bluuebunny/crossref_metadata_2025 huggingface dataset:
CSF NFL levels and neuroimaging‐derived neurite density index improve prediction of MCI and dementia clinical diagnosis within the Alzheimer’s pathologic framework
Authors: Gallagher Rigina L. , Jonaitis Erin M. , Van Hulle Carol A. , Johnson Sterling C. , Carlsson Cynthia M. , Asthana Sanjay , Blennow Kaj , Zetterberg Henrik , Bendlin Barbara B.
Published: December 2020

Background

Cognitive decline in Alzheimer’s disease (AD) may be explained by degeneration of long myelinated axons in brain white matter. Neurofilament Light Chain (NFL) protein is a cytoplasmic protein in large caliber myelinated axons, released when neurodegenerative processes occur, and elevated in AD [(Preische et al., 2019), (Skillbäck et al., 2013), (Gaetani L et al., 2019)]. A similar biomarker may be derived from neuroimaging—specifically the Neurite Density Index (NDI)—a metric generated via neurite orientation dispersion and density imaging (NODDI) [(Fukutomi et al., 2017)]. In this study, we examined the extent to which these axonal markers add value to predicting clinical diagnosis within the AT(N) framework [(Jack et al., 2018)].

Method

216 individuals from the Wisconsin Registry for Alzheimer’s Prevention study and Alzheimer’s Disease Research Center underwent lumbar puncture for CSF collection and were diagnosed as either cognitively unimpaired (CU), mild cognitive impairment due to AD (MCI‐AD), or dementia due to AD (Dementia‐ AD). Participants also underwent diffusion‐weighted MRI to derive NDI. We computed Spearman rank‐order correlations between CSF NFL levels, white matter (WM) NDI, clinical diagnosis (CU, MCI‐AD, Dementia‐AD), and CSF Biomarker Status (A‐/T‐, A+/T‐, A+/T+). The added value of CSF NFL and WM NDI in discriminating diagnosis was assessed, controlling for A+/T+ status, age and sex, and accounting for interactions with NFL and NDI, with logistic regression models and ROC analysis.

Result

Demographics are in Table 1. NFL correlated positively with biomarker status and negatively with NDI (Figure 1). NFL levels increased and NDI values decreased with diagnostic severity (Figure 2a). Modelsincorporating both A+/T+ status and NFL levels estimated diagnosis better than models relying only on A+/T+ status (Figure 2b). Models that discriminated between AD vs. CU, and incorporated WM NDI, had lower AIC compared to those relying only on A+/T+ (Figure 4a, 4b).

Conclusion

In line with prior studies, NFL—a marker of large caliber myelinated axons—provides additional information that helps discriminate clinical severity in dementia, particularly as diagnosis progresses from MCI to AD. Decreasing AIC scores for models discriminating AD from CU suggest that, like NFL, neurite density in white matter regions improves identification of clinical status, especially as diagnosis severity increases.
CSF AD‐like profile in SCD, pre‐MCI and MCI subjects: Application of the A/T/N classification model in a retrospective cohort from a memory clinic
Authors: Chipi Elena , Salvadori Nicola , Bellomo Giovanni , Biscetti Leonardo , Farotti Lucia , Lisetti Viviana , Montanucci Chiara , Cataldi Samuela , Parnetti Lucilla
Published: December 2020

Background

Subtle deficits not fulfilling Mild Cognitive Impairment (MCI) can be associated with pathophysiological AD biomarkers positivity and higher risk of clinical progression (Parnetti et al., 2019). Several attempts have been carried out in order to characterize neuropsychological features and Alzheimer’s disease (AD) biomarkers in pre‐MCI populations (Chipi et al., 2019). We aimed to explore, by applying the A/T/(N) classification scheme (Jack et al., 2018), the prevalence of cerebrospinal fluid (CSF) AD‐like profile (A+/T+) in a cohort of subjective cognitive decline (SCD), pre‐MCI and MCI subjects.

Method

Seventy‐six consecutive patients (34 M; 42F; mean age: 68.7 years; mean education: 10.7 years), referred to our Memory Clinic from 2016 to 2019, were defined as SCD (n.11) (Jessen et al., 2014), pre‐MCI (n. 28) (Duara et al., 2011) and MCI (n.37) (Albert et al., 2011) by means of an advance neuropsychological battery and underwent lumbar puncture for the analysis of CSF core AD biomarkers (Aβ42/Aβ40 ratio, total tau, phospho‐tau). According to the cut‐off used in our lab, we considered Aβ42/40 ratio <0.069 as A+, phospho‐tau >70 pg/mL as T+, total tau > 400 pg/mL as N+.

Result

No differences were found in age, gender and education among groups. AD‐like CSF profile (A+T+) was found in 10.7% of pre‐MCI and in 54.1% of MCI (p<0.001). None of SCD subjects showed AD‐like profile. Prevalence of A+ was found in 9.1% of SCD and 35.7% of pre‐MCI, compared to 73% of MCI (SCD vs MCI: p<0.001; pre‐MCI vs MCI: p=0.0049).

