bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of RCF scoring system to clinical decision for the Rey complex figure using machine‐learning algorithm
Authors: Simfukwe Chanda , Youn Young Chul , An Seong Soo
Published: December 2021

Background

The interpreting of RCF scoring requires the standard RCF scoring system and the clinical decision, based on clinical dementia rate (CDR) by clinicians. The interpretation of RCF using clinical decision might not be accurate in the detection of mild cognitive impairment (MCI), or dementia patients in comparison to the RCF scoring system. For this reason, a machine‐learning algorithm was used to demonstrate that scoring RCF using clinical decision was not as accurate as the RCF scoring system in predicting MCI or dementia patients from healthy subjects.

Method

The RCF dataset, which consisted of 2,232 subjects, was collected from formal neuropsychological assessments at Chung‐Ang University Hospital. The RCF dataset was classified according to different criteria, where the first dataset had normal and abnormal subjects. They were grouped depending on the threshold cutoff point of 16%, based on the RCF scoring system. The second dataset had normal, MCI, and dementia subjects, classified depending on the clinical decision from patient CDR scores. The models were trained using a convolutional neural network (CNN) for machine learning, and an artificial neural network algorithm Tensorflow was implemented to distinguish the prediction accuracies of cognitive states of two models: the first model (Normal, Abnormal), and the second model (Normal, MCI, and Dementia).

Result

The trained model's accuracy for predicting cognitive states was as following; 96% and 88% were from the first and second models, respectively. The first model had the sensitivity for detecting abnormal of 85% with an area under the receiver operating characteristic (ROC) curve of 0.847, and the second model had the sensitivity for detecting MCI or Dementia of 78% with an area under the ROC curve of 0.778.

Conclusion

The first model, trained using a machine learning algorithm for predicting abnormal patients, was more accurate in comparison to the second model for predicting MCI or Dementia. Based on these results, the RCF scoring system has the potential of presenting better accurate criteria in distinguishing cognitive impairment among patients in comparison to the clinical decision.
Novel models of dementia care: Evidence from national dementia behavior support programs in Australia
Authors: Atee Mustafa , Morris Thomas , Macfarlane Stephen , Alford Marie , Cunningham Colm
Published: December 2021

Background

Behaviors and psychological symptoms of dementia (BPSD) are frequently experienced by this population, as they reflect unmet biopsychosocial needs.[1] The occurrence of BPSD can be debilitating, distressing and impair quality of life, not only for the person living with dementia but also for their caregivers.[1] As such, people with BPSD have complex care needs that demand dedicated resources, tailored programs and specialized skills which are often missing in mainstream aged care services. To address these needs and to achieve a nationally consistent approach, the Australian Government has been funding the services of Dementia Support Australia (DSA). DSA is the leading national provider of 24/7 dementia‐specific behavior support programs in Australia. DSA programs include the Dementia Behavior Management Advisory Service (DBMAS) for mild‐moderate BPSD and the Severe Behavior Response Teams (SBRT) for moderate‐severe BPSD. These programs entail person‐centered and multimodal nonpharmacological, psychosocial and/or psychoeducational interventions to support people with BPSD and their caregivers. These are achieved through a case management framework that includes an onsite comprehensive/holistic assessment of medicosocial history (e.g. pain), surrounding environment (e.g. over/under‐stimulation) and prescribed medications to identify causes or triggers of BPSD (Figure 1).[1] DSA is delivered through a multidisciplinary and mobile workforce of dementia consultants, geriatricians/psychogeriatricians and support staff. DSA consultants are accredited against an industry‐specific program focused on dementia‐specific competencies and capabilities. Consultants include, but are not limited to, registered and mental health nurses, occupational therapists, physiotherapists, social workers, psychologists, dieticians, speech pathologists, and diversional therapists with significant experience working in dementia and aged care settings. Since establishment in 2016, DSA programs have supported over 30,000 client referrals from residential, community and acute care settings and have supported >80% of residential aged care homes in Australia. Typical demographics for DBMAS and SBRT clients are displayed in Figure 2. Data collected on referrals demonstrated reduced frequency and severity rates of BPSD and high levels of caregiver satisfaction. Thus, DSA programs provide a novel, effective, feasible and sustainable model of care and service delivery specifically designed to address perceived gaps in aged care systems. References [1] The IPA complete guides to BPSD‐Specialists guide. Northfield (Illinois) 2012.
B vitamins and prevention of cognitive decline and incident dementia: A systematic review and meta‐analysis
Authors: Wang Zhibin , Zhu Wei , Xing Yi , Tang Yi , Jia Jianping
Published: December 2021

Background

Elevation of homocysteine levels is a well‐established risk factor for dementia, yet controversy exists regarding whether B‐vitamin‐mediated reduction of homocysteine levels can benefit cognitive function. We aimed to investigate whether B vitamins can reduce the risk of cognitive decline and incident dementia.

Method

PubMed, EMBASE, Cochrane Library, and Web of Science were searched for articles published from the inception dates to March 1, 2020. Studies were eligible if the endpoints included MMSE changes and risk of cognitive decline and/or dementia. Random‐effect or fixed‐effect models, depending on the degree of heterogeneity, were performed to calculate mean differences (MDs), hazard ratios (HRs), and odds ratios (ORs).

