bluuebunny/crossref_metadata_2025 huggingface dataset:
Hyperbaric oxygen therapy improves cognitive function in D‐galactose‐induced aging via restoring autophagy, apoptosis, microglia activation and synaptic plasticity in hippocampus
Authors: Shwe Thazin , Bo‐Htay Cherry , Leech Tom , Pratchayasakul Wasana , Chattipakorn Nipon , Chattipakorn Siriporn C
Published: December 2020

Background

Aging is the major risk factor for the age‐related diseases such as dementia and Alzheimer's disease. Previous studies found that aging could impair autophagy, microglia morphology and synaptic plasticity in hippocampus, resulting in cognitive decline. Although there are several models that usually used to induce aging, D‐galactose exposure induced aging as similar patterns as shown in naturally aging. Among the various treatments of Alzeimer’s disease, hyperbaric oxygen therapy (HBOT), which inhales 100 % pure oxygen in a pressurized hyperbaric chamber, becomes the focus of interest because it is a non‐invasive and painless treatment. Previous studies also found that HBOT increased antioxidants, decreased oxidative stress and the number of microglia in Alzheimer’s model. However, the effect of HBOT on autophagy, apoptosis, microglia activation, Alzheimer's protein production, synaptic plasticity and cognitive function in the model of D‐galactose‐induced aging has never been studied. We hypothesize that HBOT decreases oxidative stress, microglia hyperactivation, autophagic impairement, apoptosis, synaptic dysplasticity and cognitive impairment in D‐galactose‐induced aging.

Method

Fifteen Wistar rats (6‐week‐old) were received either vehicle as control rats (0.9% NSS, s,c; n=5) or D‐galactose as D‐gal rats (150mg/kg/d, s.c; n=10) for 10 weeks. After that, control rats were given sham‐treatment (1ATA, 80L/min, 80mins/day; CS; n=5), D‐gal rats were given together with either sham‐treatment (1ATA, 80L/min, 80mins/day; DS; n=5) or HBOT (2ATA, pure O2, 250L/min, 80mins/day; DH; n=5) for 14‐day. Novel object location test and hippocampal pathologies were determined after HBOT.

Result

We found that D‐gal rats had increased hippocampal oxidative stress, autophagy impairment, BACE1, microglial hyperactivation, apoptosis and synaptic dysplasticity, which resulted in cognitive impairment. Interestingly, HBOT decreased hippocampal oxidative stress, autophagy impairment, BACE1, microglial hyperactivation, apoptosis, synaptic dysplasticity and cognitive impairment in D‐galactose‐induced aging rats (p<0.05, Figure 1).

Conclusion

HBOT decreased cognitive impairment in D‐galactose‐induced aging via reducing hippocampal oxidative stress, autophagic impairment, BACE1, microglial hyperactivation, apoptosis and synaptic dysplasticity. Therefore, HBOT may be used as a safe and effective treatment to prevent the neurodegeneration of aging.
Cognitive fluctuations of object recognition in Lewy body dementia: An EEG/MEG study
Authors: Huang Yujing
Published: December 2020

Background

Lewy body dementia (LBD) shared a common pathological core feature of cognitive fluctuations. However, the clinical identification of attention fluctuation is still controversial. In this study, we combined EEG and MEG to explore the electrophysiological and magnetic biomarkers of attention fluctuations in LBD. We hypothesized that LBD showed stronger fluctuations in sensor‐level and source‐level EEG and MEG.

Method

Nine LBD and twelve healthy controls (HC) were recruited in this study. We designed an object recognition task, in which an object stimulus appeared on the screen and then the participants were required to respond as quickly and accurately as possible to judge whether this object was an animal or not an animal. There were six blocks, each of which included 12 different animal stimuli and 12 non‐animal stimuli. The animal/non‐animal stimuli were repeated across blocks. EEG and MEG were simultaneously recorded online. Cognitive fluctuations were examined via the variations across all trials (trial‐wise fluctuations) or across blocks (block‐wise fluctuations).

Result

(1) healthy controls had shorter reaction time and higher accuracy rate than LBD but the variations of reaction time was significantly higher in LBD than healthy controls. (2) HC had stronger overall EEG amplitudes for post stimulus in line with previous studies about the deficit of object recognition in dementia. The overall single‐trial‐wise variations and block‐wise variations of MAG/GRM were higher in LBD than HC. (3)Although time frequency power didn’t showed significant differences between LBD and HC in most electrodes, lower theta phase lock value (PLV) in HC compared to LBD for central‐parietal EEG/MEG electrodes. The central‐parietal EEG/MEG PLV was significantly higher in HC than LBD for alpha, beta and gamma bands. (4) Interestingly, higher single‐trial‐wise phase‐lock values (PLV) variations in LBD compared to HC were mainly from theta band and alpha band for front‐parietal EEG/MEG electrodes. (5) The source localization results showed that trial‐wise and block‐wise source fluctuations in LBD had a tendency to involve a network of parietal areas, including postcentral gyrus, superial parietal areas et al.

Conclusion

Our study revealed the possible biomarkers of attention fluctuations in LBD by using EEG and MEG.
The association between retinal vascular fractal dimension and cognitive function in the community‐dwelling elderly cohort TIGER
Authors: Wu Ting‐Yu , Chen Jen‐Hau , Chiou Jeng‐Min , Chen Ta‐Fu , Lai Liang‐Chuan , Chen Yen‐Ching
Published: December 2020

Background

Cerebral vascular factor plays an important role in the pathogenesis of cognitive dysfunction, including mild cognitive impairment (MCI) and dementia. The small retinal vessels reflect cerebral microcirculation and its fractal dimension (Df) representing the complexity of the retinal microcirculation. However, the connection between the retinal circulation and cognitive function lacked consistent and longitudinal evidence. This study aimed to explore the association between the retinal vascular Df and cognitive dysfunction in the community‐dwelling older adults.

