bluuebunny/crossref_metadata_2025_split huggingface dataset:
Serum metabolites associate with biofluid neurofilament light chain in Alzheimer’s disease
Authors: Kim Jun Pyo , Nho Kwangsik , Saykin Andrew J. 
Published: December 2022

AbstractBackgroundNeurodegeneration is one of the main components of A/T/N (amyloid/ tau/ neurodegeneration) classification. Recently, neurofilament light chain (NFL), a neuronal protein that is expressed in myelinated axons, has been increasingly recognized as a biomarker of neurodegeneration. In this study, we performed large‐scale association analysis of serum metabolites with NFL in Alzheimer’s disease.MethodWe performed cross‐sectional and longitudinal association analysis of serum metabolome with plasma and CSF NFL in Alzheimer’s disease (AD), after adjusting for multiple testing (N=1,317 for 140 metabolites). Subjects who had both NFL and metabolomics panel data were included. Metabolites were measured using a targeted metabolomics approach using the AbsoluteIDQ‐p180 kit.ResultWe identified 70 metabolites including acylcarnitines sphingomyelins, biogenic amines, amino acids, and glycerophospholipids as significantly associated with baseline plasma NFL, where we identified sex‐specific and APOE ε4‐specific metabolites. Of those, eight metabolites (C16:1, C18:1, SM(OH) C14:1, SM(OH) C16:1, SM C20:2, PC.aa.C28.1, PC.ae.C30.2, and PC.ae. C32.2) were also associated with baseline cerebrospinal fluid NFL and 10 metabolites (C9, C10:2, citrulline, creatinine, SDMA, PC.ae.C34.2, PC.ae.C36.2, PC.ae. C36.3, SM C20:2, and SM C16:0) were associated with change rates of plasma NFL in AD. Metabolites with significant associations were related to biological functions including amyloid precursor protein processing, neuroinflammation, nitric oxide production, and renal function. There were two significant interactions between sex and two medium‐chain acylcarnitine metabolites (C8 and C10) on plasma NFL levels.ConclusionOur present study provides insight into the association of serum‐based circulating metabolites with biofluid biomarker evidence of neurodegeneration, which is closely related to overt clinical symptoms in AD. Metabolites found in our study are related to various biological functions or associated with known risk factors of AD.
Aβ oligomer elimination decreases tau oligomer concentration in CSF and enhances cognition in cognitively impaired aged Beagle dogs ‐ a model of sporadic Alzheimer’s disease
Authors: Kutzsche Janine , Schemmert Sarah , Bujnicki Tuyen , Willuweit Antje , Willbold Dieter 
Published: December 2022

AbstractBackgroundDisease‐modifying therapies to treat Alzheimer’s disease (AD) are of fundamental interest for aging humans, societies, and health care systems. More and more data suggest that the toxic protein assemblies of Aβ and tau behave prion like. The drug candidate RD2 (alias PRI‐002) has been developed to directly disassemble and disrupt toxic Aβ oligomer prions. The anti‐prionic compound is BBB penetrable and has demonstrated target engagement in vitro, ex vivo and in vivo. Treatment with RD2 has yielded improved cognition and deceleration of neurodegeneration in three different transgenic mouse models in three different laboratories. Cognitively impaired aged Beagle dogs are one of the very few non‐transgenic AD animal models that may simulate the situation of spontaneous late onset AD, i.e. sporadic AD, which is the most common form of AD in humans. The aim of this study was to investigate the efficacy of RD2 to enhance short‐term memory and cognition in cognitively impaired aged Beagle dogs ‐ a non‐transgenic model of sporadic AD.Method36 cognitively impaired aged Beagle dogs have been randomized for five months in three cohorts, placebo, low dose (3 mg/kg RD2 once daily) and high dose (30 mg/kg RD2 once daily). Treatment was done orally and for three months, followed by two months without treatment. Cognitive testing, blood and CSF drawing was done at baseline and then monthly.ResultWe demonstrate that once daily oral treatment with RD2 significantly reduced cognitive deficits in cognitively impaired aged Beagle dogs even beyond the end of the treatment. This and treatment dependent CSF tau oligomer decrease clearly suggest a neuroprotective and truly disease‐modifying effect of RD2 treatment.ConclusionDirect elimination of Aβ oligomers by disassembling them into monomers is an interesting therapeutic strategy for AD disease modification including beneficial symptomatic effects.
The impact of individual vascular risk factors on longitudinal neurodegeneration in cognitively unimpaired individuals
Authors: Da Ros Lucas Uglione , Ferrari‐Souza João Pedro , Hauschild Lucas Augusto , Brum Wagner Scheeren , Bellaver Bruna , Leffa Douglas Teixeira , Ferreira Pamela C.L. , Bieger Andrei , De Bastiani Marco Antônio , Pascoal Tharick A , Zimmer Eduardo R. 
Published: December 2022

