bluuebunny/crossref_metadata_2025_split huggingface dataset:
The use of amyloid‐PET in memory clinic patients: AMYPAD Diagnostic and Patient Management Study
Authors: Altomare Daniele , Barkhof Frederik , Caprioglio Camilla , Collij Lyduine E. , Scheltens Philip , van Berckel Bart NM , Alves Isadora Lopes , Berkhof Johannes , van Maurik Ingrid S. , Garibotto Valentina , Moro Christian , Delrieu Julien , Molinuevo Jose Luis , Grau‐Rivera Oriol , Gispert Juan Domingo , Drzezga Alexander , Jessen Frank , Nordberg Agneta K , Walker Zuzana , Demonet Jean‐François , Gismondi Rossella , Farrar Gill , Stephens Andrew W , Frisoni Giovanni B ,   AMYPAD consortium
Published: December 2022

AbstractBackgroundAmyloid‐PET allows the direct assessment of amyloid deposition, one of the main hallmarks of Alzheimer’s disease. However, this technique is currently not or incompletely reimbursed due to lack of randomized controlled studies demonstrating a clinical impact.MethodAMYPAD‐DPMS is a prospective, multicenter, randomized controlled study. Patients with subjective cognitive decline plus (SCD+), mild cognitive impairment (MCI) or dementia from 8 European memory clinics were randomized into three study arms: ARM1, amyloid‐PET performed early in the diagnostic workup (within 1 month); ARM2, late in the diagnostic workup (after 8±2 months); or ARM3, if and when the managing physician chose to. The primary endpoint was the proportional difference in ARM1 and ARM2 participants in receiving an etiological diagnosis with very high diagnostic confidence (i.e. ≥ 90%) within 3 months. Secondary endpoints included changes in diagnosis and treatment plan.ResultParticipants were recruited from April 16th, 2018, to October 30th, 2020. There were 272 participants in ARM1, 260 ARM2, and 261 ARM3 that underwent both baseline and 3‐month visit. 88% of ARM3 participants underwent amyloid‐PET within 3 months, and the average time from baseline to prescribe amyloid‐PET was 46 (IQR=58) days. After 3 months, 40% (109/272) of ARM1 participants and 37% (97/261) of ARM3 had a diagnosis with very high confidence vs 11% (30/260) in ARM2 (p<0.001). This was consistent across clinical stages (SCD+: 30%, 22%, and 6%, p<0.05; MCI: 42%, 39%, and 9%, p<0.05; dementia: 49%, 49%, and 20%, p<0.05). Changes in diagnosis were more frequent in ARM1 (44%) versus ARM3 (29%, p=0.001) and ARM2 (11%, p<0.001), and in ARM3 versus ARM2 (p<0.001). In participants for whom an etiological diagnosis of AD or non‐AD was confirmed after 3 months, changes in diagnostic confidence were greater in ARM1 (AD: +14%; non‐AD: +12%) and ARM3 (+11%; +10%) vs ARM2 (+1%, +1%; p<0.05).ConclusionAn amyloid‐PET performed in the early phases of a diagnostic workup is associated with a greater proportion of etiological diagnoses with very high confidence and more frequent changes in diagnosis and higher diagnostic confidence after 3 months. This evidence supports the implementation of this technique early in the diagnostic workup.
Relationship between stress response and mitochondrial respiration in skeletal muscle of apolipoprotein E4 (APOE4) carriers
Authors: Johnson Chelsea N. , Thyfault John P , McCoin Colin S. , Swerdlow Russell H , Wang Xiaowan , John Casey S. , Geiger Paige C , Morris Jill K. 
Published: December 2022

