bluuebunny/crossref_metadata_2025 huggingface dataset:
Differences in white matter integrity and hippocampal volumetrics across APOE genotype mice: A blinded preliminary study
Authors: Bhattrai Avnish , Raikes Adam C. , Mishra Aarti , Brinton Roberta Diaz
Published: December 2021

Background

Genome‐wide association studies have identified Apolipoprotein (APOE) as one of the strongest risk factors associated with Late‐Onset Alzheimer’s disease (LOAD) with females exhibiting a two‐fold higher incidence as compared to males. MRI studies of patients with LOAD link APOE‐e4 gene load with increased hippocampal volume loss as well as reduction in white matter integrity (WMI) in the limbic and medial temporal regions (Bagepally, 2012). However, there are few translational LOAD mouse model studies utilizing imaging. We hypothesized that hippocampal volume and WMI would be reduced in females and APOE e4 carriers in our humanized APOE (hAPOE) LOAD mouse model.

Method

Six cohorts of APOE e3 and e4 genotype (M/F; N=53; mean age = 17.95 month) skull‐extracted ex‐vivo mouse brains were imaged (7T Bruker Biospec MRI scanner). Imaging included structural and diffusion weighted imaging. Bilateral hippocampal volumes, as well as total brain volume (TBV), were extracted using a well‐validated mouse brain atlas (Dorr, 2008). Fractional anisotropy (FA) was used to quantify WMI and between‐group comparisons were made using a groupwise connectometry approach (Yeh, 2013; Yeh, 2016).

Result

MRI image analysis indicated genotypic differences in white matter FA where APOE‐e4 carriers exhibited lower FA values (mean tractography FA = 0.263 ± 0.043) compared to APOE‐e3/3 (mean tractography FA = 0.311 ± 0.067) in a total of 10657 tracts (FDR corrected p < 0.003; Figure 1). No statistically significant differences were identified across genotypes for left or right hippocampal volumes. However, right hippocampal volume was significantly greater in males as compared to females (p = 0.007) whereas no effect was observed between sexes for left hippocampus.

Conclusion

Outcomes of MRI analyses indicate a significant reduction in FA values and reduced white matter integrity across the brain in APOE e4 carriers, irrespective of sex. Contrary to human literature, no significant volumetric differences between genotypes were found in this mouse sample. Consistent with sex‐dependent literature, males exhibited greater total brain volume and additionally greater right hippocampal volume compared to females, irrespective of genotype. These findings may provide evidence of deficits in cholesterol or lipid transport manifest in decreased white matter integrity in this hAPOE mouse model.
Repeated concussions associated with worsened working memory, attention and processing speed, but preserved delayed memory: A PROTECT study
Authors: Lennon Matthew J , Thayanandan Tony , Corbett Anne , Aarsland Dag , Ballard Clive , Raymont Vanessa
Published: December 2021

Background

Approximately 5% of all dementia diagnoses may be attributable to traumatic brain injuries (TBI), but the precise pathway and required thresholds for increased dementia risk remain unclear. TBI can cause disparate degrees of damage to parts of the brain and thus may affect different subdomains of cognitive function differently. This study examined the strength of associations between traumatic brain injuries and cognitive subdomains in a healthy cohort of older adults.

Method

Cognitive and demographic data was collected from individuals aged 50 ‐ 93 (n = 12,041) participating in the PROTECT study, a large online cohort study. Self reported, cross sectional data on head injury were collected through the Brain Injury Screening Questionnaire (BISQ). Cognitive tests were standardised and grouped into four domain scores using the FLAME composite (Working Memory, Delayed Memory, Processing Speed and Attention) based on a principle components analysis (KMO test = 0.724). Regression analyses were performed, examining the association between numbers of head injuries, episodes of loss of consciousness and the cognitive domain scores.

Result

62.8% of participants reported a previous head injury and 33% of those had at least one episode of subsequent loss of consciousness (21% overall). There was a significant association between the self‐reported historical number of head injuries and poorer working memory, attention and processing speed (B = ‐0.005, ‐0.007, ‐0.014 and p=0.004, <0.001, <0.001 respectively). Self‐reported historical episodes of head injuries followed by loss of consciousness (LOC) demonstrated similar, albeit stronger, associations with working memory, attention and processing speed (B = ‐0.019, ‐0.024, ‐0.024 and p = 0.002, <0.001, <0.001). Neither numbers of head injuries or LOC were associated with poorer delayed memory performance.

Conclusion

The PROTECT study is one of the largest, healthy older adult cohorts to examine the link between TBI and cognitive outcomes. Although it is cross sectional the increasing effect sizes seen for increasing severity of head injury indicates a dose‐response relationship suggestive of causation. Our results suggest that TBI may differentially impact particular brain areas and functions and that cognitive impairment in those with a history of TBI has a distinct pathological and clinical phenotype.
Associations between obstructive sleep apnea, Alzheimer’s disease pathology, and objective daytime sleepiness measured by the psychomotor vigilance task in cognitively unimpaired adults
Authors: Plante David T , Tran Kieulinh Michelle , Cook Jesse D , Hagen Erika W , Peppard Paul E , Kollmorgen Gwendlyn , Suridjan Ivonne , Blennow Kaj , Zetterberg Henrik , Carlsson Cynthia M , Johnson Sterling C. , Bendlin Barbara B
Published: December 2021

Background

Daytime sleepiness is common among individuals with obstructive sleep apnea (OSA), and has been reported among individuals with Alzheimer’s Disease (AD) pathology. However, objective measures of decreased alertness have not been examined in the context of AD. Here, we examined performance on the psychomotor vigilance task (PVT) in relation to AD pathology as indexed by AD biomarkers in cerebrospinal fluid (CSF), among individuals with and without OSA.

