bluuebunny/crossref_metadata_2025 huggingface dataset:
Digitally interconnected tertiary old age mental healthcare services and primary healthcare services for seniors in remote areas in Greece: An exportable model?
Authors: Alexopoulos Panagiotis , Vorvolakos Theofanis , Kontogianni Evangelia , Tsibanis Konstantinos , Politis Antonios
Published: December 2023

Background

Even though communities in remote areas across the globe age, old age mental healthcare services are mainly tertiary‐ or secondary hospital‐ based and subsequently not easily accessible by seniors with mental disorders living in such communities.

Methods

The INTegRated InterveNtion of pSychogerIatric Care (INTRINSIC) network embodies a model of digitally interconnected tertiary old age mental healthcare services and primary healthcare services for seniors in remote areas in Greece. It is coordinated by the Division of Old age mental health of the 1st Department of Psychiatry of the National and Kapodistrian University of Athens. INTRINSIC network is built around five pillars: The digital platform, bridging healthcare professionals, service users and communities; The old age mental health risk factor surveillance system, enabling the generation of a map of mental health problems of older adults living in each remote community and the initiation of the adequate treatment; the Modified Problem Adaptation Therapy (M‐PATH) intervention; Hearing and vision assessment and support of service users; and an advocacy body consisting of service users, their care partners and families and active members of the local communities. The initial, six‐month phase of INTRINSIC is funded by the Greek Ministry of Health.

Results

298 seniors living in remote areas of four different Nomenclature of Territorial Units for Statistics 2 (NUTS2) regions have been enrolled in INTRINSIC. They are on average 71.8 years old and 30.5% of them are males. Approximately 18% and 26% of INSTRINSIC service users suffer from depressive and anxiety symptoms, respectively; 62.3% complained about cognitive decline. Of note, only in 8% of service users the diagnosis of dementia had been established prior their enrolment, while 33.2% were treated with antidepressants.

Conclusion

Based on amplification of existing resources through the cooperation of tertiary‐ and primary healthcare professionals who share a vision of change, the INTRINSIC model offers a pragmatic opportunity to provide high quality old age healthcare services to seniors living in remote communities. The still ongoing collection and analyses of service users’ data may provide a solid foundation for INTRINSIC feasibility and sustainability
Motor neuron symptoms and pathology burden in de medulla oblongata of FTLD‐TDP brain donors
Authors: Scarioni Marta , de Koning Florianne , Gami‐Patel Priya , Fiondella Luigi , Timar Yannick , Rozemuller Annemieke J.M. , Hoozemans Jeroen , Aronica Eleonora , Raaphorst Joost , Pijnenburg Yolande A.L. , Dijkstra Anke A.
Published: December 2023

Background

motor neuron symptoms (MNS) are the hallmark of amyotrophic lateral sclerosis (ALS), which is clinically and pathologically related to frontotemporal dementia (FTD). Up to 20% of FTD patients are diagnosed with ALS (1). However, MNS are observed in a larger proportion of FTD patients (FTD‐MNS), which do not fulfill clinical diagnostic criteria for concomitant ALS (FTD‐ALS) (2). The burden of TDP‐43 pathology in the hypoglossal nucleus (HN) is higher in FTD‐ALS compared to pure FTD brain donors (3), but little is known about the distribution of TDP‐43 pathology in the medulla oblongata in FTD‐MNS.

Method

MNS occurring at any disease stage were assessed from the records of FTLD‐TDP brain donors from the Netherlands Brain Bank (n = 38). The total amount of neurons and the percentage of neurons showing TDP‐43 pathology were counted in the HN, nucleus ambiguus (NA) and inferior olivary nucleus (ION). ANOVA was performed between pure FTD, FTD‐ALS, and FTD‐MNS.

Result

a pure FTD syndrome was recorded in 12/38 FTLD‐TDP brain donors. A concomitant FTD‐ALS diagnosis had been established during life for 4/38 brain donors, while 16/38 had FTD‐MNS. The most common MNS were dysphagia (63%), spasticity (29%) and wasting (24%). A higher TDP‐43 burden in the HN and NA was observed in FTD‐ALS compared to FTD (p < 0.05). TDP‐43 burden in the HN and in the ION was significantly higher in FTD‐MNS compared to FTD brain donors (p < 0.05).

Conclusion

MNS are common in FTD, even in the absence of ALS. MNS in FTD are linked to TDP‐43 burden in the HN, NA and ION.

References: 1) van Es et al, Lancet 2017 2) Burrell et al, Brain 2011 3) Halliday et al, J Neurol Sci 2016
Awareness and knowledge of dementia amongst Brazilian Speech and Language Therapists: An investigation of its determinants through a national survey
Authors: Beber Bárbara Costa , Alves Emily Viega , Pereira Natalie , Freitas D´Ávila Maria Isabel , Silagi Marcela , Chaves Marcia L Fagundes , Lawlor Brian
Published: December 2023

Background

Communication disorders are a frequent problem among people with dementia and can negatively affect their lives. Speech and Language Therapists (SLTs) can improve the quality of life of dementia people if they are properly trained to intervene. This study aimed to investigate the level of awareness and knowledge that practicing SLTs from Brazil have about their role in the care of people with dementia, and to identify determinants of the awareness and knowledge.

