI.

Conclusion

Increased adiposity was related to lower neurite dispersion in the hippocampus and lower neurite density in the fornix. BMI alone was associated with lower neurite coherence in the uncinate fasciculus. These results suggest that increased adiposity may be related to less complex neurite microstructure in regions important for memory. Additional research is needed to determine if adiposity‐related microstructural differences in GM and WM are related to memory decline and presage future development of dementia.
TMS for the characterization of different types of dementia disorders: A systematic review and meta‐analysis
Authors: Quintanilla‐Sanchez Carolina , Salcido‐Montenegro Alejandro , Antal Andrea , Nañez‐Terreros Homero
Published: December 2021

Background

At early stages, dementia disorders share similar clinical symptoms. For an appropriate classification, more practical and non‐invasive diagnostic methods are needed. Transcranial magnetic stimulation (TMS) assess non‐invasively the imbalance of cortical excitability and related neurotransmitters levels in the brain(1‐3). Characterizing the spectrum of dementia with TMS could enable a more accurate diagnosis and optimize interventions at earlier stages.

Method

We conducted a systematic review following PRISMA guidelines. Our search strategy included terms related to dementia of different etiologies and TMS. It was conducted in 4 databases (MEDLINE, EMBASE, Ovid and Scopus) from origin to April 2021. Two authors screened the studies in a 2‐stepwise approach. Original studies comparing dementia disorders using TMS were included. Risk of bias was assessed using QUADAS. Meta‐analyses comparing diverse TMS parameters between AD to FTD, DLB and VAD as well as FTD to DLB were made.

Result

Our search yielded 2702 results, with 227 articles reviewed in full text. Finally, 14 articles were included in the review(4,5,14–17,6–13) and 11 in the meta‐analysis(4–14). A total of 983 patients were analyzed: Alzheimer disease (AD) 50.25%, frontotemporal dementia (FTD) 28.89%, dementia with Lewy bodies (DLB) 10.57%, vascular dementia (VaD) 5.59% and other dementias 4.7%. In the comparison between AD to FTD, the mean difference of resting motor threshold (RMT) short‐latency afferent inhibition (SAI), short‐acting cortical inhibition (SICI), intracortical facilitation (ICF) and central motor conduction time (CMCT) were statistically significant (Fig 1‐2). No significant difference when comparing the AD group to DLB nor VaD. Finally, RMT and SAI were the only parameters that differed between patients diagnosed with FTD and DLB (Fig 3). The main concerns of risk of bias were the retrospective study design and differences in diagnosis method and TMS protocols.

Conclusion

The meta‐analysis of observational studies showed that TMS measurements as biomarkers seem to be useful for differentiating FTD from AD and DLB in patients with mild‐stage dementia. Accurate classification may allow more appropriate interventions and slow disease progression. However, study design and protocols may limit our results. Hence, more homogenous, and prospective studies with bigger sample size are needed.
Item‐level analysis of clinical measures in patients with early symptomatic Alzheimer’s disease following treatment with high‐dose aducanumab in the phase 3 study EMERGE
Authors: Cohen Sharon , He Ping , Benea Mihaela Levitchi , Miller Ryan , Forrestal Fiona , Pang Menglan , Castrillo‐Viguera Carmen , Harrison John E , Jaeger Judy , Mummery Catherine J. , Porsteinsson Anton P. , Cummings Jeffrey L. , Tian Ying , Yang Lili , Haeberlein Samantha Budd
Published: December 2021

Background

EMERGE (NCT02484547), 1 of 2 Phase 3 trials evaluating aducanumab in patients with early Alzheimer’s disease (AD), demonstrated a statistically significant drug‐placebo difference in the prespecified primary and secondary clinical endpoints. We examined in EMERGE participants the change from baseline item‐level scores in primary, secondary, and tertiary clinical endpoints that, in combination, comprised a set of cognitive, functional, and neuropsychiatric instruments that provide a comprehensive assessment of AD.

Method

EMERGE (N=1643) included participants aged 50‐85 years who met clinical criteria for MCI due to AD or mild AD dementia, with confirmed amyloid pathology. Participants were randomized to receive high‐dose aducanumab, low‐dose aducanumab, or placebo. The primary endpoint was change from baseline in CDR‐SB score at Week 78. Secondary outcome measures included MMSE, ADAS‐Cog13, and ADCS‐ADL‐MCI scores. NPI‐10 score was a tertiary outcome. Item‐level analyses using mixed model for repeated measures (MMRM) were conducted on these clinical efficacy endpoints using the ITT population. This analysis is considered descriptive due to its deviation from the normality assumption and thus no multiplicity adjustment was considered.