Conclusion

Consistent proportion (10.7%) of subjects with subtle cognitive deficits not fulfilling MCI (pre‐MCI) in our cohort showed evidence of AD‐like profile, while none of SCD resulted A+/T+. Amyloidosis was detectable in both SCD and pre‐MCI subjects. Accordingly, pre‐MCI with evidence of AD‐like biomarkers may be considered as the earliest clinical manifestation of AD, and may represent an important target for treatment with disease‐modifying drugs.
A novel longitudinal approach in individual subjects to investigate the movement of tau over time using graph theory in clinical and preclinical stages of Alzheimer’s disease
Authors: Protas Hillary D. , Ghisays Valentina , Chen Yinghua , Goradia Dhruman D. , Luo Ji , Malek‐Ahmadi Michael H. , Lee Wendy , Devadas Vivek , Bauer Robert , Reiman Eric M. , Chen Kewei , Su Yi
Published: December 2020

Background

We previously introduced an index characterizing inter‐regional tau deposition variability based on graph theory. Extending our method to additionally characterize the longitudinal tau spread for individual subjects based on directed graph theory, we examined the difference between longitudinal network measures and the regional tau deposit measures over time with respect to 1) differentiation of patients with AD, MCI, and cognitively unimpaired(CU) subjects, 2) correlation with memory measures in Aβ+ CU, and 3) sample size needed for a prevention trial for Aβ+/‐ CU.

Method

The longitudinal tau PET data is from 13 AD, 42 MCI, and 72 CU in ADNI . Using cerebellar grey reference region, we calculated the difference over two time points (1.1 years ± 0.2 (0.6‐1.6)) for the entorhinal, inferior temporal and metaROI SUVR, and the difference for indices, in‐strength and out‐strength each based on the directed tau longitudinal network using predefined nodes(inferior temporal and limbic). We examined regional/network based indices in term of the group differences, their correlation with AVLT‐LTM change. In addition, we also calculated sample size for a prevention clinical trial for Aβ+/‐ subjects separately with 80% power and 25% treatment effect.

Result

The longitudinal tau network measures(instrength and outstrength) are significantly different between the three groups (p<0.004) but not the SUVR change at entorhinal(p=0.62), inferior temporal(p=0.36) or tau meta ROI rates(p=0.21). In CU Aβ+ subjects, limbic outstrength significantly correlated to AVLT‐LTM rate(rs=‐0.52, p=0.013). The most significant regional value(tau metaROI) rate is not significantly correlated with AVLT LTM rate(rs=‐0.25,p=0.26). For a clinical trial, the Inferior temporal in‐out strength(net influx) requires a sample size of 584 subjects in CU Aβ+ group and a sample size of 26448 subjects in CU Aβ‐ Entorhinal tau SUVR, inferior temporal and tau metaROI SUVR needs a sample size for CU Aβ+ is 1623, 2450,2629 respectively. For CU Aβ‐ subjects, the sample size is 53537 for entorhinal SUVR, 50605 for inferior temporal SUVR and 916184 for tau metaROI SUVR

Conclusion

The network based longitudinal indices provide better power for differentiating patients at different stages, for examining tau’s effects on memory and for detecting a treatment effects in prevention trial.
Differences in everyday cognitive difficulties in demographically diverse community‐dwelling older adults using daily diaries: A comparison among older adults with and without SCD
Authors: Mogle Jacqueline , Hill Nikki L , Rabin Laura , Katz Mindy J.
Published: December 2020

Background

Neuropsychologically intact older adults who report experiencing subjective cognitive decline (SCD) likely draw on daily experiences of cognitive difficulties as an indicator of worsening cognitive functioning. Specifically, the frequency of problems (e.g., memory lapses, difficulty planning) and/or the degree that these problems interfere with their daily activities may play a role in their perception of cognitive changes. The current study examined differences in daily cognitive difficulties in older adults without SCD compared to those with SCD or MCI.

Method

Participants (n=212, Mage=76.97 years, range: 70‐90, 65% female, 50% White) completed a battery of objective cognitive performance tasks, psychosocial questionnaires, and they self‐reported experience of and interference from cognitive difficulties each day for 14 days (via smartphones). Fifty‐seven participants were classified as having mild cognitive impairment (MCI) using the Jak, Bondi (2009) criteria. One hundred and three participants not classified as MCI were classified as SCD as they reported their memory functioning worsening in the past 5 years. The remaining 52 participants with no SCD were normal controls. Generalized linear modeling was used to predict total number of and average interference from memory lapses and general thinking problems from daily reports.

Result

After accounting for age, sex, race/ethnicity, education, and depressive symptoms, cognitively normal participants with SCD and those with MCI reported significantly more everyday cognitive difficulties compared to cognitively normal participants without SCD (Figures 1‐3). The MCI and SCD groups did not differ from each other (p’s>.07). For retrospective memory lapses and general thinking problems, normal controls reported significantly lower interference than participants with SCD and those with MCI (p’s>.02; Figures 5 and 6). For prospective memory lapses, only participants with MCI reported significantly higher interference than normal controls (p=.01; Figure 4).