Method

We developed an online survey to collect information from the practicing Brazilian SLTs regarding clinical and demographic characteristics, knowledge about dementia (true or false questions), and awareness about their role in the care of people with dementia (sentences to rate in a likert scale). Uni and bivariate associations were then explored using Student´s t‐test, ANOVA and Pearson´s correlation test. Multiple regression analyses were conducted including the variables that presented p>0,2 in the bivariate analyses or that or considered relevant.

Results

227 participants were included in the study. Participants presented a greater knowledge of the general concepts of dementia, while the answers were less accurate in the statements about primary progressive aphasia (Figure 1). Regarding the awareness of SLTs about their role in the care of people with dementia, most of them agreed that SLTs might help people with dementia, but few of them answered to feel confident to assess and treat people with dementia (Figure 2). A significant model was estimated for the level of knowledge (F = 16.12; df = 3 and 223; p<0.001), which explained 16.7% of the variability (adjusted R² = 0.167), while the significant estimated model for the level of awareness (F = 24.6; df = 2 and 224; p<0.001) explained 17.3% of its variability (adjusted R² = 0.173) (Table 1).

Conclusion

The knowledge and awareness about dementia among SLTs could be higher in many aspects. Also, they depend on each other and on the age of the professionals and their time of practice with dementia. The results suggest that if we improve awareness, we can improve knowledge and vice versa, and this must be considered when we plan actions to improve the education of those professionals in the future.
Associations of mid‐life cardiovascular function with late‐life Alzheimer’s disease pathology burden in the Heart SCORE study
Authors: Royse Sarah K. , Saeed Anum , Reese Alexandria C. , Lopresti Brian J. , Snitz Beth E. , Villemagne Victor L , Nadkarni Neelesh K. , Reis Steven E. , Lopez Oscar L. , Cohen Ann D.
Published: December 2023

Background

Cardiovascular (CV) disease is associated with dementia and Alzheimer’s disease (AD), but its relationship with AD pathology remains elusive. We examined whether mid‐life arterial stiffness, endothelial function, and blood pressure are associated with late‐life beta‐amyloid (Aß) and tau burden.

Method

Participants in the Heart Strategies Concentrating on Risk (SCORE) study completed cardiovascular phenotyping between 2003‐2005 (midlife; 45‐59 years) and up to three brain PET sessions between 2018‐2022 (late‐life; >65 years). Mid‐life assessments included augmentation index (AI75; N = 134) as a measure of arterial stiffness, Framingham reactive hyperemia index (fRHI; N = 130) as a measure of endothelial function, and systolic‐blood pressure (SBP; N = 141); late‐life measures were global [11C]Pittsburgh Compound‐B (PiB) standardized uptake value ratio (SUVR) and regional (medial temporal, entorhinal, inferior temporal, amygdala) [18F]flortaucipir (FTP) SUVR as indices of Aß and tau deposition, respectively. In individual linear regression models, we tested associations of mid‐life AI75, RHI, and SBP with late‐life PiB and FTP SUVRs. We used mixed effects models to examine these relationships longitudinally. All models were adjusted for time between CV and PET measurements, baseline age, sex, racialization, apolipoprotein‐E4, BMI, and history of hypertension, high cholesterol, smoking, and diabetes.

Result

In multivariable models, higher mid‐life SBP was associated with lower late‐life FTP SUVR in the medial temporal lobe (β = ‐0.20, p = 0.04) and inferior temporal gyrus (β = ‐0.23, p = 0.01; Table 1); higher mid‐life SBP was also negatively associated with FTP SUVR trajectories in these regions (medial temporal lobe: β = ‐0.0004, p = 0.02; inferior temporal gyrus: β = ‐0.001, p = 0.01; Table 2). We did not detect significant relationships of mid‐life AI75 or RHI with late‐life FTP SUVRs (p≥0.05) or between any mid‐life cardiovascular measures and late‐life PiB SUVR (p≥0.08).

Conclusion

In this dementia‐free, community‐based cohort, higher mid‐life SBP was associated with lower late‐life regional tau deposition and accumulation. Though counterintuitive, our findings are consistent with results of cross‐sectional studies, which suggest that CV risk factors may be followed by an initial brain arteriole response that is protective against tau accumulation through early years of late‐adulthood1,2. Future studies should interrogate the potential mechanisms and age‐modifying effects that may underlie the relationship between mid‐life CV risk factors and late‐life tau deposition.
A systematic review of the impact of amyloid PET scan disclosure on psychological and behavioral outcomes for persons with cognitive impairment and their caregivers
Authors: Couch Elyse , Ashford Miriam T. , Zang Wenhan , Prina Matthew
Published: December 2023

Background

Amyloid‐β PET scans are a potentially useful diagnostic tool, however there is limited understanding of the impact of amyloid disclosure on persons with cognitive impairment and their caregivers. This study aimed to systematically review the impact of amyloid scan disclosure on patient and caregiver psychological and behavioral outcomes.

Method

We searched Medline, Embase and PsychInfo to identify relevant articles. Studies of any design including persons with subjective cognitive impairment, MCI and dementia and their caregivers were included. Outcomes were limited to psychological and behavioral outcomes recorded following disclosure. All articles were screened for eligibility by two reviewers.

Result

We identified 9 papers from 6 studies. Depression, anxiety and test‐related distress were the most common psychological outcomes and recall and knowledge of the scan result were the most common behavioral outcomes. The psychological impact of amyloid disclosure varied depending on the scan recipient’s level of impairment and scan result. Higher test related distress was observed in persons with MCI and elevated amyloid and higher levels of anxiety were found in their caregivers. Most persons with cognitive impairment and their caregivers were able to recall the scan result. However, one study found that gains in knowledge regarding the scan recipients diagnosis following disclosure were comparable to receiving psychoeducation.

