bluuebunny/crossref_metadata_2025 huggingface dataset:
The role of cognitively stimulating activities throughout the lifespan on risk and timing of conversion to dementia
Authors: Lewis Nathan A , Bennett David A , Hofer Scott M
Published: December 2020

Background

Previous research suggests that modifiable lifestyle factors, such as engagement in cognitively stimulating activities, contributes to cognitive reserve such that some individuals can tolerate more pathological burden before cognitive symptoms emerge. However, it is unclear whether such benefits persist throughout the lifespan or are limited to certain critical periods. The present study sought to explore if cognitive engagement at various points in the lifespan uniquely contributes to cognitive reserve in late life.

Method

Data were from 1977 older adults from the Memory and Aging Project without dementia at study onset (M age = 80.10 at baseline). Cognitive assessments were performed annually for an average of 7.42 years until death. Each participant agreed to brain donation for post‐mortem analysis of neuropathologies. Multistate survival modeling was used to examine the influence of lifelong cognitive engagement on risk of transitioning between normal cognition, mild cognitive impairment (MCI), dementia, and death states. Life expectancies for individuals with and without cognitive impairment were then estimated. An additional model was run for participants with available neuropathology data (n = 841), accounting for overall pathological burden.

Results

A total of 560 participants developed dementia during the follow‐up period. Cognitive activity in childhood, young and middle adulthood were included as predictors of risk of transitioning between cognitive states, controlling for age, sex, and education. Only midlife cognitive activity predicted cognitive transitions, with higher activity predicting decreased risk of developing MCI (OR = .82, 95% CI: .71, .95). In the subset of participants with pathology data, cognitive activity in midlife predicted decreased risk of transitioning to MCI (OR = .74, 95% CI: .61, .90) after accounting for pathologic burden. Midlife cognitive activity moderated the effect of pathological burden such that individuals high in pathology and high in cognitive activity were more likely to transition directly from healthy cognition to death without developing impairment.

Conclusion

With no known cure for Alzheimer’s Disease, delaying the onset of cognitive decline represents a key target for future dementia research. These findings suggest that cognitive engagement in midlife may help to delay impairment and buffer the effect of brain pathologies on cognition.
Investigating the role of neuronal oxidative stress in early Alzheimer’s disease pathology
Authors: Foret Morgan K. , Do Carmo Sonia , Welikovitch Lindsay A. , Orciani Chiara , Cuello A. Claudio
Published: December 2020

Background

While the amyloid cascade has driven drug development for decades, alternative mechanisms underlying early Alzheimer’s disease (AD) pathogenesis point towards a role of oxidative stress. Cellular responses to oxidative damage are disrupted in AD, additionally, markers of oxidative damage are elevated in the brains of individuals with mild cognitive impairment and AD as well as in AD animal models. However, the earliest role of oxidative stress that coincides with intraneuronal amyloid beta accumulation preceding plaque deposition and cognitive decline has yet to be elucidated. This study aims to investigate oxidative stress related genes as key drivers of disease mechanisms in the early, pre‐plaque AD pathology.

Methods

The McGill‐R‐Thy1‐APP transgenic rat model was utilized to study the role of neuronal oxidative stress responses during the early, pre‐plaque amyloid pathology. Hippocampal neurons from 5‐month‐old pre‐plaque transgenic and non‐transgenic control rats were excised using laser capture microdissection. The expression of 84 genes related to antioxidant response and reactive oxygen species metabolism was investigated by qRT‐PCR. Validation at the protein level was performed using immunofluorescence microscopy and biochemical assays.

Results

At the mRNA level, genes including superoxide dismutase, DNA repair enzymes, and antioxidants such as glutathione reductase were dysregulated in transgenic hippocampal neurons compared to wild type controls. At the protein level, there were increased amounts of DNA repair enzymes in the subiculum of Tg rats, reinforcing the observations made at the mRNA level. Assessments at the protein level of additional targets as well as their correlation with intraneuronal amyloid beta load are ongoing.

Conclusions

These findings show that genes related to oxidative stress responses are dysregulated specifically in neurons burdened with amyloid peptides during early, pre‐plaque stages of the AD amyloid pathology. This suggests that oxidative stress is an important contributor to the earliest AD pathology.
Apolipoprotein E genotype‐dependent nutrigenetic effects to prebiotic inulin for reducing risk for Alzheimer’s disease in a mouse model
Authors: Chang Ya‐Hsuan , Hoffman Jared D , Yanckello Lucille M , McCulloch Scott D , Lin Penghui , Lane Andrew N , Chlipala George , Green Stefan J , Lin Ai‐Ling
Published: December 2020

Background

Apolipoprotein E ε4 (APOE4) allele is the strongest genetic risk factor for Alzheimer’s disease (AD). Cognitively normal APOE4 carriers show an early decline in brain metabolic functions and gut microbiome dysbiosis before the onset of AD compared to APOE3 carriers. Our laboratory previously found that inulin, a prebiotic, is effective to restore metabolic functions and gut microbiome balance, and thus reduce risk for AD in an ApoE4 mouse model (Hoffman et al., 2019). However, whether the responses to the inulin diet are APOE allele‐dependent remains unknown. Therefore, our objective was to identify whether inulin would differently contribute to metabolic and gut microbiome changes due to APOE genotype.