Conclusion

Compared to participants without SCD, participants with SCD and those with MCI reported more frequent everyday cognitive problems and that problems were more likely to interfere in daily activities. Everyday cognitive difficulties may differentiate those individuals more likely to develop functional impairments related to declining cognition. Difficulties meeting daily cognitive demands has the potential to interfere with the ability of older adults to safely live independently.
Quantitative susceptibility mapping MRI reveals a relationship between iron accumulation, CDR score and cognition across the spectrum from healthy aging to Alzheimer’s disease
Authors: Killiany Ronald J , DeVivo Renee , Ellison Andrew , Zhao Yansong , Steinberg Eric , Alosco Michael L , Stern Robert A , Mez Jesse
Published: December 2020

Background

The objective of this study was to determine if there is a relationship between iron accumulation in the various white and gray matter regions of the brain, as assessed by susceptibility changes, measured with Quantitative Susceptibility MRI (QSM‐MRI), Clinical Dementia Rating (CDR) Score and a Cognitive Measure of Delayed Recall. Iron is an essential element for normal neuronal functioning. The accumulation of brain iron may signal a reduction in neuronal metabolism and/or trigger a neuroinflammatory response with microglia transporting iron to regions where pathology is taking place. This has led to the hypothesis that disruption of brain iron homeostasis contributes to Alzheimer’s disease symptoms.

Method

This study used a cross‐sectional design. MRI scans (T1 MPRAGE, QSM‐MRI with multi‐echo acquisition) were acquired on 57 participants from the Boston University Alzheimer’s Disease Center. Freesurfer 6.0 was used to generate regional brain volumes. The T1 maps from Freesurfer were co‐registered with the QSM scans to get regional brain QSM intensity values for each of the Desikan‐Killiany gray matter regions and Salat white matter regions. Values from the two hemispheres were combined. Associations between QSM values and clinical outcomes were assessed using stepwise ordinal logistic regression (CDR) or multiple regression (Neuropsychological Assessment Battery list learning long delay) in JMP 15 with age, sex and whole brain volume forced into the analyses as control variables.

Result

The ordinal logistic analysis produced a significant model (R Squared = 0.76). Following FDR correction, the volume of the hippocampus combined with susceptibility regions from subcortical gray matter and parietal white matter regions were important contributors to the logistic model. The multiple regression also produced a significant model (R Squared = 0.73). Following FDR correction, susceptibility values from medial temporal gray matter and parietal white matter regions were selected as important contributors to the regression model. Little overlap was found amongst the predictors chosen in these models.

Conclusion

These findings support to the notion that a disruption of brain iron homeostasis is related to clinical status and memory function. As such, it may help us to better understand the clinical syndrome of Alzheimer’s disease.
People living alone with dementia: Ethical guidelines for social research
Authors: de Medeiros Kate , Girling Laura
Published: December 2020

Background

Although it is believed that around 1/3 of people with Alzheimer’s and related dementias (ADRD) live alone in the community, the actual percentage is likely higher given dementias are often underdiagnosed and underreported. In addition, significant barriers (e.g., compromised capacity, accessibility issues, stigmatization) to the research inclusion of those residing alone with ADRD has led this population to be overlooked and/or deliberately excluded from social inquiry. Research systems that pose insurmountable barriers to the inclusion of vulnerable populations with ADRD prevent evidenced‐based knowledge that could constructively benefit future patients and caregivers. The present study was designed to create an important evidence base for ethical considerations regarding inclusion and exclusion of people living alone with ADRD into social research.

Method

Funded by the National Institute on Aging, the present study conducted a comprehensive narrative synthesis of published ADRD and gray literature and 10 in‐depth interviews with key gatekeepers (e.g., people who can provide or deny access to people living alone with ADRD) to develop data‐driven recommendations to support the research inclusion of people living alone with ADRD.

Result

The combined narrative synthesis and primary data collection underscored three areas of inclusionary/exclusionary concern: 1) fluctuating capacity to give informed consent, 2) absence of study partners or surrogate decisions‐makers and 3) social and environmental barriers exacerbating disparities by discouraging inclusion of a severely marginalized population. Detailed guidelines will be discussed in each of these three areas.

Conclusion

The developed guidelines provide significant insights into how the dementia research community can overcome barriers to research‐driven learning in order to ethically incorporate live‐alone people with dementia into social science explorations, providing direction for current and future research.
Content validity analysis of the computer proficiency and mobile proficiency questionnaires: Study on proposed Brazilian Portuguese version translated and culturally adapted
Authors: Andrade Alan Cronemberger , Sampaio Gustavo Guedes Vaz , Bertolucci Paulo Henrique Ferreira
Published: December 2020

Background

Digital technologies can enhance benefits in healthcare. Its use is increasingly present in elderly people daily life. Being a proficient user maybe important for social communication and independent living, and additionally can bring benefits to researchers in testing patients outside the office. The Computer Proficiency (CPQ) and the Mobile Proficiency Questionnaires (MDPQ) proved to be useful in English (United States) and Spanish (Spain) speakers to quantify the degree of proficiency in electronic devices in adults. We lack instruments to measure this in Portuguese.

Method

Following established practices, an instrument translation from English to Portuguese was prepared by a Brazilian bilingual neurologist. Then, a back‐translation was performed by 2 other specialists for additional adjustments. Afterwards, a panel of 7 experts (4 Cognition and Behavioral neurologists, 1 geriatric psychiatrist, and 1 information technology PhD) categorized the questionnaires items to calculate the Face Validity Index (FVI) for language clarity, and the Content Validity Index (CVI) for practical and theoretical relevance for both individual items (i‐CVI) and whole scales (S‐CVI).