Method

This study is part of a prospective cohort Taiwan Initiative for Geriatric Epidemiological Research (TIGER, 2011 to present). Participants from the 4‐year (2015–2017) and 6‐year (2017‐2019) follow‐ups were included. Global and domain‐specific cognitive function were assessed at the 4‐year and 6‐year follow‐ups. Fundus photography was taken for each participant at the 4‐year follow‐up, and retinal vessels were segmented for fractal analyses. Multivariable logistic regression analyses were performed to explore the association between Df of the retinal vessels and cognitive decline over 2 years adjusting for age, gender, years of education, diabetes, hypertension, hyperlipidemia, cardiovascular event, smoking, drinking and age‐related macular degeneration.

Result

Higher right retinal vascular complexity (right Df) was associated with the decline of logical memory‐recall I [linear right Df: adjusted odds ratio (aOR)= 0.30, 95% confidence interval (CI)= 0.11 to 0.85). No significant linear association was found between Df and global cognition or other cognitive domains. For non‐linear relationship, we found an inverted U shape association between the right Df and global cognitive decline over 2 years [quadratic right Df: aOR=0.10, 95% CI = 0.01‐0.80]. The risk of global cognitive decline (assessed by MoCA‐T) was 0.1 when right Df change 0.1 unit (increase or decrease) from the sample mean (1.36). Similar nonlinear relationship was found for the decline of logical memory‐recall II over 2 years (quadratic right Df: aOR= 0.08, 95% CI= 0.01‐0.59). No significant association was found between left Df and cognitive decline over 2 years.

Conclusion

This study demonstrated a nonlinear relationship between the retinal vascular complexity of the right eye and the decline of global cognition and logical memory. This retinal biomarker may be used for screening dementia in the preclinical stage.
Relationship between clinical symptomatology and disease burden in dementia with Lewy bodies: An overview of the DEvELOP baseline results
Authors: van de Beek Marleen , van Steenoven Inger , van der Zande Jessica J. , Teunissen Charlotte E. , Stam Cornelis J. , Raijmakers Pieter G.H.M. , Scheltens Philip , van Der Flier Wiesje , Lemstra Evelien
Published: December 2020

Background

Dementia with Lewy Bodies (DLB) is a heterogeneous disease with a highly variable presentation of core and suggestive symptoms. The relationships between these symptoms and their impact on disease burden remain unclear. The DEmentia with LEwy BOdies Project (DEvELOP) is a longitudinal cohort study that aims to phenotype DLB patients in depth and study the course of symptoms and biomarkers over time. Here, we provide an overview of our baseline results. Additionally, we investigated associations between core and suggestive features and different aspects of disease burden, i.e. instrumental activities of daily living (I‐ADL) functioning, quality of life (QoL) and caregiver burden.

Method

DEvELOP is a prospective cohort study conducted at Alzheimer Center Amsterdam. To date, we included 94 DLB patients (69±6yrs, 11%F, MMSE 25±3), who underwent extensive clinical assessment, including assessment of core features, neurological examination, neuropsychological examination, MRI(n=87), EEG(n=65), DAT‐SPECT(n =75) and CSF(n=71). Core features (hallucinations, parkinsonism, fluctuations, RBD) and suggestive features (autonomous dysfunction, neuropsychiatric symptoms) were assessed using standardized questionnaires. We evaluated how each of these features related to the functional activities questionnaire(FAQ), QoL(QoL‐AD), and caregiver burden(ZARIT), using linear regression analyses with backwards selection, adjusted for age, sex and MMSE.

Result

In the DEvELOP cohort, 19% of patients had all four core features, while 11% had merely had one (Figure 1). RBD was most frequently reported feature (75%). 87% had an abnormal DAT‐spect, 95% showed diffuse abnormalities on EEG. Abnormal CSF Aβ42 was found in 49%, abnormal CSF p‐tau in 42%. More severe fluctuations on the Clinical Assessment of Fluctuations (stβ=0.46, p<0.001) and lower MMSE (stβ=‐0.31, p=0.002) were independent determinants of higher FAQ‐scores. More depressive symptoms on GDS (stβ=‐0.51, p<0.001) and more severe obstipation(stβ=‐0.22, p=0.01) were independently associated with lower QoL‐AD‐scores. Last, NPI‐apathy associated with higher caregiver burden on ZARIT (stβ=0.49, p<0.001) (Table 1, Figure 2).

Conclusion

We deeply phenotyped our prospective cohort of DLB patients and found clinically relevant associations between symptoms and disease burden. Cognitive symptoms were related to lower I‐ADL functioning, while negative psychiatric symptoms were associated with lower QoL and higher caregiver burden. Follow‐up is currently collected to further study the course of symptoms over time.
Semantic and episodic memory performances of patients with Alzheimer’s disease and minor neurocognitive disorder
Authors: Ozel‐Kizil Erguvan T. , Bastug Gulbahar , Kirici Sevinc
Published: December 2020

Background

Modified Dead‐Alive Test (M‐DAT), which was developed and validated by Ozel‐Kizil et. al. (2018) evaluates semantic and episodic memory together. The original form was developed by Kapur et al. (1989), however it was not adequately studied.

