bluuebunny/crossref_metadata_2025 huggingface dataset:
Associations of white matter hyperintensities with cognitive decline: A longitudinal study
Authors: Wang Yan‐li , Yu Jin‐Tai , Xu Jun , Tan Lan
Published: December 2020

Background

White matter hyperintensities (WMHs), mainly caused by cerebrovascular injury, may lead to cognitive impairment. In order to identify whether the volume of WMHs is associated with cognitive decline over years, this longitudinal study involved 818 individuals from the ADNI‐2 dataset from August 2010 to May 2017.

Method

Cross‐sectional and longitudinal associations of WMHs with 8 cognitive domains were explored, using Mini‐Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Clinical Dementia Rating Sum of Boxes (CDRSB), Alzheimer Disease Assessment Scale‐Cognitive (ADAS‐Cog13), Rey Auditory Verbal Learning Test (RAVLT), Functional Assessment Questionnaire (FAQ), executive function (ADNI‐EF), and memory function (ADNI‐Mem). The association analyses were performed using multiple linear regression models, linear mixed models, Spearman rank correlation and Kaplan‐Meier survival curves.

Result

The volumes of WMHs were greater in patients with AD dementia compared with controls (p<0.001) and MCI (p=0.006) patients at baseline. The bigger volumes of WMHs correlated with worse performances on ADAS‐Cog13 and ADNI‐EF (p=0.029; p=0.0032) at baseline and MMSE, MoCA, CDRSB, ADAS‐Cog13, FAQ and ADNI‐Mem (overall p<0.05) longitudinally, after adjusting for age, sex, educational level, apolipoprotein E ε4 genotype, hypertension, hyperlipidemia, diabetes, smoking, infarction and diagnosis. And the correlations between the change rate of WMHs and change rates of MMSE, MoCA, CDRSB, FAQ, ADNI‐EF and ADNI‐Mem were statistically significant. Furthermore, patients with high WMH volumes showed an increased likelihood of dementia.

Conclusion

The results of the study suggest that WMH volume is associated with cognitive decline, and it contributes to the conversion to AD.
Determining the utility of epigenetic modulators to treat Alzheimer’s disease
Authors: Imm Jennifer L.
Published: December 2020

Background

It has been previously demonstrated that there are robust and reproducible changes in DNA methylation in Alzheimer’s disease (AD). As these epigenetic changes mediate long lasting alterations in the brain they are attractive drugs targets to reverse disease effects which are precipitated or propagated by epigenetic aberrations. The Oxford drug discovery institute have available a panel of modulators that are known to target proteins involved in epigenetic mechanisms, however, we have little understanding of the cellular effects of these modulators in brain cells. Through this project we aim to identify the target epigenetic pathways of the chemical probes and to try and relate these to the pathways known to be dysregulated in AD.

Method

Human induced pluripotent stem cell (iPSC)‐derived neurons and microglia were differentiated and treated with 30 different epigenetic modulators (at 3µM) for 24 hours. DNA was extracted, bisulfite treated before being run on the Illumina Infinium EPIC BeadChip array to assess DNA methylation. After quality control checks and normalization, we identified differentially methylated positions being altered upon treatment and subsequent cellular pathways using network‐based and pathway analysis.

Results

This study has identified methylomic variation associated with treatment. We have also shown that there are differences in the epigenetic age and mitotic age caused by cell type.

Conclusion

We have shown that there are epigenetic changes upon neuronal and microglial treatment with drugs known to alter epigenetic processes. In the future it would be interesting to test these compounds in iPSC‐derived neurons and glia from patients bearing AD‐associated genetic mutations.
Long‐term effects of work‐related sleep disruption on cognitive function and brain amyloid‐β load
Authors: Thomas Jana , Mentink Lara J. , Booij Jan , Olde‐Rikkert Marcel , Overeem Sebastiaan , Kessels Roy P.C. , Claassen Jurgen A.H.R.
Published: December 2020

Background

Recent evidence indicates that disrupted sleep could contribute to the development of Alzheimer’s disease (AD) by influencing the production and/or clearance of the amyloid‐β protein. Studies however are limited to acute, short‐term effects. Therefore, we investigated the association between long‐term work‐induced sleep disruption, cognition, and brain amyloid‐β accumulation in a case‐control setting.

Method

A sample of 25 middle‐aged male maritime pilots was recruited through the national organization of Dutch maritime pilots, with an exposure of >15 years to work‐induced sleep disruption. Men with a normal sleep pattern served as controls. Participants completed 10 days of actigraphy (Actiwatch 2, Philips Respironics) combined with a sleep‐wake diary, and 20 days of at‐home EEG sleep measurements. They underwent one night of polysomnography (PSG), followed by comprehensive assessment of cognitive function. Additionally, participants underwent amyloid PET‐CT (Positron Emission Tomography‐ Computed Tomography) to measure brain amyloid accumulation.

Results

19 male maritime pilots (mean age=53±3.4) and 19 male controls (mean age=57±2.9) completed the study. Maritime pilots reported significantly worse sleep quality (Pittsburgh Sleep Quality Index (PSQI)=8.8±2.9) in a workweek, compared to controls (PSQI=3.2±1.4; 95% CI 0.01 to 2.57; P=.049). This was confirmed with actigraphy‐based measures of sleep efficiency (controls: 89.3% ±4.3; pilots: 86% ±3.8; 95% CI 0.43 to 6.03; P=.03). Home EEG recordings in maritime pilots showed significantly reduced total sleep during work weeks compared to rest weeks (318.6 min (250.21–352.93) vs. 406.17 (340–425.98); P=.001), with reduced slow wave sleep (36.75 (32.30–58.58) vs. 51.34 (48.37–69.30); P=.005). There were no differences between maritime pilots and controls in any of the cognitive domains. Mean global cortical standard uptake value ratios for 18 F‐flutemetamol PET‐CT in maritime pilots was 1.009 (±0.059; 95% CI 0.980 to 1.037) indicating no evidence of abnormal amyloid‐β accumulation, which was confirmed by visual reads.