Result

The results of the translation are shown in the tables (final version in Portuguese included). The comparative back translations obtained good equivalences. The experts group proposed small changes in the use of idiom in a few questionnaires’ items. The expert consensus for the translation assertiveness was considered very good (S‐FVI/Average CPQ=0.96 and MDPQ=0.99), with high levels of unanimous agreement (S‐FVI/UA of 81% and 95%, respectively). The S‐CVI/Ave were considered good for practical (CPQ=0.86 and MDPQ=0.93) and theoretical relevance (CPQ=0.81 and MDPQ=0.85), although the experts’ unanimous agreement was considerably lower.

Conclusion

The CPQ and MDPQ questionnaires in their Brazilian Portuguese versions achieved satisfactory translated content quality and language clarity. They will need consequent validation and reliability studies in our population. Small changes to better improve the questionnaires in our language are discussed. We aim they can provide a useful tool for Brazilian research on digital devices. Correlation with demographic, cognitive, and functionality data may provide more information on how digital proficiency can be useful to track our patients.
Validation of EEG‐based brain age index as a biomarker for dementia
Authors: Ye Elissa M , Sun Haoqi M , Lam Alice D , Westover M Brandon
Published: December 2020

Background

Dementia is a growing cause of disability and loss of independence in the elderly, yet remains largely under‐diagnosed. A biomarker for dementia that can identify individuals with or at risk for developing dementia may help close this diagnostic gap. Deviations from the normal aging trajectory, known as Brain Age Index (BAI), have shown potential to serve as biomarkers for cognitive impairment. We aimed to investigate the association between BAI and dementia and determine whether an overnight sleep EEG‐based BAI could serve as a useful biomarker for dementia. We hypothesized that patients with dementia‐related diseases have significantly higher brain age indices than patients without dementia.

Method

Using a dataset of polysomnograms from 11,039 patients, we computed BAI using an EEG‐based brain age algorithm. Patients were categorized into four groups, including dementia, mild cognitive impairment (MCI), symptomatic, and non‐dementia, based on clinical diagnoses, Montreal Cognitive Assessment (MoCA), and/or Mini‐Mental State Exam (MMSE) scores.

Result

We found an overall significant trend across dementia groups using Cuzick's test (p=0.0007). The BAI of patients with dementia (4.11 ± 10.02 yrs) were significantly higher than those of patients with no dementia (0.516 ±10.40 yrs), with p‐value of 0.002, and those of healthy subjects (‐0.67 ± 9.52 yrs), with p‐value of 0.0002. BAI was negatively correlated with MoCA (R = ‐0.1359, p = 0.006) and MMSE (R = ‐0.1201, p = 0.005). Features related to delta activity in non‐REM sleep stages 2 (N2) and 3 (N3) tend to correlate with non‐dementia, and features related to theta and delta waves in the Wake and N1 stages tend to correlate with dementia.

Conclusion

Our results suggests a potential for an EEG‐based Brain Age Index to serve as a biomarker of dementia. This opens new possibilities for using BAI as an assessment tool for the presence of underlying neurodegenerative disease and monitoring of disease progression.
Mid‐life obesity and metabolic dysfunction in a genetically diverse mouse model of Alzheimer’s disease
Authors: Dunn Amy R. , Hadad Niran , Kaczorowski Catherine C. , O'Connell Kristen M.S.
Published: December 2020

Background

Age and genetic background are the greatest risk factors for Alzheimer’s disease, but obesity and metabolic syndrome increase the risk of developing AD, as increased BMI at mid‐life is associated with an earlier age at onset for AD dementia. Furthermore, many AD patients also present with non‐cognitive symptoms associated with metabolic dysfunction, such as weight loss, changes in appetite, and low circulating leptin levels, which often occur prior to the onset of cognitive decline. Thus, systemic metabolic function may be an important, causal factor in the etiology of AD in humans. However, the mechanisms underlying this dysfunction and its relationship to disease onset, progression, and severity are poorly understood.

Methods

We assessed metabolic function in mice from our recently developed model of human AD, the AD‐BXD genetic reference panel (Neuner, et al 2019). Metabolic function was measured in 39 AD‐ and non‐transgenic (Ntg) strains using indirect calorimetry in Promethion metabolic cages to measure energy expenditure, VO2and VCO2, respiratory exchange rate (RER), locomotor activity, food and water intake, and sleep. To model mid‐life obesity, a subset of age‐ and sex‐matched AD‐ and Ntg‐BXD mice were fed a high‐fat/high‐sugar diet (HFD) starting at ∼2.5 months of age.

Results

AD‐BXD mice weigh less than their non‐transgenic counterparts; assessment of body composition indicates this is due primarily to a loss of fat mass. AD‐BXD strains also exhibited an increase in rearing behavior, which may indicate hypervigilance. Female AD‐BXD strains exhibited increased energy expenditure and locomotor activity and failed to develop diet‐induced obesity when fed HFD. Mice fed HFD generally displayed changes in RER consistent with a shift to fat metabolism; we further observed changes in patterns of food intake.