Result

A total of 95 studies with 46175 participants (25 RCTs, 20 cohorts, and 50 cross‐sectional studies) were included. B vitamins can benefit cognitive function as measured by MMSE changes (MD, 0.13, 95% CI 0.04‐0.23), and this result was also significant in studies where placebo groups developed cognitive decline, suggesting that B vitamins slow cognitive decline. For the > 12 months interventional period stratum, B vitamins decreased cognitive decline (MD, 0.15, 95% CI 0.05‐0.25) compared to placebo; no such outcome was detected for the shorter interventional stratum. In the non‐dementia population, B vitamins slowed cognitive decline (MD, 0.15, 95% CI 0.04‐0.25) compared to placebo; this outcome was not found for the dementia population. Lower folate levels (but not B12 or B6) were associated with higher risk of dementia (OR, 1.76, 95% CI 1.24‐2.50) and cognitive decline (OR, 1.26, 95% CI 1.02‐1.55). Among the population without dementia aged 50 years and above, the risk of incident dementia was significantly decreased among individuals with higher intake of folate (HR, 0.61, 95% CI 0.47‐0.78) (but not B12 or B6).

Conclusion

Our meta‐analysis suggests that B vitamin supplementation is associated with slowing of cognitive decline, especially in populations who received early and long‐term intervention; higher intake of dietary folate is associated with a reduced risk of incident dementia in non‐dementia aged population.
Effects of education and occupational status on incident dementia: A COSMIC collaborative cohort study
Authors: Hyun Jinshil , Katz Mindy J , Hall Charles B , Lipton Richard B , Brodaty Henry , Guaita Antonio , Lobo Antonio , Riedel‐Heller Steffi G , Lipnicki Darren M , Sachdev Perminder S ,   Cohort Studies of Memory in an International Consortium (COSMIC)
Published: December 2021

Background

Education and occupational status are expected to protect against dementia, but the research findings have been inconsistent. This project aimed to examine 1) the unique contributions of education and occupational status to incident dementia, and 2) the mediating effects of occupational status on the association between education and dementia across diverse cohorts.

Method

Education and occupational status were harmonized as binary variables (education: ‘High school completion or above’ vs. ‘Less than high school completion; occupational status: ‘Mid to high status’ vs. ‘Low status’) due to the potential threshold effects and availability across datasets. Clinical diagnosis of dementia was used as an outcome. Using a Coordinated Analysis with 9 international datasets from 7 countries over 4 continents (Table 1; Australia, Germany, Italy, South Korea, Spain, and USA), the Cox proportional hazard regression model was applied to each dataset with participants’ age as the reference point, followed by meta‐analysis to provide the weighted summary effect sizes. Mediation analysis was conducted using the causal mediation approach with survival data (VanderWeele, 2011).

Result

We used data from 10,203 participants whose baseline age ranged from 58 to 103 years. Higher levels of education and occupational status were independently associated with decreased risk of incident dementia (Table 2; HR=0.70, 95% CI=[0.54, 0.92] for education; HR=0.79, HR=[0.66, 0.94] for occupational status). Heterogeneity across datasets was moderate for the education model (I
2=37%) and low for the occupation model (I
2= 0%). For the mediation analysis, the indirect effect was marginally significant (HR=0.94, 95% CI=[0.87, 1.00]) and 12% of the effect of education was mediated by occupational status.

Conclusion

Using datasets from wide geographical regions, we found that both early life education and adulthood occupational status were independently predictive of incident dementia. Occupational status showed a weak mediating effect on the association between education and dementia. This finding suggests the importance of dementia prevention efforts in any stage of life course. Policy needs to prioritize early life education (possibly up to secondary education) and also target individuals with low occupational status to deliver dementia prevention and intervention.
Effects of the COVID‐19 pandemic on healthcare and community‐based service use for people living with dementia: Perspectives from dementia care professionals
Authors: Hunt Jack FV , Schroeder Molly , LeCaire Tamara , O'Toole Smith Kathleen , Marschall Katelyn , Walaszek Art
Published: December 2021

Background

Dementia care and healthcare delivery systems have changed substantially as a result of the COVID‐19 pandemic (Wang et al., 2020). Experts have identified a number of barriers to health care access for people living with dementia (PLWD) during the pandemic, including difficulty implementing telemedicine practices, discontinuation of home care services, increased caregiver burden and financial hardship (Brown et al., 2020; Greenberg et al., 2020). Assessment of dementia care providers’ perceptions of the change in use of healthcare and community‐based services by PLWD is needed to identify gaps and to improve care for this vulnerable population during the COVID‐19 pandemic.

Methods

We designed an online survey asking about changes to PLWD and caregiver use of 14 healthcare and community‐based services during the COVID‐19 pandemic and about 15 factors that may have contributed to these changes. The survey was distributed to a network of dementia care professionals across the state of Wisconsin between August 28th and October 9th, 2020.

Result

A total of 102 individuals completed the survey. Most respondents worked in the Wisconsin Department of Health Services dementia care specialist system, were employed by Aging and Disability Resource Centers (53.5%), identified as female, White race and worked in rural settings. Services most frequently reported as no longer in use included senior center programs, adult day programs, and companion/friendly visitor services, while meal delivery was reported as having increased use by PLWD. Factors identified most frequently as barriers to service use included changes in access to caregiver support/respite services, access to natural supports, compassion fatigue/caregiver burnout and both knowledge of and access to technology/virtual tools.