Conclusion

In this study population, long‐term intermittent week‐long sleep disruption did not result in significant brain amyloid accumulation nor in cognitive decline. This may indicate that amyloid accumulation during periods with sleep disruption can be reduced in periods with normal sleep, this hypothesis must be tested in future investigations.
Risk factors and interventions for Alzheimer's disease: A systematic review
Authors: Almeida Jose Roberto , Almeida Maysa Cunha , Cunha Maria Eduarda , Silva Ana Gabriela Correia
Published: December 2020

Background

Risk of developing Alzheimer´s Disease (AD) is increased by older age, family history, sex, genetic factors (especially the presence of the APOE‐4 allele; a history of head trauma, midlife hypertension, education, obesity, diabetes and hypercholesterolemia. In the absence of medications that can halt or prevent AD, lifestyle interventions that could improve maintain cognitive function have become increasingly important.

Method

We developed evidence‐based guidelines using systematic literature searches, with criteria for study selection and quality assessment decision‐making process was selected studies published from February 2008 to June 2019 that met the following criteria: dementia, risk factors and prevention.

Result

An estimated one‐third of AD cases can be attributed to modifiable risk factors. Studies have show that certain dietary (in contrast with high‐glycemic and fatty diets, a healthy diet is associated with decrease in beta‐amyloid burden, inflammation and oxidative stress); lifestyle habits such as physical exercise (regular exercise has been showed to have direct neuroprotective effects); meditation/spiritual activity; mental and social activity (higher levels of complex mental activities measured across the lifespan, such as education, occupation, reading and writing are correlated with significantly less hippocampal, volume shrinkage over time).

Conclusion

There is increasing evidence that combining multiple lifestyle modifications may yield better out comes in maintaining to improving cognition. A combination of healthful diet steps and regular physical exercise may reduce the risk of developing AD. These lifestyle changes body weight, cardiovascular health and diabetes risk, and essentially no risk for harm.
Correlation between depressive symptom and executive function decline in amyloid positive mild cognitive impairment
Authors: Choo IL Han , Chung Ji Yeon , Chong Ari , Ha Jung‐Min , Choi Yu Yong , Kim Hoowon
Published: December 2020

Background

VDepression is a risk factor of Alzheimer’s disease dementia. We aimed to explore the correlation between depressive symptom and neuropsychological test results in mild cognitive impairment by amyloid positivity.

Method

Sixty‐eight individuals with MCI were recruited. All participants received a Clinical Dementia Rating score of 0.5 and met the Petersen’s criteria. Comprehensive neuropsychological assessment was performed using the SNSB II. The [18F]Florbetaben PET and MRI scans were performed. T1‐weighted MR 3D volumes were acquired for co‐registration with PET. All participants underwent Geriatric depression scale (GDS). Participants were classified as amyloid positive when the mean cortical SUVR was 1.20 and over. Correlation analyses between GDS score and each neuropsychological test standard score (z‐score based on age‐, education‐, and gender specific normative information) were performed.

Result

Significant negative correlation between GDS score and Rey Complex Figure Test Copy z score was found in all MCI participants (r = ‐0.299, p = 0.013). For amyloid positive MCI group (n = 30), we found GDS scores were significantly correlated with Rey Complex Figure Test Copy z score (r = ‐0.364, p = 0.048) and Trail Making Test A z score (r = ‐0.473, p = 0.008). However, for amyloid negative MCI group (n = 39), there was no significant correlation.

Conclusion

Our results suggest that amyloid positive MCI patients have significant correlation between depressive symptoms and executive function decline.
[11C]MPC‐6827: A microtubule‐based pet imaging tracer for AD and related dementias
Authors: Macauley‐Rambach Shannon , Damuka Naresh , Whitlow Christopher T. , Mintz Akiva , Craft Suzanne , Sai Kiran Solingapuram
Published: December 2020

Background

Loss of microtubule (MT) network and impairment of MT function are considered to be part of pathophysiology of several CNS disorders, including AD, Parkinson disease and other ADRS and tauopathies. A BBB penetrating MT‐based PET ligand would permit imaging a variety of CNS disorders. Our lab reported the first brain‐penetrant PET radiotracer [11C]MPC‐6827 to image MTs in vivo, in both wild and transgenic AD mice. Here, we report a pilot longitudinal [11C]MPC‐6827 PET imaging study with early, middle and late stages of Aβ and tau progression in APP/PS1 and P301S mice respectively. PET imaging in NHP brains was performed to test translational utility.

Method

Dynamic brain microPET/CT imaging was performed with [11C]MPC‐6827 in APP/PS1 mice at 3, 18 and 22 months and in P301S mice (n=4) at 5, and 10 months. Regions of interests (ROIs) were drawn in whole brain, cortex, cerebellum and hippocampus and time‐activity curves (TACs) were determined. Basic distribution volume ratios (DVRs) between high‐ and low‐uptake regions were calculated. Dynamic 2h PET/CT imaging was performed in adult male vervet monkeys (n=8).