Method

M‐DAT consists of 45 names of celebrities who had died in remote past (15), died in the last five years (15) and who are still alive (15) and participants are asked whether they are alive or dead. Correct number of items concerning celebrities who died in remote past gives the semantic memory performance, while half of the the sum of correct number of items concerning celebrities who are still alive and had died in the last five years is accepted as episodic memory performance. Semantic and episodic memory performances of patients with DSM‐5 major neurocognitive disorder due to Alzheimer’s Disease‐MND‐AD (n=69), patients with DSM‐5 minor neurocognitive disorder‐MiND (n=27) who were admitted to geriatric psychiatry clinic and volunteered healthy controls‐HC (n=29) were compared. The groups were compared either by one‐way ANOVA or Kruskal‐Wallis tests and Bonferroni or Mann Whitney U tests was used for post‐hoc analysis.

Result

MND‐AD group was older and less educated. Also MND‐AD group had lower MMSE scores while MiND and HCs had similar scores. MND‐AD had lower semantic and episodic scores than MiND and HC, also the scores of MiND group were lower than HCs. Both M‐DAT semantic and episodic scores were positively correlated with education in the whole sample (R=.53, p<0.001; R=.43, p<0.001). Although semantic memory performances were higher than episodic memory performances in all groups, two scores were positively correlated (R=.71, p<0.001).

Conclusion

The results of the study suggested a semantic memory impairment as well as episodic memory deficit in patients with major and minor neurocognitive disorder. Although previous studies have conflicting results, semantic memory deficit early in Alzheimer’s disease and in mild cognitive impairment was also reported (3). M‐DAT is an alternative for the assessment of semantic memory that is usually evaluated by verbal fluency tests. Evaluating episodic and semantic memory together is an important advantage however M‐DAT is affected by education and the items require updating.
Emotion recognition of morphed facial expressions in presymptomatic and symptomatic frontotemporal dementia, and Alzheimer’s disease
Authors: Jiskoot Lize C. , Poos Jackie M. , Vollebergh Manon , Papma Janne M. , van Swieten John C. , Kessels Roy P.C. , van den Berg Esther
Published: December 2020

Background

An increasing amount of studies are emphasizing the importance of social cognitive assessments to improve early diagnosis between frontotemporal dementia (FTD) and Alzheimer’s Disease (AD). Traditional measures of social cognition, including emotion recognition paradigms, however seem insensitive to the subtle deficits in the earliest dementia stages. The Emotion Recognition Task (ERT) was developed to identify early deficits in the recognition of facial expressions across different levels of intensity.

Method

Using the ERT, we assessed the recognition of morphed facial expressions of six emotions (anger, disgust, fear, happiness, sadness and surprise) across four intensities (40, 60, 80 and 100%) in patients with behavioural variant FTD (bvFTD; n=32), patients with AD (n=32), FTD mutation carriers (presymptomatic n=47, mildly/questionably symptomatic n=5) and controls (n=49). We examined group differences using multilevel linear regression modelling, and performed post hoc analyses on presymptomatic (MAPT, GRN and C9orf72) and mildly/questionably symptomatic mutation carriers. Classification abilities were investigated with logistic regression analyses; we determined sensitivity/specificity with ROC analyses.

Result

The lowest ERT total scores were found in bvFTD and AD patients, whereas equally highest scores were found in mutation carriers and controls. bvFTD patients scored significantly lower than AD patients on anger (p=0.023) and happiness (p<0.001), where subjects with mild/questionable FTD had an intermediate position between patients with dementia and those without (p=0.051) (Figure). Discriminative ability was better at the lowest (40%) than at the highest intensity (100%). Presymptomatic C9orf72 mutation carriers were worse at recognizing anger at the lowest (40%) emotional intensity than controls (p=0.038) and presymptomatic GRN mutation carriers (p=0.047). The ERT classified between patients with bvFTD and controls, patients with AD and controls (both p<0.001), but not between patients with bvFTD and AD, nor the total group of mutation carriers and controls (p>0.05).

Conclusion

Our results demonstrate clear emotion recognition deficits in bvFTD and AD, and suggest the presence of subtle changes in facial emotion recognition in early‐stage FTD. This provides us more insight into the discrete neural substrates involved in behavioural and emotional changes in developing FTD, but also highlights the importance of incorporating emotion recognition paradigms into standard neuropsychological assessment for early differential diagnosis.
Hospitalization expenses attributable to cognitive‐frailty in the elderly in China
Authors: Yang Ying
Published: December 2020

Background

To estimate the hospitalization expenses attributable to Cognitive‐frailty elderly in China and analyze the influencing factors in order to do a reasonable preventive measures, thereby reducing the economic burden of patients.

Method

A retrospective study. Patients hospitalized in the department of Neurology or Geriatric for comorbidity from November 2015 to June 2016 were enrolled. Geriatric Comprehensive assessment was scored using FRAIL, MMSE, and ADL respectively. Patients were divided into 4 groups (no‐frailty and no‐Cognitive (N group), no‐frailty and Cognitive(C group), frailty and no‐Cognitive (F group)and Cognitive‐frailty group (CF group )) according to the evaluation results, of which hospitalization expenses and influencing factors were analyzed using single factor and logistic regression analyses.

Result

Medicine was the predominant expense during hospitalization of all comorbidity patients, however, the cost of rehabilitation in CF group was lower than that in N group (P=0.006).The total cost of hospitalization in CF group was higher than that in N group (P < 0.001), albumin level was lower than that in N group (P = 0.016), and hospitalization time was longer than that in N group (P = 0.038).In multivariable analysis adjusting for age, gender, marital status, smoking, alcohol use, WBC,HB,PLT,ALB and LDL, the difference of hospitalization expenses between CF group and N group is still statistically significant (OR:1.00057 95%CI:1.00023‐1.00091).