Conclusion

The results highlight the increased demand for certain services like meal delivery and the need to find alternatives to in‐person enrichment/recreational and caregiver respite opportunities such as senior center and adult day programs that are being used less. Access to and knowledge of technology and increased stress on caregivers and support systems were identified as some of the more frequent barriers to service use, thus allocating resources towards these areas may be particularly impactful towards improving service use for PLWD during the COVID‐19 pandemic.
Plasma pTau isoform assessment across disease stages
Authors: Blennow Kaj
Published: December 2021

Background

Phosphorylated tau (P‐tau) in CSF is an established AD biomarker that is seemingly specific for Alzheimer’s disease (AD). Several recent papers also show highly promising results for plasma P‐tau, with a clear increase in AD, also in the very early phases of the disease. Further, increased plasma P‐tau correlates with tau pathology assessed by PET, predicts cognitive decline, and specifically identifies AD‐type pathology at post‐mortem. Several different P‐tau species can be quantified in CSF and plasma, including P‐tau181 and P‐tau217, and recently also other species such as P‐tau231 and P‐tau235.

Method

Validated immunoassays (Simoa and MS) with analytical sensitivity in the low pg/mL range has been developed for these P‐tau species are available. Further, mass spectrometry (MS) methods have been developed for absolute quantification of several of these P‐tau species simultaneously.

Result

Although measured using different assays and in different cohorts, plasma P‐tau accurately predicts progression to AD dementia in individuals with memory complaints in models including APOE and cognition (AUCs: 0.91 for P‐tau217 and 0.90 for P‐tau181), and AD pathology at autopsy in samples taken 3 years before death (P‐tau217 AUC 0.89) and 8 years before death (P‐tau181 AUC 0.98). When measured in CSF using either Simoa assays or antibody‐free quantitative MS, P‐tau181, P‐tau217 and P‐tau231 correlate tightly (R‐values around 0.90). A first study found slightly higher performance of plasma P‐tau231 than P‐tau181 to identify early amyloid pathology and to differentiate AD across the entire Braak stage spectrum.

Conclusion

Plasma P‐tau is a novel very promising class of blood biomarkers for AD. Recent studies add knowledge to the characteristics of the different P‐tau biomarker species and analytical methods to measure them, and how these biomarkers and methods perform to identify early both amyloid and tau AD pathophysiology.
Prospective and retrospective memory complaints in early and late stages of amnestic mild cognitive impairment
Authors: Ryu Seon Young , Lee Sang Bong , Lee Taek Jun , Jung Yu Jin
Published: December 2021

Background

Memory complaints are a frequent phenomenon in elderly people. These subjective memory complaints are a cardinal feature of amnestic mild cognitive impairment (aMCI) known as the first symptomatic stage of Alzheimer's disease. The objective of this study was to compare memory complaints and determine whether there were differences of types of memory complaints (i.e. prospective memory (PM) versus retrospective memory (RM) complaints) in early‐stage aMCI (EMCI) and late‐stage aMCI (LMCI).

Method

One‐hundred and twenty‐two aMCI subjects (mean age: 70.07 ± 8.54 years) were divided into EMCI (n = 72) and LMCI (n = 50) according to their Clinical Dementia Rating Sum of Boxes score. Memory complaints were assessed using the Prospective and Retrospective Memory Questionnaire (PRMQ) consisting of 16 items that describe everyday memory failure of both PM and RM. All participants underwent clinical assessment and completed detailed neuropsychological tests. Group comparisons of types of memory complaints were assessed between EMCI and LMCI subjects.

Result

LMCI subjects showed more subjective memory complaints based on PRMQ total sores than EMCI subjects. For types of memory complaints, LMCI group showed more RM complaints by PRMQ‐RM scores than EMCI group, but there were no differences of PM complaints between two groups. The results for PRMQ total scores and PRMQ‐RM scores remained significant after adjusting for age, education, and depressive symptoms.

Conclusion

LMCI showed more RM complaints than EMCI among subjective memory complaints. There might be differences in types of memory complaints according to disease stage of clinical spectrum of MCI. Therefore, more consideration for types of memory complaints might be needed in the clinical correlation of individuals with MCI.
Pathological correlates of clinical heterogeneity in Alzheimer's disease
Authors: Grinberg Lea T.
Published: December 2021

Background

Atypical variants of Alzheimer's Disease (AD) manifest predominantly with non‐memory complaints, including visuospatial (posterior cortical atrophy), language (logopenic variant of primary progressive aphasia), motor (cortico‐basal syndrome), executive or cognitive‐behavioral patterns. Compared to typical (amnestic) AD, these atypical profiles are characterized by faster cognitive decline rates, syndrome‐specific atrophy patterns, younger age at onset, and tend to be less associated with apolipoprotein E (APOE) ɛ4 allele genotype.