Result

Based on ROIs and TACs in whole brain, cortex and hippocampus, the radioactive uptake of 3 month‐old TG APP/PS1 mice was ∼30% higher compared to the uptake at 18 months, which in turn was ∼18% higher over 22 month‐old mice. Radioactive uptake of TG P301S mice at 5 months was ∼24% higher compared to 10‐month old mice. DVRs from cortex and hippocampus to cerebellum were ∼2‐fold higher in younger APP‐PS1 and P301S mice compared to their older littermates. Radioactive changes in all experiments were statistically significant, substantiating our preliminary imaging data. NHP‐PET brain analyses indicated brain penetration and high retention of the tracer.

Conclusion

[11C]MPC‐6827 demonstrated decreased radioactive uptake with increased brain Aβ and tau loads. A MT‐based PET imaging tracer could be a potential early imaging biomarker for AD and other ADRDs. PET imaging studies in monkey brains showed high BBB penetration. Binding distribution is in good agreement with the known MT‐mice distribution. Next steps are to correlate radioactive uptake with tau pathologies and in an NHP model of AD.
Higher empirical dietary inflammatory pattern scores are associated with worse cognitive performance in the Nurses’ Health Study
Authors: van Lent Debora Melo , Samieri Cécilia , Grodstein Francine , Seshadri Sudha
Published: December 2020

Background

We evaluated whether higher cumulative Empirical Dietary Inflammatory Pattern (EDIP) scores were associated lower cognitive function, in the Nurses’ Health Study.

Method

16,058 post‐menopausal women (mean age 74 (Standard deviation, 2)) completed a validated 116‐item Food Frequency Questionnaire. The EDIP score, previously derived with the use of reduced rank regression to predict circulating inflammatory markers (i.e. C‐reactive protein, tumor necrosis factor α receptor 2 and interleukin‐6), consists of ten anti‐inflammatory and nine pro‐inflammatory components. A cumulative EDIP score was calculated by averaging across five exams (1984‐1998) taking the first exam (1984) or second exam (1986) as baseline exams. The EDIP score was categorized into five quintiles, taking the first (anti‐inflammatory) quintile as the reference category. Cognitive testing was performed through telephone interviews over four follow up exams (1995‐2008). A composite global cognition score, a composite verbal memory score and the Telephone Interview for Cognitive Status (TICS) were calculated and averaged across the four exams.

Result

Higher cumulative EDIP scores (i.e. more pro‐inflammatory) were significantly associated with worse performance on global cognitive function (p for trend <0.01) and TICS (p for trend <0.001) after adjustment for age, education and body mass index, physical activity, energy intake, smoking, multivitamin use, depression. The relationship between higher cumulative EDIP scores and TICS remained (p for trend 0.04) following additional adjustments for hypertension, high cholesterol, myocardial infarction, diabetes, menopausal hormone use and nonsteroidal anti‐inflammatory drugs. But the association between the EDIP score and global cognitive function attenuated and became non‐significant. No association was observed between the EDIP score and verbal memory.

Conclusion

Higher cumulative EDIP scores strongly associated with worse performance on averaged TICS regardless of the model among older women. But the relationships between the EDIP score and global cognitive function and verbal memory were mainly explained by potential confounders and intermediates leaving findings attenuated and not significant. Our study shows that pro‐inflammatory diets not only are detrimental for risk factors of cognitive decline but also for cognitive function itself. Future studies are encouraged to investigate the relationships in men and over a long follow up period.
Determinants of early diagnosis of cognitive impairment in older Indian adults
Authors: Kumar Pramod , Dey Aparajit Ballav
Published: December 2020

Background

Diagnosis of cognitive impairment at an early stage is vital to the management of dementia like Alzheimer’s disease. Recent studies have proved that multi‐modal non‐pharmacological therapy does decrease the progression of cognitive decline in patients with subjective cognitive decline (SCD) and mild cognitive impairment (MCI). In this study, we evaluated the determinants of presentation at an early stage of cognitive impairment, to our memory clinic.

Method

Patients presenting with cognitive impairment were evaluated in our memory clinic. After reversible causes and depression were ruled out, patients were classified as those with early disease (SCD and MCI) or major neurocognitive decline (MNCD). A retrospective analysis of the data was done to evaluate the association of baseline characteristics (age, sex, education, region, occupation and cardiovascular diseases) with the stage of presentation of cognitive decline.

Result

Data of 415 patients, evaluated from 2017 to 2019, was analyzed. Reversible causes were identified in 29.2 % of the patients, including 24.1% with depression. SCD, MCI and MNCD were identified in 29.6%, 16.4%, and 24.8%, respectively. Demographic factors like male sex (p value < 0.001), higher education (p value < 0.001) and occupational skill (p value = 0.006), were significantly associated with early presentation to the memory clinic.

Conclusion

In this study, we observed 65% of the patient presented at an early stage of cognitive decline (SCD and MCI). With development of possible disease modifying agents in near future, this can be an important stage of intervention. Female patients with lower educational and occupational status, associated with late presentation, can be an important target for screening.
Resting‐state functional connectivity modulation through a combined a TDCS‐visuospatial training on object‐location memory in healthy older adults and patients with mild cognitive impairment
Authors: Antonenko Daria , Thams Friederike , Külzow Nadine , Flöel Agnes
Published: December 2020

Background

The combination of transcranial direct current stimulation (tDCS) with memory training has gained attention as a means for cognitive enhancement in the older population. Neuroimaging studies have identified changes in local brain activity and functional network connectivity as potential underlying mechanisms of tDCS‐induced performance improvement. Resting‐state functional magnetic resonance imaging (rs‐fMRI) revealed that memory improvement via multi‐session object‐location memory (OLM) training was associated with increased connectivity within the default mode network (DMN). This increase was higher in participants who received additional anodal tDCS compared to those who received sham stimulation in combination with OLM training. No previous studies assessed this association in older adults with mild cognitive impairment (MCI).