AbstractBackgroundExpression of the stress‐inducible chaperone protein, heat shock protein 70 (HSP70/72), is elevated in the Alzheimer’s disease (AD) brain. This may result from mitochondrial stress, as AD mitochondria are characterized by reduced complex IV activity and ATP levels. Further, patients with mild cognitive impairment (MCI) have reduced lipid‐stimulated mitochondrial respiration in skeletal muscle, providing evidence that mitochondrial dysfunction occurs peripherally, manifests early in the disease, and is related to lipid metabolism. Interestingly, the primary genetic risk factor for sporadic AD, the apolipoprotein E4 (APOE4) allele, plays an important role in lipid metabolism. The goal of this study was to characterize the skeletal muscle stress response in APOE4 carriers and the relationship with muscle mitochondrial function.MethodWe analyzed skeletal muscle tissue from previously collected biopsies (vastus lateralis) from 23 older adults (65+) who were cognitively healthy (CH, n=8) or MCI (n=15) and at genetic risk for AD (APOE4 carriers). We measured HSP72 protein levels via Western blot and leveraged previously collected data on APOE4 genotype, mitochondrial respiration (basal, state 3, state 3S, uncoupled), plasma cholesterol and platelet citrate synthase activity, the latter of which is a marker of mitochondrial content. Analyses were controlled for age and sex.ResultHSP72 expression negatively correlated with basal respiration (R2 = 0.518, p = 0.002), ADP‐stimulated respiration (R2 = 0.775, p = <0.001) and succinate‐stimulated respiration (R2 = 0.405, p = 0.011) in the presence of the lipid, palmitoyl‐carnitine, in skeletal muscle of APOE4 carriers with MCI, but not in CH APOE4 carriers. HSP72 expression negatively correlated with platelet citrate synthase activity (R2 = 0.518, p = 0.002) in APOE4 carriers with MCI, but not in CH APOE4 carriers. HSP72 expression positively correlated with plasma cholesterol in all participants (R2 = 0.182, p = 0.042).ConclusionThis work supports a potential role for the heat shock response in responding to peripheral mitochondrial dysfunction and elevated cholesterol levels during cognitive decline in APOE4 carriers. Further work is needed to determine if this stress response serves a protective role.
Processing of acoustically degraded speech in primary progressive aphasia and Alzheimer’s disease
Authors: Jiang Jessica , Requena‐Komuro Mai‐Carmen , Benhamou Elia , Johnson Jeremy , Sivasathiaseelan Harri , Chokesuwattanaskul Anthipa , Russell Lucy L , Warren Jason D , Hardy Chris JD 
Published: December 2022

AbstractBackgroundIn daily life, spoken messages are often “degraded” by competing sounds and vocal idiosyncrasies. Comprehension of degraded speech demands intense computations across distributed neural networks; it is likely to present a particular challenge for patients with neurodegenerative pathologies. However, this issue has not been studied systematically.MethodHere, we studied the processing of degraded speech signals in a cohort of patients representing all major variant syndromes of primary progressive aphasia (N = 32), in relation to patients with typical Alzheimer’s disease (N = 19) and healthy age‐matched controls (N = 25). As a model paradigm for the degraded ‘noisy’ speech signals of daily life, we used noise‐vocoding: digital division of the speech signal into a variable number of frequency channels constituted from amplitude‐modulated white noise, such that fewer channels convey less spectrotemporal detail and reduce intelligibility. We assessed the impact of noise‐vocoding on the recognition of spoken three‐digit numbers (e.g., ‘five‐hundred‐and‐eighty‐seven’) and used psychometric modelling to ascertain the threshold number of noise‐vocoding ‘channels’ required for intelligibility by each participant.ResultCompared with healthy controls, all patient groups showed normal comprehension of natural speech; for vocoded speech, patients with semantic variant primary progressive aphasia performed normally whereas other patient groups had a raised noise‐vocoding threshold and this was particularly marked in logopenic aphasia.ConclusionOur findings suggest that degraded speech is a promising paradigm for probing real‐world communication difficulties in people with dementia, and for stratifying syndromes and pathologies. Future work should assess the potential of this paradigm for developing new biomarkers and interventions to assess and improve communication function in these diseases.
Cumulative loneliness and subsequent memory function and rate of decline among adults aged ≥50 in the United States, 1996‐2016
Authors: Yu Xuexin , Westrick Ashly C , Kobayashi Lindsay C 
Published: December 2022

