bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neuropsychiatric symptoms and cognitive decline: Trait or state effects?
Authors: Vik‐Mo Audun Osland , Melvær Giil Lasse , Ballard Clive , Aarsland Dag 
Published: December 2020

AbstractBackgroundNeuropsychiatric symptoms (NPS) are associated with more rapid cognitive decline but the effects of specific NPS remain unknown. NPS could have distinct association with the symptomatic state (within‐person effects, WP), but also as a symptom‐trait over time irrespective of current symptoms (between‐person effects, BP). The aim of study was to disentangle these effects.MethodPatients with mild Alzheimer’s disease (AD, n = 111) and Lewy‐body dementia (LBD, n = 85) were assessed annually from diagnosis until death with a mean follow‐up of 5.4 years (range 1‐12). Total, within‐person and between‐person associations between specific NPS (assessed with the Neuropsychiatric Inventory (NPI)) and cognition (measured by annual Mini‐Mental State Examinations (MMSE)) were analysed using a Tobit mixed‐effects model. NPI items were classified using ≥ 1 and 4 cut‐offs, and the models were adjusted for age, gender, diagnosis and survival.ResultHallucinations, agitation, anxiety, apathy and appetite were associated MMSE decline in the overall analysis. Hallucinations, agitation and apathy had both WP and BP associations with more rapid MMSE decline, with BP associations being stronger. Delusions and motor disturbances had strong BP association with MMSE decline. NPI symptom severity did not impact the results.ConclusionDifferent NPS had distinct state and trait associations with cognition that also differed from the total association. Treatment of NPS might improve cognition and should be tailored for different NPS based on history and current symptoms. Importantly, the effect of mild symptoms is similar to that of severe symptoms. These findings underline the importance of treatment as well as prevention of NPS. The high degree of instability of NPS has relevance for the design of clinical trials.
Associations of peak width of skeletonized mean diffusivity with cardiovascular disease risk and cognitive decline in clinically normal older adults
Authors: Scott Matthew R. , Schultz Aaron P. , Buckley Rachel F. , Chou Hsiang‐Chin Lori , Hampton Olivia L , Hanseeuw Bernard J , Jacobs Heidi I.L. , Properzi Michael J. , Rabin Jennifer S. , Johnson Keith A. , Sperling Reisa A. , Chhatwal Jasmeer P. 
Published: December 2020

AbstractBackgroundCardiovascular disease (CVD) is associated with cognitive decline, both alone and synergistically with Aβ burden, and can have a stronger relationship with cognitive trajectories than many standard imaging biomarkers. However, the effects of CVD and Aβ on cognitive decline have not been examined alongside diffusion markers of small vessel disease (SVD). With data from the Harvard Aging Brain Study (HABS), we examined the influence of CVD risk and peak width of skeletonized mean diffusivity (PSMD; a DTI measure of SVD) on cognitive trajectories in clinically normal participants, while accounting for Aβ burden.Method264 clinically normal participants from HABS (mean [SD]: age=73.2[7.1] years; follow‐up range=6.3[1.8] years) underwent at least four longitudinal assessments of the Preclinical Alzheimer’s Cognitive Composite (PACC96), as well as PiB‐PET imaging and DTI at baseline. PSMD was calculated from skeletonized mean diffusivity maps using FSL. CVD risk was quantified using the Framingham Heart Study‐CVD risk score. We used linear mixed‐effect models to examine the influence of baseline PSMD and CVD on longitudinal PACC, while controlling for, or interacting with, PiB DVR, correcting for baseline age, years of education, and biological sex.ResultPSMD and CVD were significantly correlated (r=0.38, p<1.0x10‐9), though this weakened when correcting for age (r=0.15, p=0.01), while PSMD and PiB showed no association (r=0.09, p=0.13). Higher PSMD was associated with faster cognitive decline (t(1808)=‐2.40, p=0.02) and this effect remained (t(1806)=‐2.26, p=0.02) after correcting for PiB. The effect of PSMD was marginally significant (t(1804)=‐1.93, p=0.05) when correcting for both CVD (t(1804)=‐4.44, p<1.0x10‐5) and PiB (t(1804)=‐7.79, p<1.0x10‐13). No significant interactive effect of PSMD and PiB on cognitive decline was observed.ConclusionCVD risk and PSMD were significantly correlated, though this was largely driven by age, while PiB and PSMD were not. PSMD was significantly associated with faster cognitive decline. After adjusting for both CVD and PiB however, the effect of PSMD on cognitive decline was attenuated. It is possible that CVD risk may capture variance related to cognitive decline beyond that of PSMD. However, future research is needed to understand which domains of the CVD risk score are driving these findings.
Quantification of amyloid accumulation and glucose metabolism in Chinese Alzheimer’s disease population
Authors: Li Junpeng , Jiang Donglang , Huang Qi , Ren Shuhua , Guo Qihao , Guan Yihui , Xie Fang 
Published: December 2020

