bluuebunny/crossref_metadata_2025_split huggingface dataset:
Diagnosis of Alzheimer's disease before dementia: A study of UK psychiatrists
Authors: Walpert Madeleine , Mitchell Susan , Bamford Claire , Ivenso Chineze , McKirdy Stuart , Pattan Vivek , Rodda Joanne , Sikdar Sudip , Barber Robert 
Published: December 2021

AbstractBackgroundAlzheimer’s disease (AD) is increasingly conceptualised as a continuum spanning presymptomatic, symptomatic pre‐dementia and dementia stages. With potential disease modifying treatments emerging, this study explored the views of clinicians working in Old Age Psychiatry in the UK regarding the diagnosis of symptomatic AD before dementia, including the role of biomarkers, and the preparedness of services to deliver future disease modifying treatments.MethodThis study, conducted by the Royal College of Psychiatrists and Alzheimer's Research UK, used a two‐stage quantitative and qualitative approach consisting of an online survey (n=493) followed by focus groups (n=42) of clinicians.ResultConceptualising AD as a continuum was considered a helpful framework for thinking about disease pathology, progression and treatment. However, translating this framework into clinical practice generated a number of challenges including uncertainties about diagnostic nomenclature and criteria with at least seven diagnostic terms possible. Overall, terms referencing “mild cognitive impairment” were considered more helpful than those explicitly stating AD. Hesitancy to reference AD at this stage was influenced by concerns about the accuracy of diagnostic criteria, limitations linked to biomarkers and potential negative impacts on individuals, especially in the absence of disease modifying treatments. Access to biomarkers other than CT was sub‐optimal, 96% of responders reported insufficient or no access to CSF and 93% to PET Aβ, limited access negatively impacted on the clinician’s confidence in their utility (P<0.001).Psychiatrists indicated that it was important their services offer disease modifying treatments if licensed but recognised that services faced significant challenges to be prepared, including capacity, resources and staff expertise.ConclusionDiagnosing AD before the onset of dementia is likely to become increasingly relevant if new treatments are licensed, but this study highlights a number of important challenges to achieve this including concerns about the reliability and validity of the diagnostic criteria and access to key biomarkers. There was a clear view that Old Age Psychiatry services should be able to provide any future treatments alongside their usual care but recognition that this would require better access to biomarkers, clearer diagnostic criteria, up‐skilling of staff and changes to training as well as changes to care pathways.
The association between retinal neurodegeneration and plasma neurofilament light chain: A population‐based study
Authors: Garzone Davide , Finger Robert P. , Mauschitz Matthias M. , Santos Marina , Breteler Monique M.B. , Aziz N. Ahmad 
Published: December 2021

AbstractBackgroundBoth plasma neurofilament light chain (NfL) levels and retinal layer volumes have emerged as biomarkers of central neurodegeneration, the former highlighting neuroaxonal damage, the latter as an extension of the brain susceptible to similar injuries. To date, the extent to which plasma NfL levels and retinal layer volumes could be used as complementary biomarkers of brain health is unknown. Therefore, we assessed their association in the general populationMethodThe study is based on the first 5000 participants of the Rhineland Study, a population‐based cohort study in people aged 30 years and above in Bonn (Germany). We included all participants with complete spectral‐domain optic coherence tomography (SD‐OCT) and plasma NfL data (N=4396, after removal of three outliers due to extreme values). We applied multivariable regression analysis to investigate associations between different retinal layer volumes and plasma NfL levels, assessing effect modification by age, sex, hypertension, smoking and presence of neurological diseases (N=95, including stroke, dementia and multiple sclerosis).ResultNfL levels increased, while ganglion cell layer (GCL) volume decreased exponentially with advancing age. Among the different retinal layers, GCL volume was most closely associated with NfL levels, with a strong age‐dependent association: while no association was evident in young individuals, in older individuals lower GCL volume was related to higher NfL levels (std. beta for the interaction effect of GCL with highest tertile of age = ‐0.032, 95% CI [‐0.06 ‐ ‐0.005],p=0.02). Similarly, smaller GCL volume was associated with higher NfL levels in participants with hypertension (std.beta ‐0.06, 95% CI [‐0.011 ‐ ‐0.02],p=0.003) or a neurological disease (std. beta ‐0.018, 95%CI [‐0.035 ‐ ‐0.001], p=0.037), but not in those without disease.ConclusionOur findings indicate that retinal layers volume,in particular GCL, more closely reflect neuroaxonal damage in higher age or in the presence of cardiovascular risk factors and neurological diseases.
Alzheimer’s disease CSF biomarker assays: Impact of methodology changes in clinical practice
Authors: Campbell Michelle R. , Kian Susan Ashrafzadeh , Petersen Ronald C. , Bornhorst Joshua A , Algeciras‐Schimnich Alicia 
Published: December 2021