Conclusion

The hospitalization expenses of the elderly with Cognitive‐frailty are relatively high at present and medicine was the predominant reasons. However, the rehabilitation exercise of inpatients with cognitive‐frailty is relatively deficient and their nutritional support is insufficient and thus reducing the use of drugs and strengthening the prevention and treatment of geriatric syndrome may reduce the hospitalization costs of the patients with Cognitive‐frailty.
Anosognosia in Alzheimer’s disease associated with tau accumulation and hypometabolism in frontal areas
Authors: Yakac Guelnihan , Maier Franziska , Bohn Karl Peter , Schild Ann‐Katrin , Meiberth Dix U. , Onur Oezguer A. , Fließbach Klaus , Drzezga Alexander , van Eimeren Thilo , Bischof Gerard N , Jessen Frank
Published: December 2020

Background

Impaired insight in cognitive deficits (anosognosia) in Alzheimer’s disease (AD) is frequent and problematic, but pathophysiological mechanisms are not fully understood. So far, several regions such as the cingulate cortex or frontotemporal regions have been identified as crucial. The aim of the present study was to explore the neural substrates of anosognosia in AD by applying 18‐F fluorodeoxyglucose (FDG) and 18‐F‐AV‐1451 (Tau) positron emission tomography (PET).

Method

Seventy‐four AD‐patients with mild cognitive impairment (MCI) or dementia were included in this study. Anosognosia was assessed by a clinician, based on a structured interview compared to patient’s subjective cognitive impairment. Cognition was examined applying the Consortium to Establish a Registry for AD (CERAD‐Plus) neuropsychological assessment battery. All patients underwent FDG‐PET. Additionally, 29 patients received a Tau‐PET. Glucose metabolism and 18‐F‐AV‐1451 binding were analyzed in a whole brain approach by comparing patients with and without anosognosia. Imaging analyses were controlled for age and sex.

Result

Of the 74 patients, 28 had anosognosia and 46 were aware of their deficits. Patients with anosognosia were significantly older and less depressed. The number of MCI/dementia patients was similar between groups (MCI+/‐anosognosia 11/25, dementia +/‐anosognosia 17/21, p=.209). Neuropsychological results showed a significantly more impaired verbal fluency in patients with anosognosia (p=.025). When FDG‐PET images were analyzed, patients with anosognosia had a significantly lower glucose metabolism in the inferior frontal gyrus, rectal gyrus and medial frontal gyrus including the anterior cingulate cortex (cluster level, p‐uncorrected<0.001, FWE‐corrected p=.006). Tau‐PET analyses showed a significant higher tracer binding in patients with anosognosia in the inferior and medial frontal gyrus (cluster level, p‐uncorrected=.003, FWE‐corrected p=.048).

Conclusion

This is the first study examining FDG‐ and Tau‐PET in AD patients with and without anosognosia. Anosognosia was not only associated with reduced glucose metabolism but also with increased tau accumulation in inferior and medial frontal regions. We speculate that tau‐induced hypometabolism in regions related to self‐referential processes leads to anosognosia.
Sleep disturbances in cognitively asymptomatic patients with histopathologically confirmed AD predict rapid cognitive deterioration
Authors: Atayde Adrienne Lloyd , Fischer Corinne E. , Schweizer Tom A. , Munoz David G.
Published: December 2020

Background

The temporal relationship between sleep disturbances, Alzheimer’s Disease (AD) pathology, and related cognitive impairment remains controversial. The objective of this study is to determine whether sleep disturbances at baseline predict the rate of cognitive deterioration in cognitively intact subjects with autopsy confirmed AD neuropathology. We also examine the interaction of sleep disturbances with APOE genotype and cerebral amyloid angiopathy (CAA).

Method

The National Alzheimer’s Disease Coordinating Center (NACC) datasets was used to compare the rate of cognitive decline between subjects with nighttime behaviors [(+)NTB] or without [(‐)NTB] at baseline as assessed by the Neuropsychiatric Inventory Questionnaire Quick Version (NPI‐Q). Cognitive impairment was determined by the Mini‐Mental Status Examination (MMSE) total score. Cognitively normal subjects at baseline were defined as having an initial MMSE score ≥ 24 at the first NACC clinical visit. The rate of cognitive decline was determined based on the individual’s annual MMSE score change over the total clinical visits made. All subjects had a primary neuropathologic diagnosis of Alzheimer’s pathology as determined by both high CERAD score and Braak stage.

Result

404 subjects fulfilled the inclusion criteria. The rate of cognitive decline was greater in (+)NTB (74 cases; 3.30 points per year) compared to (‐)NTB (330 cases; 2.45 points per year) (p = 0.016). This significant difference was restricted to APOE ε4 carriers (p = 0.049) and subjects with CAA (p = 0.020), and was absent in non e4 carriers and subjects without CAA. There was no difference between (+)NTB and (‐)NTB in the prevalence of these two factors associated with the rate of cognitive decline (e4 and CAA), suggesting that NTB itself is responsible for the effect observed.