Despite clinical differences, both typical AD and atypical AD variants feature deposits of amyloid plaques and neurofibrillary tangles and can be staged using the same neuropathological guidelines. Although it is clear that AD atypical phenotypes presented different atrophy and hypometabolism patterns among themselves and compared to typical AD, it is unclear what is the neuropathological subtract underlying an atypical AD presentation. Our work, supported by the literature, suggests that the regional pattern of plaque accumulation in advanced disease is not distinctive in each of the clinical variants of AD. Conversely, cumulative evidence from neuropathology and neuroimaging studies suggests that variations in the regional tau burden are closely related to the expression of AD's clinical variants.

Method

This presentation will review published and unpublished evidence from human neuropathological studies addressing the neurobiological substrates atypical AD variants

Result

It will include a discussion on similarities and differences in plaque and tangle burden, neuropathological comorbidities. We will also present unpublished results from a systematic study with over 140 AD cases (35% atypical) showing that comorbid pathologies do not play an essential role in determining atypical AD

Conclusion

Finally, it will discuss the role of distinct mechanisms of selective neuronal vulnerability in concern with atypical AD.
Survey outcomes on neuropsychological testing in posterior cortical atrophy
Authors: Pelak Victoria S. , Holden Samantha K. , Crutch Sebastian J. , Yong Keir X.X.
Published: December 2021

Background

Posterior cortical atrophy (PCA) is a clinico‐radiological syndrome mostly commonly underpinned by Alzheimer’s disease (AD) pathology and has been referred to as the most common atypical AD clinical phenotype. PCA consensus classification criteria emphasize core clinical and cognitive features comprising visual and other posterior features in contrast to relatively spared episodic memory, language, executive functions and behavior (Crutch et al., Alzheimers Dement., 2017). However, posterior features are less commonly evaluated in standard neuropsychological batteries compared to other domains, possibly contributing towards common diagnostic delays, and memory and executive function tests that have visual or numerical demands are particularly challenging in the evaluation of relatively spared functions. Standardization of the neuropsychological assessment of PCA is vital for multi‐center research collaborations, the development of outcome measures for future clinical trials, and better characterization of the extent of overlap with related neurodegenerative syndromes. Experts were surveyed regarding their practice preferences in the assessment of the PCA syndrome.

Method

The membership of the ISTAART Atypical Alzheimer’s Disease Professional Interest Area was invited to participate in a survey examining preferences for measures employed in the assessment of the visual and core cognitive features of PCA, as defined by the 2017 PCA consensus criteria.

Result

Atypical AD PIA members included those with backgrounds in neurology, neuropsychology, psychiatry, geriatric medicine and clinical research (respondents N=55). Most commonly assessed features were space perception deficits, simultanagnosia and constructional apraxia, followed by dominant parietal features and alexia. Object perception deficits and early visual functions were less frequently assessed. A subset of respondents included preferred tests to evaluate global functioning and relatively spared features, including example measures less susceptible to visual dysfunction.

Conclusion

Variations in assessing PCA features are considered with implications for characterizing the extent of AD phenotypic heterogeneity, including proposed ventral and caudal PCA presentations. Results will inform future work to develop consensus recommendations for a short clinical PCA battery and an extended, formal PCA battery, in order to promote capacity for multi‐center studies and advance the development of appropriate outcome measures in trials enrolling patients with PCA and/or prominent posterior dysfunction.
The synaptic marker neurogranin as a disease state biomarker in Alzheimer’s disease: A systematic review and meta‐analysis
Authors: Wang Zhibin , Yang Jianwei , Zhu Wei , Tang Yi , Jia Jianping
Published: December 2021

Background

Synaptic degeneration is the pathologic foundation of cognitive decline in the Alzheimer’s disease (AD) continuum. We aimed to determine whether cerebrospinal fluid (CSF) synaptic marker neurogranin (Ng) is a disease state or a disease stage biomarker in the AD continuum.

Method

Studies comparing CSF Ng levels among AD, mild cognitive impairment (MCI) and healthy participants were included. Studies were eligible if the correlation between CSF Ng levels and Mini‐Mental Status Examination (MMSE) scores was investigated.

Result

Twenty‐one studies met our inclusion criteria (n = 4515). The magnitude of effect sizes was more apparent in AD (standardized mean difference [SMD] = 1.72; 95% confidence interval [CI] = 1.23–2.22), than in MCI (SMD = 0.82; 95% CI = 0.29–1.34) compared to control populations. These results suggest that CSF Ng can discriminate AD and MCI from control populations, implying that synaptic degeneration worsens as patients progress from MCI to AD. However, there was a very weak correlation between CSF Ng levels and MMSE scores (r = ‐0.15; 95% CI = ‐0.21–‐0.08) among the whole populations, suggesting that an increment of CSF Ng is best considered a biological evidence of disease state in the AD continuum.

Conclusion

Our study provides evidence that the synaptic marker CSF Ng can be used as a disease state biomarker for the AD continuum. Because synaptic degeneration is a distinct pathologic event from amyloid deposition and neurofibrillary tangle formation, CSF Ng may provide an important supplementation to the AT(N) biomarker system to reveal the sequence of neuropathology.
The incidence of young onset dementia: A systematic review and meta‐analysis
Authors: Hendriks Stevie , Peetoom Kirsten , Bakker Christian , Koopmans Raymond , van der Flier Wiesje M , Papma Janne M , Verhey Frans RJ , de Vugt Marjolein , Koehler Sebastian
Published: December 2021

Background

Young‐onset dementia (YOD) denotes persons who have an onset of the disease before the age of 65. Information on the epidemiology of YOD, especially the incidence, is scarce. Insight into the incidence can contribute to further research on the etiology, mechanism and risk factors of YOD. Therefore, we aimed to conduct a systematic review and meta‐analysis collecting all published data on the incidence of YOD worldwide.

