bluuebunny/crossref_metadata_2025 huggingface dataset:
Spatiotemporal imaging phenotypes of tau pathology in Alzheimer’s disease
Authors: Vogel Jacob W. , Young Alexandra L. , Oxtoby Neil P. , Smith Ruben , Ossenkoppele Rik , Aksman Leon M. , Strandberg Olof , La Joie Renaud , Grothe Michel , Medina Yasser Iturria , Rabinovici Gil D. , Alexander Daniel C. , Evans Alan C. , Hansson Oskar
Published: December 2020

Background

The Braak staging scheme describes a stereotypical spread of tau pathology in Alzheimer’s disease (AD). However, apparent subtypes described at autopsy and clinical variants of AD both suggest variability in the pattern of tau spreading across the population. To address this discrepancy, we applied a validated spatiotemporal clustering algorithm to a large, multisite dataset of tau‐PET images. We verified these findings both longitudinally and on a separate tau‐PET dataset using a different radiotracer, and we characterized the phenotype and potential biological determinants of each subtype.

Method

Subtype and Stage Inference (SuStaIn, Young et al., 2018 ) is a data‐driven, probabilistic algorithm that combines disease progression modeling with clustering to extract distinct spatiotemporal patterns (subtypes) from large cross‐sectional datasets. We applied SuStaIn to a multisite dataset (n=1143) of [18F]‐flortaucipir tau‐PET baseline scans to identify spatiotemporal subtypes of tau spreading. We investigated differences in demographic, cognitive and genetic measures. In a subsample of individuals with multiple tau‐PET scans over time (n=536), we tested longitudinal subtype stability and change in disease stage over time. We verified these subtypes in a second single‐site dataset (n=509) of [18F]‐RO948 tau‐PET scans. Finally we used the Epidemic Spreading Model (ESM, Iturria‐Medina et al., 2014) and imaging or transcriptomic analysis to determine if anatomical brain networks or specific cell‐types, respectively, could explain the differing spatial patterns across subtypes.

Result

In those subjects with significant tau‐PET signal in the brain, SuStaIn identified four spatiotemporal subtypes of tau‐PET spreading: Typical (worse memory, more APOE4 carriers), limbic‐sparing (younger, less APOE4 carriers), posterior (worse visuospatial cognition), and lateral‐temporal (worse language and executive function scores; Fig 1A, Fig 2). These same four subtypes were observed in a separate cohort using a different radiotracer (similarity 0.7–0.9; Fig 1B). 86% of subjects exhibited the same subtype at multiple visits (Fig 1C), and of that group, 83% advanced in disease stage or remained stable within model uncertainty. The ESM suggested different epicenters for each subtype, and each subtype pattern exhibited a different profile of cell‐type enrichment (Fig 3).

Conclusion

Four stable tau‐spreading phenotypes were observed with distinct cognitive profiles, which may be characterized by vulnerability of different corticolimbic networks involving distinct cell classes.
Investigating retinal blood flow characteristics and amyloid formation in patients with type 2 diabetes and mild cognitive impairment
Authors: DeBuc Delia Cabrera , Sapahia Rishav , Watane Arjun , Cho Kyoung‐A , Rege Abhishek
Published: December 2020

Background

Patients with type 2 diabetes (T2D) have almost a two‐fold greater risk of developing Alzheimer’s disease. Recent studies suggest that one link between the two conditions may be the processes underlying amyloidosis. Our previous studies have demonstrated that cognitive impairment (CI) is not limited to the brain but also affects the retina. In this pilot study, we quantified blood flow within the optic nerve head (ONH) using the XyCAM RI (Vasoptic Medical Inc.), an investigational non‐invasive, laser speckle‐based retinal imager, in cognitively healthy subjects (HC) and patients with mild cognitive impairment (MCI) and T2D.

Method

Thirty‐six individuals (8 HC, 16 T2D, and 12 MCI) were imaged using the XyCAM RI. One imaging session of 6 seconds duration was conducted on each eye of each subject. Only one eye (OS) was used in the analysis. Retinal blood flow (RBF) was agregated in a circular region of interest (ROI), spanning all vessels around the optic nerve head (ONH) (Figure 1). RBF was determined for one complete cardiac cycle without motion artifacts at its trough, mean, and peak per eye. The details of the RBF metrics extracted are included in the Table 1 legend.

Result

Patients with MCI had a longer TtS and SSVI than HC (p=0.007 and p=0.046 as per the independent sample t‐test, respectively, Table 1). Also, a significantly higher SSVI in MCI subjects demonstrated increased contractility compared to HC and T2D subjects. The Kruskal‐Wallis test confirmed that there is a statistically significant difference in the TtS between HC, MCI, and T2D (p=0.043). The average BFVI results are reported in Table 2.

Conclusion

Individuals with MCI and T2D have different RBF characteristics compared to cognitively healthy subjects. These results may be related to systemic changes in parameters such as arterial stiffness and increased blood pressure, which have been correlated with declined cognition. While our results obtained from a limited study population are suggestive, larger studies are needed to confirm the clinical applicability of our approach and the use of RBF‐based metrics as potential biomarkers of amyloidosis status.
Resting state functional connectivity associated with financial capacity in mild cognitive impairment
Authors: Nowrangi Milap , Naaz Farah , Chen Liuyi , Outen John D. , Bakker Arnold , Rosenberg Paul B.
Published: December 2020

Background

Financial capacity (FC) is a complex, multi‐dimensional neurocognitive construct that is commonly impaired and disables older individuals with cognitive impairment but the underlying mechanisms are not well understood. Resting state functional connectivity was measured in individuals with mild cognitive impairment (MCI) and impaired FC compared to cognitively normal controls (NC) in order to identify relevant network components that may help drive future interventions.