Method

We fed 3‐month‐old asymptomatic ApoE3 (E3FAD) and ApoE4 (E4FAD) mice a prebiotic inulin diet or a control diet containing cellulose for 4 months (N=15/group; Male:Female=1:1). After 4 months, we used magnetic resonance spectroscopy to measure in vivo brain scyllo‐inositol level, a compound that has been demonstrated to inhibit amyloid β aggregation (Fenili, Brown, Rappaport, & McLaurin, 2007). We collected the fecal samples for gut microbiome sequencing, and cecal and blood samples for metabolomic profiling.

Result

Inulin induced scyllo‐inositol in hippocampus of the brain with a higher level in E4FAD mice. Inulin increased blood metabolites in tryptophan and tyrosine metabolic pathways that enhance nervous system in E3FAD mice. It increased blood metabolites in pentose phosphate pathway and citric acid cycle that support nucleotides and nucleic acids biosynthesis and energy production in E4FAD mice. These alterations in hippocampus and blood showed inulin’s impacts on systemic metabolism depending on mouse ApoE genotypes. Inulin enhanced short chain fatty acids in cecum with a greater increase in E3FAD mice. E3FAD mice showed more distinct gut microbiome patterns between inulin and control groups compared to E4FAD mice.

Conclusion

Inulin‐induced systemic metabolism and gut microbiome changes are APOE genotype‐dependent. Our study contributes to the gut‐brain axis research and potential AD prevention. Future studies can design human interventions that facilitate the guide of personalized nutrition in APOE3 and APOE4 population to prevent AD.
Grip strength and gait speed as early biomarkers of brain amyloid and tau deposition
Authors: Jacob Mini Elizabeth , Terbojevich Tommaso , O’Donnell Adrienne , Gonzales Mitzi , Satizabal Claudia L , Beiser Alexa S , Johnson Keith A , Seshadri Sudha
Published: December 2020

Background

Screening biomarkers, accessible and measurable at a primary care clinic, may hold the key to risk stratification and prevention efforts in Alzheimer’s and related dementias. Among potential candidates that could fulfill this role, gait speed and grip strength have garnered strong evidence as early predictive factors. The pathophysiologic basis for this association is not clear; it is possible that functional performance is impaired by early tau/amyloid deposition. To test this, we examined the cross‐sectional relationship between gait speed and grip strength measures with amyloid and tau PET in middle‐aged Generation 3 participants in the Framingham Heart Study.

Method

Among 190 participants, examined in 2016‐2019, average age was 55.1 (SD 7.7), and 44% were women. Fast walk speed was measured over 4 meters, and grip strength was assessed using a hand‐held Jamar dynamometer. PET amyloid imaging was done using [11C]PiB tracer and tau using [18F]AV‐1451. We tested associations between fast walk speed (FWS) and grip strength (GS) with amyloid in the frontal and lateral retrosplenial (FLR) regions and tau in parahippocampal, entorhinal, inferior temporal regions. Linear regression models were performed with adjustment for sex, time from exam to PET scan, total cholesterol, diabetes, cardiovascular disease, smoking status, systolic blood pressure, waist‐hip ratio, APOEe4 status and physical activity. We also tested interactions between FWS/GS and APOE status /gender.

Result

FWS and GS did not demonstrate independent associations with tau or amyloid PET imaging in the full sample, however significant interactions were noted between FWS/GS and both gender and APOE. In the APOE status stratified analysis, higher FWS was associated with higher parahippocampal tau levels among e4 negative, while higher GS was associated with lower parahippocampal tau among e4 positive individuals. Additionally, higher GS was associated with lower parahippocampal Tau in men, but not in women.