Conclusions

Our data indicate that AD‐BXD mice exhibit some degree of metabolic dysfunction and that this is exacerbated by HFD. Analyses indicate that metabolic dysfunction at cognitively presymptomatic ages is correlated with memory deficits later in life. Ongoing work will quantify the impact of genetic background on these traits and relationships between metabolic and cognitive phenotypes.
Interrogating the role of the noradrenergic locus coeruleus in memory encoding in aging
Authors: Ludwig Mareike , Hammerer Dorothea , Lüsebrink Falk , Düzel Emrah
Published: December 2020

Background

The locus coeruleus‐norepinephrine system (LC‐NE system) supports the process of encoding of emotionally salient events. LC integrity varies in healthy elderly and is associated with altered cognitive functions in aging. Post‐mortem as well as structural indicators suggest that the modulation of the LC‐NE system is reduced in elderly. This reduction in ageing is also of note as it might be one of the earliest pre‐symptomatic indicators of dementia‐related brain pathology. Indeed, LC neuron degeneration is already observable in early stages of tau pathology before any cognitive symptoms are clinically notable in Alzheimer´s disease (AD). The main aim of this study was to investigate age differences in functional activations of the LC during (emotionally) salient events.

Method

A total of 50 people (28 younger, 22 older healthy adults) participated in the experiment. A reversal learning task has been chosen as it provokes the release of NE. The study used neuromelanin (NM) ‐ sensitive magnetic resonance imaging (MRI) and high‐resolution functional MRI (fMRI) to visualise age differences in LC structure and function. Functional indicators can add sensitivity over structural indicators, which is important considering the fact of neuronal function loss before cell death occurs.

Result

Reduced LC integrity was related to lower memory performance for negative emotional events in elderly only. Moreover, unexpectedly, stronger functional responses of dopaminergic and noradrenergic midbrain structures to (emotionally) salient events during memory encoding were observed in older adults.

Conclusion

These results are discussed in light of age differences in adapting to high and low levels of task difficulty. The study has shown the feasibility of investigating age differences in neuromodulatory nuclei. Therefore, the observed reduction in LC integrity might be a typical sign of healthy ageing or a sign of mild cognitive impairment (MCI) and thus also for AD.
Fibronectin accumulation and oxidative modification in Alzheimer’s disease
Authors: Farr N. Drew , Kraner Susan D. , Nelson Peter T. , Norris Christopher M. , Sompol Pradoldej
Published: December 2020

Background

Oxidative stress in Alzheimer’s disease (AD) alters the structure of brain proteins, complicating the pathophysiology of AD while suggesting potential drug targets. Fibronectin mediates cell attachment and function, in part by directing the reorganization of the extracellular matrix. High molecular forms of fibronectin appear more frequently and in higher amounts in AD while oxidative stress can cause nitration of fibronectin by 3‐nitrotyrosine. Considering the role of fibronectin in maintaining vessel function, accumulation/oxidative modification of fibronectin may alter vessel function. Astrocytes are also damaged in AD, with significant physiologic consequences. In healthy brain, astrocytes maintain the integrity of the neurovascular unit by maintaining molecular, metabolic, and cellular homeostasis. In AD, phenotypically distinct astrocytes may play a role in neurovascular function. Combined with compromised astrocyte function, oxidative modification of fibronectin may further damage AD brains that are already less capable of repair.

Method

Astrocytic fibronectin and β‐amyloid were quantified in WT and 5xFAD mice (n = 6‐8 mice/group) using confocal microscopy and Western blot. GFAP, fibronectin, nitrotyrosine, and β‐amyloid were also immunolabeled in postmortem human AD and age‐matched control tissue and imaged using confocal microscopy.

Result

We showed that fibronectin was increased in hippocampal astrocytes in 5xFAD vs. WT mice (p = 0.032). In 5xFAD brain homogenates, fibronectin was increased by 30% compared to WT. In human tissue, both fibronectin and nitrotyrosine were increased compared to control. Fibronectin also accumulated around β‐amyloid plaques while fibronectin and nitrotyrosine colocalized in perivascular astrocytes, suggesting oxidative modification of fibronectin in human AD compared to control. We also observed morphologic changes in human AD astrocytes. AD white mater showed more fibronectin and nitrotyrosine in astrocytes compared to gray matter as well as more fibronectin in the extracellular space. Fibronectin was especially concentrated in the perivascular white matter.

Conclusion

Oxidative changes to fibronectin in AD clustered in perivascular astrocytes, suggesting the central role of astrocytes in AD‐related vascular dysfunction.
Examination of a composite walking measure to inform physical activity guidelines for improving or maintaining cognitive functioning
Authors: Desai Pankaja , Halloway Shannon , Dhana Klodian , Holland Thomas Monroe , de Leon Carlos Mendes , Evans Denis A , Morris Martha Clare
Published: December 2020

Background

Fewer than half of all U.S. adults achieve recommended levels of aerobic activity (150 minutes or more at moderate intensity) (CDC, 2013; USDHHS, 2018). Information related to frequency, dose, duration, and intensity of walking needed to positively impact cognitive function in older adults remains unclear in current U.S. Physical Activity Guidelines (Piercey et al., 2018; Paterson et al., 2010). A paucity of studies have been conducted which examine the association between physical activity (PA), much less PA types, and cognitive function, using a longitudinal, population‐based approach with a racially diverse sample, which limits generalizability of existing findings. Self‐report PA measures often evaluate types of walking separately (e.g., walking for exercise, leisure time, occupational, transportation‐related), without considering total effect of all types of walking on cognitive function. A composite walking measure could provide a more comprehensive picture of perceived daily walking. We examine the association between composite walking and cognitive function and perceptual speed among participants in the Chicago Health and Aging Project (CHAP) over time.