Method

Resting state functional MRI scans were obtained from individuals with MCI (N=17) and age, gender, and education matched NC (N=15). Table 1. All participants completed the Financial Capacity Instrument (FCI) and neuropsychological assessment. Based on previously reported imaging findings in this population, the left Angular Gyrus (lAG) was used as the seed region in functional connectivity measurements. Connectivity beta values (Fisher transformed correlation coefficients) were calculated for each connection that showed significantly altered connectivity between control and MCI cases. A Pearson’s correlation was calculated between the connectivity beta values from relevant regions and cognitive measures.

Result

A total of 26 brain regions showed significant increased functional connectivity (p <0.05 uncorrected) with the lAG in NC compared to MCI. Of these regions 14 were identified as relevant to higher‐level cognitive function and carried forward in the correlation analysis (Fig. 1). Pearson’s correlation showed significant negative association between the FCI and increased connectivity with the right temporal fusiform cortex (rTFC, r = ‐0.455, p = 0.009); negative correlation between Clock drawing and increased connectivity with the intraparietal sulcus (r = ‐0.38, p = 0.03); positive correlation between Trails B and increased connectivity with postcentral gyrus (r = 0.39, p = 0.03) and left central operculum (r = 0.36, p = 0.04). Table 2.

Conclusion

There is a significant correlation between a well‐validated measure of FC and increased functional connectivity between the lAG and the rTFC in controls compared to MCI. This novel finding suggests that integration of visuoperception, memory, and mathematical function is critical for FC. No other significant correlation between the lAG and rTFC was found with other tests of executive function or visuospatial cognition.
Risk and vulnerabilities of Filipinos in the identification and management of dementia through knowledge, attitudes and practices about dementia in adults aged 18‐65 years old who consult at the outpatient department of a tertiary hospital in Quezon City
Authors: Pura Maria Angela Bobiles , Cano Jemellee , Pabellano‐Tiongson Ma Luisa Gwenn
Published: December 2020

Background

Dementia is an overwhelming disease that pose a burden in the society. Health information and education about dementia in the Philippines is still limited. Lack of awareness entails low identification and diagnosis rate, limited health care options and under‐utilization of existing programs and interventions. The paper aims to describe the risks and vulnerabilities of Filipinos in the identification and management of Dementia among adults through assessment of their knowledge, attitudes and practices.

Method

A descriptive, cross‐sectional study was performed in a government tertiary hospital in Quezon City, Philippines. The primary investigator facilitated interviews guided by an experts reviewed‐interview schedule. A sample of 170 individuals aged 18‐65 years old who seek consult or is accompanying a patient were selected using a random sampling method.

Result

The study showed only 27.65% were knowledgeable of Dementia. Seventy percent of the participants considered it as a normal part of aging. Majority of the respondents (95.29%) showed accepting attitudes towards people with dementia. At least 33% showed a possibility of gearing towards negative practices towards those having the condition. One hundred fifteen out of 170 (67.75%) recognizes that patience is needed in taking care of people with dementia. No significant relationship identified between level of knowledge and attitude (95% CI, Fisher’s p = 0.115). Practices towards people with dementia showed significant relationship with level of knowledge (95% CI, Fisher’s p = <0.001). However, in terms of health seeking behavior, those who showed poor health seeking behavior were not knowledgeable of dementia (72.73%) showing significant correlation (95% CI, Fisher’s p = <0.001).

Conclusion

Despite the increasing prevalence of dementia in the Philippines, awareness and understanding of the condition remain limited. Though only a few was considered knowledgeable, majority showed accepting attitudes and positive practices. However, the health seeking behavior is influenced by their knowledge on dementia. Limited awareness and understanding, and the fear associated with dementia substantiates the urgency to come up with programs on public education and stigma reduction. These strategies could prevent neglect and social isolation of people living with dementia, help them achieve quality of life by maintaining self‐esteem and improve health‐seeking behaviors.
Greater apathy is associated with faster rate of cognitive decline in older adults with type 2 diabetes
Authors: Soleimani Laili , Ravona‐Springer Ramit , Lin HungMo , Liu Xiaoyu , Sano Mary , Heymann Anthony , Beeri Michal Schnaider
Published: December 2020

Background

Although depression is known to be highly associated with cognitive impairment and dementia, it is unclear how its different dimensions affect cognition. Here, we examined the relationships between baseline dimensions of depression with cognitive decline in a sample of initially non‐demented older adults with type 2 diabetes (T2D) participating in the Israel Diabetes and Cognitive Decline (IDCD) study.

Methods

Subjects [n=1023; mean age= 71.6 (SD= 4.6); 41.1% female] completed the 15‐item geriatric depression scale (GDS) at baseline and a neuropsychological battery approximately every 18 months. Cognitive domains included episodic memory, attention/working memory, executive functions, and language/semantic categorization. Global cognition was the average of the four domains z‐scores. The GDS dimensions were defined as Dysphoric Mood, Withdrawal–Apathy–Vigor (WAV), Anxiety, Hopelessness and Memory Complaint, based on previous studies. Mixed regression models adjusting for age, sex, and education assessed associations of baseline depression dimensions with cognitive decline.