Method

We analyzed resting‐state fMRI data of 47 older adults with age‐associated cognitive decline (15 MCI patients and 32 healthy older adults) before and after a combined tDCS‐training intervention. All participants underwent a 3‐day visuospatial object‐location memory training paired with either anodal tDCS over the right temporoparietal cortex (1 mA, 20 min) or sham (1 mA, 30 sec), using a cross‐over design. In order to examine the effect of the combined tDCS‐training‐approach on functional connectivity, a seed‐based analysis was conducted between the stimulation target and the DMN using the CONN toolbox. The change from before to after training was compared between tDCS and sham stimulation conditions in all participants using linear mixed‐model analysis.

Result

ROI‐to‐ROI functional connectivity between the stimulation target (region of interest: middle temporal gyrus, temporo‐occipital part right) and the DMN (region of interest: posterior cingulate cortex of the DMN) showed higher increases in functional connectivity in anodal tDCS compared to sham stimulation condition over the entire cohort (F(1,43)=4.126, p=0.048; mean difference: 0.086, 95%‐confidence interval: 0.001 to 0.171).

Conclusion

Our findings lend support to the hypothesis that neuronal modulation of functional coupling between the stimulation target and the DMN may be one of the mechanism underlying tDCS‐accompanied OLM enhancement in older adults. Modulation in rs‐fMRI metrics assessing intrinsic functional brain connectivity may constitute a sensitive biomarker for the investigation of intervention‐induced changes in healthy and pathological aging, and may even guide long‐term interventional approaches on an individual level.
The role of Alzheimer’s disease polygenic risk scores in changes of cognitive function in older adults: A longitudinal cohort study
Authors: Pan Gongbu , King Anna E. , Bindoff Aidan , Summers Mathew J. , Vickers James C. ,   Tasmania Healthy Brain Project
Published: December 2020

Background

Previous studies show evidence that more than 21 genetic variants and polygenic risk were associated with Alzheimer’s disease (AD). But the relationship between AD polygenic risk scores (ADPRS) and cognitive function/decline was unclear due to the lack of longitudinal data. This study investigated the potential association between ADPRS and changes in cognitive function.

Method

The TBHP is an ongoing longitudinal prospective study of 459 healthy older adults. Participants with available genotype data (N = 325) were included in analysis. ADPRS was calculated by using sets of AD susceptibility variants identified by a meta‐analysis of GWAS data. The cognitive function domain scores at baseline and year 1, 2, 3 and 5 were calculated using factor analysis (principal components extraction method). Single factor scores for episodic memory, working memory, executive function, and language processing domains were combined by using factor coefficients via regression analysis. Linear mixed‐effects model analysis was performed to investigate the association between ADPRS and cognitive function longitudinally.

Result

The ADPRS was significantly associated with an increase of working memory and executive function over 60 months, particularly in APOE ε4 carriers. In BDNF met carriers, ADPRS was associated with the decline of executive function. There were no direct associations between ADPRS and longitudinal changes in cognitive function.

Conclusion

The relationship between ADPRS and changes in specific cognitive domains were highly being driven by APOE and BDNF status. These findings strongly support the potential role of common variants in predicting the changes in cognitive function before AD.
Ethnic and socioeconomic determinants of dementia risk: A nested case‐control study in the population of East London
Authors: Bothongo Phazha LK , Jitlal Mark , Parry Eve , Foote Isabelle F , Waters Sheena , Dobson Ruth , Noyce Alastair J , Bestwick Jonathan P , Marshall Charles R ,   Preventive Neurology Unit, Wolfson Institute of Preventive Medicine
Published: December 2020

Background

The influence of ethnicity and socioeconomic status on dementia risk, and the extent to which this is mediated by known risk factors remain incompletely understood. We addressed this issue using health records data from the diverse and deprived population of East London (<50% White and >50% in the most deprived quintile of the UK).

Method

We performed a nested case‐control study in over 1,000,000 East London inhabitants. We identified 4137 cases of all cause dementia, and matched on age and gender to controls with ratio 1:4. Logistic regression was used to calculated odds ratios (ORs) for exposures of ethnicity and UK Index of Multiple Deprivation (IMD), before and after inclusion in the model of established modifiable risk factors (type II diabetes, hypertension, smoking, body mass index, depression and hearing loss). In order to reflect the relative importance of known modifiable risk factors in this deprived multiracial population, we calculated weighted population attributable fractions (PAF) for each factor.

Result

Risk of dementia was higher in the Black and South Asian groups relative to White (ORs (95%CI) Black 1.43 (1.31, 1.56), South Asian 1.17 (1.06, 1.29)). Risk of dementia was reduced in all IMD quintiles relative to the most deprived (ORs (95%CI) 2nd 0.71 (0.66, 0.77), 3rd 0.52 (0.44, 0.60), 4th 0.71 (0.53, 0.94), 5th 0.59 (0.38, 0.87)). The effects of ethnicity and deprivation persisted after adjusting for known risk factors. Weighted PAFs for modifiable risk factors were notably higher in this population for depression (9.2%) and diabetes (6.2%) than those estimated in the Lancet Commission meta‐analyses (4% and 1.2% respectively).