Conclusion

NPI‐Q assessed nighttime behaviors, a surrogate for sleep disturbances, are associated with more rapidly declining cognition in subjects with Alzheimer’s neuropathology. In addition, this relationship is enhanced in carriers of APOE e4 and cerebral amyloid angiopathy.
Tissue‐specific genetically regulated expression in late‐onset Alzheimer’s disease implicates risk genes within known and 30 novel loci
Authors: Chen Hung‐Hsin , Petty Lauren , Lee Bommi , Sha Jin , Zhao Yi , Gamazon Eric , Bush William S. , Naj Adam C. , Below Jennifer
Published: December 2020

Background

Late‐Onset Alzheimer Disease (LOAD) is the most common neurodegenerative disease. Its heritability is estimated to be 40‐80%, yet the numerous genome‐wide studies (GWAS) conducted to date have identified risk variants that explain only ∼8% phenotypic variance.

Method

To improve understanding of the functional genetic etiology of LOAD, we used 39 GWAS datasets including 58,713 cases and controls from the Alzheimer’s Disease Genetics Consortium (ADGC) and the International Genomics of Alzheimer's Project (IGAP). For the 31 ADGC datasets, high quality variants were used to impute gene expression with PrediXcan, an approach that infers the genetically‐regulated portion of gene expression (GReX) from common expression quantitative trait loci. GReX was modeled using models from 50 different tissue types including 48 tissues from Genotype‐Tissue Expression Project, whole blood samples from the Depression Genes and Networks dataset, and dorsolateral prefrontal cortex samples from the CommonMind Consortium. Also, a multi‐tissues model was applied principal components analysis to extract the common expression pattern across all tissues. In addition, the summary GWAS statistics from the 8 IGAP studies were used to evaluate the GReX‐phenotype associations through S‐PrediXcan with the same 50 diverse tissue models.

Result

Meta‐analysis across all studies identified 225 unique genes reaching Benjamini‐Hochberg (BH)‐corrected genome‐wide significance (BH‐adjusted p < 0.05) across all tissue‐specific models, including 26 with no previously‐reported GWAS associations with LOAD. Top hits included BLOC1S3 (p = 2.95 × 10−273), CD3EAP (p = 7.19 × 10−239), and RELB (p = 1.52 × 10−167). In a multi‐tissues model, 33 genes had significant effect, including BLOC1S3 (p = 1.21 × 10−64), APOC1 (p = 2.94 × 10−61), and CD3EAP (p = 1.10 × 10−56). Conditional analysis of previously reported loci using prior LOAD GWAS risk variants identified 8 genes reaching genome‐wide significance independent of known signals, including SLC39A13, SDHD, and MTCH2. Further independent validation of identified genes was performed in ∼23,000 individuals in a large, electronic health record‐linked DNA databank. In a phenome‐wide enrichment analysis with a million times permutation, our identified genes were enriched for associations with insomnia (p < 1 × 10−5) and degenerative disease of the spinal cord (p = 1 × 10−5).

Conclusion

In conclusion, leveraging genotype‐based GReX in ∼60,000 individuals illustrates the utility of gene regulatory models in the discovery of new loci and function‐based fine mapping of known regions for LOAD and highlights other potential clinical consequences of disrupted regulation at LOAD‐associated genes.
Network diffusion model enhances predictions of future tau‐PET burden in Alzheimer’s patients
Authors: Damasceno Pablo F. , La Joie Renaud , Shcherbinin Sergey , Southekal Sudeepti , Kotari Vikas , Higgins Ixavier A. , Collins Emily C. , Rabinovici Gil D. , Mintun Mark A. , Raj Ashish
Published: December 2020

Background

Precisely measuring longitudinal tau PET is important for clinical trial design. Here we use a group of patients diagnosed with AD dementia (N = 28) and mild cognitive impairment (MCI) (N = 60) to investigate whether a network‐based pathological spread model could predict future tau accumulation based on regional standardized uptake value ratios (tau‐SUVR) and amyloid values determined at baseline.

Method

Baseline and 18‐month follow‐up flortaucipir and MRI images were analyzed from the Avid A05 phase 2 study (NCT 02016560, (Pontecorvo et al. 2019)). PET images were aligned to their respective Freesurfer‐conformed MRI images. Regional mean SUVR were extracted for 68 cortical regions using a white matter reference region (Southekal et al. 2018). The Network Diffusion Model (NDM) (Raj et al. 2012; 2015) was used to estimate longitudinal tau following a simple regression Δτr = ‐mLτr, where Δτr is a vector of regional change in tau‐SUVR, the difference between tau‐SUVR at month 18 and baseline (Figure 2), L is the Laplacian matrix of the healthy‐based structural connectome, τr is the regional tau‐SUVR vector at baseline (Figure 2), m is a linear model proportional to baseline features (see Figure 1B). For each model m, the parameters were fit via Ordinary Least Regression and the resulting R2 was computed via bootstrapping. When fitting those parameters, predictions of Δτr were made either per region (Figure 3A), averaging over all cortical regions (Figure 3B); or averaging over selected ROIs – estimated via the NDM to have Pareto optimal Δτr (Figure 3C‐3D).

Result

For patients diagnosed with AD dementia, the explained variance increases as the number of regions decreases, independently of the model used for m (columns in Figure 3). The highest explained variance (R2 = 0.69) was found when predicting mean Δτ over four regions: (L/R) Superior Temporal, (L/R) Lateral Occipital, and when m is a linear combination of 3 baseline features: total cortical amyloid, total cortical tau, and ratio between these two quantities.

Conclusion

Structural brain connectivity may contribute to future tau accumulation, indicating its potential impact in monitoring patient’s progression and the design of future clinical trials. Further validation using independent datasets is warranted.
Frequency of comedication in patients with dementia
Authors: Wurm Raphael , Stamm Tanja , Reichardt Berthold , Parvizi Tandis , Silvaieh Sara , König Theresa , Cetin Hakan , Stögmann Elisabeth
Published: December 2020

Background

Comorbidity, especially cardiovascular disease, is frequent in people with dementia. At the same time, access to healthcare professionals and appropriate treatment might be more difficult to obtain. We used the Austrian prescription claims database to analyse the treatment of common comorbidities in patients with dementia and controls.