Results

Cross‐sectionally, there were numerous associations between depression dimensions and cognitive outcomes (Table 1). Overtime, WAV was significantly associated with greater decline in global cognition (p=0.004), executive function (p=0.002) and episodic memory (p=0.039). Dysphoric mood was associated with a faster rate of episodic memory decline (p=0.022). Anxiety was not associated with neither cross sectional nor longitudinal cognitive outcomes. Adjusting for cardiovascular risk factors did not alter substantively the results.

Conclusion

Similar to non‐diabetic populations, different dimensions of depression in T2D elderly were associated with variable cognitive outcomes. Longitudinally, among the aspects of depression, apathy was consistently associated with greater rate of cognitive decline. This highlights the possibility of shared mechanisms between depression and dementia, an example of which could be cerebral microvascular disease, which is highly prevalent in T2D patients.
Multivariate prediction of rate of decline in memory functioning over six years using imaging biomarkers
Authors: Woodard John L. , Bellaali Youssef , Dricot Laurence , Lhommel Renaud , Malotaux Vincent , Quenon Lisa , Hanseeuw Bernard , Ivanoiu Adrian
Published: December 2020

Background

A number of biomarkers have shown utility for predicting cognitive decline and conversion from mild cognitive impairment (MCI) to dementia. However, few studies have investigated the effectiveness of biomarkers combinations and their individual contributions for predicting rate of memory decline. This study evaluated the utility of several imaging biomarkers for predicting annual rate of decline in memory performance, as indexed by the Buschke Free and Cued Selective Reminding Test (FCSRT) Free Recall (FR), Cued Recall (CR), and Delayed Recall (DR).

Method

At baseline, 153 individuals (31 controls, 87 persons with MCI, and 35 persons with subjective cognitive impairment (SCI)) underwent neuropsychological evaluation (including the FCSRT), fluorodeoxyglucose (FDG) positron emission tomography (PET), amyloid PET and MRI measurement of bilateral hippocampal volume (HV) and bilateral entorhinal cortical thickness (EC). Follow‐up neuropsychological evaluations were performed after a mean of 2.05, 4.1, and 6.4 years. Individual intercepts and slopes (annualized rates of decline) for FCSRT indexes were computed for each participant using latent growth curve modeling. Bayesian linear regression identified the optimal models for predicting annual rate of change for each memory index. After adjusting for age, sex, and sociocultural level, baseline amyloid and FDG PET, bilateral HV, and bilateral EC were entered as predictors. Bayes Factors (BF10) grade the intensity of support in favor of the alternate hypothesis over the null hypothesis.

Result

Using Bayesian ANOVA, all groups differed significantly in rate of decline for each of the three memory indexes (Figure 1). Amyloid PET, FDG PET, and EC were the best predictors of FR decline (BF10=3.26e+12, R2=0.45), Amyloid PET and EC were the best predictors of CR decline (BF10=3.31e+13, R2=0.39), and the combination of all four biomarkers was the best set of predictors of DR decline (BF10=1.95e+12, R2=0.43).

Conclusion

Different combinations of baseline imaging biomarkers were highly sensitive to rate of decline in specific aspects of memory functioning. Amyloid PET and entorhinal cortex thickness were among the significant predictors for all three memory indexes, implicating their particular sensitivity to all FCSRT memory indexes. The predictive power of entorhinal cortex thickness may be due to early accumulation of tau in this region.
Sleep disturbance is associated with longitudinal Aβ accumulation in healthy older adults
Authors: Winer Joseph R. , Mander Bryce A. , Jagust William J. , Walker Matthew P.
Published: December 2020

Background

Work in rodent models of Alzheimer’s disease has demonstrated that sleep disturbance leads to increased β‐amyloid (Aβ) production and decreased clearance. Impaired sleep quality has been shown to predict Aβ burden in healthy older populations cross‐sectionally. It remains untested whether objective measures of sleep quality predict the rate of Aβ accumulation over time.

Method

32 healthy older adults (age 75.5 ± 4.3 at baseline, 23 female) received overnight sleep EEG recording to assess sleep architecture and slow wave activity (SWA). All subjects additionally received multiple 11C‐PIB PET scans to assess longitudinal change in Aβ burden (Figure 1, 2.5 ± 0.8 scans over 3.6 ± 2.3 years). A global cortical 11C‐PIB DVR (0‐90 min, cerebellar gray reference) was calculated for every PET image, and a linear mixed‐effects model was used to derive slopes of 11C‐PIB DVR change over time for every subject. All analyses were adjusted for age at baseline and gender, and longitudinal analyses were additionally adjusted for number of PET scans per subject.

Result

Lower <1Hz SWA at baseline predicted not only higher cross‐sectional 11C‐PIB DVR, but further predicted an accelerated rate of 11C‐PIB DVR increase over time (Figure 2A, 3A&B). This was similarly true for the measure of poor sleep efficiency, predicting both baseline and rate of 11C‐PIB DVR increase (Figures 2B, 3C&D). The significance of these associations were attenuated when baseline 11C‐PIB DVR was included in the models, due to the strong correlation between 11C‐PIB DVR baseline and longitudinal change (Figure 3E).