AbstractBackgroundDecreased amyloid β1‐42 (Aβ42) and increased tau (t‐Tau and p‐Tau) concentrations in cerebrospinal fluid (CSF) reflect the pathological changes of Alzheimer’s disease (AD) and aid in the diagnosis of AD dementia. In the United States, the ADmark® assay has been almost exclusively used for the measurement of these biomarkers in clinical practice. Recently, our institution switched from the ADmark® assay to the Roche Elecsys assays. The goal of this study was to determine if differences exist between these methods in classification of patients as having changes indicative of AD pathology.MethodPatients undergoing ADMark® testing (n= 73) were recruited to participate in this IRB‐approved study. Two simultaneous CSF aliquots were obtained. For ADMark®, 2.0mL were collected into a 5mL polypropylene (PP) tube and shipped frozen to Athena Diagnostics per collection instructions for testing (Innotest® immunoassays for Aβ42, t‐Tau, and p‐Tau). For the Roche Elecsys assays (Aβ42, t‐Tau, and p‐Tau), 2.0mL were collected into a 2.5mL low bind PP tube, frozen, and then tested at Mayo Clinic Laboratories. Comparative analysis was performed between the two testing methodologies and to clinical findings.ResultOverall concordance between the ADMark® Aβ42/t‐Tau index (ATI) and Roche p‐Tau/Aβ42 was 89% with 8 (11%) discrepant cases. Four cases were classified as normal by the Roche p‐Tau/Aβ42 but borderline (n=3) or abnormal (n=1) by ADMark® ATI. Four cases were classified as abnormal by the Roche p‐Tau/Aβ42 and borderline by ADMark® ATI. In these cases, the normal Roche p‐Tau/Aβ42 result was most consistent with clinical diagnosis. When compared to clinical diagnosis, cases with clinical suspicion of AD dementia were abnormal in 84% and 92% of cases with the ADMark® ATI and the Roche p‐Tau/Aβ42, respectively. In cases without clinical suspicion of AD dementia, results were abnormal in 19% and 21% of cases with the ADMark® ATI and the Roche p‐Tau/Aβ42, respectively. There were 2 cases with clinical suspicion of AD dementia and 5 cases without suspicion of AD dementia that were classified as borderline by ADMark® ATI.ConclusionRoche p‐Tau/Aβ42 showed comparable performance to ADMark® ATI when correlating results to clinical diagnosis of AD dementia.
Gender differences in the association between persistent pain and cognitive decline over 14 years among Mexicans aged 50 and older
Authors: Milani Sadaf Arefi , Gutierrez Sirena , Wong Rebeca , Samper‐Ternent Rafael , Downer Brian 
Published: December 2021