Methods

Insurance claims data covering 98% of the Austrian population were used. We identified patients treated with one of the four approved antidementives (Rivastigmine, Galantamine, Donepezil, Memantine) in the period of 2005‐16, and extracted age‐ and sex‐matched controls that were not being treated with an antidementive. Total number of medication was recorded and odds ratios (OR) for being prescribed that specific medication were calculated separately for the most common classes.

Results

We identified 127896 patients treated with an antidementive and matched them to controls in a 1:1 fashion. The median age was 82.3 (IQR 76.7 ‐ 86.6) and 65% were female. Those treated with an antidementive were prescribed significantly fewer drugs in total, including the antidementive drug, compared to controls (median 8 [IQR 5 ‐ 11] vs 9 [5 ‐ 15], p < 0.001, Table 1). The odds of receiving any of the recorded somatic comedication were significantly lower in patients treated with antidementives, with OR ranging from 0.96 for antidiabetics to 0.5 for antihypertensive and 0.34 for anti inflammatory drugs. Conversely, the odds for treatment with psychiatric drugs were significantly higher in this group, with an OR for antidepressants of 1.8 and 4 for antipsychotic drugs (Figure 1).

Conclusion

Patients treated with antidementives are less likely to receive treatment for common somatic comorbidities and more likely to receive treatment for psychiatric comorbidities than age and sex‐matched controls. Since available data overwhelmingly suggests that patients with dementia suffer from more comorbidities than those without, this data can be interpreted as evidence for undertreatment of somatic comorbidities in this patient group. with dementia and controls. Additionally, usage of antipsychotic was very frequent and exceeded previously published numbers, emphasizing the need for integrated care for patients with dementia.
Evaluating the implementation of a memory clinic using the RE‐AIM model: The experience of the “memory and neuropsychiatry clinic” in Hospital Del Salvador, Chile
Authors: Leon Tomas , Castro Loreto , Mascayano Franco , Lawlor Brian , Slachevsky Andrea
Published: December 2020

Background

The prevalence of dementia in Chile is 1.06%, meaning that over 200,000 people are affected. In 2017, the Ministry of Health launched the National Plan of Dementia in Chile which proposed establishing a range of health‐care services from primary care to Memory Units (MU). MUs have emerged as a new health care service composed of multidisciplinary teams with the goal of improving diagnosis and/or management of dementia patients. The creation and implementation of an MU should take into consideration policies and the organization of a particular healthcare system. In this context, the evaluation of a Chilean MU might provide information for the standardization and replication of such a health service nationwide. The objective of this paper was to evaluate the implementation processes of an MU using the RE‐AIM model, a multi‐component model aimed to assist the evaluation of the implementation of ongoing programs.

Method

We analyze the interventions made during the MU lifespan using the RE‐AIM model, a multi‐component model useful in evaluating the implementation of ongoing programs

Result

From March 2018 up to June 2019, a total of 510 patients were referred and assessed at the Hospital del Salvador, Santiago, Chile. Most patients came from primary care (51.9%) and from outpatient services at the Hospital (39.2%), particularly from the Neurology (63.3%) and Psychiatry (16.0%) departments. We estimated that MU assessed 5.39% of dementia patients in the referring area. Of all the patients evaluated by the MU, 11.11% were discharged. Of these, 66.1% were referred to primary health care, 16.94% to other outpatient services, 10.16% to a specialized mental health care centre, and 6.77% % to a daycare centre.

Conclusion

This was the first evaluation of the implementation of an MU as part of the Plan. It showed that it is possible to implement an MU in a low‐middle income country and improve access to dementia diagnosis, management, and treatment. Ongoing challenges include continuing to collect clinical data, creating research projects as part of the MU, and developing an MU protocol that can be adopted elsewhere in Chile.
Characteristics of amyloid‐PET‐negative/tau‐PET‐positive individuals
Authors: Yoon Bora ,   the Alzheimer’s Disease Neuroimaging Initiative
Published: December 2020

Background

Little is known about tauopathy without β‐amyloid (Aβ) (A‐T+). Since the introduction of the term primary age‐related tauopathy (PART) several clinicopathological studies have revealed the characteristics of this syndrome. We performed this study of people characterized as A‐T+ with PET biomarkers to describe these individuals, and to determine how such individuals did or did not reflect characteristics of AD.

Method

We included 506 nondemented participants from the ADNI dataset. We used Aβ (18F florbetapir or florbetaben) and tau (18F‐AV1451) PET. We subdivided them into 3 groups (A‐T‐ 324 vs A‐T+ 55 vs A+T+ 127) using predefined thresholds for Aβ (A) and tau (T). We compared these groups by demographics, brain amyloid, brain tau level and distribution, hippocampal volumes, and cognition.

Result

The A‐T+ group was the oldest among the 3 groups and showed a prevalence of the apolipoprotein E (APOE) ɛ4 genotype similar to A‐T‐ and lower than A+T+. Both the proportion of individuals who were diagnosed with mild cognitive impairment (MCI) and the severity of tau deposition in the A‐T+ group was intermediate between A‐T‐ and A+T+. There was no evidence of even subtly elevated Aβ in the A‐T+ group. A‐T+ showed no asymmetry of tau deposition, and the brain region with the highest tau deposition was the amygdala in both A‐T+ and A+T+ groups (Figure 1). However, the A+T+ group showed a more widespread distribution of tau including temporal, parietal, and occipital areas compared to A‐T+ (Figure 1). Hippocampal volumes (Figure 2) and cognition (Figure 3) were also intermediate to A‐T‐ and A+T+ after adjustment by age, sex, and education. In the A‐T+ group, tau deposition showed a negative association with hippocampal volume and cognition.