Conclusion

These findings demonstrate that impaired electrophysiological sleep quality (<1Hz SWA) and objective poor sleep quality are not only sensitive to an individual’s Aβ burden at the time of measurement, but also predictive of subsequent accelerated Aβ aggregation. Sleep may therefore serve as an informative, non‐invasive and scalable biomarker for assessing pathological progression of Alzheimer’s disease. If replicated in larger cohorts with high sensitivity, specificity, and accuracy, these objective sleep metrics may also provide a practical and cost‐effective measure for tracking treatment intervention efficacy.
Evidence of hot flash–induced awakenings in menopausal women
Authors: Van Doorn Jacob , Paget‐Blanc Alexandra , Drogos Lauren L. , Rubin Leah H. , Maki Pauline M.
Published: December 2020

Background

Women are disproportionately afflicted with dementias, though the exact risk factors explaining why are yet to be determined. Additionally, perimenopausal women experience deficits in verbal memory during menopause compared to their pre‐ and postmenopausal state. Because sleep debt also leads to verbal memory deficits, we explored whether one of the hallmark symptoms of menopause, hot flushes, cause an increase of sleep disturbances.

Methods

N = 63 perimenopausal and postmenopausal women (mean age of 53.1 ± 1.1 years old) with hot flushes were recorded using actigraphy for sleep/wake activity and skin conductance for objective hot flushes over one night. The two time series were compared to each other using Granger causality to establish statistical causality. The number of objective hot flushes, determined by skin conductance, and amount of time spent awake were compared with linear regression.

Results

Of the 63 women, 76.2% were found to have skin conductance which granger‐caused more awake activity at night. Additionally, we have reinforced that a greater number of nightly objective hot flushes is associated with greater time spent awake (b = 28 minutes/hot flush, p < .001).

Conclusion

Those women who have hot flush granger‐caused awakenings may be at a higher risk of sleep disturbances during and following menopause. The relationship between hot flushes and lower sleep quality has previously been shown, but here we show that there may be a causal link of hot flushes causing night‐time awakenings. These hot flush granger‐caused awakenings may represent a female‐specific risk factor for cognitive impairment.
Investigating neuroimaging differences by cognitive and metabolic status in a community‐dwelling cohort
Authors: Lockhart Samuel N. , Okonmah‐Obazee Stephanie , Bateman James R. , Williams Benjamin J. , Cleveland Maryjo , Yang Mia , Haq Ihtsham , Rogers Samantha D. , Sachs Bonnie C. , Espeland Mark A. , Hughes Timothy M. , Fischer Eric , Sai Kiran Solingapuram , Williamson Jeff D. , Jung Youngkyoo , Whitlow Christopher T. , Craft Suzanne
Published: December 2020

Background

Little is know about how metabolic function relates to late‐life physical and cognitive health. In a community‐dwelling cohort of older adults with normal cognition (CN) and mild cognitive impairment (MCI), we investigated whether cognitive and metabolic status predicted neuroimaging biomarkers, and cognitive and physical function.

Method

Participants enrolled in the Wake Forest Alzheimer’s Disease Research Center (ADRC) Clinical Core cohort received neuropsychological assessment, MR imaging (T1, FLAIR, DTI, NODDI, pcASL), and PiB PET imaging on a subset. Participants were adjudicated as CN or MCI using NIA‐AA criteria. T1 MRI were processed (FreeSurfer v5.3) to calculate “AD‐signature” meta‐ROI cortical thickness. A set of AD‐sensitive cortical ROIs was used to extract mean PET SUVR signal. White matter hyperintensity (WMH) volume was calculated on FLAIR with LST in SPM12. DTI were processed using FSL, and NODDI using AMICO, to generate mean white matter (WM) Fractional Anisotropy (FA) and Free Water (FW), to assess WM microstructure. PcASL were processed to yield mean GM and WM cerebral blood flow (CBF). Cognitive measures included Montreal Cognitive Assessment (MoCA) and Free and Cued Selective Reminding Test (total free recall; FCSRT). Mobility function was assessed using the expanded Short Physical Performance Battery (eSPPB). Oral Glucose Tolerance Testing (OGTT) assessed blood glucose 120 minutes post‐challenge; OGTT was thresholded (>=140 mg/dl) to classify participants with impaired glucose tolerance (IGT) or normoglycemic (NG). We assessed group differences using t‐tests and multivariable linear regression (covariates: age, sex, race).

Result

Among 391 participants with both MRI and cognitive testing, MCI participants were older, less educated and had fewer females relative to CN (Table 1). IGT participants were older and less educated than NG participants. MCI participants had lower cortical thickness, higher WMH volume and FW, and higher PiB than CN (Table 2). MCI participants had lower MOCA and FCSRT (as expected) and eSPPB scores than CN, which remained significant in fully adjusted models. GM CBF differences did not survive adjustment. IGT was only associated with lower eSPPB score (p=.00004; adjusted p=.0051).

Conclusion

Cognitive impairment is associated with reduced brain health and physical function, while IGT relates more specifically with reduced physical function.
A mixed‐methods approach to establish clinically meaningful categories of impairment in instrumental activities of daily living
Authors: Dubbelman Mark A. , Verrijp Merike , Visser Leonie N.C. , Terwee Caroline B. , van Der Flier Wiesje , Scheltens Philip , Sikkes Sietske A.M.
Published: December 2020

Background

Although often used as outcome measure in treatment studies, the clinical meaningfulness of scores on instrumental activities of daily living (IADL) questionnaires is not yet well‐established. We aimed to establish cut‐offs for clinically meaningful categories of IADL functioning, as determined by caregivers of dementia patients using the Amsterdam IADL Questionnaire (A‐IADL‐Q). Secondly, we examined category change within a 1‐year follow‐up period in memory clinic patients.