Method

CHAP is a longitudinal, population‐based study, which examined risk factors of Alzheimer’s Disease and chronic conditions among diverse older adults (Bienas et al., 2003). Data collection included self‐report walking frequency and duration, demographics, chronic conditions, cognitive activities, APOE ϵ4, and cognitive function during three‐year cycles. A composite walking measure was developed. Composite walking was divided into three categories determined by sample size: no walking, < 105 minutes/ week, and >105 minutes/ week of walking. Mixed effects regression analyses were conducted to test the association between walking and cognitive function and perceptual speed.

Result

The sample consists of N=4,320 CHAP participants (Black/ African American: 65%; Female: 65%; Mean Education: 13 years; Mean Age: 75 years). Findings show that composite walking had a statistically significant association with global cognitive function (category 2 β=.0084, p=.0389; category 3 β=.0099, p=.0187) and perceptual speed (category 2 β=.0117, p=.0164; category 3 β=.0162, p=.0013), after controlling for covariates.

Conclusion

Although it is best to follow PA guidelines, walking for lesser than the recommended amount may still be beneficial for cognitive function, which is useful for promotion of PA among sedentary older adults.
Alzheimer’s disease variant portal (ADVP): Harmonized genetics data and evidence collection for Alzheimer’s disease
Authors: Leung Yuk Yee , Kuksa Pavel , Qu Liming , Zhao Yi , Katanic Zivadin , Kuzma Amanda B. , Fu Wei , Liu Chia‐Lun , Tzeng Kai‐Teh , Valladares Otto , Chou Shin‐Yi , Naj Adam C. , Schellenberg Gerard D. , Wang Li‐San
Published: December 2020

Background

Alzheimer’s disease (AD) genetic findings span progressively large genome‐wide association studies (GWASs) and meta‐analyses, with no single resource providing unified, searchable information on identified genetic variants and genes and supporting functional genomic evidence. We developed ADVP (Alzheimer’s Disease Variant Portal), a curated and harmonized interactive platform that provides unified access and visualization of a uniquely extensive up‐to‐date collection of GWAS data for AD.

Methods

The contents of ADVP database are curated from high quality genome‐wide significant loci reported in literature. We included all AD GWAS publications by Alzheimer’s Disease Genetics Consortium (ADGC) over the last ten years as a starting point and all other AD studies in GWAS catalog/GWAS central (MeSH D000544). For each publication, we systematically recorded all the association results reported in the main text. To facilitate curation, we developed a minimal set of information (meta‐data schema) to ensure all findings are annotated with the same information, including publication, association (variant rsID, genomic position, gene, association test results (p‐value, beta, odds ratio), effect allele, etc), phenotype, study design, target population, GWAS characteristics (size, number of cases/controls) among others. Collected data were organized into publication, variant, association, and evidence (functional genomics) database tables.

Results

ADVP web interface provides multiple views of underlying data allowing browsing individual variants, genes, studies, genomic regions, genome‐wide/chromosome variant maps (interactive ideograms), and genome browser views incorporating functional genomics data. ADVP is also integrated with National Institute on Aging Genetics of Alzheimer’s Disease Data Storage Site (NIAGADS) GenomicsDB, a database that provides genetic and functional evidence for AD, to allow researchers cross‐reference other public resources (e.g., dbSNP, ClinVAR, ENCODE, Roadmap), and view functional evidence available for each genetic variant or gene.

Conclusions

ADVP is the largest collection of systematically curated, harmonized and comprehensively annotated literature‐derived AD‐associated genetic variants. This current ADVP collection contains genetic findings from more than 60 cohorts and >200 studies across a variety of populations including Caucasians, Hispanics, African‐Americans, and Asians. Currently, ADVP contains ∼7,000 AD‐association records corresponding to over 913 unique loci, 1803 unique genetic variants and 951 associations published in multiple studies. ADVP is freely accessible at http://advp.niagads.org.
Effects of acute exercise on functional connectivity in young and older adults
Authors: Goerlich Katharina S. , Xin Yuanyuan , van Asselt Manon , Thioux Marc , Renken Remco , Aleman André
Published: December 2020

Background

Physical activity has protective effects on cognition and brain health. Regular exercise contributes to better cognition, promotes functional and structural brain changes, and may even reverse age‐related decline to some extent. However, the effects of a single session of acute exercise on functional connectivity are currently unclear.

Method

The study sample comprised 59 healthy participants, 31 young adults (mean age: 22.3; 8 females) and 28 older adults (mean age: 55.8; 9 females). During their first visit, participants performed a submaximal exercise on a bicycle ergometer to measure their fitness level. During the second and third visits, participants took part in two counterbalanced MRI sessions: an Exercise session and a Relax session. In the Exercise session, participants received a 10‐minute resting‐state scan, followed by a 15‐minute period of aerobic exercise. After the exercise, participants received the second resting‐state scan. For the Relax session, the exercise was replaced by a 15‐minute rest period. Data analysis was performed in SPM8. For the functional connectivity (FC) analysis, 30 seeds were selected from the brain’s major functional networks and relevant subcortical regions. Seed2voxel FC was computed as Pearson’s correlation and transformed to Fisher’s Z. A cluster‐level FEW correction p < 0.05 was applied. Effects of acute exercise on FC were tested across and between the two groups using within‐subject ANOVAs controlling for fitness level and scan order. In addition, correlations and interactions were calculated between fitness level and exercise effects on rsFC.