Conclusion

Psychological responses to amyloid PET scan disclosure depends on the recipient’s level of impairment and the scan result itself. Persons with MCI and a positive scan result, and their caregivers were at greater risk of distress or anxiety and may benefit from additional post‐diagnostic support. Participants were able to correctly recall their scan results and reported an increase in knowledge regarding their diagnosis. However, psychoeducation may be equally effective at enhancing patient and caregiver knowledge, at a lower cost.
Lifestyle for Brain Health Score, Genetic Risk and Incidence of Dementia
Authors: Neuffer Jeanne , Moreno Elisa , Grand Quentin Le , Leffondre Karen , Foubert‐Samier Alexandra , Berr Claudine , Tzourio Christophe , Helmer Catherine , Debette Stéphanie , Samieri Cécilia
Published: December 2023

Background

Assessing whether modifiable factors are associated with dementia risk regardless of genetic risk for the disease is primordial for precision prevention. So far, studies on gene‐by‐environment interactions (GxE) in dementia have been controversial. We leveraged a large cohort of older persons to investigate the association between numerous modifiable factors, reflected by the lifestyle for brain‐health (LIBRA) score (defined in figure 1), and the incidence of dementia, evaluating effect modification by genetic risk.

Method

We included participants from the Three‐City (3C) study, free of dementia at baseline and followed for up to 17 years. The LIBRA score and a genetic risk score (GRS) based on the latest Alzheimer’s disease GWAS (excluding the apolipoprotein E {APOE} locus) were constructed. Illness‐death models for interval‐censored data were used to assess the relation of LIBRA, GRS and carriership of the e4 allele of the APOE gene (and their interactions) to the incidence of dementia, accounting for potential competing risk by death.

Result

The population included 5170 3C participants aged on average 73.8 years at baseline. Both genetic factors and LIBRA were significantly associated with dementia risk. In multivariable‐adjusted models, each one‐point increase in LIBRA was associated with a 10% higher risk of dementia (95% CI 1.07‐1.13). We found no evidence of GxE interaction (p≥0.2 for two‐order [LIBRA by each genetic variable] and three‐order interaction terms [LIBRA‐by‐GRS‐by‐APOE4]); a higher LIBRA was significantly associated with increased dementia risk in both APOE4 carriers and non‐carriers (figure 1) and in low, medium or high GRS level (figure 2), with similar magnitude of associations in all strata. Although power was limited to examine APOE4 carriers by GRS strata, the trend of association of LIBRA (continuous) to dementia risk was not meaningfully different from what found in other groups (figure 3).

Conclusion

In this large cohort of older persons, increasing number of health and lifestyle risk factors for dementia was associated with higher dementia risk in all levels of genetic risk. These findings suggest prevention programs with targeted lifestyle modifications and health management may be efficient even in those with highest risk for dementia based on their genetic susceptibility.
The prioritization of biomarkers in the diagnostic workup of motor tauopathy
Authors: Agosta Federica
Published: December 2023

Motor tauopathies represent a spectrum of degenerative, poorly levodopa‐responsive parkinsonisms unified by the pathological accumulation of hyperphosphorylated tau protein fragments in the brain. The principal entities, progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD), are rare conditions (<10 per 100,000) and present with non‐amnestic cognitive impairment ‐ mostly involving frontal‐subcortical networks – in around 40% of patients at baseline. Additionally, the phenotypic PSP spectrum expresses with oculomotor dysfunction, falls and bulbar symptoms at varying degrees. On the other hand, CBD tauopathy is the most frequent aetiology underlying the corticobasal syndrome (CBS) that is a multifaceted disorder characterized by a markedly asymmetric Parkinsonism with apraxia and neocortical deficits. Paralleling the clinical symptoms, the distribution of functional and metabolic impairment specifically involves different brain regions in PSP and CBD. Hence, metabolism assessment by FDG‐positron emission tomography (PET) allows for accurate distinction of motor tauopathies from other parkinsonisms or one with another (AUC 0.80 and 0.92‐0.97, respectively). In this context, the European Intersociety Consensus Diagnostic Task Force recommends the use of FDG‐PET as the first‐level diagnostic biomarker to achieve early and accurate differential diagnosis of motor tauopathies. Afterwards, the assessment of CSF biomarkers of Alzheimer’s disease (AD) is advised to identify that minority of cases of CBS underpinned by an AD aetiology (10‐20%). With this sequence of biomarkers, the diagnostic workflow aims to an early identification of motor tauopathies and advocates in‐depth etiological investigation of CBS where access to AD‐specific drugs, when available, should be considered in a non‐negligible proportion of patients.
Investing in hope in dementia care practice: What do we need to consider?
Authors: Dasgupta Jayashree
Published: December 2023

Although most countries have ratified the United Nations Convention on the Rights of Persons with Disabilities, only a quarter have a national dementia plan which outlines a strategy to support People Living with Dementia (PLWD) and their families. Majority of PLWD reside in low‐and‐middle‐income countries where the numbers are expected to increase disproportionately over the coming decades. Healthcare systems in these regions are already overburdened, and resources for dementia are often inaccessible or unaffordable for most of the population. Factors like low public awareness, misconceptions about early symptoms being a natural part of aging and societal stigma also contribute to delays in diagnosis and hesitancy in help seeking.