AbstractBackgroundExtracellular amyloid‐β (Aβ) neuritic plaques, intracellular neurofibrillary tangles (NFTs) and neurodegeneration, such as glucose hypometabolsim were the main biomarkers of Alzheimer’s disease (AD). The uptakeof Aβ radiotracers, such as Flortabetapir, and uptake of FDG for glucose metabolism in subjective cognitive decline (SCD), mild cognition impairment (MCI) and Alzheimer’s disease (AD) is very important for diagnosis and management. Currently, no study was found to investigate the uptake of Flortabetapir and FDG in these cohorts. In this study, we try to figure out the standard uptake value ratio (SUVr) of different brain regions in Chinese SCD, MCI, AD.Methods93 normal cognition (NC) healthy volunteers, 37 SCD, 34 MCI and 36 AD patients were enrolled in this study. 3 cognitive domains (2 neuropsychological tests of each domain) and MMSE, Moca B were performed in these participants. FDG and 18F‐Flortabetapir were conducted in these participants. 18F‐FDG and 18F‐FlortabetapirPET images were coregistered to the individual structural MRI images and then spatially normalized into MNI space. SUVr values were calculated with cerebellum as referencefor Flortabetapir and whole brain for FDG.ResultsIn Chinese NC, SCD, MCI and AD, SUVr of flortabetapir in precuneus were 0.87 ± 0.25, 0.84 ± 0.18, 0.83 ± 0.32, 1.08 ± 0.46, respectively. 1.09 ± 0.24, 1.02 ± 0.15, 1.05 ± 0.28, 1.24 ±0.38 in posterior cingulate. SUVr of flortabetapir in AD is significant higher (p < 0.05) than other groups. SUVr of FDG in precuneus were 1.17 ± 0.08, 1.19 ± 0.07, 1.13 ± 0.12, 1.07 ± 0.10, 1.05 ± 0.10, respectively. 1.08 ± 0.10, 1.03 ± 0.12, 0.90 ± 0.18 in posterior cingulate. SUVr of FDG in AD is significant lower (p < 0.05) than other groups.ConclusionThe uptakes of Flortabetapir were signifigant higher and uptakes of FDG were lower in Chinese AD than in NC, SCD, MCI in precuneus and posterior cingulate.
Cross‐sectional relations of subclinical cardiovascular disease to AD blood biomarkers in cognitively intact older adults
Authors: Wright Regina Sims 
Published: December 2020

AbstractBackgroundSubclinical cardiovascular disease (CVD) is a key, early step in the development of frank CVD. Generally characterized by an age‐related increase in atherosclerosis and arterial stiffness, and/or reduced endothelial function, emerging evidence suggests subclinical CVD confers risk for Alzheimer’s disease and related dementias (ADRD) well before the onset of frank CVD. However, despite increasing recognition of the utility of blood biomarkers for understanding the pathophysiological events and progression of AD, little research has examined the association between markers of subclinical CVD and AD blood biomarkers. Thus, we sought to examine these associations in a sample of cognitively intact older adults enrolled in the Healthy Heart & Mind Study.MethodParticipants were 34% male and 41.7% African American with a mean age of 68.43y. Participants completed a health and medication screening, a battery of cognitive tests, a psychosocial assessment, a fasting blood draw, vascular testing (including assessment of carotid intimal‐media thickening (IMT), pulse wave velocity (PWV), and brachial artery flow‐mediated dilation (FMD), and structural brain MRI. Serum Ab1‐40 and Ab1‐42 (and ratio) were available for 99 participants at the time of this analysis.ResultBivariate correlation results showed a significant, positive association between % FMD change and Ab1‐40 only (p<.05). Ordinary least squares regression was run to further examine this association adjusting for the following potential confounding variables: age, gender, education, depression, and mean arterial BP. Results showed the significant, positive association between % FMD change and Ab1‐40 persisted after adjustment (p<.05).ConclusionFindings showed that worse endothelial function may be associated with lower Ab1‐40 in healthy older adults. While some research illustrates Ab1‐40 is reduced in AD, other research suggests increased levels are associated with vascular conditions such as hypertension, ischemic heart disease, and white matter lesions. Thus, our findings suggest a need to further examine the association between endothelial function and AD blood biomarkers to confirm the directionality of the relationship. Longitudinal research is also needed to examine the association over time.
Validating digital cognitive biomarkers for Alzheimer’s disease
Authors: Bock Jason R , Lee Michael D , Hara Junko , Fortier Dennis , Mangrola Tushar , Shankle William R 
Published: December 2020