Conclusion

Membership of non‐White ethnic groups and socioeconomic deprivation are important determinants of dementia risk, with effects larger than many of the more established risk factors. These effects cannot be completely accounted for by known modifiable risk factors and further work is required to establish the responsible mechanisms. Depression and diabetes are of greater relative importance, and should be prioritised as targets for dementia prevention in more diverse and deprived populations.
The prevalence of limbic‐predominant age‐related TDP‐43 encephalopathy in the Sydney brain bank
Authors: Jeżewski René C. , Poljak Anne , Mather Karen A. , Sachdev Perminder S. , Shepherd Claire E.
Published: December 2020

Background

‘Limbic‐predominant age‐related TDP‐43 encephalopathy’, or ‘LATE’, is a recently identified neuropathological entity that may account for up to 25% of clinically diagnosed dementias in the oldest‐old (Nelson et al., Brain. 2019;142:1503).

Method

We analysed the clinical records and pathology from all prospectively followed cases held by the Sydney Brain Bank (SBB) to determine the association between the presence of limbic‐predominant TDP‐43 pathology and age, clinical diagnosis and pathological co‐morbidities. The study cohort was stratified into six age groups: 50‐54y, 55‐64y, 65‐74y, 75‐84y, 85‐94y and 95‐105y. Cases were assigned into broad clinical groups: asymptomatic, dementia and movement disorders. TDP pathology was assessed blindly and cases were categorised as either limbic TDP‐positive or limbic TDP‐negative according to the presence or absence of pathological TDP in the amygdala, hippocampus and entorhinal cortex, regardless of other contributing pathologies. Cases with neuropathologically confirmed primary TDP proteinopathies, i.e. motor neuron disease and the TDP variant of frontotemporal lobar degeneration, as well as those with known genetic mutations were excluded.

Result

In the total SBB cohort (n=427, mean age=80.0y ±10.3), 70% of cases fulfilled the criteria for positive limbic TDP pathology. The presence of limbic TDP pathology correlated significantly with age (r=0.220, p<0.01) and was 1.3‐fold more likely to occur after the age of 85 years (n=114). Concomitant Alzheimer’s disease neuropathology (46.5%) was most common in this 85+ subcohort (mean age=91.5y ±4.9) and was present in 75.9% of cases with clinically diagnosed dementias. ‘Pure’ LATE neuropathology was identified in 8.8% of cases over the age of 85 years (10/114, mean age=94.4y ±5.0) and was predominantly clinically asymptomatic (8/10, mean age=93.8y ±5.4). Only 3.7% of clinical dementias could be attributed to ‘pure’ LATE (2/54, mean age=97.0y), while concomitant tau pathology and Lewy body pathology explained the majority of remaining dementia cases.

Conclusion

Our data suggests that ‘pure’ LATE occurs less frequently than expected and only accounts for a small proportion of clinical dementias over the age of 85 years. Whether the severity of TDP pathology can discriminate early, transitional and advanced stages of the disease process and whether these stages correlate with clinical diagnosis is yet to be elucidated.
Global system segregation enhances reserve in normal aging and Alzheimer’s disease
Authors: Ewers Michael , Frontzkowski Lukas , Neitzel Julia , Rubinski Anna , Habeck Christian , Gordon Brian A , Benzinger Tammie LS , Levin Johannes , Cruchaga Carlos , Goate Alison M , Fagan Anne M , Karch Celeste M , Morris John C , Holtzman David M , Bateman Randall J , Stern Yaakov , Franzmeier Nicolai ,   ADNI
Published: December 2020

Background

Epidemiological studies suggest that reserve capacity is associated with a significant delay of cognitive decline by up to 4 years in aging and dementia. Identifying brain substrates of reserve is a pivotal step to define potential intervention targets for brain stimulation in order to enhance reserve. We previously showed that higher global connectivity of specific richly connected hub regions contribute to reserve (Franzmeier et al. Brain 2018, Neitzel et al. Neurology 2019). However, apart from the role of local hubs, functional mechanisms at the level of major functional networks that support reserve are poorly understood. The segregation of the brain’s major functional network is a fundamental brain property that supports higher cognitive function (Chan et al. PNAS 2014, 2018). We hypothesized that higher system segregation is associated with attenuated cognitive decline in normal aging and Alzheimer’s disease (AD).

Method

We included 255 cognitively normal elderly subjects (age=52.48±16.12) from the RANN study, 108 individuals with autosomal‐dominant AD and their sibling non‐mutation carriers (n=71) from DIAN, and 152 amyloid‐positive subjects across the clinical AD‐spectrum from ADNI. Based on resting‐state fMRI‐assessed 400‐ROI functional connectivity matrix, we computed system segregation as the difference of within‐network and between‐network connectivity normalized to the within‐network connectivity. Higher segregation scores indicate higher segregation between the networks. In linear regression analyses, we tested whether higher system segregation was associated with 1) higher cognitive performance in elderly subjects, and 2) for AD, attenuated cognitive decline at a given level of disease severity (as measured by “estimated years from dementia symptom onset” (EYO) in autosomal‐dominant AD, and by 18F‐AV1451 tau‐PET in early‐Braak‐stage ROIs in sporadic AD).

Result

In cognitively normal subjects, higher system segregation was associated with higher composite scores of global cognition (p=0.001, Figure 1). For AD, higher system segregation was associated with an attenuated effect of disease severity on global cognition in autosomal‐dominant AD (interaction EYO by system segregation: p = 0.007, Figure 2), and an attenuated association between tau‐PET and ADAScog in sporadic AD (p=0.0009, Figure 3).