Method

This systematic review and meta‐analysis was conducted using the PRSIMA guidelines. A thorough literature search was performed in PubMed, Embase, CINAHL and PsychINFO. Eligible studies were prospective or retrospective population‐based studies reporting on the incidence of dementia under the age of 65. No restrictions on language were applied, and studies published between 1990 and March 2020 were screened. Random‐effect meta‐analyses were used to pool 5‐year incidence rates together. Incidence rates were age‐standardized for the World Standard Population whenever possible. Subgroup analyses and meta‐regression were used to identify factors influencing heterogeneity between studies. The study is registered with PROSPERO, number CRD42019119288.

Result

50 articles were included in the systematic review, of which 42 were included in the meta‐analysis. Studies were mostly conducted in Europe, with few studies from North America, Asia and Oceania. Age‐standardized incidence rates of YOD increased from 0.15/100,000 in the age group 30‐34 years, to 4.83/100,000 in the age group 60‐64 years, resulting in an overall incidence rate of 11/100,000 in the total age group 30‐64. This corresponds to 360,000 new cases globally per year. Heterogeneity between studies was high. Subgroup analyses showed incidence rates between males and females were similar. Meta‐analyses of different dementia subtypes showed incidence was highest for Alzheimer’s disease, followed by vascular dementia and frontotemporal dementia. Meta‐regression showed geographic location of the studies significantly influenced heterogeneity.

Conclusion

This review showed current age‐standardized incidence rates of YOD are estimated to be 11/100,000 person‐years. However, there are still knowledge gaps to address in future research, such as differences in incidence by ethnicity and subtypes of dementia.
Lower nutritional indicators associated with higher mortality in patients with MCI and dementia—the Amsterdam Ageing Cohort study
Authors: Verhaar Barbara JH , Van de Schraaf Sara AJ , Meester Hanneke FM Rhodius‐ , Trappenburg Marijke C , Peters Mike JL , Muller Majon
Published: December 2021

Background

Our objective was to investigate associations between indicators of nutritional status, including weight and body composition, and survival across cognitive diagnosis groups within a geriatric population.

Method

From the ongoing Amsterdam Ageing cohort study, 719 patients were included, comprising 111 with subjective cognitive decline (SCD; 76±7 years, 54.1% female, MMSE 28[27‐29]), 213 with mild cognitive impairment (MCI; 79±6 years, 44.6% female, MMSE 26[24‐27]) and 395 with dementia (81±7 years, 53.9% female, MMSE 22[18‐24]). Indicators of nutritional status were measured and dichotomized, including body mass index (BMI), fat percentage (Fat%), skeletal muscle mass index (SMI) and Mini Nutritional Assessment Short‐Form (MNA‐SF) scores. Survival data were requested from the municipality population registry on January 22nd 2020. Associations between indicators of nutritional status and survival among different cognitive diagnosis groups were analyzed using Kaplan Meier analyses, and cox regression models adjusted for age, sex and number of prescribed drugs.

Result

The overall mortality was 15.8% during a median follow‐up duration of 610 [256‐964] days, with a significant difference between the cognitive diagnosis groups (p<0.0001). Kaplan Meier survival curves stratified for BMI and MNA are presented in Figure 1 and 2. Low BMI (<20 kg/m2) was associated with higher mortality risk in patients with dementia in the adjusted cox regression model (HR 3.1, 95%‐CI 1.7‐5.9). In patients with MCI, the association with BMI was not significant (HR 3.0, 0.6‐14.4). Low MNA‐SF scores (<12) were associated with higher mortality in both patients with MCI (HR 3.55, 1.23‐10.18) and patients with dementia (HR 2.1, 1.3‐3.5). However, there were no significant associations with Fat% and SMI. In patients with SCD, there were no significant associations between the indicators of nutritional status and mortality.

Conclusion

Lower indicators of nutritional status were associated with higher mortality in patients with MCI and dementia, warranting increased focus on nutritional status in patients with cognitive decline. We plan to repeat these analyses after a longer follow‐up in this ongoing cohort study. Dietary intervention studies aimed at preventing weight loss could shed light on causality in the association between nutritional status and progression of disease.
Theta phase‐gamma amplitude coupling during working memory and its relationships with demographic, clinical, genetic, neurochemical, and neurostructural measures in older adults at risk for dementia
Authors: Patterson Rachel A. , Brooks Heather J. , Mirjalili Mina , Rashidi‐Ranjbar Neda , Zomorrodi Reza , Blumberger Daniel M. , Kumar Sanjeev , Fischer Corinne E. , Flint Alastair , Graff‐Guerrero Ariel , Herrmann Nathan , Kennedy James L. , Lanctôt Krista L. , Mah Linda , Mulsant Benoit H. , Pollock Bruce G. , Voineskos Aristotle N. , Rajji Tarek K.
Published: December 2021

Background

Theta phase‐gamma amplitude coupling (TGC) is a neurophysiological mechanism that underlies working memory (WM)1. WM is also associated with demographic, clinical, genetic and neuroimaging measures. However, the relative contributions of TGC and these measures to WM, and the relationship between TGC and these measures, remains unclear. We examined the relative contributions of TGC and these measures to WM performance in a group of participants at‐risk for Alzheimer’s dementia.