Method

Forty‐eight cognitively unimpaired adults (32 women), mean age 66.3±7.9 years, enrolled in the Wisconsin Alzheimer’s Disease Research Center (ADRC) completed a multifaceted sleep assessment. Presence and severity of OSA was evaluated using WatchPAT at‐home overnight recordings. Habitual sleep‐wake patterns were assessed using actigraphy. Neurobehavioral alertness was quantified using the 10‐minute PVT. CSF biomarkers were quantified using the exploratory Roche NeuroToolKit assays, a panel of automated robust prototype immunoassays (Roche Diagnostics International Ltd). Generalized linear models examined associations between AD biomarkers, apnea‐hypopnea index (AHI), and PVT performance. Primary AD biomarkers of interest were phosphorylated‐tau (p‐tau), total tau (t‐tau), and amyloid‐beta (Aβ) 42/40 ratio, measured in CSF. The primary PVT variable of interest was the mean response time of the 10% slowest responses, which is associated with daytime sleepiness and default mode network activity. Log transformations for PVT and AHI+1 were utilized for analysis. Covariates included age, sex, body mass index, total sleep time, sleep efficiency, APOEε4 status, years of education, and parental history of AD.

Result

AHI was associated with lower Aβ 42/40 (β=‐0.005,p=0.03) and higher p‐tau (β=2.22,p=0.03), but not t‐tau (β=20.28,p=0.20). Significant AHI*PVT interactions were observed for p‐tau (p=0.0002) and t‐tau (p=0.02), but not for Aβ 42/40 (p=0.18). Specifically, among individuals with OSA (AHI>5/hour;n=20), PVT performance was correlated with p‐tau (r=0.68,p=0.0009) and t‐tau (r=0.39,p=0.09), an association that was not observed in those without OSA in this preliminary dataset.

Conclusion

OSA was associated with amyloid and tau pathology, in individuals without cognitive impairment. Furthermore, PVT performance may be an objective measure of sleepiness associated with elevated p‐tau and t‐tau among individuals with OSA. Replication and expansion of these findings in larger and longitudinal datasets are indicated. Funding: Supported by R03AG063274 and P30‐AG062715.
The effect of bilingualism on the brain is modulated by language experience
Authors: Calabria Marco , Voits Toms , Rothman Jason , Robson Holly , Marín Lidón Marín , Costumero Víctor , Aguirre Naiara , Pliatsikas Christos
Published: December 2021

Background

Research has shown that lifelong bilingualism may contribute to cognitive reserve in neurodegenerative diseases as shown by a delay of the age at symptom onset in bilinguals with different types of dementia. However, the study of the neural mechanisms behind this bilingual advantage is limited, especially for the preclinical stages of dementia, such as Mild Cognitive Impairment (MCI). Additionally, most of the studies have operationalised bilingualism as a dichotomous variable, despite the fact that language experience results from a combination of different factors (language usage, frequency of language switching, age of second language acquisition, and language proficiency).

Method

In the present study we investigated cortical and subcortical grey matter structure volume, and episodic memory performance, in a group of bilingual individuals with MCI by considering their linguistic profile. Specifically, we compared active bilingual speakers of Spanish and Catalan and bilinguals who have good knowledge of their second language but without any active usage of it. This classification is based on the results of a previous study in which we found that actively speaking the two languages promotes the delay of symptoms in individuals with MCI.

Result

The results reveal that active bilingualism significantly delays the onset of MCI symptoms. Additionally, active bilingualism is also shown to result in increased cortical grey matter in the right supramarginal gyrus, increased bilateral hippocampal volume and reshaping of the right amygdala and right caudate nucleus.

Conclusion

These results are compatible with the hypothesis that bilingualism protects against cognitive decline via neural compensation mechanisms and by increasing neural efficiency in individuals with MCI.
Using a multi‐staged translation method to develop socio‐culturally and language‐sensitive study materials: Lessons learned from an Asian cohort for Alzheimer’s disease
Authors: Lee Haeok , Tzuang Marian , Tee Boon Lead , Li Clara , Gu Yian , Lu Anna T , Lee Sang A , Seo Eun Hyun , Kang Younhee , Kim Kyungmin , Tran Binh , Chae Wonjeong , Nguyen Dat , Nguyen Dam , Vuong Quyen , Jun Gyungah R , Wang Li‐San , Yu W. Haung , Park Van Ta ,   The Asian Cohort for Alzheimer's Disease Study
Published: December 2021

Background

Alzheimer’s disease (AD) is a global health crisis on multiple levels. A major impediment to AD research is the availability of socio‐culturally and language appropriate study materials and instruments and inclusion of under‐represented minorities. To fulfill this need, we apply best practices and lessons learned to translate study materials for use in the Asian Cohort for Alzheimer’s Disease’s (ACAD) study of AD in Asian Americans and Asian Canadians (ASAC) with the overarching goal in inclusivity of these populations to better understand the etiology of AD.