Conclusion

System segregation is associated with higher cognitive abilities in aging and enhances reserve capacity in Alzheimer’s disease.
SuperAging: A model for studying mechanisms of resilience and resistance
Authors: Rogalski Emily J , Sridhar Jaiashre , Martersteck Adam , Makowski‐Woidan Beth , Engelmeyer Janessa , Parrish Todd , Besson Pierre , Cobia Derin , Paxton Holly , Weintraub Sandra , Katsaggelos Aggelos , Bandt Katie , Bigio Eileen H , Geula Changiz , Mesulam Marsel
Published: December 2020

Background

Memory complaints are widespread among the elderly and aging is a major risk factor for Alzheimer’s disease (AD), leading to the impression that gradual loss of memory ability is a nearly universal consequence of getting old. Our longitudinal studies of SuperAgers, 80+ year‐olds with episodic memory performance that remains in the range that is at least normal for 50‐60 year‐olds suggests an alternative aging trajectory is possible. This session will highlight some of the emerging biologic features of the SuperAgers.

Method

Participants include SuperAgers and cognitively average 80+ year‐old cognitively average normal controls. Data from detailed neuropsychological assessments, quantitative neuroimaging measurements (MR and amyloid PET), genetic features and neuropathologic findings will be reported.

Result

Initial evidence suggest SuperAgers tend to show mismatch between chronologic and biologic age, including maintenance of cortical but not necessarily hippocampal volume, a tendency to resist significant amyloid PET retention, an abundance of anterior cingulate Von Economo neurons, and some with resistance to cortical Alzheimer’s pathology.

Conclusion

These studies contribute to our understanding mechanisms of resilience and resistance in cognitive aging and may help isolate factors that are potentially important for promoting successful cognitive aging and avoiding age‐related brain diseases such as AD.
Understanding caregiver profiles of older adults reporting cognitive decline: A descriptive study from North India
Authors: Dasgupta Jayashree , Faqurudheen Hena
Published: December 2020

Background

As India gets closer to an expected 7.6 million dementia cases by 2030, families are tasked with care‐giving in the absence of affordable healthcare and adequate health systems. Those most impacted include elderly caregivers, and are mostly female spouses of persons with dementia. With transitions from joint family systems to more nuclear structures due to urbanization and migration, understanding characteristics of family caregivers will be critical to developing adequate support systems and enabling better home‐based care in urban areas.

Method

Screening camps were conducted in 8 locations across a North Indian urban area over 7 months, including a government hospital, communities, and senior centers. Assessment measures involved a brief cognitive assessment and screening for mental health, neurological, and preexisting medical issues. Sociodemographic information was collected from the accompanying family member. Both caregiver and the person reporting cognitive complaints were provided information about dementia symptoms with referrals to neurologists, psychiatrists or medical professionals based on screening results.

Result

A total of 194 persons (112 men, 82 women) were screened after reporting subjective cognitive decline; on evaluation, 4% and 5% had symptoms indicative of dementia and definite cognitive decline, respectively. Findings also indicated that 58% of participants also had symptoms of depression and anxiety, causing concern for caregivers. Majority of participants were accompanied by a family member and only 7 participants lived on their own. Sociodemographic information was collected for a total of 187 caregivers (58% women, 42% men). 67% of caregivers were aged 55 years and above, indicative of caregivers themselves ageing whilst having to take care of an aging relative; 33% were aged 20‐34 years. 97% were immediate family members taking on primary care‐giving responsibilities (51% wives, 26% husbands, 16% sons, 4% daughters) indicating high risk for caregiver burden. More than 75% of those surveyed were educated above high school, indicating rising levels of educational achievement in urban areas. 35% of caregivers were homemakers and women, highlighting necessity for low‐cost or cost‐effective models of home‐based care services.

Conclusion

Health systems and support mechanisms for the elderly are underdeveloped in India and require effective home‐based care models taking into consideration caregiver characteristics.
Effectively training professional caregivers to screen and refer persons with dementia and intellectual/developmental disability
Authors: Walaszek Art , Schroeder Molly , Krainer Jody , Prichett Gregory , Wilcenski Mickell , Endicott Sarah , Albrecht Tammi , Carlsson Cynthia M , Mahoney Jane
Published: December 2020

Introduction

By age 40, almost all people with Down syndrome, the most common cause of intellectual/developmental disability (I/DD), have neuropathological changes consistent with Alzheimer’s disease; by age 60, about half have dementia. Detecting dementia in persons with I/DD can be challenging because baseline cognitive impairment can be severe and because persons with I/DD may have difficulty reporting symptoms. The National Task Group Early Detection Screen for Dementia (NTG‐EDSD) was developed to aid detection of cognitive impairment in adults with I/DD. We implemented an educational curriculum to increase the ability of professional caregivers to screen for dementia in persons with I/DD using the NTG‐EDSD.

Methods

In November 2018 to April 2019, we held five training sessions for professional caregivers of persons with I/DD, partnering with various managed care organizations (MCO), aging and disability resource centers, adult day programs, and adult family homes. We assessed knowledge and attitudes at baseline, immediately after training, and one week, one month and six months after training.