AbstractBackgroundVascular risk factors (VRFs) have an important role in the etiology and progression of Alzheimer´s Disease (AD). We recently described that VRF burden interacts with AD pathophysiology increasing plasma neurofilament light (NfL) levels, a biomarker of neuroaxonal damage. However, whether individual VRFs interact with AD pathophysiology to promote longitudinal neurodegeneration remains to be elucidated. Here, we aimed to assess the impact of individual VRFs in the longitudinal trajectory of plasma NfL in cognitively unimpaired (CU) individuals.MethodWe assessed 269 CU individuals from the ADNI cohort with available baseline medical data and cerebrospinal fluid (CSF) Elecsys biomarkers (Aβ1‐42 and p‐tau181), as well as longitudinal measures of plasma NfL. Individuals with both Aβ1‐42 and p‐tau181 positivity were defined as having preclinical AD (A+T+). The VRFs assessed in our analysis were history of cardiovascular disease (CAD), hypertension (HTN), diabetes mellitus (DM), hyperlipidemia (HLP), stroke or transient ischemic attack, smoking, atrial fibrillation, and left ventricular hypertrophy. Only those VRFs with at least 5% prevalence in the studied population were included in our analysis.ResultThe following VRFs were included in the final analysis based on prevalence: HTN, CAD, DM, and HLP. Linear mixed‐effects (LME) models revealed that no individual VRF significantly interacted with AD pathophysiology to increase longitudinal values of plasma NfL (HTN X AD pathophysiology X time, β =0.97 p=0.63; CAD X AD pathophysiology X time, β = 2.68, p= 0.36; HLP X AD pathophysiology X time, β= ‐2.1, p=0.3). DM was not present among individuals positive for AD pathophysiology. On the other hand, VRF burden significatively interacted with AD to increase NfL levels (VRF burden x AD pathology x time; β = 5.08, P = 0.016).ConclusionWe observed that no individual VRF interacted with AD pathophysiology to promote longitudinal neurodegeneration in CU individuals. Our findings suggest that the cumulative number of VRFs, rather than any VRF individually, impacts on neurodegeneration in the context of AD.
6‐month global cognitive function in Mexican older adults recovered of COVID‐19: a prospective cohort study using telemedicine
Authors: Mimenza Alberto , Palma Abdías Ambrosio , Funes José Alberto Avila , Aguilar‐Navarro Sara Gloria 
Published: December 2022

AbstractBackgroundSARS‐CoV2 infection affects the central nervous system, one of the manifestations is the cognitive function impairment (1,2). It is currently unknown to what degree and which cognitive domains are involved in this disease (3,4). This study aims to know the effect on global cognitive function in older adults recovered of COVID‐19MethodA prospective cohort study recruited adults aged over 60 years old. As dependent variable, the Global Cognitive Function (GCF) was assessed using the Mini‐Mental State Examination (MMSE) test via telemedicine in patients recovered of moderate and severe COVID‐19 6 months after hospital discharge. Patients with uncontrolled neurological, metabolic, and psychiatric diseases were excluded. Multivariate models were constructed, as well as Cox regression model to assess the association between GCF impaired with history of moderate and severe COVID‐19, adjusted for age, sex, and educationResultWe studied 607 patients, of which 108 survived the SARS‐CoV‐2 infection. One patient dies during the follow‐up. 107 patients were analyzed, median age was 70 years (SD 7.3), 54% were women, with 9.2 (SD 3.8) years of education, the mean of MMSE was 26.2 (SD 3.2). Regarding the severity of the COVID‐19, 74% presented a moderate infection and 26% was severe. 12% had GCF impaired, of which 14.3% were severe COVID‐19 and 11.4% with moderate infection. Cognitive domains most affected were episodic memory (43%) and constructional praxis (86%) in all patients, without statistic difference for infection severity. Factors associated with GCF impaired was the history of depression (HR 6.8; 95%CI: 1.4‐31.5, p = 0.01), higher education (HR ‐0.20; 95%CI: 0.68‐0.95, p = 0.01), and C‐RP level (HR 1.07; 95%CI: 1.01‐1.13, p = 0.01)ConclusionGlobal cognitive function in older adults recovered of severe COVID‐19 was impaired 6 months after hospital discharge. Cognitive domains of episodic memory and constructive praxis were the most altered. Future studies are needed in this geriatric population to confirm this long‐term outcome, especially in those patients with risk factors such as history of depression, lower education, and severe illness
Utility of the Repeatable Batter for the Assessment of Neuropsychological Status (RBANS) as Endpoint in AD Trials
Authors: Negash Selam , Randolph Christopher 
Published: December 2022