AbstractBackgroundThis study sought to validate a pragmatic method to predict impending cognitive decline in Alzheimer’s disease (AD) patients, prior to the development of hallmark symptoms. The method, a Hierarchical Bayesian Cognitive Process (HBCP) model, uses item responses to a wordlist memory (WLM) test to generate digital cognitive biomarkers (Table 1). We replicated our earlier study, performed on AVLT item response data from Mayo Clinic, by applying the HBCP model to distinguish non‐decliner and decliner groups of normal subjects at baseline from a novel dataset, the Alzheimer’s Disease Neuroimaging Initiative (ADNI), with a distinct WLM test, ADAS‐Cog.MethodFrom the ADNI dataset, we classified non‐decliner subjects (n = 442) as those whose diagnosis remained normal for 3 or more years after normal baseline assessment and decliner subjects (n = 61) as those who developed amnestic MCI or AD within 3 years of normal baseline assessment. Three analytic approaches were compared: 1) Traditional summary scores per ADAS‐Cog task were assessed for group differences with a commonly‐used statistical approach, logistic regression; 2) summary scores were assessed with a Bayesian modeling approach; and 3) item response data were assessed with our HBCP model, generating digital cognitive biomarkers.ResultLogistic regression of summary scores generated β coefficients (Table 2) that did not significantly discriminate between groups. Bayes Factor assessment of fitted Gaussian distributions to the per‐task group recall by summary score measurement provided moderate evidence that the groups were measurably the same (BF
sd = 3.4, 3.1, 2.9, and 1.4, respectively). The HBCP model produced posterior distributions of group differences. Bayes Factor assessment identified three with notable group differences: Immediate Retrieval from Durable Storage, L1 (BF
ds = 11.8, strong evidence), One‐shot Learning, r (BF
ds = 4.5, moderate), and Partial Learning, a (BF
ds = 2.9, weak; Figure).ConclusionThe obtained strong evidence for L1 group differences represents successful replication of previous work with our HBCP model on this novel dataset. The ability to identify differences in subjects diagnosed cognitively normal at time of assessment demonstrates the HBCP model’s advantage over summary score assessment and its applicability for detection of impending cognitive decline in asymptomatic AD patients.
The accumulation rate of tau aggregates is higher in females and younger individuals
Authors: Smith Ruben , Strandberg Olof , Mattsson Niklas , Leuzy Antoine , Palmqvist Sebastian , Pontecorvo Michael J. , Devous Michael D. , Ossenkoppele Rik , Hansson Oskar 
Published: December 2020