Method

First, we performed a qualitative study to determine four clinically meaningful categories on the A‐IADL‐Q: ‘no impairment’, ‘mild’, ‘moderate’, or ‘severe impairment’. T‐scores ranged from 20–70, with lower scores representing more severe impairment. In focus groups, caregivers (n=6) were invited to rate written scenarios representing various levels of IADL impairment (‘vignettes’). The vignettes were based on the most likely item responses at given total scores of the A‐IADL‐Q, to which caregivers were blinded. First, caregivers individually categorized the vignettes. Based on nominal group technique, they subsequently placed votes for a category on each vignette. Then, they engaged in group discussion to reach consensus about the categorization. From this, we derived cut‐offs on the A‐IADL‐Q T‐score. Second, in a quantitative study, we applied the cut‐offs in a longitudinal sample of 169 patients (Table 1) from the Amsterdam Dementia Cohort, diagnosed with either subjective cognitive decline, mild cognitive impairment, Alzheimer’s disease dementia, and other dementias. We assessed what proportion of patients changed to worse categories.

Result

There was some discussion about the categorization, in particular for deciding which vignettes represented ‘moderate’ and ‘severe impairment’. Consensus cut‐offs were established for mild (≥57.5), moderate (≥47.5), and severe impairment (≥42.5). Figure 1 shows the proportion of patients in each category for the different diagnoses, at baseline and after 1 year. Within one year, 45 patients (26.6%) progressed to a worse clinical category.

Conclusion

This study provides cut‐off values for clinically meaningful categories, which seem to be in correspondence with disease severity. Over a relatively short follow‐up period of 1 year, approximately one quarter of patients declined to a worse category, providing support for the ability of the A‐IADL‐Q to measure clinically meaningful change.
Pilot study of remote monitoring technologies for frontotemporal lobar degeneration (REMOTE FTLD): Feasibility and compliance
Authors: Taylor Jack Carson , Heuer Hilary W , Vento Stephanie , Bajorek Lynn , Ong Elise , Wang Ping , You Michelle , Rosen Howard J , Staffaroni Adam M , Boxer Adam L
Published: December 2020

Background

Familial frontotemporal lobar degeneration (fFTLD) is a group of inherited neurodegenerative diseases that present with alterations in speech and language, motor abilities, cognition, and behavior. Because fFTLD is inherited in an autosomal dominant fashion, asymptomatic participants with mutations can be studied before symptom onset. To date, early detection strategies have focused on data collected in person, usually annually. Although more frequent monitoring would likely improve detection of the earliest clinical manifestations of fFTLD, repeated assessments over shorter intervals would place undue burden on patients and study staff. We evaluated the feasibility and compliance of frequent, remote assessment using a custom smartphone application in participants at risk for or diagnosed with fFTLD.

Method

Ten older adults, five functionally intact members of fFTLD kindreds (unknown mutation status), and five symptomatic FTLD participants completed the Revised Self Monitoring Scale and Corticobasal Functional Scale at baseline on their mobile device. They also completed five cognitive tests (e.g., flanker, Stroop, 2‐back) and several speech and language tasks (e.g., picture description) on their mobile phone, three times over the course of ten days. Cognitive pretesting was conducted during the first exposure to the application, and an interview was conducted with participants and study partners at completion. We present qualitative results related to compliance and feasibility.

Result

Qualitative analysis of cognitive pretesting interviews suggested that participants generally described their experience as positive. Feedback about specific concerns were used iteratively to improve the user experience. Compliance in the first 10 participants was 97.8%. Post‐study interviews with participants and their caregivers suggested that remote monitoring of cognition, language, and behavior is feasible in this cohort.

Conclusion

Early results suggest that a mobile phone application is a feasible methodology for frequent remote data collection in fFTLD. The majority of participants showed high rates of compliance. Future analyses will inform whether this approach can improve early detection and monitoring of people at risk for fFTLD, and allow for symptom tracking in those who are have already developed a clinical syndrome.
Mid‐life blood pressure and microstructural white matter: Findings from the 1946 British birth cohort
Authors: Storey Mathew , James Sarah‐Naomi , Lane Christopher A , Barnes Jo , Sudre Carole H , Parker Thomas D , Lu Kirsty , Keshavan Ashvini , Buchanan Sarah M , Keuss Sarah E , Wagen Aaron , Cash David M , Malone Ian B , Coath William , Prosser Lloyd , Nicholas Jennifer M , Murray‐Smith Heidi , Wong Andrew , Hughes Alun , Chaturvedi Nishi , Fox Nick C , Richards Marcus , Schott Jonathan M
Published: December 2020

Background

Mid‐life hypertension is an established risk factor for late‐life cognitive impairment. Whilst previous studies demonstrate mid‐life hypertension is associated with larger white matter (WM) hyperintensity volumes, Differences in normal appearing white matter (NAWM) microstructure may provide an earlier indication of WM injury. In a population‐based life‐course study of cognitively healthy individuals, we explored the relationship between blood pressure (BP) over 30 years and NAWM microstructural metrics in later life.

Method

Participants from Insight 46, a sub‐study of the 1946 British birth cohort, underwent multi‐modal MR imaging including T1, T2, FLAIR and multi‐shell diffusion‐weighted sequences at age 69‐71. Diffusion‐weighted images were processed by automated pipelines, NAWM masks were derived by subtracting the BaMoS‐derived white matter hyperintensity mask from GIF pipeline generated WM mask (eroded by 1 voxel) using FSL. Mean values of microstructural integrity metrics (fractional anisotropy (FA), mean diffusivity (MD), neurite density index (NDI), orientation dispersion index (ODI)) were extracted from T1‐registered diffusion maps using FSL and NODDI toolbox. Individuals with a major brain or neurodegenerative disorder such as dementia, neuroinflammatory condition or stroke were excluded. Linear regression analyses examined relationships between systolic blood pressure (SBP) and diastolic blood pressure (DBP) at ages 36, 43, 53, 60‐64 and 69 and microstructural metrics at age 69‐71 adjusting for sex, age, socioeconomic class, educational attainment, childhood cognition and antihypertensive medication.