Method

Our multi‐stag translation process is guided by the World Health Organization’s (WHO) process of translation (forward and reverse translation, consensus verification and reconciliation) to achieve parity with the English materials for our target groups (Chinese (simplified and traditional; Mandarin and Cantonese), Korean and Vietnamese). ACAD’s collective experience partnering with aging Asian adults has revealed not only a language barrier, but also issues with socio‐cultural communication traits, and literal translations that stigmatize AD and dementia. Consequently, we have taken into account the varying perceptions and expressions of words in a social context. The translation process was implemented by a team of multi‐lingual researchers/clinicians/community leaders with extensive practical translation experience. Since language influences how a speaker views the world, we employed a cross‐section of translators and emphasized conceptual (vs. literal) culturally appropriate translations for the community.

Results

To date, we have developed Asian language versions of ACAD documents (informed consent, data collection, community and social media outreach materials, website) for all our target groups and continue the process of beta‐testing our study materials (including the cognitive assessment instruments).

Conclusion

The multi‐stage translation process accounts for distinctive Asian socio‐cultural‐language backgrounds, providing an important guideline for AD researchers to promote health literacy in the health and general community in an effort to reduce health disparities in underrepresented groups, like Asians. In order to ensure fidelity across languages, we will continue validating the original English version in Chinese, Korean, and Vietnamese versions in the ACAD study.
Treatment for anomia in bilingual speakers with progressive aphasia
Authors: Grasso Stephanie M , Kazemi Nina , Mirzapour Haideh , Neupane Rozen , Peña Elizabeth , Bonakdarpour Borna , Tempini Maria Luisa Gorno , Henry Maya L
Published: December 2021

Background

Anomia is an early and prominent feature of primary progressive aphasia (PPA) and other neurodegenerative disorders. Research investigating treatment for lexical retrieval impairment has focused primarily on monolingual speakers.

The purpose of this study was to examine the benefits of a naming intervention administered to bilingual speakers with PPA. We predicted that participants would show improved naming for trained stimuli, with maintenance at follow‐ups. In addition, we predicted that cognate pairs (e.g., rose and rosa) would demonstrate advantages in cross‐linguistic transfer.

Method

In this case series, treatment was administered to ten bilingual speakers with PPA using a single‐subject multiple‐baseline design. Treatment was administered in two phases, with one language targeted per phase. Cognates were included as treatment targets to investigate their potential to facilitate cross‐linguistic transfer. Participants spoke a variety of languages (Table 1), and underwent cognitive‐linguistic testing at pre‐treatment (Table 2). Performance on trained and untrained stimuli was evaluated before, during, and after treatment, and at 3‐, 6‐, and 12‐months post‐treatment.

The Lexical Retrieval Cascade (Henry et al., 2013; 2019) was used to target individually tailored and matched word sets. The intervention targets naming by leveraging relatively spared cognitive‐linguistic abilities, with the goal of retraining specific vocabulary as well as instilling word‐retrieval strategies more broadly. Treatment sessions occurred twice weekly (Table 3) and were complemented with daily home practice. Participants’ performance was analyzed via d‐statistics (Beeson & Robey, 2006) and simulation analysis.

Result

Participants demonstrated significant treatment effects in each of their treated languages, with maintenance up to one‐year post‐treatment for the majority of participants (Figure 1). Most individuals in the cohort showed a significant cross‐linguistic transfer effect for trained cognates in both the dominant (8/10) and nondominant (7/10) language, with fewer than half of participants showing a significant effect for noncognates.

Conclusion

Findings support the implementation of dual‐language intervention approaches for bilingual speakers with PPA, irrespective of language dominance. In addition, our findings indicate that monolingual clinicians may select cognates to support gains across languages. Further research is needed to determine whether measures related to disease severity or language history are predictive of treatment and transfer effects.
Developing best practices for outreach for the Asian Cohort for Alzheimer’s Disease (ACAD) study
Authors: Yu W Haung , Tzuang Marian , Thomas Carlos , Vogel Briana , Lu Anna T , Lee Haeok , Chow Tiffany W , Jun Gyungah R , Wang Li‐San , Park Van Ta ,   The Asian Cohort for Alzheimer’s Disease (ACAD) Study
Published: December 2021

Background

Alzheimer’s disease (AD) is a leading cause of death worldwide. Despite the global impact, clinical research in AD and, in particular, clinical trials, biomarker and genome‐wide association studies are underrepresented for racial/ethnic minorities such as Asian Americans and Asian Canadians (ASAC). The Asian Cohort for Alzheimer’s Disease (ACAD) is the first large AD cohort for ASAC to address this disparity, building on best practices in community recruitment and outreach strategies with the goal of identifying genetic and non‐genetic risk factors of AD in populations of Asian descent. ACAD will include individuals of Chinese, Korean and Vietnamese ancestry, representing the first multi‐cultural Asian cohort analysis for AD.

Method

Community‐Based Participatory Research (CBPR) principles are embedded through all activities as a fundamental strategy to increase research participant engagement of ASAC. CBPR engages the community in all phases of research (i.e., recruitment; resource sharing; study design; data interpretation) as a collaborative process between the community and researchers that leverages each other’s strengths/assets, and requires commitment to sustainability. ACAD’s Recruitment and Outreach Workgroup aims to: a) coordinate and monitor recruitment activities across all 8 recruiting sites in the US and Canada; b) develop and disseminate recruitment and community outreach/education material; c) work with ACAD’s community advisory board (CAB) to address community partner needs; d) work with AD and Asian community partners; and e) develop best practices for community outreach in Asian and immigrant populations.