Results

Participants (N=154) included direct care workers, case managers, healthcare providers, and other social services staff. Participants reported a marked increase in confidence in their ability to detect changes associated with mild cognitive impairment or dementia (p<0.001), decline in activities of daily living (p=0.02), and changes in behavior and affect (p<0.001). Satisfaction with the training was very high, and 94.0% of participants agreed or strongly agreed they could use the NTG‐EDSD tool with their clients. Following the training, one MCO we partnered with, serving 62 of 72 counties in Wisconsin, made the NTG‐EDSD a standard part of the assessment of adults with Down syndrome starting at age 40.

Discussion

A wide variety of social services and healthcare professionals can be effectively trained to screen for dementia in persons with I/DD using a standardized screening tool, the NTG‐EDSD. Satisfaction with the training was high, and use of the NTG‐EDSD was thought to be feasible. This educational intervention led to change in practice at a systems level within an MCO. Next steps could include assessing impact of such training on the quality of life and healthcare outcomes of persons with I/DD.
A longitudinal GWAS in patients with mild cognitive impairment identifies modifiers for the speed of cognitive decline
Authors: Kleineidam Luca ,   EADB
Published: December 2020

Background

The clinical progression of Alzheimer’s disease (AD) is driven by multiple pathophysiological processes but their influence may change over the disease course. Supporting this hypothesis, amyloid pathology shows a rapid increase at early disease stages reaching a plateau as the disease progresses. The impact of genetic determinants of AD may also change over the disease course. In line with that, among AD‐related loci, only variants in APOE and CLU predict conversion from mild cognitive impairment (MCI) to AD‐dementia. These findings led us to propose that genetic factors modulating the speed of disease progression in MCI go beyond AD genetics discovered by case‐control studies. Consequently, a major aim of the EADB consortium is to uncover genetic determinates of the rate of cognitive decline in patients with MCI.

Method

Genome‐wide data was generated for 8313 MCI patients and imputed using the TOPMed reference genome. Cognitive decline was operationalized using follow‐up information on the normalized Mini‐Mental‐State‐Examination. To perform the GWAS, a novel method for the fast conduction of genome‐wide association studies (GWAS) and meta‐analysis using longitudinal data was developed based on generalized least squares. All analyses were corrected for age, gender, education, and principal components.

Result

Simulation studies suggested that our novel method for longitudinal GWAS provided precise estimates and high statistical power. First analyses of longitudinal cognitive change in 2984 MCI patients revealed a genome‐wide significant effect of APOE (p = 1.3*10−15) and two additional suggestive loci (p < 5*10−7) on chromosome 7 and 10 that have previously been associated with education. Gene‐based test analysis identified two additional genes on chromosome 4 and 12 (p < 2*10−6) that remained significantly associated after Bonferroni‐correction. None of these loci have been linked to AD before. Currently, we are exploring the predictive value that a polygenic risk score derived from the case‐control GWAS of EADB has on progression to dementia in MCI.

Conclusion

Our GWAS on cognitive decline in the largest sample of MCI patients with longitudinal data to date reveals novel insights into the genetic underpinnings of disease progression in at‐risk stages of AD. Results from the full EADB sample of 8313 MCI patients will be provided at AAIC.
Impact of MR‐guided PET reconstruction on tau detection and quantification with [18F]‐MK‐6240
Authors: Chen Jenny , Schramm Georg , Ades‐Aron Benjamin , Vahle Thomas , Chen Qi , Turner Arlener D. , Royse Sarah , Lopresti Brian , Shepherd Timothy M. , Osorio Ricardo , Fieremans Els
Published: December 2020

Background

Tau PET offers the potential of in vivo imaging neurofibrillary tangles (NFT) in the brain to assess Alzheimer’s disease (AD) progression and help guide the development of disease‐modifying treatments. In this study, we evaluate visualization and quantification of NFT using simultaneous acquisition of MRI and PET using [18F]‐MK‐6240 [1]. To overcome limitations in PET spatial resolution resulting in partial volume effects (PVE), MRI‐guided PET reconstruction using an asymmetrical Bowsher prior [2,3] was tested.

Method

Cognitively normal volunteers from the NYU Center Sleep and Brain Health Center (n=18, 15 female, age=65.4±5.6) underwent examination on a 3‐T integrated PET‐MRI system (Biograph mMR (Siemens Healthcare, Erlangen, Germany). MRI and PET were performed simultaneously; MRI contrasts included MPRAGE (1‐mm isotropic) for anatomy and ultrashort echo‐time (UTE) (1.6‐mm isotropic) for attenuation correction. [18F]‐MK‐6240 was injected intravenously and PET data was reconstructed 70‐90 min post‐injection. Standard iterative reconstruction (OSEM) (2‐mm isotropic) was compared to asymmetrical Bowsher [2,3] reconstruction with MPRAGE prior regularization weight β=30 (1x1x2mm3). PET standard uptake value (SUV) maps were co‐registered to respective MPRAGE, and (cerebellum or pons normalized) SUVR values were extracted from FreeSurfer‐derived regions of interest (ROIs).

Results

Example SUVR maps of standard PET and MR‐guided PET (Fig.1) reveal the Bowsher reconstruction to have more localized and increased focal uptake in the amygdala and cortical regions including the entorhinal, posterior cingulate and precuneus, with regional SUVR‐increases of 39%, 53%, 32%, and 16% respectively. Over all subjects (Fig.2), Bowsher reconstruction results in 30% or 48% higher SUVR, and an 64% or 84%‐increase of dynamic SUVR‐range (Fig.3) when normalized versus cerebellum or pons, respectively. These trends are emphasized for entorhinal cortex (Fig.4).