Result

379 participants were included (mean age at imaging 70.7 years, 50% female). Higher SBP at ages 53 and 69 was associated with lower FA and NDI; and higher MD, and SBP at 69 was associated with higher ODI. Similarly, higher DBP at ages 53, 60‐64 and 69 were associated with lower FA and NDI; and higher MD. There was no evidence of associations between BP at age 36 or 43 and NAWM diffusion metrics.

Conclusion

Higher systolic and diastolic blood pressure from age 53 onwards are shown to be associated with differences in diffusion‐based measures of white matter microstructural integrity later in life, suggesting that systolic or diastolic hypertension in over 50’s may contribute to cognitive impairment risk via alterations in NAWM microstructure differences in later life.
Comparison of obesity, diabetes, hypertension and depression in two parallel, aging study cohorts from rural and urban India: SANSCOG study and TLSA
Authors: Sundarakumar Jonas , Sivakumar Palanimuthu T , Rao Naren P , Ravindranath Vijayalakshmi ,   SANSCOG and TLSA Investigators
Published: December 2020

Background

Population aging has contributed to high global prevalence of dementia, particularly in developing countries like India. Increasing evidence indicates that the pathogenesis of dementia starts several decades before its symptoms become manifest, thus making it important to identify the risk and protective factors even before the onset of its clinical features. Longitudinal, population‐based, aging studies offer an excellent opportunity to do this.

Method

Srinivaspura Aging, Neuro Senescence and COGnition (SANSCOG) study and Tata Longitudinal Study on Aging (TLSA) are parallel, prospective, community‐based, cohort studies in India – rural and urban, respectively – for comprehensive evaluation of risk and protective factors associated with cognitive changes due to normal ageing, dementia and other related disorders. Both the study cohorts comprise of cognitively healthy individuals aged ≥ 45 years. However, they have distinct population characteristics with respect to socio‐economic status, migration, literacy and lifestyle. Participants in the SANSCOG study are recruited from the villages of Srinivaspur Taluk in Kolar District in southern India, through an area sampling strategy, whereas, those in TLSA are recruited through convenience sampling, from urban Bangalore, India. Participants undergo detailed clinical and neuro‐psychiatric assessments that provide valuable data on a variety of health parameters, including vascular risk factors. Harmonization in clinical evaluations across the two studies enable head‐to‐head comparison of clinical outcome measures. Preliminary analysis was done on parameters such as obesity, hypertension, diabetes and depression that are assessed in the above two cohorts.

Result

There was a statistically significant difference in BMI between the two cohorts – the urban cohort had substantially higher proportion of those with obesity than the rural cohort. Diabetes was over two‐fold more common in the urban cohort than the rural cohort. The proportion of persons with Hypertension was also much higher in the urban than in the rural cohort. Depression (Geriatric Depression Scale score ≥ 10) was slightly higher in the rural cohort than the urban cohort.

Conclusion

Vascular risk factors were strikingly higher in the urban cohort than the rural cohort. Long‐term follow‐up of these risk factors along with parallel monitoring of cognitive changes will help in predicting risk factors for dementia in this population.
The association between mesial temporal tau with age, cognition and neocortical tau in Aβ cognitively unimpaired individuals using MK‐6240
Authors: Krishnadas Natasha , Groot Colin , Dore Vincent , Burnham Samantha C. , Huang Kun , Masters Colin L. , Martins Ralph N. , Maruff Paul T. , Ames David , Fripp Jurgen , Bourgeat Pierrick , Goh Anita M.Y. , Villemagne Victor L.L. , Rowe Christopher C.
Published: December 2020

Background

It has been proposed that tau deposition in the mesial temporal lobe (MTL) is an age‐related occurrence. We investigated the effects of high mesial temporal tau on age, cognition and neocortical tau in Aβ‐ cognitively unimpaired individuals (CU).

Method

187 Aβ‐ cognitively unimpaired older adults (≥60 years) from the AIBL cohort were included in this study. MK‐6240 retention was assessed in the amygdala, hippocampus, parahippocampus and entorhinal cortex and in a composite mesial temporal (Me) region. We assessed the association between regional and neocortical retention, age and cognition (MMSE, composite memory scores (CMS), composite non‐memory scores (CNMS) and the AIBL preclinical Alzheimer cognitive composite (AIBL‐PACC)). Two thresholds were used to stratify the cohort into two groups according to Me tau SUVR: 1) using the 95th percentile of the cohort; and 2) using two standard deviations (SD) above the mean.

Results

MK‐6240 Me retention was correlated with age (rs = 0.19, p = 0.01). Those with higher Me retention also had higher retention in all other neocortical regions, as well as higher retention in all four Me sub‐regions. Using the 95th percentile cut‐point, those with higher Me retention performed significantly worse on the CMS (t = 1.89, p = 0.03, Cohen’s d = 0.66) and the CNMS (t = ‐1.90, p=0.03, d = 0.69), which remained significant for the CMS after correction for age. There was a trend toward significance on the MMSE (t =‐1.40, p = 0.08, d =0.43) and PACC (‐1.37, p= 0.09, d = 0.47). These findings should be interpreted with caution, given the small sample of participants above the cut‐off (n =10). When stratified using the 2 SD cut‐point, the resulting sample size of the higher retention group was too small (n =5) to be reliably interpreted.