Method

Older participants (age=71.2±6.0, N = 206) with Mild Cognitive Impairment (MCI), Major Depressive Disorder (MDD), or MCI+MDD completed clinical assessment, N‐back WM task with EEG to measure TGC, genetic testing, PET with [11C]‐Pittsburgh Compound B ([11C]‐PIB PET) and brain 3T MRI. Linear regressions were used to assess the relationships among 2‐back WM performance; demographic and clinical variables; TGC; ApoE4 carrier status; total beta‐amyloid SUVR ([11C]‐PIB PET); and regional cortical thickness, subcortical volumes, and white matter fractional anisotropy (MRI).

Result

2‐back WM performance was associated with age and TGC after controlling for all other measures (Age: β=‐0.253; p=0.039, TGC: β=0.300; p=0.005). TGC was not associated with any other measures after correction for multiple comparisons.

Conclusion

TGC predicts WM performance in contrast to demographic, clinical, genetic, and PET and MRI imaging measures. Our findings underline the strong association between WM and TGC, a dynamic time‐based neurophysiological measure that is capturing a functional process which may not be captured by these static measures. Future studies could explore other dynamic measures with other imaging modalities and their relationships with TGC or other neurophysiological measures.

1. Rajji, T.K., et al., Ordering Information in Working Memory and Modulation of Gamma by Theta Oscillations in Humans. Cerebral Cortex, 2017. 27(2): p. 1482‐1490.
Superiority of the Dépistage Cognitif de Québec (DCQ) over the Montreal Cognitive Assessment in differentiating dementia with Lewy bodies from Alzheimer's disease
Authors: Poulin Elizabeth , Sarao Pamela , D'Amours Marie‐Frédérique , Laforce Robert
Published: December 2021

Background

Recent criteria for dementia with Lewy bodies (DLB) are available but early diagnosis remains a challenge since few cases display all core clinical features. Discriminating Alzheimer’s disease (AD) from DLB is also complex given the overlap in cognitive dysfunctions between the two conditions. We aimed to study their differential neurocognitive profile using the Dépistage Cognitif de Québec (DCQ), a newly developed screening tool for atypical dementias. Moreover, we explored whether the DCQ was superior to the Montreal Cognitive Assessment (MoCA) in identifying DLB.

Methods

We compared the performance of 15 patients with DLB to 72 patients with the amnestic variant of AD on the five indexes of the DCQ (Memory, Visuospatial, Executive, Language and Behavioral) as well as the MoCA test, administered in random order. Participants were recruited prospectively in a tertiary memory clinic and diagnosed according to current clinical criteria for AD and DLB.

Results

There were no significant differences between the groups in age (AD: 72.97; DCL: 72.13) or level of education (AD: 12.88; DCL: 12.40). Mean Total MoCA score was similar across conditions (19.01 vs 20.00, p = .54) whereas the Total DCQ score revealed a significant difference between AD and DLB (66.39 vs 72.60, p < .05) (Fig. 2). Further analyses showed superior Area Under the Curve for the DCQ (69.23%; moderately strong) over the MoCA (55.26%; weak) in discriminating DCL from AD (Fig. 1). Bivariate analyses on the DCQ and MOCA indexes were performed using Wilcoxon‐Mann‐Whitney tests. When compared to AD, DLB participants performed worse on the Visuospatial Index (5.04 vs 4.10, p < .05) (Fig. 4), particularly the visuospatial construction task (1.33 vs 0.67 p < .05) while AD participants were significantly more affected on the Memory Index (recall and recognition) (16.13 vs 24.73, p < .0001) (Fig. 3). The remaining DCQ indexes (Executive, Language and Behavioral) were similar between groups.

Conclusions

Our data suggests that the DCQ may be a superior tool than the MoCA in distinguishing AD from DLB. The DCQ allowed better characterization of the neurocognitive profile between AD and DLB, where DLB preferentially affects visuospatial skills while AD targets memory abilities.
Quantitative measurement of CSF Aβ1‐38, Aβ1‐40, Aβ1‐42, and Aβ1‐43 by high sensitivity liquid chromatography mass spectrometry
Authors: Kawarabayashi Takeshi , Nakamura Takumi , Takatama Masamitsu , Shoji Mikio
Published: December 2021

Background

High sensitivity liquid chromatography mass spectrometry (LC‐MS/MS) was recently introduced to measure amyloid‐ß (Aß) species, allowing for a simultaneous assay that is superior to ELISA, which requires more assay steps with multiple antibodies. We validated the Aß1‐38, Aß1‐40, Aß1‐42, and Aß1‐43 assay by LC‐MS/MS and compared it with ELISA using cerebrospinal fluid (CSF) samples to investigate its feasibility for clinical application.

Method

CSF samples from 120 subjects [8 Alzheimer's disease (AD) with dementia (ADD), 2 mild cognitive dementia due to Alzheimer's disease (ADMCI), 14 cognitively unimpaired (CU), and 96 neurological disease subjects] were analyzed. Aβ species were separated using the Shimadzu Nexera X2 system and quantitated using a Qtrap 5500 LC‐MS/MS system. Aß1‐40 and Aß1‐42 levels were validated using ELISA.