However, a recent Alzheimer’s Disease International report highlights that challenges in dementia care are not limited to low resource settings, and up to an astounding 85% of PLWD worldwide may not receive post‐diagnostic support. Research using paradigms like patient public involvement have highlighted how PLWD and their families often feel devalued as dementia has ‘no‐cure,’ drawing attention to experiences which have made them feel unsupported during interactions with health systems. Globally, the majority of dementia care is actually provided at home and by family members until a stage where institutional care is possible in settings where these resources exist. This highlights the importance of interventions which can support at‐home care, particularly since home care has also been shown to be a more cost effective model when compared to institutional care. Along with building public awareness and making society more dementia inclusive, training of healthcare professionals is also required for more hopeful communication. Using the value of hope can extend support to PWLD and their families by encouraging meaningful engagement within the family context and encouraging PLWD to continue participating in socially enriching activities.

Whilst endeavors to find a cure for dementia must continue, greater investment is required in interventions that instill realistic hope in PLWD and empower their families to provide care within the community. These interventions play a critical role in reducing the negative impact that social withdrawal and social isolation can have on the well‐being of PWLD and their families.
Alzheimer’s Disease as a potential diabetes type III: Pilot Study of comorbidities related to AD
Authors: González Andrea , Camila Calfio , Maccioni Ricardo Benjamin , Farías Gonzalo , Fuentes Patricio
Published: December 2023

Background

Alzheimer’s disease (AD) is the most prevalent cause of dementia in the elderly population. It is a multifactorial disease in which metabolic dysregulation and glucose metabolism impairment plays a major role in the etiopathogenesis. In this research, we evaluate the comorbidities in a clinical trial for the novel biomarker Alz‐tau®, based on platelet tau, in cognitive healthy controls, mild‐cognitive impairment (MCI) and AD patients, in particular TII diabetes. Alterations in this biomarker appear to indicate high risk of developing AD, as demonstrated in previous clinical trials.

Methods

From a cohort of 111 subjects, neuropsychology tests were performed to assign the respective group (control, MCI or AD). In addition, a health questionnaire to evaluate comorbidities. For the Alz‐tau® biomarker, platelets were obtained from plasma by centrifugation, lysed to obtain platelet protein extracts (containing tau) and further processed for a western blot analysis. The immuno‐ detection was performed with our novel monoclonal antibody tau51, which detects two variants of tau protein: a high molecular weight variant (HMW) and a low molecular weight variant (LMW). The results obtained were subjected to a densitometric analysis with ImageJ and the algorithm HWM/LMW was obtained.

Result

From 111 patients, 17 presented diabetes type 2 as a comorbidity (15,3%). Out of them, 11 were cognitive healthy subjects (64.7%), 4 EA patients (23.5%) and 2 MCI (11.8%). Out of the control patients, 6 have the Alz‐tau® biomarker altered (54.5%), which was similar to what was observed in the EA patients (2 patients, 50%) and the MCI (1 patient, 50%). Of the 17 patients with diabetes, 53% presented an altered Alz‐tau® biomarker (cut‐off 1.2 algorithm), which is considered a risk factor for AD. It should be considered that the area under the curve (AUC) of this novel biomarker Alz‐tau® is 0.69, appropriate for a novel technique.

Conclusion

Here, we discovered that this early detection biomarker is correlated with the high‐risk factor of having AD in the future, since non‐symptomatic subjects exhibited an altered biomarker. Moreover, more than 50% of the TII diabetic positive cognitive healthy controls, exhibit an altered biomarker, sustaining our hypothesis of the correlation between glucose‐metabolism impairment, AD and oligomeric tau.
Associations between neuropsychiatric symptoms and ADRD serum biomarkers in Mexican American and non‐Hispanic white adults with mild cognitive impairment
Authors: Garbarino Valentina R. , Kautz Tiffany F , Trevino Hector , Vela Gabriel A. , Philip Vinu , LaRoche Ashley , Saklad Amy R. , Shipp Eric L. , Satizabal Claudia L. , Maestre Gladys E. , Royall Donald R. , Teixeira Antonio L , Seshadri Sudha , Gonzales Mitzi M.
Published: December 2023

Background

Mild cognitive impairment (MCI) is a heterogenous diagnostic category with trajectories ranging from reversion to unimpaired cognition to progression to dementia. Neuropsychiatric symptoms such as depression and irritability are common and influence quality of life of patients and caregivers. The role of neuropsychiatric symptoms on disease biology, presentation, and course remains poorly understood. The goal of this study was to evaluate the associations between neuropsychiatric symptoms and serum ADRD biomarkers in Mexican American and non‐Hispanic white participants diagnosed with MCI.

Method

Participants from the Texas Alzheimer’s Research and Care Consortium underwent a blood draw and clinical evaluation, including psychopathological and cognitive assessments. Diagnoses of MCI were adjudicated in consensus reviews. The presence and severity of neuropsychiatric symptoms were assessed by informant report using the Neuropsychiatric Inventory (NPI). Serum levels of total tau, neurofilament light (NfL), and glial fibrillary acidic protein (GFAP) were assessed using Simoa HD‐X Analyzer. Associations between NPI total score and individual items with serum biomarker levels were assessed using linear regression adjusted for age and sex.