AbstractBackgroundThe Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) is a brief neurocognitive battery that is commonly used in clinical settings to detect and track early symptomatic Alzheimer’s disease (AD) and other neurodegenerative conditions that involve neurocognitive compromise. The RBANS has also been used as an endpoint in trials involving presymptomatic and early symptomatic AD. As the RBANS generates scores that are scaled to population norms, it theoretically may be subject to floor effects in more impaired populations. The present study examined screening RBANS data from several multinational clinical trials of presymptomatic and early symptomatic AD as a function of CDR sum of box (CDR‐SB) stages.MethodAggregated data from six multinational clinical trials of presymptomatic and early symptomatic AD were analyzed. There were 19,126 subjects with screening CDR‐SB scores ranging from 0–7. RBANS total scale index score was evaluated as function CDR‐SB scores at each stage. Descriptive statistics, including skewness and kurtosis, were also summarized. Frequency distributions of RBANS total were plotted at each CDR‐SB stage.ResultThe overall mean for the RBANS total scale index score was 84.3 (SD = 17.3). The distributions of RBANS total scale index score remained reasonably normal across the range of CDR‐SB, but the largest magnitude of change on the RBANS total scale index score as a function of CDR‐SB was over the range of CDR‐SB 0–1.5 (CDR‐SB = 0: n = 4,154, mean = 100.7, SD = 12.35, skewness = 0.19, kurtosis = 0.37; CDR‐SB = 1.5: n = 1,575, mean = 78.7, SD = 12.91, skewness = 0.22, kurtosis = 0.24).ConclusionThe findings from this study suggest that the standard normative‐referenced index scoring of the RBANS may be most useful in preclinical trials, although alternative scoring approaches de‐linking the raw scores to population norms (e.g., baseline z‐score transformations) could provide greater sensitivity to change in samples with more significant neurocognitive impairment.
Reorganizing tasks in primary dementia care – A randomized, controlled, crossover intervention trial to test the efficacy and cost‐effectiveness of advanced nursing care in Germany
Authors: Mühlichen Franka , Raedke Anika , Platen Moritz , Michalowsky Bernhard , Mohr Wiebke , Scharf Annelie , Kleinke Fabian , Penndorf Peter , Hoffmann Wolfgang 
Published: December 2022

AbstractBackgroundThe increasing prevalence of dementia with the constant availability of general practitioners is a significant challenge for healthcare systems worldwide. Advanced nursing practice (ANP) was implemented in several countries as one possible solution to overcome this challenge. However, this concept of care is not yet implemented in Germany. The InDePendent study (“Advanced nursing practice and interprofessional dementia care”) is the first study in Germany, aiming to implement and evaluate a model of ANP for persons with dementia (PwDs) living at home and their caregivers where tasks were reorganized between dementia‐specific qualified nurses and physicians.MethodsThe Independent study is a multi‐center, cluster‐randomized, controlled, crossover interventional trial. Whereas the waiting‐control group receive care as usual, the InDePendent intervention of the intervention group aims to provide optimum care for PwD and their caregivers by integrating multimodal strategies of an individualized care within the framework of the German healthcare system by a reorganization of tasks between general practitioners and nurses. Dementia‐specific qualified nurses, who passed a specific state exam, conduct the interventions. Based on evidence‐based guidelines a comprehensive set of 115 intervention modules were defined. Each module consists of predefined trigger conditions and recommendations of actions. The intervention starts with a set of assessment instruments for PwD to identify the unmet needs, individual situation and resources of PwD and caregiver. Subsequently, an intervention tasks list was generated to address each of the identified unmet needs. The tasks lists were carried out by the dementia‐specific nurse in close cooperation with general practitioners. For the first time in Germany, nurses were able to carry out tasks that are usually carried out by general practitioners, like prescription of care aids and outpatient care.Expected results: We expect statistically significant differences between waiting‐control‐group and intervention‐group across the primary (unmet needs) and secondary outcomes (quality of life, caregiver burden, acceptance, cost‐effectiveness). This study can provide evidence concerning the safety, efficacy, and cost‐effectiveness of ANP in Germany, supporting the implementation of the ANP concept into German routine care.
Trial Enrichment using Siamese Neural Networks and PET imaging
Authors: Weatheritt Jack , Peraza Luis R , García David Vállez , Collij Lyduine E. , Gispert Juan Domingo , Barkhof Frederik , Wink Alle Meije , Wolz Robin 
Published: December 2022