Conclusions

These initial results demonstrate that MR‐guided PET reconstruction of tau data may improve NFT localization and quantification. Study limitations include small number of high uptake tau‐cases and lack of standard such as histology for comparison. Future work will compare against CSF tau‐markers, cognition and comparison to other PVE correction methods. References: [1] Betthauser et al, JNM 2018;60(1):93–99; [2] Bowsher et al, Proc. IEEE Nucl. Sci. Symp., 2004(4):2488–2492; [3] Vunckx & Nuyts, Proc. IEEE Nucl. Sci. Symp., 2010:3262–3266.
Characterising the spatiotemporal heterogeneity of neurodegenerative diseases using subtype and stage inference
Authors: Young Alexandra L , Bocchetta Martina , Cole James , Williams Steven CR , Rohrer Jonathan D , Alexander Daniel C
Published: December 2020

Background

Neurodegenerative diseases are highly heterogeneous, consisting of multiple disease subtypes with different spatiotemporal patterns of pathology. These patterns evolve dynamically with disease stage, making it challenging to disentangle disease subtypes in vivo from biomarker data where precise staging information is unavailable.

Method

Subtype and Stage Inference (SuStaIn) is an unsupervised learning technique that disentangles biomarker heterogeneity into subgroups of individuals (subtypes) with distinct progression patterns (stages). SuStaIn evaluates the optimal grouping of individuals into disease subtypes, where each subtype consists of a sequence in which biomarkers transition between different z‐scores. We used SuStaIn in a number of conditions to identify subgroups of individuals with distinct patterns of brain volume loss using structural MRI data. We present results from several datasets, reviewing results in Alzheimer’s disease (ADNI dataset), and presenting new results in genetic frontotemporal dementia (GENFI dataset), and in the aging population (UK Biobank). In each dataset we explored genetic, neuropsychological, clinical and biomarker associations with each of the subtypes identified by SuStaIn. We used longitudinal data to assess the consistency of the subtypes and stages assigned by the SuStaIn model at follow‐up visits.

Result

In Alzheimer’s disease we identified multiple spatiotemporal patterns of neurodegeneration associated with differences in memory and executive function scores. We found a genetic link between a ‘limbic‐predominant’ atrophy pattern and type 2 diabetes through a GWAS and analysis of polygenic risk scores. In genetic frontotemporal dementia we identified and confirmed two distinct atrophy patterns amongst C9orf72 mutation carriers (N=182). In MAPT mutation carriers (N=82), we identified two atrophy subtypes that were strongly associated with different MAPT mutations: a ‘temporal’ subtype, which had a one‐to‐one mapping with IVS10+16 and R406W mutations, and a ‘frontotemporal’ subtype, which had a near one‐to‐one mapping with P301L mutations. The subtype assignments showed strong stability at follow‐up visits (99% consistency). In the UK Biobank (N=21390), we identified multiple patterns of brain volume loss associated with distinct characteristics.

Conclusion

Our results demonstrate the utility of SuStaIn for identifying disease subgroups and associating imaging patterns with genetics and cognition. We show that SuStaIn can provide enhanced patient stratification capability across multiple conditions.
Latent patterns of task‐related functional connectivity relate to hyperactivation and associative memory impairment in SCD+ and MCI
Authors: Corriveau‐Lecavalier Nick , Rajah Natasha , Mellah Samira , Belleville Sylvie ,   CIMA‐Q
Published: December 2020

Background

Hyperactivation is commonly observed in prodromal Alzheimer’s disease (AD). It is however unknown if it relates to functional network dysfunction, and how hyperactivation‐networks relate to cognitive impairment. We used seed‐based connectivity to assess differences in correlations between activation of hyperactive regions, whole‐brain task‐related activation, and memory performance in persons with subjective cognitive decline plus (SCD+) and mild cognitive impairment (MCI).

Method

Data from 108 participants from the CIMA‐Q cohort were used in this study: 28 participants with SCD+ which presented with memory complaint and worry in addition to small hippocampal volume and/or were APOE4 carriers, 26 participants with MCI and 54 were healthy controls (HC). Task‐related activation was measured while participants memorized 78 pictures and their location in a four‐position grid. Multivariate seed‐partial least squares (seed‐PLS) analysis was used to identify latent variables (LVs) that assess between‐group differences and similarities in the three‐way association between 1) activation in hyperactive regions of interest (ROIs: left hippocampus, right inferior temporal gyrus (riTG), left superior parietal lobule (lsPL)), 2) whole‐brain activation associated with associative memory encoding, and 3) subsequent associative memory performance. Significance of the seed‐PLS effects were assessed with permutation testing and boostraps.

Result

Three LVs were significant (p < 0.05). LV1 (32.11 % of covariance explained) accounted for group similarities in the correlation between activity in all ROIs and activity in the fronto‐parietal and default mode networks. Interestingly, left hippocampus activity did not correlate in SCD+. LV2 (19.17 % of covariance explained) identified a network that was correlated with left hippocampal activity in all three groups; however, left hippocampal activity correlated with better memory in HC but with poorer memory in SCD+. LV3 (10.91 % of covariance explained) identified a network that was positively correlated to lsPL activity in SCD+, and correlated with seed activity in all ROIs and poorer memory performance in MCI.

Conclusion

Hyperactivation is associated with latent patterns of connectivity in prodromal AD, but different hyperactivation‐network associations relate to memory in SCD+ and MCI. Hyperactivation could serve as an early marker of network dysfunction in AD, and reflect the incoming cognitive symptomatology associated with the disease.