AbstractBackgroundTo investigate the association between the cumulative duration of loneliness and subsequent memory function and rate of decline over a 20‐year period in middle aged and older adults.MethodData were from biennial interviews with 9,032 adults aged ≥50 in the population‐based US Health and Retirement Study from 1996‐2016. Loneliness status (yes vs. no) was assessed biennially from 1996‐2004 and its duration over this period was categorized as never, 1 time point, 2 time points, and ≥3 time points. Episodic memory was assessed biennially from 2004‐2016 as a composite of immediate and delayed recall trials combined with proxy‐reported memory. We used multivariable‐adjusted mixed effects regression to estimate the association between loneliness duration and subsequent memory function and decline. Three‐way interaction terms were included to test effect modification by sex and age.ResultMean (SD) age at baseline was 64 (9) years, 63% of the sample was female (5,646/9,032), and the median follow‐up time was 10 years, contributing 46,890 observations from 2004‐2016. A total of 1,624 adults (18%) experienced loneliness at one time point, 825 (9%) experienced loneliness at two time points, and 1,069 (12%) experienced loneliness at ≥3 time points. Annual memory decline among non‐lonely adults was 0.08 standard deviation (SD) units (95% CI: ‐0.08, ‐0.07) per year. A longer duration of loneliness was associated with a faster rate of memory decline (1 time point: 0.01 SD additional annual decline, 95% CI: ‐0.01, ‐0.01; 2 time points: 0.02 SD additional annual decline, 95% CI: ‐0.02, ‐0.01; ≥3 time points: 0.03 SD additional annual decline, 95% CI: ‐0.03, ‐0.02; P trend <0.001). The association was stronger among women than men (three‐way interaction P trend <0.001) and adults aged ≥65 years than those aged <65 years (three‐way interaction P trend = 0.01).ConclusionLong‐term loneliness may be a salient risk factor for accelerated memory aging, especially among women aged 65 and over. Our findings could help rule out reverse causation between loneliness and memory outcomes, suggesting that loneliness could be part of a preclinical syndrome of Alzheimer’s disease and related dementias.
Relationships between hearing impairment with 7‐year cognition and cognitive change: Results from the Study of Latinos‐ Investigation of Neurocognitive Aging (SOL‐INCA)
Authors: Mendoza Alonzo , Stickel Ariana M , Tarraf Wassim , Kuwayama Sayaka , Kaur Sonya , Paredes Alejandra Morlett , Daviglus Martha L , Testai Fenando D , Zeng Donglin , Isasi Carmen R , Baiduc Rachael R , Dinces Elizabeth , Lee David J , González Hector M 
Published: December 2022

AbstractBackgroundHearing impairment among Hispanics/Latinos has been associated with poorer cognition, potentially increasing mild cognitive impairment (MCI) and dementia risk. We aimed to examine associations between baseline hearing impairment with 1) cognition at visit 2 (7‐years later, on average), 2) 7‐year average change in cognition, and 3) mild cognitive impairment (MCI) at visit 2 among diverse Hispanics/Latinos.MethodHispanics/Latinos (n = 6031, average baseline age 56.4‐years) from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) were enrolled in the SOL ‐ Investigation of Neurocognitive Aging (SOL‐INCA) ancillary study. Hearing impairment was defined as a pure tone average (500, 1,000, 2,000, 4,000 Hz) >25 dBHL in the better ear. Cognitive testing was performed at Visit 1 and again an average of 7‐years later. Tests included measures of learning and memory, verbal fluency, and executive functioning and processing speed, and global cognition (a z‐score composite from averaging each test). MCI was calculated based on NIA‐AA criteria. Survey linear regressions were used to separately model the associations between hearing impairment with outcomes of interest, controlling for age, gender, education, Hispanic/Latino background, field center, marital status, depressive symptoms, income, and Framingham cardiovascular disease risk.ResultPerformance at visit 2: In fully adjusted models, hearing impairment at baseline was associated with lower scores in global cognition (B = ‐0.12; SE = 0.03; p<0.0001) evident in learning, memory and verbal fluency, but not executive function or processing speed at visit 2 (7 years later). 7‐year (average) cognitive change: Hearing impairment was associated with significant change (declines) in processing speed (B = ‐0.12; SE = 0.06; p<0.05) but not with change in global cognition or other cognitive domains. MCI: Hearing impairment was not associated with prevalent MCI.ConclusionWe found that hearing impairment was related to lower cognitive function and increased cognitive decline compared to Hispanics/Latinos with normal hearing. Hearing impairment was not associated with MCI among Hispanics/Latinos, and further longitudinal data are needed to determine if this holds as the cohort continues to age. Future studies should also examine comorbid sensory impairments and type of hearing impairments (noise induced hearing loss, conductive, sensorineural) with cognitive trajectories and MCI risk.
Connections between reproductive health and cognitive aging among women enrolled in the HCHS/SOL and SOL‐INCA
Authors: Stickel Ariana M , Tarraf Wassim , Wu Benson , Sundermann Erin E. , Gallo Linda C , Lamar Melissa , Daviglus Martha L , Zeng Donglin , Thyagarajan Bharat , Isasi Carmen R , Lipton Richard B. , Cordero Christina , Perreira Krista M , González Hector M , Banks Sarah J 
Published: December 2022