Result

We have gathered local/regional/national leaders representing the three target ASAC cultural groups (Chinese, Korean, and Vietnamese) of ACAD as our CAB. Four significant activities thus far include: curation of information for public use; translation of ACAD educational/outreach materials; development and dissemination of social media information; and, identifying outreach and enrollment metrics as enduring documents for the research and community stakeholders.

Conclusion

The overarching goal of ACAD is to include this underserved and underrepresented group, reducing health disparities, while increasing our knowledge about the risk of AD among ASAC. Our multifaceted outreach and recruitment strategies will help to optimize ACAD’s success in recruitment and engagement with the ASAC community.
Decorin is an early CSF biomarker of Alzheimer’s Aβ amyloidosis
Authors: Jiang Richeng , Smailovic Una , Haytural Hazal , Haret Robert Mihai , Shevchenko Ganna , Tijms Betty , Gobom Johan , Abelein Axel , Johansson Jan , Zetterberg Henrik , Winblad Bengt , Frykman Susanne , Jelic Vesna , Bergquist Jonas , Visser Pieter Jelle , Nilsson Per
Published: December 2021

Background

Alzheimer’s disease (AD) brains are characterized by extracellular amyloid‐beta (Aβ) deposition and autophagy dysregulation. Here we aimed at deepening the understanding of these brain pathologies and how they translate to the CSF using App knock‐in mice.

Method

AD postmortem brain tissues and App knock‐in mouse models (AppNL‐F
and AppNL‐G‐F
) were used for autophagy characterization. The cerebrospinal fluid (CSF) from App knock‐in mice was analyzed by label‐free mass spectrometry (MS) and compared with previously reported CSF MS results from patients. The expression of decorin in the mouse brains was analyzed by immunohistochemistry and western blot. The autophagy‐activating effect of decorin was measured in the mouse primary neurons.

Result

p62 and LC3 II levels were increased in AppNL‐G‐Fmice similar to the marked accumulation of p62 in AD brains. Several extracellular matrix (ECM) proteins, including decorin, were significantly increased in the CSF of both AppNL‐F mice and amyloid‐positive/tau‐negative subjects with normal cognition. Decorin was decreased in parvalbumin‐positive interneurons but increased in choroideus plexus of AppNL‐Fmice, both of which correlated with Aβ pathology. Decorin‐treated mouse primary neurons exhibited lowered p62 and LC3 II levels.

Conclusion

Autophagy is similarly inhibited in the brains of AppNL‐G‐Fmice and AD patients. The similar increase of decorin in CSF of AppNL‐F mice and amyloid‐positive/tau‐negative subjects with normal cognition indicates a potential of decorin as an early biomarker of Aβ amyloidosis. In addition, decorin activates neuronal autophagy by increasing autophagosomal‐lysosomal degradation linking changes in ECM to autophagy.
iLoF: a blood‐based optical fingerprinting tool for Alzheimer’s disease screening
Authors: Mumtaz Mehak , Faria Simão , Santos Paulo , Carpinteiro Cristiana , Pinto Vanessa , Rodrigues Sandra , Marques Filipe , Rocha Sara , Sampaio Paula , Paiva Joana S. ,   iLoF
Published: December 2021

Background

The high cost and invasiveness of state‐of‐the‐art ATN diagnostic methods underscore the need for alternative approaches for Alzheimer's Disease (AD) patient screening. Blood‐based biomarkers have opened unrivalled opportunities to make AD diagnostics cost‐ and time‐efficient. However, single biomarkers are failing to provide accurate diagnosis/prognosis information for patients suffering from this heterogenous disease, hence the need to combine multiple biomarkers to generate disease‐specific signatures. Here, we present a blood‐based optical fingerprinting tool as a unique ‘holistic’ cost and time efficient solution for frontline AD diagnostics.

Method

Plasma samples from 96 subjects with AD (n=33), mild cognitive impairment due to AD (MCI, n=29), and nondemented controls (n=33) were analyzed with the iLoF technology to generate an optical fingerprint of each sample. Briefly, samples were exposed to a fixed wavelength light‐beam guided through a single mode optical fibre and their back‐scattered signal was acquired and processed to calculate signal‐associated features. The combination of optical features was computed by supervised machine learning algorithms, and four‐fold validation was done to fit the best model. Spike‐and‐recovery experiments for amyloid‐β42, total/phospho‐tau were performed to derive their specific optical fingerprints in blood samples.

Result

The iLoF method classified AD, MCI, and nondemented subjects with an AUC of 0.83. The iLoF measurements correlated with amyloid‐β42 (r=0.783, p>0.0001), total tau (r=0.815, p>0.0001), and phospho‐tau (r=0.782, p>0.0001) concentration in CSF, MMSE score (r=0.759, p>0.0001), and amyloid‐PET scan results (p>0.0001). Additionally, spike‐recovery experiments showed that iLoF technology can identify and quantify relevant AD biomarkers in blood at pathophysiological concentrations. A coefficient of determination between predicted and real concentrations of r2=0.968, r2=0.996 and r2=0.984 was obtained for amyloid‐β42, total tau and phosphor‐tau, respectively. These biomarker‐directed optical fingerprints can be used to further improve the classification model.