AbstractBackgroundBiomarker‐based patient selection is expected to increase success rates in AD clinical trials (e.g. identifying subjects that are at highest risk of cognitive decline). We present a computationally feasible modelling framework that provides a score for predicted decline based on a model trained through a Siamese Neural Network.MethodIn this proof‐of‐concept study, we use baseline data from the 1469 ADNI subjects (388 control, 798 MCI, 272 AD) with an FDG PET scan. 80% of the data was used to train a Siamese neural network after clustering subjects into ‘stable’ or ‘decline’ through the method of Bhagwat et al (2018), see Figure 1. 20% of the data was left out for testing.The model outputs points in a metric space, indicating likelihood of future decline (measured using 2‐year MMSE change from baseline). The first PCA component of the model metric space is used as a screening criterion (See Fig 2). Subjects below the threshold (screen failure rates of 30% and 50%) are not included in the trial simulation. Sample sizes are estimated assuming a 25% effect size, 95% alpha and 80% power (Fig 3). Enrichment performance of the model is compared with FDG SUVR and baseline MMSE score.ResultThe neural network provides a separable metric space of future declining and stable subjects. ‘Screening’ out 30% and 50% of subjects based on model‐predicted decline resulted in a sample size reduction of 45% and 64% respectively, a 5% and 10% improvement over the enriched FDG SUVR cohort. MMSE score yields marginal enrichment. Saliency analysis showed the model is sensitive to the precuneus, hippocampus, temporal lobe and cerebellum.ConclusionDeep learning models enable automated trial enrichment strategies, instead of handcrafted features and centralised processing. The saliency analysis shows that the nonlinear framework has identified the relevant regions for the pathology, providing additional support to their use. More work is needed to assess the ability of the developed method to capture multi‐modal biomarker (e.g. Amyloid, Tau, Neurodegeneration) data to obtain a more precise prediction of decline and to assess the trial operational and economic impact of the proposed screening process.
Improving Dementia Screening in India with Telemedicine and Artificial Intelligence: A Scalable Solution to Address Clinical Gaps in Care
Authors: Kainth Tejasvi , Singh Gagandeep , Prasanna Prateek , Manjila Sunil , Rao Anitha 
Published: December 2022

AbstractBackgroundOver 4.4 million people live with Alzheimer’s and related dementia (ADRD) in India. There is significant clinical service gap of 90% and only 1 in 10 patients affected with ADRD in India receives screening, diagnosis, treatment, and care. Combining telemedicine with an “Expert system,” can help evaluate, screen, and triage patients with ADRD and reduce the time to diagnosis. We demonstrate early results from a feasibility study that uses state‐of‐the‐art Artificial Intelligence (AI), data analytics, and a HIPAA‐compliant Telehealth platform to screen patients over 65 years in India for ADRD.MethodWe integrated AI‐based platform and a standardized cognitive test into the telemedicine‐based primary‐care workflow. A primary care provider (PCP) screened every consenting patient aged 65 years and older on a telemedicine platform in India. The screening used an algorithm‐based intake tool, baseline Mini‐Mental Status Exam (MMSE), and clinical judgment of the PCP. We compared the final screening assessment generated by AI with the MMSE evaluation and clinical judgment of PCP for nine patients.ResultsNine patients (4 females, 5 males) in age group of 65‐90 years consented and enrolled in this initial study. Using the intake data as inputs, the AI model predicted MCI in 5 out of 9 patients (55%) and mild ADRD in 4 out of 9 patients (44%). The clinical severity from the tele‐encounter was rated as mild ADRD in 3 out of 9 patients (33%) and no ADRD/Mild Cognitive Impairment in 6 out of 9 patients (66%). Neuropsychological testing with the MMSE demonstrated scores from 24‐30 in 7 out of 9 patients (77%) and <24 in 2 out of 9 patients (22%). The AI model accurately predicted the severity in 6 out of 9 patients (66.6%) of cases.ConclusionIt is feasible to combine AI and telemedicine to improve ADRD screening and clinical service gaps for healthcare delivery in India. AI severity models also demonstrated adequate predictability to triage patients who have cognitive impairment using digital intake data. The accuracy of the AI prediction models may be further improved with supplemental electronic medical data and translating the intake to a local language.
Public policy and Alzheimer care in India
Authors: Sethurathinam Pushpanathan S 
Published: December 2022