Result

The aducanumab high‐dose group demonstrated a consistent drug‐placebo difference across 5 clinical efficacy endpoints, slowing clinical decline over 78 weeks. Treatment effects were observed across all 6 domains of the CDR. An aducanumab treatment effect was evident by slowing of decline on the ADAS‐Cog13 items sensitive to change in early symptomatic AD (e.g., orientation, word recall [immediate and delayed], word recognition, and number cancellation). Additionally, clinical benefit of aducanumab with respect to preserving daily function was observed across a broad range of items on the ADCS‐ADL‐MCI. Finally, aducanumab treatment was associated with an attenuation of behavioral and psychiatric symptoms associated with AD, as measured by NPI‐10, and an accompanying decrease in caregiver distress.

Conclusion

Aducanumab treatment effects, observed across a broad array of outcome measures, are clinically relevant. Item‐level analyses demonstrated consistency across cognitive, function, and behavioral domains sensitive to impairments that are detectable even in the early stages of AD. Holistically, these measures reflect the perspectives of patients, caregivers, and clinicians, thereby supporting the importance and meaningfulness of an aducanumab treatment effect in early AD.
CSF SNAP‐25 dynamics in healthy aging and across the spectrum of Alzheimer's disease
Authors: Lewis Alexandria , Darrow Jacqueline A. , Zhang Yifan , Ball Andrew J. , Mendes Muriel , Jeromin Andreas , Moghekar Abhay
Published: December 2021

Background

The turnover of synaptic proteins with aging and in different phases of AD is poorly understood. We measured CSF SNAP‐25, a protein localized to the presynaptic processes, using a novel SIMOA assay across 2 cohorts comparing cognitively normal young vs cognitively normal older adults as well as those with early and late MCI, in addition to those with dementia due to AD.

Method

Subjects from the CSF Clinic were classified as cognitively normal or MCI based on NIA‐AA criteria in cohort 1. Subjects from the Johns Hopkins ADRC were classified clinically as cognitively normal, early MCI, late MCI and dementia in cohort 2. CSF SNAP‐25 was measured using a SIMOA assay on the Quanterix HD‐X. CSF AD biomarkers (abeta42, abeta40, total tau, ptau181) were measured using Fujirebio Lumipulse assays.

Result

Levels of CSF SNAP‐25 were similar in cognitively normal young controls (YN) vs older controls (ON) in the first cohort with elevated levels in MCI (median [IQR] YN 66.0 [53.0,74.6], ON 57.7 [44.9,76.8], MCI 105.5 [97.3,124.1]; YN vs. ON p=0.44; ON vs. MCI p<0.001). In a validation cohort, CSF SNAP25 was similar in cognitively normal controls vs early MCI (median [IQR] ON 70.7 [60.3,86.8] EMCI 75.3 [60.3,92.6]; p=0.55). However, levels were elevated in late MCI and were higher than even in those with AD dementia (median [IQR] LMCI 150.5 [115.4,193.6] AD 97.8 [89.0,122.3]; LMCI vs. ON p<0.001; LMCI vs. AD p=0.014). CSF SNAP25 correlated better with CSF ptau181 across both cohorts (r=0.85, p <0.001) as compared to CSF amyloid ratio, abeta42/abeta40 (r=‐0.38, p <0.001). A CSF SNAP25 cut‐off of 121.85 pg/ml provided a sensitivity of 75% (95% CI: 51‐90%) and a specificity of 96% (95% CI: 81‐99%) in differentiating early and late MCI.

Conclusion

The turnover of presynaptic SNAP25 as measured in CSF is relatively stable across the lifespan in healthy individuals. CSF SNAP25 levels correlate better with tau pathology rather than amyloid suggesting that increased SNAP25 turnover in CSF is not present the early preclinical phase of AD. Levels of CSF SNAP25 are elevated in the late MCI phase as compared to those in early MCI or dementia.
Physical activity and amyloid beta in middle‐aged and older adults: A systematic review and meta‐analysis
Authors: Rodriguez‐Ayllon Maria , Arroyo‐Avila Cristina , Alvarez‐Ortega Miriam , Molina‐Garcia Pablo , Solis‐Urra Patricio , Molina‐Hidalgo Cristina , Erickson Kirk I , Esteban‐Cornejo Irene
Published: December 2021

Background

Alzheimer’s disease is the main cause of dementia in the world. Particularly, amyloid beta (Aβ) plaques are the primary hallmarks of this disease. Previous research has shown that higher levels of physical activity might be associated with lower levels of Aβ accumulation. However, a synthesis of evidence is needed to confirm or refute this hypothesis. The aim of the present study is to determine the overall effect of physical activity on Aβ by conducting a systematic review and meta‐analysis of available randomized clinical trials and interventions, and to systematically synthesize observational evidence on the association between physical activity and Aβ in middle‐aged and older adults.