Result

A total of 425 participants (mean age: 71 ± 9 years, 62% female, 74% Mexican American) had a diagnosis of MCI and serum ADRD biomarkers (Table 1). Total NPI score was not associated with total tau (ß = 0.002, p = 0.609), NfL (ß = 0.001, p = 0.658), or GFAP (ß = 0.001, p = 0.777). However, endorsement of appetite changes was associated with higher NfL (ß = 0.077, p = 0.006) and GFAP (ß = 0.088, p = 0.002) levels. Stratified analyses indicated associations of appetite changes with serum NfL (ß = 0.108, p = 0.002) and GFAP (ß = 0.095, p = 0.003) in Mexican Americans, but not in non‐Hispanic whites (NfL: ß = 0.022, p = 0.633, GFAP: ß = 0.102, p = 0.066).There were no other significant associations between individual items on the NPI with serum biomarkers (p>0.05, Bonferroni adjustment p±0.003).

Conclusion

Within Mexican American adults with MCI, changes in appetite were associated with higher serum NFL and GFAP levels. As elevations in circulating NfL and GFAP levels are associated with ADRD pathology and accelerated disease progression, appetite changes, a non‐invasive and easily discernible behavioral phenotype, may predict higher likelihood of worsening cognitive course. Future longitudinal studies will be necessary to confirm predictive utility of appetite changes for disease progression.
Cardiovascular health and the risk of Alzheimer’s dementia in a biracial population‐based study
Authors: Dhana Anisa , Decarli Charles , Dhana Klodian , Desai Pankaja , Holland Thomas Monroe , Evans Denis A , Rajan Kumar B
Published: December 2023

Background

The cardiovascular health (CVH) index, created by the American Heart Association (AHA) to assess and monitor the risk of cardiovascular disease, has been related to dementia risk. However, evidence is limited, and most studies originate from populations comprised of primarily white participants. We examined the association of the CVH index with the risk of incident Alzheimer’s dementia in a biracial population‐based study.

Method

Our study consisted of 1,702 non‐Hispanic Black and white participants of the Chicago Health and Aging Project, a population‐based cohort. CVH was based on seven risk factors: diet, physical activity, body mass index, smoking, dyslipidemia, hypertension, and diabetes. Following AHA recommendations, we assigned points of 0, 1, or 2 based on adherence to each factor, with an overall score ranging from 0 to 14 – a higher score indicates better cardiovascular health. Clinical diagnosis of Alzheimer’s dementia was based on the NINCDS‐ADRDA criteria. Cox proportional hazard models were used to compute the hazard ratio and 95% confidence interval. Models were adjusted for age, sex, race, education, ApoE4 allele, cognitive activities, and cardiovascular disease.

Result

The average baseline age of the study population was 73 years and comprised 62% women and 53% black participants. During 14,226 person‐years of follow‐up, there were 351 incident Alzheimer’s dementia. In a multivariable‐adjusted model, CVH was linearly associated with a lower risk of incident Alzheimer’s dementia. For each additional CVH score, the HR was lower by 0.84 (95% CI 0.76 ‐ 0.94). Compared to individuals with inadequate CVH (score: 0‐6), the HRs (95% CIs) of incident Alzheimer’s dementia in participants with average (7‐9) and optimal CVH (10‐14) was 0.44 (95%CI 0.28 ‐ 0.69) and 0.37 (95%CI 0.21 ‐ 0.65), respectively. We found similar associations between CVH score, per one additional score, and risk of Alzheimer’s dementia in Black (HR 0.84, 95%CI 0.74 ‐ 0.95) and white (HR 0.83, 95%CI 0.7 ‐ 0.98) individuals.

Conclusion

In a biracial cohort of older adults, the cardiovascular health burden was higher among Black individuals. However, promoting a better CVH in the general population may help lower dementia risk in Black and white older adults.
Bile acids inform about a sex‐specific resilience phenotype against Alzheimer’s disease implicating a role for the gut microbiome and the exposome
Authors: Kristal Bruce , Sniatynski Matthew J , MahmoudianDehkordi Siamak , Kastenmuller Gabi , Nho Kwangsik , Arnold Matthias , Borkowski Kamil , Jia Wei , Kaddurah‐Daouk Rima F. ,   for the Alzheimer’s Disease Neuroimaging Initiative and the Alzheimer Disease Metabolomics Consortium
Published: December 2023

Background

Bile acids (BAs) are byproducts of cholesterol metabolism involved in lipid absorption, signaling and energy homeostasis. BA synthesis and metabolism, regulated by human and gut bacteria co‐metabolism, are influenced by the exposome. Our prior studies at a population level illustrated a correlation between altered BA profiles and cognitive and brain imaging changes in MCI and AD. More information is needed to determine if these are causal in sub‐populations, and if their modulation can impact disease course.

Method

Absolute serum levels of 33 primary, secondary, and conjugated BAs were measured on a targeted mass spectrometry‐based platform in 1117 fasted subjects (502 women) drawn from the AD Neuroimaging Initiative (ADNI‐1/GO‐2; AD (N = 180), MCI (N = 607) and CN (N = 330). Analysis centered on adjusted and/or stratified linear models with an interpretative focus emphasizing individual‐level granularity.