Result

Across groups, acute exercise was associated with decreased FC of the caudate and the amygdala to the pre and postcentral gyrus. Significant group differences were observed for the putamen and intraparietal sulcus, PreCG and superior frontal gyrus: exercise effects on FC between these regions were significantly larger in young compared to older adults. A significant interaction effect between fitness level and group was found for FC of NAcc‐PCC/Precuneus, with a positive association in young individuals and a negative association in older individuals.

Conclusion

Even a single session of acute exercise affects functional connectivity in neural networks involved in motor processing and motivation. This relationship is different for young compared to older individuals.
Transcranial magnetic stimulation distinguishes patients with behavioral variant fronto‐temporal dementia from primary progressive aphasia patients
Authors: Lorenzo Francesco Di , Motta Caterina , Bonnì Sonia , Assogna Martina , Caltagirone Carlo , Martorana Alessandro , Koch Giacomo
Published: December 2020

Background

In the recent years the use of neurophysiological techniques, combined with other clinical and neuroimaging biomarkers, allowed to further deepen physiopathological mechanisms of neurodegeneration. Fronto‐temporal Dementia (FTD) patients showed an impairment of intracortical circuits investigated with SICI/ICF and LICI protocols, while there is a normal activity of central cholinergic circuitry (investigated with SAI protocol), reflecting the relative sparing of cholinergic system in this disease. In the current work we aimed to determine whether a transcranial magnetic stimulation (TMS) multiparadigm approach can be used to distinguish the behavioral variant of frontotemporal dementia (bvFTD) from non fluent variant of Primary Progressive Aphasia (nfPPA)

Method

30 patients with bvFTD and 30 nfAPP patients have been enrolled for this study. Paired‐pulse TMS was used to investigate short‐interval intracortical inhibition (SICI) and facilitation (ICF), long‐interval intracortical inhibition (LICI) , and short‐latency afferent inhibition (SAI) to measure the activity of different intracortical circuits in all the participants to the study. We also tested Long‐term Potentiation (LTP) cortical plasticity with iTBS protocol. All the patients underwent an extensive neuropsychological evaluation, MRI and CSF sampling.

Result

bvFTD patients exhibited a deficit of SICI, consisting in a disinhibition, while on the other hand nfPPA patients had a weakened ICF resulting in a weakened facilitation. No difference was observed for SAI, reflecting the sparing of cholinergic neurons for both nfPPA and bvFTD patients. bvFTD patients showed a deficit of LICI evident at 100 msec, expression of an impairment of GABA‐B receptors, resulting in a disinhibition of the MEP compared to nf‐PPA. bvFTD patients had a weakened iTBS after effects, oppositely to nfPPA patients that showed the expected LTP‐like cortical plasticity.

Conclusion

Intracortical circuitry investigation and iTBS protocol showed clear differences among bvFTD patients and PPA, probably reflecting distinct phisiopathological mechanisms. TMS is a noninvasive procedure able to distinguishes between different variants of FTD. These preliminary findings pave to way for a more spread use of neurophysiological techniques in the study and management of neurodegenerative disease such as FTD, not just for better understanding of phisiopathological mechanisms of disease but also in case of monitoring of therapeutical efficiency.
Hypercholesterolemia accelerates Aβ deposition in regions associated with early amyloidosis
Authors: Souza João Pedro Ferrari , Povala Guilherme , Brum Wagner Scheeren , De Bastiani Marco Antônio , Pascoal Tharick A. , Benedet Andréa Lessa , Therriault Joseph , das Ros Lucas U. , Bieger Andrei , Rosa‐Neto Pedro , Zimmer Eduardo R.
Published: December 2020

Background

Hypercholesterolemia is a well‐established risk factor for developing Alzheimer's disease (AD). Mechanisms underlying this relationship, however, are still unclear. Recent experiments have reported conflicting findings regarding the relationship between amyloid‐beta (Aβ) and cholesterol. While in vitro studies have shown that cholesterol accelerates Aβ aggregation, an epidemiological investigation demonstrated that total serum cholesterol is not associated with Aβ load. Nevertheless, it is still unclear whether total serum cholesterol affects Aβ deposition in the human brain. Here, we aimed to assess whether high levels of total serum cholesterol are associated with the rate of Aβ aggregation in the brain. We hypothesized that high total serum cholesterol levels could accelerate cerebral amyloidosis of non‐demented subjects.

Method

We selected 207 non‐demented – cognitively unimpaired and mild cognitive impairment – participants from Alzheimer's Disease Neuroimaging Initiative (ADNI) who had available data for baseline cholesterol and longitudinal amyloid PET scans with [18F]AV45. Subjects were divided into two groups regarding their total serum cholesterol levels, being classified as normal (<200mg/dL; n=158) or abnormal (>200mg/dL; n=107). We performed a voxel‐wise general linear modelling to assess Aβ load differences between groups at baseline. Then, a longitudinal comparison was carried out to evaluate the rate of Aβ deposition in 4 years, calculated as "(IMAGE4_YEARS ‐ IMAGEBASELINE)x100/IMAGEBASELINE". Age, gender, APOEε4, cholesterol treatment and diagnostic group were used as covariates.