AbstractBackgroundPain is associated with cognitive decline, but research has not considered low‐ and middle‐income countries (LMICs) such as Mexico and gender differences. This is an important gap, as individuals living in Mexico have a large burden of chronic pain due to exposure to risk factors over the life course.MethodsUsing data from the Mexican Health and Aging Study (MHAS), a nationally representative study of Mexicans aged 50 and older, we assessed the association of persistent pain with cognition from 2001 to 2015. Persistent pain was defined as moderate or severe pain reported in 2001 and 2003. Non‐persistent pain was defined as pain that was not moderate or severe in 2001 and 2003. Cognition was measured using the MHAS cognitive battery and was standardized for global cognition, memory, and non‐memory domains. We used linear mixed models to evaluate the association between persistent pain and cognition over time, adjusting for demographic, socioeconomic, and health factors. We evaluated heterogeneity by respondent’s gender.ResultsOur sample was 55.8% female with a mean baseline age of 61.8 (n=10,053). About 13% of participants reported persistent pain and 45% reported non‐persistent pain. Persistent pain was associated with a higher rate of decline for global (β: −0.005, 95% CI: ‐0.008, ‐0.002), memory (β: −0.004, 95% CI: ‐0.008, ‐0.001), and non‐memory (β: ‐0.005, 95% CI: ‐0.009, ‐0.002) domains, compared to no pain. Among women, persistent pain was associated lower global (β: ‐0.006, 95% CI: ‐0.010, ‐0.002), memory (β: ‐0.005, 95% CI: ‐0.009, ‐0.0003), and non‐memory (β: ‐0.008, 95%CI: ‐0.012, ‐0.003) scores over time, while among men, persistent pain was only associated with lower memory (β: ‐0.008, 95% CI: ‐.014, ‐0.002) scores over time. Non‐persistent pain was not associated with cognition for women, while for men, it was associated with lower global (β: −0.004, 95% CI: ‐0.006, ‐0.001) and memory (β: −0.004, 95%CI: ‐0.007, ‐0.001) scores over time.ConclusionsPersistent pain may impact cognitive decline for years and differentially impact individuals by gender. Treatment may result in population‐level benefits in cognition for those living with persistent pain. This is important in LMICs, where most individuals requiring pain relief have their needs unmet.
Tool and chemical probe development for emerging targets in Alzheimer’s disease: The Emory‐Sage‐SGC TREAT‐AD Center
Authors: Mangravite Lara M , Betarbet Ranjita , Carter Gregory W , Frye Stephen V. , Fu Haian , Gileadi Opher , Greenwood Anna K , Leal Karina , Longo Frank M. , Omberg Larsson , Pearce Kenneth H. , Edwards Aled M , Levey Allan I 
Published: December 2021

AbstractBackgroundAlzheimer’s disease (AD) is the most common form of dementia, with no effective preventative strategies or treatments. The drug development pipeline in AD has been marked by repeated failures to find an effective treatment. Increasing evidence supports the need for greater pipeline target diversity and new approaches to target the disease. The Emory‐Sage‐SGC TREAT‐AD Center (https://treatad.org) was established to forge a new path forward with the aim of developing drugs for emerging targets in AD beyond the two pathological hallmarks. By casting a wider net, we aim to develop tools and chemical probes that target the multifaceted dysregulation in the brains of AD patients, and expand the portfolio of therapeutic approaches to break the cycle of failure. We believe that this more‐inclusive perspective will enrich the AD field and advance the discovery of potential drug targets for AD.MethodThe Emory‐Sage‐SGC TREAT‐AD Center has selected a diverse set of novel AD targets derived from systems biology studies within the Accelerating Medicines Partnership in AD (AMP‐AD) consortium and further evaluated using data from multiple AD consortia and existing literature. Targets nominated through the AMP‐AD consortium were scored based on unbiased bioinformatic assessments across multiple lines of evidence including genetic, multi‐omic, neuropathological, and literature‐based metrics and were mapped to mechanistic hypotheses residing in distinct biological domains that are altered in AD. Target Enabling Packages, including expression constructs, knockout cell lines, assays, antibodies and crystal structures, are being generated for 20 proteins prioritized using this approach. Hit characterization and chemical probe development has started for targets in which the evidence for AD biology is strong. All data and reagents will be publicly shared through standard repositories and cataloged at the Agora site (https://agora.adknowledgeportal.org).ResultThe Emory‐Sage‐SGC Center goals are: to identify and prioritize novel emerging targets for AD; to generate reagents and tools for emerging targets to encourage the community to expand the pipeline of potential AD therapeutic targets; and to share all data, tools, and reagents openly, rapidly, and without restriction.ConclusionAll data, protocols, reagent sets, and chemical tools and will be made widely available. For more information see www.treatad.org.
Brain state instability as a biomarker of Alzheimer’s disease progression: A dynamic functional network connectivity study
Authors: Sendi Mohammad S.E. , Zendehrouh Elaheh , Miller Robyn L , Mormino Elizabeth C. , Salat David H , Calhoun Vince D 
Published: December 2021