Result

CSF levels in CU were 666±249 pmol/L in Aß1‐38, 2199±725 pmol/L in Aß1‐40, 153.7±79.7 pmol/L in Aß1‐42, and 9.78±4.58 pmol/L in Aß1‐43. The ratio of the amounts of Aß1‐38, Aß1‐40, Aß1‐42, and Aß1‐43 was approximately 68:225:16:1. Linear regression analyses showed correlations among the respective Aß species. Both Aß1‐40 and Aß1‐42 values were strongly correlated with ELISA measurements. No significant differences were observed in Aß1‐38 or Aß1‐40 levels between AD and CU. Aß1‐42 and Aß1‐43 levels were significantly lower, whereas the Aß1‐38/1‐42, Aß1‐38/1‐43, and Aß1‐40/Aβ1‐43 ratios were significantly higher in AD than in CU. The basic assay profiles of the respective Aß species were adequate for clinical usage.

Conclusion

A quantitative LC‐MS/MS assay of CSF Aß species is as reliable as specific ELISA for clinical evaluation of CSF biomarkers for AD.
A phase 1b open label study of sodium selenate as a disease‐modifying treatment for behavioural variant fronto‐temporal dementia
Authors: Vivash Lucy E , Malpas Charles B , Hovens Christopher M , Velakoulis Dennis , O’Brien Terence
Published: December 2021

Background

Hyperphosphorylated tau is a pathological hallmark of ∼45% of behavioural variant frontotemporal dementia (bvFTD). For this reason, hyperphosphorylated tau represents a promising treatment target for this population. Sodium selenate stimulates the PP2A enzyme, which directly dephosphorylates hyperphosphorylated tau. This Phase 1b, open‐labelled, study investigated sodium selenate as a disease‐modifying treatment for patients with bvFTD.

Method

Twelve patients with bvFTD were treated with sodium selenate (15mg tds) for twelve months. Participants underwent a cognitive and behavioural battery, MRI, lumbar puncture and safety assessments at screening, baseline, and at regular intervals following treatment commencement. Adverse events were monitored via diary cards between clinic visits.

Result

All 12 patients completed the study. Safety analysis found that sodium selenate was safe and well tolerated, with no study withdrawals. Commonly reported mild‐moderate adverse events were nail changes (n=6), muscles aches (n=4), headache, fatigue, hair loss and fall (n=3). Five patients reduced their dose to 10mg tds due to adverse events. No treatment‐related serious adverse events occurred. Analyses of efficacy data are ongoing. A mixed‐effects analysis showed an overall small but significant decline on cognition and behaviour, including total NUCOG score (b=‐0.18, 95% CI=‐0.28–0.08) Cambridge Behavioural Index (b=0.32, 95% CI=0.18‐0.46) and Carer Burden Scale score (b=0.1, 95% CI = 0.02‐0.18). Percentage change in whole‐brain volume from baseline to week 52 ranged from ‐0.26% to ‐6.51% (n=7 >‐1.8%, n=4 <‐1.8%). Plasma tau levels (n=6) did not change from baseline (3.73±0.26pg/mL) to week 52 (4.66±0.24pg/mL). CSF tau also showed no change from baseline (167.8±11.2pg/mL) to week 52 (156.1±2.49pg/mL). Although not significant, the directional changes are in line with the proposed mechanism of sodium selenate.

Exploratory analyses of “responders” (brain volume change >‐1.8%, n=7) found no change in NUCOG total score (b=‐0.03, 95% CI ‐0.14‐0.07) or CBS score (b=‐0.05, 95% CI ‐0.04‐0.13) over time.

Conclusion

Sodium selenate is safe and well tolerated in patients with bvFTD. Exploratory analyses indicate it may reduce atrophy and halt cognitive decline in a subset of bvFTD patients. Sodium selenate should be further investigated as a potential treatment for bvFTD, and biomarkers to identify the subset of “responder” patients explored.
Health care utilization patterns in early symptomatic AD prior to enrollment into Phase 2/3 clinical trial AMARANTH
Authors: Chandler Julie , Zimmer Jennifer A , Kubisiak Emily , Kubisiak Joanna
Published: December 2021

Background

In Alzheimer’s disease (AD), pathogenic changes occur decades before clinical symptoms and diagnosis. Pre‐diagnostic medical history and healthcare resource utilization (HCRU) patterns of patients with early symptomatic AD may aid patient identification earlier in the disease. This study examined HCRU in a subgroup of clinical trial patients to detect early indicators of cognitive, functional and/or behavioral decline.

Methods

AMARANTH (NCT02245737) was a double‐blind, placebo‐controlled multi‐center trial that enrolled amyloid‐positive patients with early symptomatic AD (mild cognitive impairment (MCI) due to AD or mild AD dementia). This addendum study analyzed baseline characteristics and Medicare claims of a subgroup of participants compared to two larger age‐matched cohorts of Medicare beneficiaries (Cognitive impairment (CI)/AD and non‐CI/AD matched controls) (Figure 1). AMARANTH participants consented to access of 8 years of prior Medicare claims data and had baseline data available from the parent study. Participants were stratified by APOE4 carrier status, disease, and gender. Descriptive statistics and regression models assessed differences in participant costs across strata and the diagnostic histories between participants and controls. Variables considered in stepwise selection of model covariates included observation months, age, frailty, geography, and comorbidities.