Conclusion

In conclusion, blood optical fingerprinting provides a rapid, low‐cost, and convenient tool to enable agnostic screening of AD patients. This disruptive and agnostic technology is expected to become a front‐line screening tool to empower AD diagnosis and may deliver simultaneous screening for multiple diseases underlying dementia. Further work will focus on expanding testing to larger cohorts and addition of other common forms of dementia.
The risk of cognitive impairment in spouses of patients with cognitive impairment
Authors: Park Hee Kyung , Jeong Jee Hyang , Kim Geon Ha
Published: December 2021

Background

We aimed to investigate demographics, neuropsychological performance, and amyloid pathology in spouses of people with cognitive impairment.

Method

A total of 30 patients and 30 spouse controls were enrolled in a prospective cohort for Alzheimer’s disease between June 2018 and December 2020. All subjects had a comprehensive interview, laboratory findings, formal neuropsychological test battery, brain computed tomography or magnetic resonance imaging, and 18F‐ Florbetaben positron emission tomography (FBB PET).

Result

There were no differences in age, sex, education level, family history of dementia, and vascular risk factors between the patient group and spouse group. APOE e4 carriers were more common in the patient group (40.0%) than in the spouse group (10.0%). Although none of the spouses complained of impaired cognition, 40.0% of them were shown to have mild cognitive impairment. Visual analysis of FBB PET showed that 24.1 % of spouses showed amyloid deposition.

Conclusion

Forty percent of spouses of people with cognitive impairment showed mild cognitive impairment and about 24% of them had amyloid pathology. This finding implicates high risk of cognitive impairment in spouses of people with cognitive impairment, which may be associated with shared environmental factors and psychosocial burden as a caregiver. Early diagnosis and intervention for spouses of people with cognitive impairment may be necessary for both patients and spouses. In the future, further investigations in a larger cohort is warranted to confirm findings from this study.
Alzheimer’s disease heterogeneity explained by polygenic risk scores based on brain transcriptomic profiles
Authors: Chung Jaeyoon , Panitch Rebecca , Hu Junming , Zhu Congcong , Mez Jesse , Farrer Lindsay A. , Stein Thor D. , Crane Paul K. , Nho Kwangsik , Jun Gyungah R.
Published: December 2021

Background

Considering the complex etiology of Alzheimer’s disease (AD), classifying AD patients into clinically‐relevant subtypes is important for precision medicine. We proposed a novel way to decompose AD heterogeneity using AD polygenic risk scores (PRSs) from biologically coherent gene‐sets, which were developed based on coexpressed genes in AD brains.

Method

We conducted network analysis using RNA‐sequencing data from 64 autopsied AD brains in the Framingham Heart Study and Boston University Alzheimer’s Disease Research Center and validated preservation of modules in independent AD brain RNA‐Seq datasets from Religious Orders Study and Memory and Aging Project (n=363) and Mayo Clinic Study of Aging (n=82). Next we identified AD‐associated modules by enrichment analyses using a false discovery rate (FDR)<0.05 with gene‐sets informed by GWAS for neuritic plaque and neurofibrillary tangles. Based on the genes ascribed to each module, we computed and evaluated associations of module‐based PRS (mbPRS) for NP and NFT mbPRSs with i) domain‐specific neuropsychological performances, ii) cognitively‐defined subgroups including memory (n=196), executive functioning (n=16), language (n=52), visuospatial functioning (n=91), multiple domain (n=28), and no domain (n=289) (Mukherjee, 2018), and iii) cortical thickness across whole brains in the 672 AD patients of Alzheimer’s Disease Neuroimaging Initiative (ADNI).

Result

Among the 143 co‐expressed gene‐sets (modules) identified in the discovery, 14 modules were preserved in both validation datasets with significant enrichment FDR<0.05 for AD associated genes. PRSs from three modules were significantly associated with performance on a particular cognitive test (logical memory test, Boston Naming test, and Clock copy score) each representing a distinct cognitive domain (memory, language, and visuospatial functioning, respectively). Importantly, mbPRS was significantly associated cortical atrophy in module‐specific regions. Further analysis showed that PRS for each of these three modules significantly differentiated subgroups of AD patients by memory (P=0.02), language (P=0.01) and visuospatial (P=0.04) dysfunction, respectively.

Conclusion

Our findings indicate that an approach integrating genetics and transcriptomic data can differentiate subtle variations in neuropsychological performance among AD patients and clinically‐defined AD subgroups (especially, memory, language, and visuospatial domains), which can be utilized for genetically‐informed AD patient classification.
Herpes zoster diagnosis and treatment in relation to incident dementia
Authors: Weinmann Sheila , Rawlings Andreea , Koppolu Padma , Prado Yolanda K , Rosales A Gabriela , Schmidt Mark A
Published: December 2021

Background

Recent evidence suggests that some infectious diseases, such as herpes zoster (HZ), are positively associated with cognitive impairment and dementia, while certain anti‐viral medications have been reportedly associated with lower risk. We sought to evaluate associations between HZ diagnosis and treatment with incident dementia in a large, retrospective matched cohort.