Result

In stratified analysis, men but not women showed strong association between levels and ratios of BAs and diagnosis. Inclusion of two (informative) bile acids and their ratios increases AUCs for AD vs control from ∼0.72 to ∼0.82‐0.85 (p<0.001) in APOEε4 genotype‐stratified analyses. Some specific associations were APOEε4 genotype‐dependent; some specific microbiome‐mediated ratios in BAs were associated with AD diagnosis in APOEε4− only and secondary bile acid synthesis was associated with AD diagnosis in APOEε4+ only. Other associations were APOEε4 genotype‐independent ‐ higher ratios of primary BAs to total BAs were associated with reduced AD prevalence. Levels of cholic acid below sharp thresholds 25 or 50 nM (in APOEε4+ and APOEε4−, respectively) at 24 months were associated with 5‐ to 7‐fold increased relative risk of MCI to AD progression, establishing a potential biomarker for a resilience phenotype.

Conclusion

Leveraging the combined power of ADNI and metabolomics with a focus on granularity and complementarity revealed previously unobserved relationships between BAs, sex, APOEε4 genotype, and AD etiology. These data identify a resilience class and provide a roadmap for stratifying subjects and targeting therapies in a precision medicine approach while gaining deeper insights linking peripheral‐central metabolism influenced by the exposome. BAs are a potential modifiable factor that mediates causal linkages between endogenous and exogenous factors in the susceptibility or resilience against AD.
Effect of calcineurin/NFAT inhibitors on biomarkers and cognition in a canine model of Alzheimer disease
Authors: Sordo Lorena , Ubele Margo F. , Boaz Kathy , Mefford Jennifer L. , Jones Erin D. , McCarty Katie , Smiley Jeffrey , Bailey Stasia A. Bembenek , Perpich Jessica A. , Meacham Beverly , Powell David K , Bresch Fred , Phelan Michael J. , Noche Jessica A. , Stark Craig E.L. , Puskas Laszlo G. , Norris Christopher M. , Head Elizabeth
Published: December 2023

Background

Calcineurin/NFAT signaling increases in Alzheimer disease (AD) and is associated with neurodegeneration, neuroinflammation, amyloid‐β (Aβ) production, and cognitive decline. Hence, calcineurin/NFAT inhibitors (e.g., tacrolimus and Q134R) are attractive potential therapeutics to improve/prevent AD‐associated cognitive impairments. In AD mouse models, both tacrolimus and Q134R improved cognition and ameliorated neuroinflammation and synapse dysfunction.

We hypothesized that 1) chronic low‐dose administration of tacrolimus and Q134R will delay cognitive decline over time in middle‐aged beagles, a model of human brain aging and AD; and 2) canine plasma and CSF biomarkers will be improved with treatment.

Methods

Cognitive outcomes were evaluated in 37 middle‐aged beagles at baseline and during follow‐up (years 1‐3) by assessing spatial learning [landmark‐discrimination (1, 2 and 4cm)], visual discrimination learning, reversal learning (executive function), and spatial working memory (20‐, 70‐, and 110‐second delays). Dogs were ranked for cognition at baseline and randomized into treatment groups: Control (n = 12; placebo), Q134R (n = 12; 8mg/day), and tacrolimus (n = 13; 0.075mg/kg/day). Concentrations of Aβ40, Aβ42, and NfL in plasma and CSF were measured using the Quanterix SIMOA.

Results

Accuracy at all landmark‐discrimination distances declined significantly among controls 20% faster than tacrolimus, and 15% faster than Q134R dogs, at the most difficult distance of 4cm. Accuracy on spatial working memory task declined 21% faster/year among controls than tacrolimus (years 2&3); and 18% faster than Q134R dogs (year 1). Performance on visual discrimination and reversal tasks declined with age but there was no treatment effect.

Biomarkers in plasma tended to increase over time with no significant differences between treatment groups. In CSF, relative decreases in Aβ40 and Aβ42 in tacrolimus (2.9 and 2, respectively) and Q134R (5.4 and 3.7, respectively) were less than in control dogs. Finally, relative increases of NfL in tacrolimus and Q134R were less than in control dogs (2.3 and 3.7, respectively).

Conclusion

Both tacrolimus and Q134R showed beneficial preventative effects on age‐related decline in spatial functions and memory but not on associative learning nor executive function in a canine model of AD. Finally, only CSF biomarkers tended to improve relative to treatment and are suggestive of less Aβ deposition in brain and higher clearance.
Comparison of Expert Reads vs. Local Clinical Reads of Amyloid PET Scans in IDEAS
Authors: Windon Charles , Zeltzer Ehud , Hanna Lucy , Carrillo Maria C. , Iaccarino Leonardo , La Joie Renaud , March Andrew , Mejía Jhony Alejadro , Mundada Nidhi , Arora Anupa , Bullich Santiago , Sherwin Paul , Siegel Barry A , Gatsonis Constantine , Rabinovici Gil D.
Published: December 2023

Background

Amyloid‐directed therapies will increase the clinical use of amyloid PET. IDEAS captured >17,000 clinical scan interpretations from local radiologists and nuclear medicine physicians. This study aimed to establish accuracy of these interpretations by comparison to expert readers across identical scans.

Method

Randomly selected amyloid PET/CT scans performed using one of three FDA‐approved agents [18F‐Florbetaben (FBB), 18F‐Florbetapir (FBP), 18F‐Flutemetamol (FMM)] and previously interpreted by local readers from the Imaging Dementia ‐ Evidence for Amyloid Scanning (IDEAS) study were assigned to vendor‐selected panels of 3 expert readers for interpretation; 500 scans per agent and 1 panel per agent. Scans were stratified to match frequencies observed in the overall study by 1) participant age; 2) MCI vs dementia; 3) positive/negative interpretation; and 4) type of PET facility. Respective vendors performed quality control on attenuation‐corrected PET/CT images.