AbstractBackgroundTau pathology is a key hallmark of Alzheimer’s disease (AD), but factors modifying the rate of tau accumulation are still largely unknown. Tau‐PET allows tau pathology to be visualized in vivo in AD. Our aim was to study factors associated with the accumulation rate of tau pathology, using [18F]flortaucipir PET.Method419 participants from four longitudinal cohorts in the United States (AVID05, n=157; Expedition 3, n=82; and ADNI, n=123) and Sweden (n=57) were scanned between June 2014 and May 2019. Study participants were cognitively unimpaired (CU, n=153), or patients with mild cognitive impairment (MCI, n=139) or AD with dementia (AD, n=127).Participants underwent two to four [18F]‐flortaucipir PET scans with a mean of 538 (±163[SD]) days between the first and last scan. Amyloid‐β(Aβ) status was determined using PET. [18F]‐flortaucipir was quantified in a temporal meta‐region of interest (ROI) and a neocortical ROI. Subject‐specific slopes (reflecting annual change) of [18F]‐flortaucipir SUVR were derived from linear regression models for each ROI. Generalized linear models were used to predict the subject‐specific slopes using the following variables: diagnostic group, age, sex, baseline tau‐PET SUVR, baseline Aβ‐status, APOE‐ε4 status and study cohort.ResultAccelerated increase in [18F]‐flortaucipir retention was observed in Aβ+ MCI and AD dementia, respectively, when compared to either Aβ‐ CU and Aβ‐ MCI (Figure 1). We found associations between change in [18F]‐flortaucipir over time and female sex (temporal meta‐ROI: t=2.93, p=0.004; neocortical ROI: t=2.96, p=0.003), younger age (temporal‐meta ROI: t=‐2.42, p=0.02), and baseline [18F]‐flortaucipir retention (temporal‐meta ROI: t=3.60, p<0.001; neocortical ROI: t=4.88, p<0.001) (Figure 2). There was a significant interaction between age and Aβ‐status on change in [18F]‐flortaucipir SUVR (temporal‐meta ROI: t=‐2.50, p=0.013). There was no effect of study cohort or APOE‐ε4 genotype. In a similar analysis on longitudinal Aβ‐PET (in ADNI subjects only, n=639) we found significant associations between the rate of Aβ‐accumulation and APOE‐ε4 positivity, older age and baseline Aβ‐positivity, but no effect of sex.ConclusionThese findings indicate that the tau accumulation rate is increased in females and Aβ‐positive younger individuals, in contrast to Aβ‐accumulation which is increased in APOE‐ε4 carriers and older individuals.
Protocol of a cluster randomised controlled trial to assess the effectiveness of a care management programme for caregivers of people with dementia (GAP study)
Authors: Klein Olga A , Kilimann Ingo , Thyrian Jochen René , Teipel Stefan J , Keller Armin , Boekholt Melanie , Michalowsky Bernhard , Zwingmann Ina , Dreier‐Wolfgramm Adina , Hoffmann Wolfgang 
Published: December 2020

AbstractBackgroundAbout 75% of dementia care is provided by family caregivers who often experience adverse health outcomes. The identification of unmet healthcare needs of family caregivers is crucial to provide appropriate support thereby relieving the economic burden of dementia. As the first point of contact, general practitioners (GPs) have a key role in identifying burden and care needs of family caregivers. However, in routine care, this opportunity is hampered by time constraints and even if caregiver needs are being recognised, GPs often lack detailed information on regionally available support and healthcare services. Aim: To assess the clinical and cost‐effectiveness of a GP‐ and computer‐based care management programme to reduce unmet care needs of family caregivers of people with dementia (PwD).MethodThis is a multi‐site, cluster randomised, controlled trial comparing a digital care management programme (intervention) with usual care (control). Five hundred family caregivers will be randomised at GP offices, specialist practices, and memory clinics, with about n=250 participants per arm. A computer‐based assessment will identify needs of family caregivers of PwD and will automatically generate an individual management plan. The treating GP will carry out the management plan generated in close collaboration with specifically qualified nurses, so‐called dementia care managers, who support and monitor the implementation of the care plan via four monthly telephone follow‐ups. All participants will receive a final follow‐up assessment at six months after randomisation. Participants in the control group will receive usual care at first and the individual management plan at the six months follow‐up. Primary outcomes are the Camberwell Assessment of Need for the Elderly and the EQ‐5D. Secondary outcomes include the Zarit Burden Interview, the Social Lubben Network Scale, and use of medical and non‐medical services. This trial is funded by the German Federal Joint Committee (G‐BA) and registered in the clinical trials database under NCT04037501.ResultWe expect to obtain significant differences in primary and secondary outcomes between groups in favour of the intervention group.ConclusionThe findings of this trial will be useful in informing and improving current healthcare system structures to support family dementia caregivers within routine care practice.
The impact of protocol design on MMSE changes in the screening period
Authors: Kott Alan , Miller David S. 
Published: December 2020