AbstractBackgroundFinding a biomarker predicting the Alzheimer’s disease (AD) progression from a healthy stage to mild cognitive impairment (MCI), mild dementia (MD) and further to AD is an essential step toward early medical intervention. In recent years, dynamic functional network connectivity (dFNC) from resting state‐fMRI, which estimates brain states during the scan, revealed excellent knowledge about AD progression's underlying mechanism. The current study explored whether the AD brain produces similar and stable dFNC states across different scanning sessions and introduced dFNC state (or brain) instability as a potential biomarker of AD progression.MethodThe data from the longitudinal Open Access Series of Imaging Studies (OASIS)‐3 cohort were used in this study. The dataset contains two rs‐fMRI sessions on the same day of 1048 healthy controls or HC (clinical dementia rating sum of boxes or CDR‐SOB=0, age= 70.80± 8.57), 193 MCI (4.5=<CDR‐SOB<=9, age= 71.00±9.48), and 75 MD patients (with clinical dementia rating 4.5=<CDR‐SOB<=9, age=71.90±9.65). We did not observe a significant age and gender difference across groups (ttest p>0.2). We used Group‐independent component analysis to extract independent components of the whole‐brain for each subject. Next, we applied the sliding window with Pearson correlation to estimate dFNC of each individual in each session. Subsequently, k‐means clustering (k=3, L1‐norm as a distance metric, and 1000 iterations) separately was applied to put the dFNCs of each group and session in three distinct states. Pearson correlation between the cluster (state) centroid was used to assess the similarity of state across two sessions.ResultWe found that HC and MCI groups generate similar dFNC states in both sessions in which The correlation between inter‐session “matched” states for HCs and MCIs was more than 0.99 (p<0.0001). But, MD patients did not generate similar brain states across two sessions. This points to a degradation in the stability of functional brain integration among MD patients.ConclusionOur findings highlight brain instability as a potential biomarker of Alzheimer’s disease progression. Also, the instability of dFNC observed in mild dementia patients suggests a need for multiple scanning sessions to analyze rs‐fMRI data in this group of patients.
Association between body weight change in late life and risk of dementia: A population‐based cohort study
Authors: Guo Jie , Marseglia Anna , Shang Ying , Dove Abigail , Grande Giulia , Fratiglioni Laura , Xu Weili 
Published: December 2021

AbstractBackgroundAdiposity in midlife is a modifiable risk factor for dementia. However, the effect of adiposity in late life on dementia remains unclear. We investigated the association of body mass index (BMI) and weight changes after age 60 with the incidence of dementia.MethodWithin the Swedish National Study on Aging and Care‐Kungsholmen, 1,673 dementia‐free participants with data on BMI/weight both at baseline and the 6‐year follow‐up were followed to detect subsequent incident dementia cases. BMI change was assessed as the percentage of the difference between BMI at baseline and the initial 6‐year follow‐up and categorized into large (>10%) or moderate (5–10%) loss, stable (≤5%), and moderate (5–10%) or large (>10%) gain. Weight change (difference between weight at baseline and the 6‐year follow‐up) was categorized into large (>7.5 kg) or moderate (2.5–7.5 kg) loss, stable (≤2.5 kg), and moderate (2.5–7.5 kg) or large (> 7.5 kg) gain. Dementia was diagnosed following the DSM‐IV criteria. Data were analyzed using Cox regression models.ResultDuring the follow‐up (median 5.78 years), 102 incident dementia cases were identified. BMI/weight change showed U‐shaped associations with dementia. Compared with stable BMI, the hazard ratios (95% confidence intervals) of dementia were 2.93 (1.72−4.91) for large BMI loss and 2.61 (1.09−5.54) for large BMI gain. Similar results were observed for a large weight loss (2.92 [1.67−5.07]) or gain (2.95 [1.16−6.53]). BMI and weight loss/gain were dose‐dependently related to dementia risk. These associations became stronger among participants carrying an ApoE ɛ4 allele or with diabetes. No significant associations between moderate BMI and weight loss/gain and dementia were detected.ConclusionBoth large bodyweight loss and gain are associated with almost 3‐fold higher risk of dementia. ApoE ɛ4 and diabetes appear to play a role in this association.
The cumulative effect of cognitive engagement on cognitive function in middle‐aged adults
Authors: Bransby Lisa , Buckley Rachel F , Yassi Nawaf , Pase Matthew P , Lim Yen Ying 
Published: December 2021