Visual interpretations (positive or negative for Aβ cortical deposition) were performed according to agent‐specific validated interpretation criteria. Expert panel readers were blinded to clinical and demographic data. Cohen’s kappa statistic with two‐sided 95% confidence interval estimates examined agreement between local reader and majority expert panel visual interpretation.

Result

Expert panel readers’ visual interpretations totaled 4489. Median age for scanned participants was 75 (range 65‐96), 51.4% were female and 60.5% had MCI. Local readers interpreted 60.9% of scans positive and 39.1% negative (Table 1).

Across all radiotracers, agreement between majority expert read and local readers was excellent (k coefficient 0.76; 95% CI 0.73 – 0.80, p<.0001) with 86.6% (791/913) agreement for positive scans and 90.9% (532/585) agreement for negative scans (Figure 1). Agreement by individual radiopharmaceuticals was good to excellent: k coefficient 0.78 (95% CI 0.72 – 0.83, p<.001) for FBB, k coefficient 0.72 (95% CI 0.66 – 0.78, p<.001) for FBP, and k coefficient 0.78 (95% CI 0.73 – 0.84) for FMM (Figure 1). Agreement levels between local readers and individual experts varied from good to excellent (Figure 2).

Conclusion

We found good to excellent agreement between local readers and majority assessment of three‐member expert panels for all combined scans and scans by individual agents. Visual interpretation of Aβ PET can be performed in a clinical setting with high reliability.
Detecting Unrecognized Cognitive Impairment and Dementias Using Clinical Health Systems Bioinformatics and Electronic Health Records from a National Population
Authors: Khachaturian Ara S , Beeri Michal S , Li Gang , Ravona‐Springer Ramit
Published: December 2023

Globally there are upwards of 35 million people living with dementia and other cognitive impairments, with total annual costs of approximately US$ 1 trillion by 2025. Yet, this estimate does not consider the impact due to the lack of specialized personnel and health care infrastructure to provide timely access for dementia diagnosis, treatment, and care. These factors are complicated by the lack of valid and equitable means for detecting signs of impending cognitive impairment or dementia. Also, these same symptoms are not easily recognized by many primary care physicians who do not make referrals to specialists. These negative dynamics on access to quality brain healthcare may impact under‐represented, underserved, and vulnerable populations at disproportionately greater levels. Although more AD/ADRD interventions will be approved, this will not assure equal market access.

There is an immediate need to provide accurate, affordable, appropriate, and equitable clinical care profiles. One approach is to develop digital tools to access electronic health record (EHR) data. Yet, generic EHR data on dementia status are limited to people who have received a formal diagnosis. Worse, in the community setting, most people enduring cognitive impairment or living with dementia will not receive generally a timely diagnosis to support useful clinical care decision‐making.

Fortunately, several international health data reservoirs exist that integrate routine EHR data with dementia research‐driven cohort studies with affiliated biobanks, including Sheba Medical Center (SMC) with its ongoing ‐omics and neuroimaging research. As Israel has socialized medicine, and all residents have healthcare provided through the Israeli National Health Insurance law, the Sheba data offers a unique opportunity to develop
valid
,
reliable
, and
transportable
EHR derived assessment tools for cognitive impairment and dementia.

The project in collaboration with SMC and Maccabi Healthcare Service—one of four national Israeli medical service providers—demonstrates the advanced capabilities to use electronic medical records linked with a national network of primary care physicians, and the ability to conduct deep‐source data mining in the absence of a clinical diagnosis of cognitive impairment or dementia. The project reports the performance characteristics (i.e., sensitivity and specificity) of assessment tools to detect cognitive impairment or dementia.
Inhibition of EV biogenesis reduces tau propagation in Alzheimer’s Disease mouse models
Authors: Huang Meixiang , Tallon Carolyn , Bell Benjamin J , Kapogiannis Dimitrios , Haughey Norman J , Rais Rana , Slusher Barbara S
Published: December 2023

Background

Mounting evidence correlates the propagation of hyperphosphorylated tau (pTau) along synaptically connected networks in the brain with progressive cognitive decline in Alzheimer’s Disease (AD). Recent findings have highlighted extracellular vesicle (EV)s in enabling transcellular transmission of pathological tau and identified the partial inhibition of EV biogenesis via small‐molecule inhibitors of nSMase2 as a potential therapeutic avenue. However, there are no suitable compounds for clinical development so far.

Method

Through high‐throughput screening, we identified PDDC, a highly selective and potent nSMase2 inhibitor with excellent brain penetration and oral bioavailability. To evaluate PDDC’s effect on tau propagation in vivo, we chronically administered PDDC‐containing chow to PS19 transgenic mice and measured brain ceramides, nSMase2 activity, tau levels, glial activation, hippocampal neuronal cell layer thickness, and mossy fiber synaptophysin staining. In addition, neuronally‐derived EVs from plasma were isolated and characterized. To directly monitor the effect of PDDC on tau propagation, we developed a murine model where an AAV encoding for P301L/S320F double mutant human tau was stereotaxically‐injected unilaterally into the hippocampus and transfer to the contralateral dentate gyrus (DG) was monitored ± PDDC treatment.