Conclusion

There is no clear evidence that the A‐T+ group is on the AD continuum. Brain Aβ shows no evidence of elevation and APOE genotypes do not show a high prevalence of ɛ4. These individuals are intermediate between A‐T‐ and A+T+ on most characteristics. Such individuals could reflect PART, although longitudinal follow‐up will be necessary to confirm whether any proportion develops overt Aβ‐positive dementia consistent with AD.
Predicting Alzheimer's disease progression: Results from the TADPOLE Challenge
Authors: Marinescu Razvan V. , Bron Esther E. , Oxtoby Neil P. , Young Alexandra L. , Toga Arthur W. , Weiner Michael W. , Barkhof Frederik , Fox Nick C. , Golland Polina , Klein Stefan , Alexander Daniel C.
Published: December 2020

Background

Accurate prediction of progression in subjects at risk of Alzheimer's disease is crucial for enrolling the right subjects in clinical trials, at the right time. However, an unbiased comparison of state‐of‐the‐art algorithms for predicting disease onset and progression is currently lacking.

Method

We present the findings of The Alzheimer's Disease Prediction Of Longitudinal Evolution (TADPOLE) Challenge, which compared the performance of 92 algorithms (Fig. 1) from 33 international teams at predicting the future trajectory of 219 individuals at risk of Alzheimer's disease (demographics in Fig. 2). Challenge participants were required to make predictions, for each month of a 5‐year future time period, of three key outcomes: clinical diagnosis, ADAS‐Cog13, and total volume of the ventricles.

Results

No single submission was best at predicting all three outcomes. For clinical diagnosis and ventricle volume prediction, the best algorithms strongly outperformed simple baselines (Fig. 3). However, for ADAS‐Cog13 no single submitted prediction method was significantly better than random guessing. On a limited cross‐sectional dataset emulating clinical trials, performance of the best algorithms at predicting clinical diagnosis decreased only slightly (+3% error) compared to the full longitudinal dataset (Fig. 4). Two consensus methods — mean and median over all predictions — obtained top scores on almost all tasks (Fig. 3‐4). Better‐than‐average performance at predicting clinical progression was associated with the additional inclusion of features from cerebrospinal fluid (CSF) and diffusion tensor imaging (DTI) (Fig. 5). On the other hand, better performance at ventricle volume prediction was associated with inclusion of summary statistics, such as patient‐specific biomarker trends (Fig. 5). Full results can be found on the website https://tadpole.grand‐challenge.org, while code for submissions is being collated by TADPOLE SHARE: https://tadpole‐share.github.io/.

Conclusion

Our work suggests that current prediction algorithms are accurate for biomarkers related to clinical diagnosis and ventricle volume, opening up the possibility of cohort refinement in clinical trials for Alzheimer's disease.
Alzheimer’s disease biomarker roadmap 2020: Time for tau
Authors: Dodich Alessandra , Boccardi Marina , Ashton Nicholas J , Barthel Henryk , Bischof Gerard N. , Carrillo Maria C. , Chiotis Konstantinos , Corre Julie , Démonet Jean‐François , Drzezga Alexander , Gietl Anton F. , Hansson Oskar , Johnson Keith A. , Leuzy Antoine , Lorenzi Marco , Nordberg Agneta K. , Ossenkoppele Rik , Rabinovici Gil D. , Ratib Osman , Sabri Osama , Treyer Valerie , Unschuld Paul G. , Villemagne Victor L.L. , Winblad Bengt , Wolters Emma E. , Frisoni Giovanni B. , Garibotto Valentina
Published: December 2020

Background

In the last decade, the research community has focused on defining reliable biomarkers for the early detection of the pathological hallmarks of Alzheimer’s Disease (AD). In 2017, the Geneva AD Biomarker Roadmap Initiative adapted the framework for the systematic validation of oncological diagnostic biomarkers (Pepe et al., 2001) to AD, with the aim to accelerate their development and implementation in clinical practice (Frisoni et al., 2017). With this work we assess the maturity of tau biomarkers and we define the research priorities.

Methods

In a two‐day workshop (Geneva, November 2019), we convened a panel of experts in AD biomarkers. The level of maturity for first and second generation tau PET tracers, CSF, and blood biomarkers was assessed based on the Biomarker Roadmap (Frisoni et al., 2017). Biomarker maturity and research priorities were processed by thematic subgroups before the meeting, and presented and discussed during the workshop.

Results

Tau PET biomarkers showed partial evidence of analytical and clinical validity, particularly in their efficiency to distinguish AD dementia patients from healthy controls. First‐generation and second‐generation tracers showed different properties in terms of specific binding and accuracy in distinguishing AD from other neurodegenerative diseases. Plasma biomarkers showed promising achievements in analytical validity for p‐tau and Aβ42, while total tau was judged as unsuccessful by the experts. Compared to the recent introduction of tau PET and plasma, cerebrospinal fluid (CSF) biomarkers have been explored for decades in AD, and consistently they showed the highest level of maturity according to the strategic roadmap, with significant improvements compared to 2017, the development of fully automated assays being the most valuable. Research priorities consequently mainly concern analytical and clinical validity aims, with a main focus on covering assay definition and validation versus post‐mortem specimens. In view of studies on clinical utility, the definition of appropriate patient‐ and clinically‐relevant outcomes emerged as an urgent priority.