Method

A systematic search of 5 electronic databases (PubMed, Web of Science, PsycINFO, Cochrane Central Register of Controlled Trials and SportDiscuss) was performed from inception to 1st of April 2020. Studies were eligible if they included physical activity and Aβ data (i.e., any Aβ isoform measured by Positron Emission Tomography ‐PET‐, blood samples or lumbar puncture) in adults aged 45 years or older. Meta‐analyses were performed to examine the effect of physical activity on Aβ in randomized controlled trials (RCTs) and non‐RCTs (i.e., quasi‐experimental studies).

Result

A total of 26 articles were included in this systematic review: 6 RCTs, 2 non‐RCTs, 4 prospective longitudinal studies, and 14 cross‐sectional studies. Of the 8 intervention studies, 5 were included in the meta‐analysis. In brief, the overall effect of physical activity on Aβ in middle aged and older adults was not significant (pooled SMD= ‐0.12; 95% CI ‐0.40 to 0.016; I2=3%). Additionally, 19 observational associations were synthesized in this systematic review. Overall, there was an unclear association between physical activity and Aβ at any of its isoforms (11 of 19 studies, 58%)].

Conclusion

Due to the small number of intervention studies included in the meta‐analysis (5 intervention studies) and the controversial findings provided by the observational studies, more studies are needed to understand the role of physical activity on Aβ in middle‐aged and older adults.
A patient who gradually progressed to corticobasal syndrome after traumatic brain injury
Authors: Chung Eunjoo
Published: December 2021

Background

Traumatic brain injury (TBI) occurs when an external force injury the brain, and leads adult disabilities and death. A recent retrospective investigation found that TBI history was associated with a 1.6 higher risk for FTD diagnosis. Traumatic white matter injury has been already accepted as a critical contributor to post‐TBI neurological dysfunction. Now, we report changes of neurological features and serial followed up brain magnetic resonance images (MRI) in a patient with TBI.

Method

A 48‐year‐old man visited the dementia clinic because of cognitive impairment. A month ago, an electric pole, which had been repairing by the patient, was broken and then it crashed to his head. Brain CT on the 7th day after the accident and brain MRI after one month were performed. First neuropsychological assessment was analyzed one year later since the accident occurred. B‐CT and B‐MRI were also performed in 4 years later.

Result

Brain CT on the 7th day after the accident and brain MRI after one month, showed multifocal old infarctions, extensive rarefactions involving both periventricular and subcortical white matter, and moderate to severe diffuse brain atrophy. One year later since the accident occurred, he showed personality changes and the aggravated cognitive impairments. According to his wife, before he was injured, he easily memorized several phone numbers well. First neuropsychological assessment showed memory impairments (verbal and visual) and frontal executive dysfunctions. Fluency was decreased and naming difficulty was observed. He showed poor personal hygiene and delusion. Weight loss and dysphagia appeared since 4th year after the accident. He could not use his right arm and hand at will, and his parkinsonism seemed to be progressed. Brain CT and MRI still showed confluent cerebral white matter lesions and diffuse cerebral atrophy. He muttered only meaningless words and showed delusions.

Conclusion

He showed changes in cognitive impairments, abnormal behavior and personality changes, parkinsonism, and aphasia in order after TBI. Brain MRI revealed an extensive white matter leukoaraiosis and brain atrophy. We thought that extensive white matter leukoaraiosis is associated with delayed various and complex complications after TBI.
Cognitive outcomes of anti‐amyloid‐β monoclonal antibodies in patients with Alzheimer's disease: A systematic review and meta‐analysis of randomized controlled trials
Authors: Fernandez Paulo Eduardo Lahoz , Silva Guilherme Diogo
Published: December 2021

Background

For the last 20 years, the amyloid‐beta (Aβ) cascade hypothesis has been dominant in the research of disease‐modifying therapeutics, with spent of financial and clinical resources in potential drugs targeting Aβ peptide production or clearance. (1) In this context, monoclonal antibodies targeting beta‐amyloid (Aβ‐mAbs) are being tested to reduce the amyloid burden in patients with Alzheimer’s Disease (AD). (2) However, the cognitive impact of Aβ‐mAbs remains controversial. (3) We aim to evaluate the conflicting results of previous studies using a meta‐analysis.