Result

PS19 mice exhibited robust elevation of multiple ceramide species and nSMase2 enzymatic activity in the brain, both of which were normalized by PDDC treatment. PS19 mice treated with PDDC had significantly reduced hippocampal total tau and Thr181 pTau, reduced glial activation, protected synapses, and improved pyramidal and granule cell layer thickness. Plasma NEVs of treated mice were fewer in number and had lower p181‐Tau levels than the untreated group; FCA confirmed the decrease of NEVs carrying p262‐Tau at the single EV level. Similarly, the AAV‐hTau‐seeded mice treated with PDDC had reduced tau staining intensity in the contralateral DG.

Conclusion

Data in two AD models using PDDC provides strong preclinical support for using nSMase2 inhibition as a therapeutic strategy to slow tau propagation in AD.
Transforming genetic data for a convolutional neural network using genotype posterior probability: Algorithm for handling incorrectly imputed multiallelic variants for multiple genetic datasets
Authors: Bae Jinhyeong , Nudelman Kelly N. H. , Apostolova Liana G.
Published: December 2023

Background

Alzheimer’s disease (AD) genetic research utilizing genome‐wide association study data often requires imputation. Genotypes are imputed probabilistically by the Hidden Markov Model and converted into one‐dimensional categorical variables for a convolutional neural network (CNN). Such a conversion, however, contains uncertainty, which can mislead CNN in determining AD‐risk factors when added up. Also, the imputed genotypes are quality‐controlled (QCed) by using PLINK, a widely used whole genome data analysis toolset. However, the QC process of PLINK cannot exclude all incorrectly imputed multiallelic genetic variants (IMGs). To address such issues, we proposed a post‐quality control algorithm to transform the genetic dataset into three‐dimensional one‐hot encoding weighted by genotype posterior probabilities.

Method

We collected 1876, 173, and 384 participants from the Alzheimer’s Disease Neuroimaging Initiative, Imaging and Genetic Biomarkers for AD, and Longitudinal Early‐Onset Alzheimer’s Disease Study, respectively. Genotypes were imputed through Markov Chain Haplotyping and QCed using PLINK (Fig. 1). Then the data was transformed into 5×2xN three‐dimensional one‐hot encoding; 5 indicates the number of nucleotides (4) including insertion (1), 2 indicates genotype copy, and N indicates the number of all available markers. One‐hot encoding data was weighted by genotype posterior probabilities obtained by Genome Analysis Toolkit. The weighting algorithm also re‐imputes IMGs based on their genotype posterior probabilities (Fig. 2).

Result

All genotypes were successfully transformed into one‐hot encodings composed of genotype posterior probabilities. Each participant had about 6,980 IMGs with a standard deviation of 822 (Fig. 3). The percentage of IMGs for each chromosome was about 0.274% with a standard deviation of 0.234 (Table 1). All IMGs were corrected based on genotype posterior probabilities and transformed into one‐hot encodings (Fig. 4).

Conclusion

The QC process is essential for minimizing possible bias and errors that would be imposed on computational models. Transforming genetic data into one‐hot encodings weighted by genotype posterior probability can present genotypes with their imputation quality. Furthermore, it can fully utilize CNN’s capacity by allowing it to determine various features.
Speech and Language characteristics of Kannada and Hindi speaking individuals with Primary Progressive Aphasia
Authors: J Darshini K. , Kumar S Sandeep , Arshad Faheem , P Vandana V. , Philip Mariamma , Paplikar Avanthi , Ramakrishnan Subasree , Alladi Suvarna
Published: December 2023

Background

Linguistic typology plays an important role in identifying clinical markers of language deficits that characterise Primary Progressive Aphasia (PPA). The current International criteria to diagnose PPA were primarily developed for English. Typological characteristics of Indian languages however differ from English in their morpho‐syntactic complexity, a flexible‐word order, richer morphology, ‘pro‐drop’ languages with absence of prepositions and transparent orthography. We aimed to develop a novel test in Kannada (Dravidian) and Hindi (Indo‐Aryan) to identify language deficits in Indian language speakers with PPA.

Method

The speech‐language test systematically developed for Kannada and Hindi consisted of unique tasks for syntax, semantics, phonology, motor speech and working memory. Participants underwent assessment of cognition and language with Addenbrooke’s Cognitive Examination‐III, Western Aphasia Battery‐Revised and Indian Semantic Memory Battery (ISMB) in addition to the novel test.

Results

Of 26 patients with PPA (Kannada 13, Hindi 13), 15 had non‐fluent variant (nfvPPA), 8 semantic variant (svPPA) and 3 logopenic variant (lvPPA). On the novel test, PPA had higher phonological, motor speech, syntactic and semantic errors compared to 60 controls. nfvPPA had higher phonological, motor speech and syntactic errors and lesser semantic errors compared to svPPA. Semantic and working memory errors discriminated between nfvPPA and svPPA. On qualitative analysis, 5 patients of nfvPPA had significant apraxia of speech. The other 10 had a unique syntactic profile: agrammatism was not prominent in their spontaneous speech and picture description. Sentences were relatively fluent, complete and sufficient for functional communication. The consistent abnormality observed was a reduction in overall length of utterance. Agrammatisms such as inappropriate use of case markers were restricted to specific tests of syntax. svPPA patients had increased verbal output and prominent paragrammatisms. Testing for surface dyslexia was not relevant due to the orthographic transparency of Indian languages.

Conclusion

The novel language test for evaluation of Indian speakers of PPA revealed unique findings for diagnosis of nfvPPA. Reduction in length of utterances and lack of prominent agrammatism was a consistent clinical marker and owes itself to morpho‐syntactic complexity of Indian languages. Our study emphasises the need to account for linguistic typology in diagnosis of PPA.