Conclusions

Despite the recent development of PET‐ and plasma‐based tau biomarkers, both so far provide partial evidence for clinical validity. However, completion of studies on analytical validity is a key step required to properly investigate their clinical utility.
Intermediate outcomes of a randomized trial of Tele‐Savvy: An online psychoeducation program
Authors: Hepburn Kenneth , Griffiths Patricia , Nocera Joe R , Higgins Melinda , Lindauer Allison , Morhardt Darby , Shah Raj C , Epps Fayron , Brewster Glenna S , Bonds Kalisha , Nash Rachel
Published: December 2020

Background

This presentation provides an intermediate report on the outcomes of the first twenty cohorts of family caregivers (N=220) engaged in a NIA‐supported randomized, three‐arm trial of Tele‐Savvy, a fully online version of the Savvy Caregiver, an evidence‐based in‐person psychoeducation program. Tele‐Savvy is specifically aimed at enhancing caregivers’ capacity to manage the day‐to‐day challenges of caregiving by promoting caregiving mastery; the intended outcome is the reduction of caregiving distress. Tele‐Savvy engages groups of 5‐8 caregivers in 7 weekly synchronous online groups led by a trained facilitator; in between, caregivers are provided with 36 daily video lessons they can view whenever and as often as they wish. Caregivers were recruited in cohorts of 15 from 34 states and 2 Canadian provinces and randomly assigned (in a 2:2:1 ratio) to immediate participation in Tele‐Savvy, an attention control condition (Healthy Living), or usual care.

Method

Data reported here were gathered on key outcomes at baseline and then 3 and 6 months. Multilevel mixed models were used to test for group, time, and group‐by‐time effects for each of the outcomes.

Result

We found a significant group‐by‐time effect on CES‐D‐assessed caregiver depression (p<.001) with the active group showing significant decreases over time (p<.001). Of note, 35% of the active group reported clinically significant depression at baseline; this reduced to 22% by six months. In contrast, 25.5% those in the waitlist group scored as clinically depressed, a figure that increased to 33% by six months. We found a significant group‐by‐time effect on caregiver perceived strain (p<.001) with the active group demonstrating significant reductions over time (p<.001) and the waitlist control group demonstrating significant increases (p=.010). Likewise, there was a significant group‐by‐time effect (p=.001) on caregivers’ reactions to care recipient behaviors (RMBPC) with significant reductions over time among the active caregivers (p=.001). Caregiver competence demonstrated a significant group‐by‐time effect (p‐.009) with the active group demonstrating significant increases over time (p<.001). Findings regarding caregivers’ management of the situation were comparable: a significant group‐by‐time effect (p=.003) with the active group demonstrating significant increases over time (p<.001).

Conclusion

At this point, Tele‐Savvy appears to be achieving its aims of enhancing mastery and decreasing distress.
Effect of metabolic syndrome risk factors on processing speed in three racial groups
Authors: Bouges Shenikqua , Norton Derek L , Wyman Mary F , Lambrou Nickolas H , Zuelsdorff Megan , Van Hulle Carol A , Ennis Gilda E , James Taryn T , Johnson Adrienne L , Clark Lindsay R , Carlsson Cynthia M , Gleason Carey E
Published: December 2020

Background

Metabolic syndrome (MetS) in mid‐life is a known risk factor for Alzheimer’s disease & related dementias (ADRD). Racial and ethnic minorities represent under‐represented groups (URGs) in ADRD research. Targeted outreach, recruitment and retention initiatives broaden the reach of Alzheimer Disease Research Centers (ADRC) within prioritized communities. Understanding the association between MetS risk factors and cognition during preclinical ADRD in URGs may elucidate avenues for ameliorating ADRD risk in URGs prior to dementia onset. Generalizability of findings vary by the population represented within an analytic sample. We describe MetS‐cognition relationships within URGs and referral source, a key determinant of our sample composition.

Methods

Cognitively unimpaired adults from the Wisconsin ADRC and the Wisconsin Registry for Alzheimer’s Disease Prevention (WRAP) completed blood‐work and neuropsychological testing. Sample sizes varied based on the outcome analyzed and ranged from 714 to 1088 subjects. The 6 cognitive outcomes were: Trails A, Trails B, Animal Fluency, Digit Symbol, a Simple Speed composite, and Speed/Executive composite. Linear mixed effect models with an Age‐by‐Race‐by‐MetS interaction tested whether MetS count moderated age‐related cognitive trajectories differently in White (N=990), African American (AA; N=85), and Native American (NA; N=15) participants. In secondary analyses, referral source was examined for WRAP and ADRC cohorts to assess the potential for selection‐based effects in our data.

Results

Only Trails A had a significant 3‐way interaction (p=0.004). Graphing this interaction revealed that the cognitive trajectory in Whites remained stable as MetS count increased, while the NA trajectory appeared to worsen with increasing MetS count. AA and Whites appeared to have similar longitudinal trajectories despite a faster processing speed in White group. A small NA sample limits the precision of our results. Examinations of referral source data (Figure 5) suggest that enrollment differed between WRAP and the Wisconsin ADRC participants.

Conclusion

Results indicate disparities for level and decline in cognitive function for racial minority participants. Affected cognitive domain varies by race, but overall findings highlight the importance of prioritizing recruitment and retention of URG participants. Sample size, social & enrollment factors are all possible contributors to our findings and need to be examined in the future.