AbstractBackgroundEngagement in cognitively stimulating work and activities is proposed to slow cognitive decline and delay dementia. Few studies have considered the cumulative effect of multiple cognitively engaging factors on cognitive function. In middle‐aged adults, this study aimed to determine the individual and combined associations of four cognitive engagement factors (i.e., educational attainment, occupational complexity, social engagement and cognitively stimulating leisure activities) with objectively measured cognitive performance and subjective ratings of cognitive function.MethodA total of 1864 cognitively normal middle‐aged adults (aged 40‐70) enrolled in the Healthy Brain Project, a study with an online remote assessment platform seeking to understand midlife risk factors for dementia. Cognitive engagement factors were measured by online self‐report questionnaires. The Cogstate Brief Battery was used to measure cognitive domains of attention and memory. Subjective ratings of cognitive function were measured using the Cognitive Function Instrument.ResultAfter controlling for age, sex, ethnicity and mood symptomatology, participants with high educational attainment or high occupational complexity performed significantly better on attention and memory tasks and reported less subjective ratings of cognitive concern. Higher participation in cognitively engaging leisure activities was significantly associated with better attention and memory performance, but not with subjective ratings of cognitive function. Social engagement was not associated with any outcome. The magnitude of these effects was small and trivial (Cohen’s d ranging from 0‐0.17). Participants were then classified into five groups based on whether they rated highly in 0‐4 cognitive engagement factors. Compared to participants with no factors, participants scoring highly in 2 or more factors performed significantly better on the memory tasks, with the magnitude of difference moderate (Cohen’s d ranging from 0.30‐0.49).ConclusionThese results suggest a cumulative relationship between high cognitive engagement across several domains of life and better memory performance in cognitively normal middle‐aged adults.
Apathy in Dementia Methylphenidate Trial 2 (ADMET2): Results of a phase III, placebo‐controlled, double‐blind, 6‐month, multi‐center, randomized clinical trial
Authors: Mintzer Jacobo E. , Scherer Roberta , Drye Lea T. , Lanctôt Krista L. , Rosenberg Paul B. , Herrmann Nathan , Padala Prasad R , Brawman‐Mintzer Olga , Lerner Alan J. , Levey Allan I , Porsteinsson Anton P. , van Dyck Christopher H 
Published: December 2021

AbstractBackgroundApathy is one of the most common and debilitating neuropsychiatric symptoms of Alzheimer’s Disease (AD). Two previous trials that suggested methylphenidate was safe and efficacious involved only 60 participants each, followed for 6 weeks. A larger, longer‐lasting trial was required to confirm those promising findings.MethodsADMET 2 was a phase III, placebo‐controlled, 6‐month, multi‐center, randomized (1:1, 20 mg methylphenidate per day or placebo) clinical trial that randomized 200 participants with AD and apathy. Primary outcomes included: (1) the mean difference on the Neuropsychiatric Inventory Apathy (NPI‐A) subscale scores measured as change from baseline to 6 months, and/or (2) the odds of a rating of improvement on the modified AD Cooperative Study Clinical Global Impression of Change (ADCS‐CGIC) at month 6 compared with baseline. Secondary outcomes included change in cognition, safety, and cost‐effectiveness measured monthly for up to 6 months.Results200 individuals were randomized (65.8% were males; 34.2% were females; avg age=76 years; 75.3% had some college education or greater; mean Mini‐Mental State Examination score at baseline was 18.9). There was a larger difference in the methylphenidate group compared with the placebo group in NPI‐A score from baseline to 6 months using a mixed model (Mean difference = ‐1.25; 95% CI: ‐2.03, ‐0.47, p = 0.002) with the largest change observed during the first two months. At 6 months, the ADCS‐CGIC showed that 43.8% (39/89) of participants in the methylphenidate group improved compared with 35.2% (32/91) of study participants in the placebo group (odds ratio 1.90 (95% CI: 0.95, 3.84), favoring methylphenidate, but not reaching statistical significance (p = 0.071)). There were no significant differences in other assessments. The safety profile was similar between the two groups.ConclusionADMET 2 showed a small to medium benefit for methylphenidate in the treatment of apathy in AD. The effect was observed at 2 months and was sustained throughout the 6 months of the study. Adverse events were mild. These results support previous observations in smaller studies. Methylphenidate offers a viable treatment for patients suffering from apathy in AD.