AbstractBackgroundAnecdotally, we have observed subgroups of subjects who in the screening period of clinical trials in early Alzheimer’s disease exhibit unexpectedly large changes in MMSE scores. Such changes could be explained by a number of reasons, such as learning effects, regression to the mean, measurement error, or intentional score manipulation. If the latter was the case, differences in MMSE changes between screening and baseline should be observed between protocols where MMSE inclusion criteria are required to be met at screening only and protocols requiring the criteria be met at screening and baseline. We hypothesized that MMSE changes would be larger in protocols with criteria required only at screening.MethodData were pooled from multi‐national dementia clinical trials in early AD where MMSE was collected at screening and baseline. Subjects were categorized into 2 groups depending on whether the inclusion criteria were applied to screening alone or to both the screen and baseline visits. T‐test was used to compare the change between screening and baseline between the two groups of subjects. Additionally we compared the distribution of subjects changing by a) 3 and b) 5 MMSE points in either direction between screening and baseline between the two protocol groups using a chi‐square test.ResultData were collected from 1,409 subjects. The MMSE change in subjects with criteria required at screening only was ‐1.2 points compared to ‐.05 points in subjects with criteria required at screening and baseline (t(1,407) = 5.99, p < 0.001). MMSE changes of 3 or 5 points were seen significantly more often in studies where the requirement was applied at screen alone (chi2(1)=18.2, p < 0.001 and chi2(1)=13.1, p < 0.001, respectively).ConclusionOur analyses indicate that protocol design has a significant impact on the MMSE change observed in the screening period. Given the only difference between the two groups was the absence of inclusion criteria at baseline, we hypothesize that the MMSE score change observed differences can most likely be explained by score manipulation happening at either screening only or screening and baseline, depending on protocol type. We plan to replicate these results in larger datasets.
Chronic phospholipase D1 inhibition via small molecule inhibitors ameliorate dendritic spine dystrophy in ADRD mouse models via phosphocofilin mediated changes
Authors: Natarajan Chandramouli , Bourne Krystyn Z. , Medina Perez Carlos X. , Krishnan Balaji 
Published: December 2020

AbstractBackgroundPhosphatidyl choline phospholipase D (PC‐PLD), a lipolytic enzyme that breaks down membrane phospholipids via two isoforms ‐ a constitutively expressed PLD2 and an inducible PLD1 isoform ‐ are also involved in developmentally important signaling mechanisms that regulate synaptic function. We were the first to propose and present a systematic study that established PLD1 as the aberrantly elevated isoform in AD and related dementia using human clinical samples and provided functional proof using mouse models to demonstrate the underlying synaptic dysfunction and memory deficits.MethodSynaptosomal Western blot analysis on 3xTg‐AD mice hippocampi were used to investigate neuronal PLD1 expression and function. Long term potentiation of PLD1 dependent changes using pharmacological approaches in ex vivo slice preparations from wildtype and transgenic mouse models were used to assess synaptic perturbations that were first studied using the novel object recognition memory (NOR) and fear conditioning (FC) paradigms. Chronic PLD1 small molecule inhibitor treatment was assessed in different age groups to ascertain the efficacy of treatment at different stages of Aβ and tau‐driven AD‐like memory deficit progression in transgenic animal models. Lastly, brain tissues from these animals were subjected to Western Blot analyses, Golgi analysis, immunohistochemical analysis to ascertain the potential signaling mechanism(s) that is/are perturbed/altered by overexpression of PLD1 in such diseased states.ResultChronic PLD1 inhibition ameliorates the synaptic dysfunction and underlying memory deficits in the 3xTg‐AD mouse model by specific action on preserving mushroom spine dendritic spine integrity. Further analysis using Western Blots revealed an underlying mechanism that increases the levels of phosphocofilin in the crude synaptosomal fractions.ConclusionUsing chronic administration of a well‐tolerated halopemide derivative of the specific PLD1 isoform inhibitor in the preclinical mouse models of synaptic dysfunction and memory deficits associated with amyloidogenic effects of Aβ and tau, we demonstrated neuroprotective aspects involving changes in the dendritic spine integrity that contributes to the preservation of memory. Furthermore, we also observed that the mechanism involves actin cytoskeletal dynamics that are modulated via phosphocofilin.