Result

No differences were found in Aβ load at baseline. By contrast, we observed a significantly higher rate of Aβ accumulation for the abnormal group in brain regions associated to early amyloidosis, including lateral temporal (peak t(200) = 4.498, p<0.0001) and parietal (peak t(200) = 4.504, p<0.0001) lobes, over a 4‐year period when compared to the normal group (Figure 1).

Conclusion

Our findings suggest that serum cholesterol dysmetabolism could influence cerebral Aβ aggregation. In addition, our analysis points to a potential communication between central and peripheral cholesterol compartments (perhaps intensified by hypercholesterolemia‐related inflammation). Also, it corroborates with the hypothesis that higher serum cholesterol levels accelerate the process of brain amyloidosis, stressing the need for further investigation on the mechanisms involved in this process.
Early developmental abnormalities in hippocampal synapse distribution in a mouse model of Alzheimer’s disease
Authors: Ray Ajit , Bernhard Sarah M. , Kuljis Dika A. , Bruchez Marcel P. , Barth Alison L
Published: December 2020

Background

Alzheimer’s disease (AD) has long been described as a disease arising from progressive loss of synapses and cell death. While this is certainly true for the late stages of AD when patient present with clinical symptoms, it has increasingly become a focus of research that early AD may be paradoxically characterized by hyperexcitability and hyperactivity of neurons, specifically in hippocampal CA1 pyramidal neurons. In this study using a transgenic animal model of AD, we investigated whether an alteration in input‐specific synapse numbers could explain this early hyperactivity.

Method

B6C3‐Tg(APPswe,PSEN1dE9) mice (APP/PS1) and wild‐type littermates of different ages and both sexes were injected with our novel pan‐synaptic labeling reagent (AAV1‐FAPpost) (Kuljis et al, 2019) in the dorsal hippocampal CA1 region. Labeled pyramidal cells were reconstructed and quantitative synaptic analysis across dendritic compartments was performed.

Result

Even at postnatal day 21, CA1 pyramidal neurons from mutant mice showed an increase in the number of medial apical synapses (site for CA3 inputs) and a decrease in distal apical tuft synapses (site for entorhinal inputs), that may persist through adulthood. Proximal apical and basal synapses remained unaffected. Similar analysis in aged transgenic animals (13‐14 months) showed a uniform loss of synapses across all compartments.

Conclusion

The compartment‐specific increase in CA3 to CA1 synapses during early development suggests that APP/amyloid‐β may be associated with abnormal synapse formation or stabilization. This increase in excitatory connectivity is consistent with hippocampal hyperexcitability that has been described in preclinical AD. This aberrant increase in CA3 may arise to compensate for the loss of entorhinal inputs and delay the onset of behavioral deficits. Our study demonstrates how AD pathology may progressively damage neural circuit function by inducing primary synaptic deficits and aberrant compensatory reweighting of other synaptic connections.
Limited cerebral microbleeds effect on regional magnetic susceptibility measured by MRI
Authors: Fazlollahi Amir , Raniga Parnesh , Bourgeat Pierrick , Yates Paul A , Bush Ashley I , Salvado Olivier , Ayton Scott
Published: December 2020

Background

Cortical iron accumulation has been reported as a pathological feature of Alzheimer’s disease (AD). The cause of cortical iron elevation in AD is unknown but may be contributed by hemosiderin deposits in cerebral microbleeds (CMBs) that frequently occur in this disease. In this study, we investigate the impact of CMBs (which are more frequent in AD) on the magnetic susceptibility of the surrounding brain tissue.

Method

Thirty‐two cross‐sectional MRI scans from the Australian Imaging, Biomarker and Lifestyle (AIBL, www.aibl.csiro.au) study were found to have 77 definite CMBs by manual assessment of susceptibility weighted images (SWI). The subjects were classified as cognitively normal (CN; N=17; Age:77.4 ± 6.1; CMB:48), mild cognitive impairment (MCI; N=10; 79.1±7.3; 18), or AD (N=5; 77.6±6.2; 11). Quantitative susceptibility mapping (QSM; an MRI technique that is sensitive to iron) was used to estimate iron content in the tissue surrounding the microbleed in four concentric spheres of increasing radius of 1 voxel (∼0.93x0.93x1.75 mm3; regions R1‐4) starting from the boundary of each microbleed. Furthermore, regions R1‐4 were compared to QSM measured in mirror regions of the opposing hemisphere.

Result

The results are presented in Figure 1. The ipsilateral side had significant elevation of QSM in the microbleed compared to the same region on the contralateral side (P<1 x 10‐10). The immediate region surrounding the microbleed, R1, also had elevated QSM signal in the ipsilateral side compared to the contralateral side (P=0.0083). However, there was no difference between ipsilateral and contralateral QSM values in regions R2‐4. These data indicate the QSM is elevated in the brain tissue in the immediate vicinity of the microbleed, but this does not extend beyond 1 voxel.

Conclusion

The local changes in susceptibility due to CMBs could be caused by iron from the CMBs extruding into the surrounding tissue, or it could be caused by partial voluming effect. Regardless, the susceptibility change in this relatively small proportion of tissue suggests that increased iron deposition observed in more widespread cortical regions in AD may be due to a more generalized process or very small lesions below the threshold of detection of these imaging modalities.