Conclusion

These findings demonstrate an association between mesial temporal tau with age and neocortical tau deposition. The relationship to cognition should be further validated in a larger cohort.
Amyloid‐positive individuals with subjective cognitive decline present increased CSF neurofilament light levels that relate to hippocampal volume
Authors: Sánchez‐Benavides Gonzalo , Suárez‐Calvet Marc , Milà‐Alomà Marta , Arenaza‐Urquijo Eider M. , Grau‐Rivera Oriol , Operto Greg , Gispert Juan Domingo , Vilor‐Tejedor Natalia , Sala‐Vila Aleix , Crous‐Bou Marta , González‐de‐Echávarri José Maria , Minguillón Carolina , Fauria Karine , Simon Maryline , Kollmorgen Gwendlyn , Zetterberg Henrik , Blennow Kaj , Molinuevo Jose Luis ,   ALFA Study
Published: December 2020

Background

Neurofilament light chain (NfL) is a biomarker of neurodegeneration. While cerebrospinal (CSF) NfL is increased in individuals with AD dementia as compared to controls and mild cognitive impairment, studies in cognitively unimpaired individuals with subjective cognitive decline (SCD) are scarce. SCD may represent the first clinical symptom of AD. We aimed at investigating the association between presence of SCD and CSF NfL levels, the interaction between SCD and amyloid‐β (Aβ) status on NfL, and their relationship to hippocampal volume.

Method

We analyzed 78 SCD and 200 controls from the Alfa+ cohort [mean age 61(4.6)] with Roche NeuroToolKit. We defined SCD as a positive answer to the question “Do you perceive memory or cognitive difficulties?” from the SCD‐Questionnaire. We assessed vascular risk factors and mood with the CAIDE score and the Hospital Anxiety and Depression Scale (HADS), respectively, and calculated hippocampal volumes using FreeSurfer V6.0. ANCOVA models accounting for covariates (age, gender, and HADS) were used to test the association between log10(NfL) levels and SCD status, and between log10(NfL) and bilateral total intracranial volume (TIV)‐adjusted hippocampal volume. The interactions SCD*Aβ42/Aβ40 and SCD*hippocampal*dichotomized amyloid status [Aβ+ (n=88) vs Aβ‐ (n=190), defined by the cut‐off of 0.071 for Aβ42/Aβ40] were also tested, and within group analysis performed when interactions were significant.

Result

SCD subjects displayed higher NfL (p=0.002, Partial Eta2=0.033) and lower Aβ42/Aβ40 (p=0.044, Partial Eta2 =0.015) than controls, after adjusting by age, gender and HADS (Table 1, Figure 1). Adding the cardiovascular risk factor score CAIDE as a covariate did not change these associations. We observed a significant SCD*Aβ42/Aβ40 interaction (p=0.028) on NfL. A sensitivity analysis stratifying for Aβ‐status showed that the association between SCD and NfL was significant only in Aβ+ individuals (p=0.006, A‐ p=0.21) (Figure 2). Further, the association between hippocampal volume and NfL was only significant in the Aβ+ individuals with SCD (p=0.04, age‐adjusted r=0.38, n=30) (Figure 3).

Conclusion

Aβ+ individuals with SCD displayed increased levels of CSF‐NfL. This association was independent of age, gender, anxiety/depression and vascular risk, and was related to hippocampal atrophy. The presence of SCD in Aβ+ may represent an early symptom related with neurodegeneration.
Educational video increases patients’ knowledge regarding the lumbar puncture procedure: Results of a randomized controlled trial in clinical practice
Authors: Mofrad Rosha Babapour , Fruijtier Agnetha D , Visser Leonie NC , Hoogland Nina , Bouwman Femke , Smets Ellen , Teunissen Charlotte E , van Der Flier Wiesje
Published: December 2020

Introduction

Patients’ LP‐related anxiety was previously associated with a higher risk for post lumbar puncture (LP) complications. Since better understanding of the LP procedure might reduce anxiety, we developed an educational video explaining the LP procedure and potential complications. Here, we assessed the impact of the video on patients’ LP‐related knowledge, anxiety, uncertainty, and post‐LP complications.

Methods

Consecutive participants (n=148, n=94 underwent LP) who visited the Alzheimer center Amsterdam (table 1, data collection ongoing) were randomly assigned to one of three conditions: 1) home‐provision of the video (home‐viewers), 2) viewing the video in the clinic (clinic‐viewers), or 3) care as usual (controls). Questionnaires measured LP‐related knowledge (self‐developed), anxiety (STAI‐s) and uncertainty (MUIS) prior to (T0), at the start (T1) and end (T2) of participants’ visit (figure 1). Post‐LP complications were reported via telephone‐consultation two weeks thereafter. The video was viewed after T0 and prior to T1. LP‐related knowledge, anxiety, uncertainty, and post‐LP complications were compared between conditions using either one‐way (LP‐ knowledge, post‐LP complications) or repeated measures ANOVA (anxiety, uncertainty) adjusted for age, sex and diagnosis. Since information processing can be affected in dementia patients, analyses were repeated in a subgroup (n=64) of non‐demented participants who underwent an LP.