Method

We searched PubMed, Embase, and Cochrane databases, following until April 2021, using the search terms: ''Alzheimer's disease'' OR ''dementia'' cross‐referenced with ''monoclonal antibodies'', considering the synonyms. Eligible articles were randomized clinical trials with Aβ‐mAbs that reported cognitive outcomes. The cognitive function was assessed by Alzheimer’s Disease Assessment Scale (ADAS‐cog) and Mini‐Mental State‐Exam (MMSE). We performed a meta‐analysis comparing mAbs and placebo, considering a minimal significant clinical change of 3 points in ADAS‐Cog and 2 points in MMSE.

Result

We found 12 eligible studies in 443 identified records, involving 6736 patients, mean age 71.4 ± 2. We found a small benefit in cognitive outcomes in patients treated with Aβ‐mAbs: ADAS‐Cog: mean difference (MD) = ‐ 0.65; 95% CI (‐1.05 to ‐ 0.26); I² = 12%; (p = 0.001) and MMSE: MD = 0.40; 95% CI (0.18 to 0.63); I² = 10%; (p = 0.0004). The Funnel plot and Egger’s test did not show publication bias. MD was below the minimal clinically relevant change in both scales.

Conclusion

Aβ‐mAbs may have a positive cognitive benefit in AD patients. However, the impact magnitude is small, not reaching minimal clinically relevant change for these scales. References: (1) Panza F, Lozupone M, Seripa D, Imbimbo BP. Amyloid‐β immunotherapy for alzheimer disease: Is it now a long shot? Ann Neurol. 2019 Mar;85(3):303–15. (2) Liu J, Yang B, Ke J, Li W, Suen W‐C. Antibody‐Based Drugs and Approaches Against Amyloid‐β Species for Alzheimer’s Disease Immunotherapy. Drugs Aging. 2016 Oct;33(10):685–97. (3) Panza F, Lozupone M, Logroscino G, Imbimbo BP. A critical appraisal of amyloid‐β‐targeting therapies for Alzheimer disease. Nat Rev Neurol. 2019 Feb;15(2):73–88.
Exosomal levels of soluble amyloid precursor fragments in aging and dementia
Authors: Martins Tânia Soares , Rosa Ilka Martins , da Cruz e Silva Odete , Henriques Ana Gabriela
Published: December 2021

Background

Alzheimer’s disease (AD) neuropathological alterations begin around 15 years before clinical symptoms´ manifestation, highlighting the need to identify new molecular signatures that can assist in early and differential diagnosis. Alzheimer´s amyloid precursor protein (APP) can be cleaved to produce soluble fragments (sAPP), either by amyloidogenic (sAPPβ) or non‐amyloidogenic processing (sAPPα). The biomarker potential of both sAPP forms have been explored in CSF, plasma and plasma neuronal‐ and astrocyte‐derived exosomes, but some controversy arises regarding sAPP changes in AD.

Method

The levels of sAPPα and sAPPβ were measured by ELISA in serum and serum‐derived exosomes of Controls and individuals with dementia (Clinical Dementia Rating ≥1 and positively scored for Mini‐Mental State Examination) from a primary care‐based cohort (pcb‐cohort). ANOVA was used to assess sAPP differences in demographic and clinical data; Mann‐Whitney t‐test for sAPP median comparisons; and Spearman correlation coefficients to assess sAPP levels correlations in dementia. Statistical analyses were performed using SPSS v27 or Graphpad 7.00.

Result

A tendency for lower sAPPα or sAPPβ levels and higher sAPPα/β ratios could be observed for serum and serum‐derived exosomes in the CDR≥1/MMSE+ and the AD subgroups when compared with Controls (CDR=0), although without statistical significance. Positive correlations were observed between sAPPα and sAPPβ levels, in exosomes but not in serum, for the CDR≥1/MMSE+ (r=0.63;p≤0.0001) and AD subgroups (r=0.79;p≤0.05). In addition, exosomal sAPPβ level significantly differ with age (p≤0.05), when individuals were separated in two groups (cut‐off stablished based on the age median), but only for the CDR=0 group (p≤0.05).