AbstractBackgroundLifetime risk for Alzheimer’s disease is higher among women than men, and reproductive health factors may contribute to differential risk. Reproductive health and cognitive aging among Hispanic women/Latinas is understudied, so we examined such relationships in the Hispanic Community Healthy Study/Study of Latinos (HCHS/SOL) and the SOL‐Investigation of Neurocognitive Aging (SOL‐INCA).MethodThe sample included Hispanic/Latina post‐menopausal women (n = 1,903, baseline age 44‐74 years). Exposures included oral contraceptive use, number of live births (parity), number of pregnancies, age at menarche, age at menopause, and reproductive span (years with menses). Outcomes included visit 2 cognitive performance (7‐years after baseline on average), 7‐year cognitive change (reliable change index), and NIA‐AA criteria mild cognitive impairment (MCI) prevalence. Cognitive measures included verbal learning and memory, verbal fluency, executive functioning (Trail B, higher scores = worse performance), and processing speed (Digit Symbol Substitution = DSS; Trail A, higher scores = worse performance), and a global composite (average of all individual z‐scores). Survey linear regressions were used to separately model the associations between reproductive health measures and outcomes, controlling for baseline age, education, language preference, Hispanic/Latina background, field center, income, birthplace, marital status, insurance status, and body mass index.Result
Performance at visit 2: Oral contraceptive use was associated with higher global cognitive performance (β = 0.129 [SE = 0.043], p<0.01), learning (β = 0.197 [SE = 0.062], p<0.01), and processing speed (βDSS = 0.147 [SE = 0.049], p<0.01 and βTrailA = ‐0.142 [SE = 0.071], p<0.05) than non‐use. Higher parity was associated with worse executive functioning (β = 0.035 [SE = 0.017], p<0.05) and processing speed (βDSS = ‐0.054 [SE = 0.015], p<0.001). 7‐year (average) cognitive change: Oral contraceptive use, higher parity, and higher pregnancies were each protective against change in learning (β = 0.147 [SE = 0.064], β = 0.040 [SE = 0.019], and β = 0.034 [SE = 0.014], respectively; all ps<0.05). Older age at menarche was protective against change in global cognition (β = 0.045 [SE = 0.016], p<0.01), learning (β = 0.035 [SE = 0.017], p<0.05) and memory (β = 0.037 [SE = 0.017], p<0.05). MCI: No exposures were associated with MCI.ConclusionReproductive health was linked to later life cognition among diverse Hispanic/Latina women. Future work should examine potential hormonal (e.g., estrogen) mechanisms. Although not associated with MCI In the present study, reproductive health may be linked to MCI status as the cohort ages and more women transition to MCI or dementia.
Findings from Dialogue with Patients and Families of Persons with Dementia
Authors: Splaine Michael 
Published: December 2022

AbstractBackgroundPatient v.Voice in clinical guidelines has become a standard practice in medical and care community.MethodFocus groups (online) were held with members of the IPA work group on Agitation and Dementia with early stage advisory groups to Alzheimer’s Associations and family caregivers.ResultLanguage about agitation was tested, refined, clarified in the overalL IPA guidelines. Many early stage persons also voiced strong opinions about non pharmacological treatments as preferred.ConclusionOur work group and documents were enhanced by taking time for consitituency consultation.
Resilience to Alzheimer’s Disease in a pathologicaly confirmed cohort
Authors: Ahangari Narges , Fischer Corinne E. , Schweizer Tom A. , Munoz David G. 
Published: December 2022