Method

Using ICD‐9 and ICD‐10 diagnosis codes in electronic medical records, we identified members of Kaiser Permanente Northwest who were age 50 and older between 2000‐2019 inclusive with a HZ diagnosis during this period. A comparison group without HZ diagnosis was individually matched 3:1 on age at HZ diagnosis date (index date), sex, and membership length prior to index date. We excluded subjects with dementia diagnosed before the index date. Follow‐up time started at the index date and ended on the date of dementia diagnosis (based on ICD‐9 and ICD‐10 codes), membership end date, death, or end of follow‐up, whichever came first. Medication for HZ was identified using the first anti‐viral pharmacy fill within 6 months before or after the index date. We used survival analysis to examine the associations between dementia and HZ diagnosis (yes/no, overall, by sex, age), HZ medication (yes/no), and HZ medication by tertiles of cumulative dose of medication dispensed. We adjusted models for demographic and clinical factors.

Result

109,830 persons (27,500 with HZ) were included. The mean age was 65.5 years, and 61.5% were female. Over a mean follow‐up of 6.3 years, 11,386 developed dementia. HZ diagnosis, overall or within subgroup, was not associated with higher risk of dementia (Figure). Among persons with HZ, receipt of anti‐viral medication (any vs. none) was not statistically associated with lower dementia risk. None of the hazard ratios for tertiles of cumulative anti‐viral dose was statistically significant, though the one for the highest tertile was suggestive.

Conclusion

In our retrospective study of over 27,000 persons with HZ and matched comparison persons without HZ, we found no evidence for an association between HZ diagnosis and dementia. Anti‐viral medications prescribed around the time of the HZ diagnosis were not statistically associated with lower risk of dementia.
Defining physical activity: A comparison of actigraphy monitoring and self‐report measures
Authors: VandeBunte Anna M. , Djukic Nina , You Michelle , Fonseca Corrina , Kramer Joel H , Casaletto Kaitlin B
Published: December 2021

Background

Physical activity (PA) helps preserve age‐related brain health. However, PA is a broad construct and its operationalization can vary. Actigraphy monitors are gold‐standard measures of PA, but not always feasible. The Community Healthy Activities Model Program for Seniors (CHAMPS) and Physical Activity Scale for the Elderly (PASE) are widely‐used self‐report questionnaires of PA for older adults, but are limited by scope and subjectivity. We aimed to examine the ecological validity of objective and subjective measures of PA and determine how self‐reported PA relates to distinct actigraphy metrics.

Method

104 functionally normal older adults completed 30‐day Fitbit monitoring (average daily steps and calories burned), and reported PA levels via PASE (total activity) and CHAMPS‐METs (metabolic expenditure calories burned). Participants also completed measures of vascular (hypertension diagnosis, resting heart rate), neurobehavioral (cognition, Perceived Stress Scale, Everyday Cognition Scale), and brain MRI (medial temporal lobe volume) outcomes. Spearman’s rank correlations and regression models evaluated the associations among PA measures and with outcomes of interest.

Result

Greater Fitbit step count associated with higher PASE (r=0.30, p=0.005), but not CHAMPS‐MET scores (r=0.15, p=0.20). On the other hand, Fitbit calories burned related to higher CHAMPS‐METs (r=0.35, p=0.003), but not PASE scores (r=0.16, p=0.15). Only Fitbit measures demonstrated expected positive associations with cognitive outcomes, with slightly stronger associations shown with step count (r range=0.23‐0.26). All 3 PA measures demonstrated expected negative associations with perceived stress and cognitive complaints (r range=‐0.07‐0.26). Greater PA, as measured by Fitbit metrics or CHAMPS‐MET, was associated with less hypertension (Fitbit steps t=0.15; CHAMPS‐METs t=‐2.04) and lower resting heart rate (Fitbit calories burned r=‐0.26). PASE did not significantly associate with vascular health (HTN t=0.93; HR r=‐0.02, ps>0.05). Lastly, greater Fitbit step count (β=0.32, p<0.01) and calories burned (β=0.29, p<0.01), but not PASE or CHAMPS‐MET (β range=0.05‐0.15, ps>0.05), were associated with larger medial temporal lobe volumes.

Conclusion

Objective indicators of PA demonstrate greater overall ecological validity compared to self‐report. Our findings suggest PA is comprised of several constructs. Metrics capturing PA intensity via calories burned may not be interchangeable with metrics of overall movement. Careful understanding what PA metrics represent will facilitate better‐informed recommendations for healthy aging.
Non‐fluent/agrammatic variant of primary progressive aphasia with progressive supranuclear palsy
Authors: Castro‐Suarez Sheila , Osorio‐Marcatinco Victor , Guevara‐Silva Erik Alberto , Caparo‐Zamalloa Cesar , Meza‐Vega Maria
Published: December 2021

Background

Non‐fluent/agrammatic variante of primary progressive aphasia (nfvPPA) is a neurodegenerative disorder characterized by speech production impairment (1). The overlap of nfvPPA and progressive supranuclear palsy (PSP) and corticobasal syndrome cases have been reported (2). As nfvPPA progresses, a parkinsonian disorder often co‐occurs (3). There are different kinds of language impairment including articulatory deficits, agrammatism, reduced speech rate, and anomia (1). Here we present a Peruvian woman with nfvPPA with single‐photon emission computed tomography (SPECT) and parkinsonian syndrome.

Method

We describe a 73‐year‐old woman with progressive speech production impairment and parkinsonian syndrome. She completed standard neurological, neuropsychological, and speech‐language evaluations, as well as brain MRI and SPECT scan.

Result

The patient is a right‐handed woman with 16 years of education. No family history of dementia, parkinsonism or motor neuron disease was reported. At age 71, she presented progressive difficulty in speaking, anomia and verbal hesitancy; but she can understand conversations, send and read text messages. She also had depressive symptoms. MRI showed mild left frontal and perisylvian > right atrophy (fig 1).