Results

Preliminary results show that viewing the video resulted in more LP‐related knowledge compared to controls at T1 (F(2,131)=14.0, p<0.001,η2p=0.18) and T2 (F(2,131), p=0.001,η2p=0.11; figure 2A). Anxiety levels decreased over time (F(2,248)=5.8, p=0.004, η2p=0.04) irrespective of condition (figure 2B). Within non‐demented participants who underwent an LP, knowledge was highest in clinic‐viewers compared to controls at T1 (F(2,58)=7.6, p=0.001, η2p=0.21), but not T2 (F(2,58)=0.73,p=0.49,η2p =0.03; figure 2C). In this subgroup, there was an interaction between condition and time (F(4,108),p=0.03, η2p=0.09): anxiety levels increased in controls in anticipation of their memory clinic visit, whereas this decreased in clinic‐viewers after viewing the video (figure 2D). Change in uncertainty (F(4,228)=1.8,p=0.13,η2p=0.03) or post‐LP complications (F(2,89)=0.58,p=0.56, η2p=0.01) did not differ between conditions.

Discussion

Preparing patients for an LP through an educational video increased patients’ knowledge about the LP procedure and its potential complications. The benefits of watching the educational LP‐video might even be greater for non‐demented subjects.
Safety, tolerability and immunogenicity of an active anti‐Aβ40 vaccine (ABvac40) in patients with amnestic mild cognitive impairment (A‐MCI) or very mild alzheimer’s disease (VM‐AD): A randomized, double‐blind, placebo‐controlled, phase II trial
Authors: Molina Elisabet P. , Pesini Pedro , Sarasa‐SanJose Manuel , Marcos Ivan , Lacosta Ana M. , Allué Jose A. , Fandos Noelia , Sarasa Manuel , Boada Mercè ,   ABvac40 Phase 2 Study Group
Published: December 2020

Background

Alzheimer's disease is one of the biggest burdens of society with a dramatic and growing worldwide incidence rate. Notwithstanding scientific and medical advances, the condition remains incurable. Immunotherapies intended to act on the amyloid cascade are currently among the most hopefully disease modifying approaches Αβ40 is in the core of the amyloid plaques and is the main component of vascular amyloid deposition which is associated with earlier dementia onset in AD. These data leads further the hypothesis that it should be targeted in treatment strategies. Araclon Biotech is developing an active vaccine directed specifically against the Aβ‐40 peptide.

Method

This is a phase II, double‐blind, randomized, placebo‐ controlled study in patients with amnestic mild cognitive impairment (a‐MCI) or very mild Alzheimer’s Disease (Vm‐AD). The study will last for 104 weeks (from V0 to V25) during which the patients will receive five monthly (every four weeks) immunizations plus a booster shot. The primary objective of this trial is to confirm the safety, tolerability and biological activity (immunogenicity) results obtained in phase I and to explore the effect of the treatment on disease biomarkers (neuroimaging, CSF and plasma) and cognition as secondary efficacy variables.

Result

Recruitment has been completed. 124 patients aged 55 to 80 have been included in the study (a‐MCI, n= 80; Vm‐AD, n= 44). Baseline demographics and characteristics were balanced. To date, fifty patients have completed the first year study (treatment period).

Conclusion

Interim findings to be presented at the congress.
Working memory modulation using multifocal transcranial direct current stimulation in stable and decliner older adults
Authors: Vaqué‐Alcázar Lídia , Abellaneda‐Pérez Kilian , Solé‐Padullés Cristina , Bargalló Nuria , Sala‐Llonch Roser , Bartres‐Faz David
Published: December 2020

Background

The combination of transcranial direct current stimulation (tDCS) with functional magnetic resonance imaging (fMRI) is able to provide original data about how brain change in aging. Furthermore, tDCS procedures might moderate age‐related brain functional changes associated to cognitive decline. In the present study, we aimed to investigate in which manner two multifocal tDCS procedures based on two distinct working memory (WM) patterns entail capability to modulate neural activity in older adults showing cognitive stability or decline.

Method

Two multifocal tDCS montages were designed to generate two distinct electric field distributions fitting either ‘compensatory’ or ‘maintenance’ fMRI patterns underlying high WM performance, described in a previous publication from our group (Fernández‐Cabello et al., Neurobiol Aging, 2016). A sham‐controlled crossover study was undertaken on three separate experimental sessions, where 24 healthy elders (mean age: 71.73±2.65 years, 14 females) performed a verbal N‐back task while fMRI data was acquired. During the fMRI acquisitions, tDCS was applied using ‘compensatory’, ‘maintenance’ or sham stimulation in a randomized counter‐balanced order. Each subject was retrospectively classified as showing WM stability (N=12) or decline (N=12) at baseline (i.e. during sham condition) based on the WM scores obtained 4 years before. We studied differences in fMRI between group’ trajectories and across the different tDCS montages.

Result

There was a significant time*group interaction, where the decliners evidenced a longitudinal progression marked by an over‐activation of non‐related WM areas. Focusing on the stimulation intervention, we identified a significant interaction group (stables vs. decliners) * condition (‘compensatory’ vs. sham). Regarding the specific effects for each group and montage, only in the decliner group, the ‘compensatory’ tDCS induced an activity reduction overlapping posterior cortical regions, whose longitudinal hyperactivation was characteristic of this group.

Conclusion

The present results reinforce the notion that tDCS effects depend on the underlying age‐related functional organization and that these effects might be larger as more compromised is a system. Moreover, our findings are also in accordance with the hypothesis that tDCS is able to normalize functional patterns subtending cognitive decline in aging.