AbstractBackgroundIn India we do not have proper data in respect of Alzheimer disease and its impact on the social and demographic set up.MethodSome studies have been conducted in Kerala West Bengal and some parts of North India. The present study is aimed at analyzing the challenges faced by family caregivers and also institutional caregivers. The methods employed cause both quantitative and qualitative. The study was conducted in care centers run by ARDSI (Alzheimer’s Related Disorder Society of India) and family caregivers were interviewed at homes were Alzheimer’s patients are living. A total of197 caregivers and 70 Alzheimer’s patients were selected for the study overs a period of one year from Jan 2021to Jan2012. To analyze the burden level Zarit Burden Interview was adopted.ResultsThe study revealed that caregiving is a complex experience which involves strong inter professional collaboration and proper education among caregivers regarding elimination of social stigma. The results also revealed more than 80% of the caregivers belong to female gender and more than 90% of the Alzheimer’s patients are in the age group of 65 years and above. In Indian conditions institutional caregiving is highly selective and it has been utilized by high income group of families as they have to spend around 25000 per month for keeping the AD patient at care homes.ConclusionThrough the study it has been identified Government support in taking care of Alzheimer’s patients has been extraordinarily effective in the entire Kerala state whereas from available literature, such type of care centers are yet to be established in other states. Regarding family caregivers more awareness programs are needed which will facilitate proper care of Alzheimer’s patients without any social stigma.
Cognitive changes and circadian timekeeping disturbances in aging
Authors: Montgomery Karienn S , Powell Andrew s , Reyes Jocelin s , Jackson William C , Earnest David J 
Published: December 2022

AbstractBackgroundCognitive changes in aging and Alzheimer’s disease (AD) are often accompanied by pronounced disturbances of circadian timekeeping, especially sleep‐wake cycle. Normal circadian timekeeping has an important impact on human health and performance by providing the temporal coordination of internal processes to insure their occurrence at the “right time” relative to each other and to the external environment. Aging of the rodent circadian system is characterized by changes comparable to those in human aging and AD. Common disturbances in the sleep‐wake rhythms of aged rodents include alterations in the light‐dark entrainment of this circadian rhythm. However, not all aged rodents show these changes, demonstrating the variability characteristic of human aging in pre‐dementia. The aging population also shows variability in onset and magnitude of cognitive impairment, but the relationship between these deficits with circadian rhythm disturbances has not yet been identified.MethodInitially, we tested young (3‐5 mon) and aged (18‐24 mon) C57Bl6 mice on wheel running activity continuously for 30‐40 days for circadian rhythm of locomotor activity. We then assessed learning and memory in the same mice using the Barnes maze task. Next, we wanted to determine if behavioral deficits occurred earlier in the lifespan (middle age) and whether changes in circadian activity occur prior to cognitive impairment.ResultAged mice were significantly impaired in all measures of activity rhythm entrainment and cognition. Interestingly, we observed a gender‐specific relationship between cognitive impairment in the Barnes maze and activity onset in aged female mice (20‐24 mon). Changes in activity rhythm entrainment were observed as early as 12‐14 months in middle aged mice. We also tested these mice for cognition (Barnes maze, novel and spatial recognition tests, 3 chamber sociability test) and motor behavior (rotarod, open field and digigait).ConclusionThis data will be the foundation of our model to further understand the relationship between circadian synchronization and age‐related cognitive impairment, and to probe possible mechanisms of action.