By age 73, she developed a prominent reduction in spontaneous speech, mild difficulties in reading and writing, occasional paraphasia, less empathy, dietary change, moria and, mild parkinsonism (she expresses less emotion, tremor, slowly walk and falls). Her episodic memory starts to decline thereafter.

On examination, she had mild‐moderate telegraphic speech, imitation behavior, mild facial masking, bradykinesia and mild postural instability but no abnormal extraocular movement. Speech‐language assessment showed non‐fluent aphasia and apraxia of speech. Impaired comprehension of syntactically complex sentences. Naming was mildly impaired. Syntactic errors were present. Executive function was also impaired, but visuoperceptual skills were preserved.

Serological analyses were unrevealing. Brain SPECT scan showed left frontal and perisylvian > right cortical hypoperfusion (fig 2).

Conclusion

We report a Peruvian case of an elderly woman presenting with a 3‐year history of nfvPPA features and PSP. Her SPECT scan showed left frontal and perisylvian > right cortical hypoperfusion. Consider early evaluating motor function in nfvPPA patients in light of the possibility of CBS or PSP overlap.
A Canadian cohort with the IVS10+14 MAPT mutation
Authors: Maxwell Selena P , Cash Meghan K , Rockwood Kenneth , Fisk John D , Darvesh Sultan
Published: December 2021

Background

The IVS10+14 microtubule‐associated protein tau gene (MAPT) mutation causes dysregulated protein splicing of MAPT, resulting in abnormal 4‐repeat isoform tau accumulation and associated with neurodegeneration. Three families expressing the IVS10+14 MAPT mutation have been reported who express the IVS10+14 MAPT mutation displaying a high degree of interfamilial heterogeneity in their clinical presentation. Herein, we describe the clinical and neuropathological presentation of a new Canadian cohort with this mutation.

Method

Clinical and neuropathological records, including neuropsychological and cognitive assessments, and stained neuropathological sections, were obtained for three family members with the IVS10+14 MAPT mutation. The records were reviewed and compared to previously reported families with this mutation.

Result

The Canadian cohort displayed many of the symptoms previously described in cases with the IVS10+14 MAPT mutation, including prominent motor, cognitive, behavioural, and behavioural symptoms. Additionally, consistent with the interfamilial heterogeneity described in literature, our cohort exhibited profound sensory and sleep abnormalities. Neuropathological information was available for two cases, in which one had widespread cortical and subcortical tau deposition and atrophy, while neuropathological changes in the other case was milder with the exception substantia nigral atrophy.

Conclusion

Our cohort demonstrate that while the IVS10+14 MAPT mutation often results in motor, cognitive and behavioural clinical features, sensory and sleep abnormalities are also manifestations of the mutation. Clinicopathological correlations were able to explain symptom presence and severity for two of the three examined cases. This underlines the need to explore alternate mechanisms and metrics of brain dysfunction in tauopathy in addition to tau burden and neuronal loss. Reference: Maxwell SP, Cash MK, Rockwood K, Fisk JD, Darvesh S. 2021. Clinical and Neuropathological Variability in the Rare IVS10+14 Tau Mutation. Neurobiology of Aging. In Press. DOI: 10.1016/j.neurobiolaging.2021.01.004.
Intra‐individual variability in processed EEG (bispectral index monitor) under general anesthesia predicts postoperative cognitive change after total knee arthroplasty
Authors: Dion Catherine , Tanner Jared J. , Hernaiz Carlos , Parvataneni Hari K. , Price Catherine C.
Published: December 2021

Background

Previous research shows 1) clock drawing performance slows for older adults after total knee arthroplasty (TKA; Hizel et al., 2018), and 2) brain‐behavioral associations with intra‐individual variability on an EEG‐derived index during TKA (Hernaiz et al., 2019). The current study expanded upon these findings by examining how preoperative cognition and intraoperative responses to anesthesia may predict postoperative clock drawing performance. We hypothesized greater intraoperative intra‐individual BIS variability would explain a significant portion of variance in four primary latency measures to command and copy condition at 3‐weeks following surgery.

Method

The final prospectively recruited IRB consented participant sample included 54 non‐demented patients age 60+ receiving TKA under general anesthesia. Consistent with Hernaiz et al., (2019), derived 2‐channel EEG variability was studied from tourniquet inflation to tourniquet release, thereby establishing a consistent period of examination. Intra‐individual variability was calculated as the squared deviation from the mean BIS value over the duration of measurement. Clock drawing to command and copy was recorded with digital pen technology and scored with semiautomatic rater‐guided software (Souillard‐Mandar et al., 2016). Outcome latency variables of interest: 1) total completion time in seconds (TCT), 2) time prior to setting the first hand in seconds (pre‐first hand latency; PFHL), 3) seconds after drawing the clock face to next pen stroke (post‐clock face latency; PCFL).

Result

At 3‐weeks, participants took, on average, six seconds longer to complete the drawing compared to baseline performance, and two seconds longer to set the first clock hand. Correcting for baseline performance, separate hierarchical regressions showed intra‐individual EEG‐derived variability explained an additional 4.3% of variance in postoperative command TCT (F(2,51)=28.301, p<.038, R2=.536, ∆R2=.043), such that those with greater intraoperative BIS variability took longer to complete the drawing to command.