AbstractBackgroundWhy some individuals with significant Alzheimer’s disease(AD) lesions in their brain retain their cognitive abilities while others with the same level of pathology manifest symptoms of dementia remains incompletely understood. The term cognitive resilience refers to this phenomenon. With limited success in pharmacological interventions that prevent the onset of AD pathology, more efforts are aiming toward developing strategies to delay the clinical expression of AD; acetylcholinesterase inhibitors serve as an example, and compounds with similar pharmacodynamics such as nicotine may play a similar role. Here we sought to identify demographic, clinical, genetic, and neuropathological features associated with cognitive resilience in participants with severe AD neuropathology.MethodData for this retrospective cohort was collected from the datasets developed by the National Alzheimer’s Coordinating Centre (NACC). Individuals with severe AD pathology and no other primary neuropathology diagnoses who had their last visit within 2 years of their time of death were included. Severe AD pathology definition was based on National Institute on Aging–Reagan (NIA‐Reagan) criteria pathology, i.e., frequent neuritic plaques and Braak & Braak stage V/VI pathology. Cognition was assessed using the Mini‐Mental Status Examination (MMSE) score at their last visit and cases with scores ≥24 were defined as being cognitively intact, and thus resilient. Following bivariate analysis to compare resilient with non‐resilient groups, significantly different variables were adjusted for demographics using logistic regression analysis. Subsequently, statistically significant characteristics were entered in a multivariable model.ResultsWe classified 59(9%) individuals as resilient and 595(91%) as non‐resilient. The binary logistic regression model showed that resilient subjects were older (odds ratio[OR] = 1.03;95% confidence interval[CI] = 1–1.07), had more years of education (OR = 1.16;95%CI = 1.04‐1.29), had lower BMI (OR = 0.91;95%CI = 0.85‐0.99), were more likely to be a smoker (OR = 2.78;95% CI = 1.45‐5.34), and were more likely to use an anticoagulant/antiplatelet at last visit compared with subjects with impaired cognition (OR = 1.87;95%CI = 1.01‐3.48).ConclusionsOur results corroborated previous findings that lower BMI and higher education are associated with AD cognitive resilience, and additionally demonstrated that the level of smoking and usage of anticoagulant/antiplatelet medication have a direct relationship with cognitive resilience to AD severe pathology. Nicotine mimetics could be explored as a potential option for preventing AD clinical expression.
Stress, anxiety and depression in older adults at increased risk for cognitive decline: association with biomarkers and sex/gender differences
Authors: Arenaza‐Urquijo Eider M , Akinci Muge , Palpatzis Eleni , Peña‐Gomez Cleofé , Suárez‐Calvet Marc , Gispert Juan Domingo , Minguillón Carolina , Grau‐Rivera Oriol , Sánchez‐Benavides Gonzalo , Fauria Karine 
Published: December 2022

AbstractBackgroundAnxious depressive symptomatology and stress are associated with cognitive decline. Recent evidence suggests a relation between these factors and Alzheimer’s disease (AD) pathophysiology early in the continuum. With the current increases in anxiety, depression and stress due to the Covid19 pandemic ‐ notably in women ‐ unrevealing the biological mechanisms underlying these associations with a sex/gender approach appears fundamental.MethodWe included a total of 1170 participants in a series of observational cohort studies. Participants were cognitively unimpaired with increased risk of AD dementia (family history, APOE ε4, subjective cognitive decline). We investigated stressful life events with a lifespan perspective, stress perception, and changes in anxiety/depression in late life in relation to CSF, PET and MRI biomarkers of AD pathologies, neuroinflammation and brain atrophy. To that end, we performed multiple regression models adjusted by age, sex and education level. We also carried out stratified analyses by sex and explored sex differences in lifestyle and anxious‐behaviors (e.g., eating and sleep patterns).ResultThe accumulation of stressful life events as well as late‐life anxious depressive symptoms were associated with neuroinflammation markers, notably in women. Midlife stress was associated with increased tau and brain atrophy, together with lifetime history of anxiety/depression. In late life, amyloid positivity predicted longitudinal increases in anxiety and depression in the face of stressors, i.e., the covid19 pandemic, in women. Stress perception was not itself associated with any biomarker tested but mediated the increases in anxiety/depression. Women showed higher anxiety/depression and stress‐perception than men. While sex‐differences were identified in eating and sleep patterns, these did not explain the reported associations.ConclusionsOur results suggest that mental health factors and stress should be tackled from a life‐span and sex/gender perspective in people at risk for cognitive decline (Fig1): midlife stress may enhance tau pathology and brain atrophy. Accumulation of stress and anxiety/depression may enhance neuroinflammation pathways in women as well as brain atrophy. Once amyloid is present, women may be more prone to show increases in anxiety and depression in the face of stressors. Finally, stress‐perception represents an intervenable factor that may prevent increases in anxiety and depression.