Conclusion

Blood‐derived exosomes recently emerged as peripheral sources of biomarkers for AD, reflecting disease stages. Exosomal sAPP forms did not exhibit a significant diagnostic relevance in discriminating AD or dementia. Interestingly, a significant difference was reported for sAPPβ in Controls with age. Since aging is the strongest risk factor for dementia, future studies should also address the advancing aging effect, when monitoring biomarkers for AD and/or other dementia‐related conditions. To this end research was funded by the Alzheimer’s Association 2019‐AARG‐644347 grant and supported by iBiMED UIDB/04501/2020,FCT,COMPETE program,QREN,European Union; T.S.M. is supported by an FCT individual PhD grant SFRH/BD/145979/2019.
Bioinformatic analysis of senile plaques and neurofibrillary tangles proteomes
Authors: Ferreira Maria José , Martins Tânia Soares , da Cruz e Silva Odete , Vitorino Rui , Henriques Ana Gabriela
Published: December 2021

Background

Senile plaques (SPs) and neurofibrillary tangles (NFTs) are the main histopathological hallmarks of Alzheimer’s disease (AD). Although these two deposits have main components, like amyloid fibrils in SPs and hyperphosphorylated tau protein in NFTs, the molecular composition underlying these lesions has not been completely unraveled. Hence, this work aims to characterize the SPs and NFTs proteomes’ by applying a bioinformatic analysis, to identify new possible biomarkers candidates for AD.

Method

An extensive literature research was carried out on Pubmed, using keywords that allowed the recovery of information regarding SPs and NFTs proteomes in AD brains. The data obtained was loaded and analysed on Cytoscape v3.8.2. For the Gene Ontology (GO) analysis, the plugins ClueGO v2.5.8 + CluePedia v1.5.8 were employed.

Result

More than 800 proteins were identified for SPs and more than 600 for the NFTs. GO analyses allowed the characterization of both proteomes at the biological process, molecular function, and cellular component levels. The top biological processes for SPs were related to cell development, secretion, and exocytosis, while for NFTs these were related to protein localization, vesicle‐mediated transport in synapse, and response to oxidative stress. Overlap of both proteomes revealed more than 300 proteins that represent interesting targets for AD. GO analyses revealed that these proteins are involved in biological processes like vesicle‐mediated transport in synapse and apoptotic signaling pathway. Additional experiments using antibody‐based methodologies need to be carried out to validate the potential of these candidates for AD.

Conclusion

This study allowed the identification of several proteins, present in both SPs and NFTs, that can not only assist in unraveling pathways common to both histopathological hallmarks but also constitute possible biomarker candidates for AD diagnosis and/or therapeutics. To this end research was funded by a grant from the Alzheimer’s Association (2019‐AARG‐644347) and supported by iBiMED UIDB/04501/2020, FCT, COMPETE program, QREN, European Union. T.S.M. is supported by the FCT through the individual PhD grant (SFRH/BD/145979/2019). RV’s Fellowship Grant (IF/00286/2015).
The role of physical health on the relationship between subjective memory complaints, anxiety, and depression in older adults during the COVID‐19 pandemic
Authors: Sheffler Julia L , Taylor Diamond , Saliga Hollyn
Published: December 2021

Background

Research demonstrates that subjective memory complaints (SMCs) are associated with anxiety and depression; however, few studies have longitudinally examined the relationship between SMCs and new onset of anxiety and depression symptoms in older adults. In the context of the COVID‐19 pandemic, it is also important to consider how existing health conditions may impact these associations. We examined (1) if SMCs predict new onset of anxiety and depression symptoms during the COVID‐19 pandemic in older adults and (2) if physical health problems exacerbate this association.

Method

We performed hierarchical linear regression analyses to evaluate associations between SMCs and depression and anxiety symptoms during the COVID‐19 pandemic, controlling for age, sex, education, income, baseline anxiety and depression, and cognition. Next, we assessed the interaction between SMCs and health conditions on anxiety and depression symptoms.

Result

SMCs (β= 0.021, p= .017) and health (β=.165, p<0.001) were directly associated with increased anxiety symptoms; however, the interaction effect was not significant (β=0.002, p=0.697). SMCs (β=0.006, p=0.493) and health (β=0.075, p=0.069) were not directly associated with increased depression symptoms; however, the interaction was significant (β=0.017, p<0.001).

Conclusion

SMCs and health problems exert independent effects on the development of anxiety symptoms; whereas the effect of SMCs on the development of depression symptoms depends on the presence of health problems. These findings highlight the role health plays in the development of depression and anxiety symptoms in older adults during societal stressors such as the COVID‐19 pandemic.