Conclusion

In non‐demented older adults undergoing TKA, higher intra‐individual BIS variability significantly contributed to total clock drawing time during the command condition. Command total completion time is sensitive to numerous cognitive domains including processing speed, language, working memory, and declarative memory (Dion et al., 2020). Fluctuations during general anesthesia as recorded on an EEG‐derived index may help explain postoperative slowing during clock drawing at 3‐weeks post‐surgery.
INVOKE‐2: A phase 2 randomized, double‐blind, placebo‐controlled study to evaluate the efficacy and safety of AL002 in participants with early Alzheimer’s disease
Authors: Paul Robert , Jackson Sam , Ward Michael , Joshi Aashka , Castro Abraham , Yeh Felix L , Liao Yijie , Morrison Glenn
Published: December 2021

Background

Triggering receptor expressed on myeloid cells 2 (TREM2) is expressed in the brain predominantly by microglia. Mutations in TREM2 cause an increased risk of developing Alzheimer’s Disease (AD). E.g., the R47H coding variant confers similar risk for AD as does one copy of APOE4. AL002 is a humanized monoclonal IgG1 antibody (mAb) that activates the TREM2 signaling pathway to increase the ability of microglia to clear pathology and protect neurons. AL002 is believed to be the first anti‐TREM2 mAb in clinical development for the treatment of AD. AL002 was generally well tolerated in a Phase 1 study (INVOKE) and has demonstrated proof of target engagement and proof of mechanism. These results have supported progressing AL002 to the INVOKE‐2 Phase 2 study of AL002 in patients with early AD.

Method

INVOKE‐2 is a randomized, double‐blind, dose‐ranging, placebo‐controlled study to evaluate the efficacy and safety of AL002 in participants with early AD (NCT04592874). This is a global study that will enroll approximately 265 participants in North America, Australia, New Zealand, Europe, and South America. Participants will be randomized to receive one of 3 doses of AL002 or placebo, administered via IV infusion every 4 weeks, for up to 96 weeks. The objectives of this Phase 2 study are to assess the efficacy and safety of AL002.

Result

All participants must have a diagnosis of early AD with evidence of cerebral amyloidosis and a clinical severity consistent with Stage 2 to early Stage 4 (2018 Research Framework), including a CDR‐GS of 0.5 or 1, MMSE from 22 to 30, and RBANS DMI of 85 or lower. Efficacy will be assessed with clinical outcome assessments (including CDR‐SB and ADAS‐Cog13), and fluid and imaging biomarkers. Safety will be assessed through monitoring of AEs, suicidality assessments, changes in laboratory and vital signs, ECG and MRI. PK in serum and CSF will be assessed.

Conclusion

INVOKE‐2 is designed to investigate the efficacy and safety of AL002, representing a novel, first‐in‐class neuro‐immunological approach for treating AD. Enrollment is ongoing.
The Addenbrooke’s Cognitive Examination–Revised in the differential diagnosis between Alzheimer's disease and behavioral variant frontotemporal dementia: A new model
Authors: Carvalho Viviane Amaral , Lima‐Silva Thais Bento , Mariano Luciano Inácio , de Souza Leonardo Cruz , Guimarães Henrique Cerqueira , Bahia Valeria S , Nitrini Ricardo , Barbosa Maira Tonidandel , Yassuda Monica Sanches , Caramelli Paulo
Published: December 2021

Background

The increase in life expectancy implies the emergence of chronic‐degenerative and disabling conditions, such as cognitive impairment and dementia. Among the frequent disorders in clinical practice, the differential diagnosis between Alzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD) may be challenging, which justifies the improvement in cognitive tools to be used in clinical practice.

Method

The Addenbrooke’s Cognitive Examination‐Revised (ACE‐R) was administered to 102 patients diagnosed with mild dementia due to probable AD and 37 with mild probable bvFTD from two Brazilian research centers (Table 1). All individuals were submitted to the Mattis Dementia Rating Scale (DRS) and the ACE‐R. The performance of the patients was compared and analyzed. ROC curve analyses were conducted to assess the ACE‐R accuracy in the diagnosis of AD and bvFTD. Multivariate logistic regression analysis was used to develop a new model to refine the diagnostic accuracy of the ACE‐R.

Result

Mean total scores in the ACE‐R were 70.2 (standard deviation ‐ SD = 10.8) in patients with AD and 72.2 (SD = 11.1) in bvFTD. The VLOM ratio showed an area under the curve (AUC) of 0.816, with 87% sensitivity (Sens.) and 71% specificity (Spec.), 73% positive predictive value (PPV) and 86% negative predictive value (NPV) for the differential diagnosis between AD and bvFTD. The logistic regression method with cross‐validation showed that the relationship between Attention and Orientation, Fluency, Language and Age, as independent variables, shared the importance to the diagnostic differentiation between bvFTD and AD (p <0.05; Table 2). The proposed logarithm was superior in discriminating bvFTD and AD than the VLOM ratio, with AUC of 0.865 (Figure 1) with 78% Sens., 85% Spec., 65% PPV and 91% NPV (Table 3).

Conclusion

The ACE‐R achieved very good diagnostic power to discriminate AD and bvFTD in the present sample. Furthermore, the final ROC curves showed the superiority of the model proposed in relation to the analysis of the subscales individually. Further analysis in larger samples, with biomarkers or pathological confirmation, are necessary to confirm these findings.