Results

Addendum participants were representative of the AMARANTH cohort but were older and less functionally and cognitively impaired at study entry. Medicare costs did not differ across APOE4 or disease status, but costs for men were lower. Pre‐diagnosis, participant and control costs were comparable, while an increase at diagnosis was observed in the CI/AD controls. A summary of diagnostic histories between participants and controls is shown in Table 1. Post‐diagnostic drug utilization was higher in participants. They were more likely than CI/AD controls to have used psychotherapeutic and neurological agents, and more likely than non‐CI/AD controls to have used antidepressants/anticonvulsants and analgesics/anti‐inflammatory/genitourinary agents.

Conclusions

Post‐diagnostic HCRU patterns and costs were higher in CI/AD controls than participants, who did not differ from non‐CI/AD controls; however, participants may not be representative of the broader Medicare CI/AD population. This study provides descriptive HCRU patterns of participants years prior to diagnosis; future analysis with larger cohorts may refine and better identify diagnostic indicators in early symptomatic AD patients.
A network‐based drug‐screening platform for Alzheimer’s disease by integrating mathematical modeling and pathological features of human brain organoids
Authors: Park Jong‐Chan , Jang So‐Young , Lee Dongjoon , Lee Jeongha , Kang Uiryong , Chang Hongjun , Kim Haeng Jun , Han Sun‐Ho , Seo Jinsoo , Choi Murim , Lee Dong Young , Byun Min Soo , Yi Dahyun , Cho Kwang‐Hyun , Mook‐Jung Inhee
Published: December 2021

Background

Developing effective drugs for Alzheimer’s disease (AD), the most common cause of dementia, has been difficult because of complicated pathogenesis. The difficulty of acquiring human brain samples and the lack of a disease model that adequately recapitulates the pathological hallmarks pose significant challenges in the field.

Method

Here, we report an efficient, network‐based drug‐screening platform developed by integrating mathematical modelling and the pathological features of AD with human iPSC‐derived cerebral organoids (iCOs), including CRISPR‐Cas9‐edited isogenic lines. We use 1,300 organoids from 11 participants to build a high‐ content screening (HCS) system and test blood‐brain barrier‐permeable FDA‐approved drugs.

Result

Our results confirmed that our iCOs had pathological features of AD, and thus could be an appropriate model reflecting characteristics of the actual disease‐related human brain lesions. Also, We completed the construction and validation of the molecular regulatory network model for AD. We proposed candidate drugs based on systems analysis of the dynamical network model with detailed regulatory mechanisms. We found that all of the candidate drugs were effective to some degree in reducing Aβ or tau deposition and enhancing or maintaining neuronal cell viability.

Conclusion

Our study provides a strategy for precision medicine through the convergence of mathematical modelling and a miniature pathological brain model using iCOs. With further generation of the iCOs or iPSC‐derived microglia (iMG) from various types of AD patients, our approach may propose strategies for the precision medicine therapy.
Traditional healing and medicine in dementia care for indigenous populations in North America, Australia, and New Zealand: A scoping review protocol
Authors: Shrestha Hom Lal , McArthur Michael , Rowe Robyn L , Wabie Joey‐Lynn , Maar Marion , Walker Jennifer D
Published: December 2021

Objective

In this scoping review we aim to explore approaches to the integration of traditional healing and medicine in dementia care for Indigenous communities in North America, Australia, and New Zealand. We aim to understand the roles and experiences of traditional healers, strategies and their evaluation, and the barriers and opportunities for integration of Indigenous and western dementia care approaches. Introduction: Access to culturally safe geriatric care and dementia assessment, diagnosis, and care in Indigenous populations worldwide is an emerging challenge. The World Health Organization recognizes traditional healers as stakeholders in dementia care. Traditional healers can provide dementia assessment and care in unique ways and play a catalytic role in the process of dementia care planning. This scoping review will inform Indigenous health service providers about the potential integration of traditional healing and medicine into dementia care and support systems. Inclusion criteria: This review will include all types of study designs, that examine the integration of Indigenous approaches and traditional healers in dementia care in Indigenous communities in North America (Canada and U.S.), Australia and New Zealand.

Methods

In close collaboration with Indigenous community advisors, we will search for OVID MEDLINE, PsycINFO, CINAHL and EMBASE include English literature from 1990 to 2020. After two independent screens of title and abstract, and then full text, we will extract the study population, participants, intervention type, aims, methods, key findings, and knowledge gaps. The results will be summarized and presented to Indigenous community advisors for contextual interpretation and validation prior to being finalized.

Results

Our initial search of CINAHL, Embase, Medline and PsycINFO identified 516 records published between 2000 and 2020 that met our search criteria. After 164 duplicates were removed, we screened 352 titles and abstracts and excluded 209 that did not meet inclusion criteria. Our second stage review of 143 full text studies resulted in the further exclusion of 113 studies. Of these, 84 studies did not include traditional medicine and 13 did not involve Indigenous populations or meet our study design criteria. Results were extracted from the 30 eligible and relevant studies that were included in the final scoping review.