Conclusion

Grip strength and gait speed may be early markers of tau deposition in cognitively normal middle‐aged individuals. Further studies with larger samples are required to confirm the relationship and identify sub‐groups who may benefit from screening and preventive interventions.
Dementia: Vitamin D deficiency is associated with lower Mini‐Mental State Exam (MMSE) scores
Authors: Komatsu Caroline , Komatsu Ricardo S , Belem Dinah , Ariosa Rodrigo Hara , David Caroline Casolari Araújo Mansur , Garcia Isabelle Belmonte
Published: December 2020

Background

Patients with Alzheimer's disease (AD) have a high prevalence of vitamin D deficiency, which is also associated with impaired cognitive performance in older adults. According to the systematic review and meta‐analysis conducted by Anweiler et al. (2013), AD cases had lower serum vitamin D concentrations than matched controls. The quality assessment of systematic reviews of vitamin D, cognition and dementia conducted by Aghajafari et al. (2018) also corroborated the potential link between low serum vitamin D concentrations and dementia.

Method

40 outpatients with the diagnostic of AD according to criteria proposed by NINCDS‐ADRDA (2011), followed – up at a public university hospital, had their vitamin D levels assessed and MMSE scores evaluated.

Results

9 patients (22,5%) presented vitamin D normal range (vitamin D level ≥ 30 ng/mL) and 31 patients (77,5%) presented vitamin D deficiency (vitamin D level < 30 ng/mL). From the vitamin D normal range group 5 patients (55,56%) presented moderate cognitive impairment (MMSE = 10 – 20) and 4 (44,44%) patients presented mild cognitive impairment (MMSE > 20). From the vitamin D deficiency group 4 patients (12,90%) presented severe cognitive impairment (MMSE < 10), 10 patients (32,27%) presented moderate cognitive impairment and 17 patients (54,83%) presented mild cognitive impairment. Both groups, vitamin D normal range and vitamin D deficiency, had on average the same educational level: 2,89 and 3,19 years respectively.

Conclusion

In this sample of patients with AD, vitamin D deficiency is associated with lower MMSE scores when compared to vitamin D normal range.
Different patterns of β‐amyloid pathology in the cerebellum of early‐onset Alzheimer’s disease individuals
Authors: de Luca e Tuma Raphael , Rodriguez Roberta Diehl , Brucki Sonia Maria Dozzi , Suemoto Claudia Kimie , Leite Renata Elaine Paraizo , Ferretti‐Rebustini Renata Eloah de Lucena , Jacob‐Filho Wilson , Pasquallucci Carlos Augusto , Grinberg Lea Tenenholz , Nitrini Ricardo
Published: December 2020

Background

The cerebellum has not been extensively studied in the setting of Alzheimer’s disease (AD). As the disease progresses, the cerebellum is one of the last brain regions to accumulate β‐amyloid (βA) deposits usually as diffuse plaques. However, distinct morphologies are described in the cerebellum in early‐onset Alzheimer’s disease (EOAD).

Method

To investigate the presence of βA deposits in the cerebellum, we analyzed brain sections immunostained with βA antibody (4G8) of 46 individuals with cognitive impairment and neuropathological diagnosis of AD. Of them, cerebellum sections of 19 individuals with Thal phase 5 were evaluated regarding the distribution and morphology of the βA deposits. All cases are from the Biobank for Aging studies of the University of São Paulo. AD‐type pathology was scored using the Braak and Braak staging, CERAD criteria and the Thal phase system. Diagnosis of AD required at least intermediate AD neuropathological changes. Presence of cognitive impairment (CI) was evaluated according to the Clinical Dementia Rating Scale (CDR>0,5).

Result

Cerebellar βA pathology was found in 19 cases (41%). Higher frequency of amyloid pathology was observed in the group of individuals who developed CI before 65 years of age (87%). In this group of individuals, focal deposits such as compact plaques were more frequently observed than the typical diffuse deposits often seen in molecular layer. Additionally, EOAD individuals had more involvement of Purkinje cell, and granular cell layers than in the molecular layer. Amyloid angiopathy with capillary involvement was observed in the cerebellum of 3 individuals. Of them, only one had EOAD, but all had two APOE ε4 genes.

Conclusion

The βA cerebellar involvement can be influenced by the patient’s age, particularly in EOAD cases. These changes observed in the cerebellum may reflect a different vulnerability pattern of βA pathology in individuals with early‐onset AD.
Enriching early‐life activities and cognition in later life: Results from the Health and Retirement Study (HRS)
Authors: Crane Breanna M , Carlson Michelle C
Published: December 2020

Background

The positive association between engagement in mid‐ and late‐life enrichment activities and cognitive function in late‐life has been presented in many studies. However, the effect of enriching early‐life activities (EELAs) on cognition in late‐life has been relatively unexplored. Recently, we have found that greater enrichment in early‐life was linked to positive late‐life cognition and brain biomarkers (i.e., larger amygdala and hippocampal volumes, etc.). In this study, we examined the relationship between EELAs and late‐life cognition using the 2017 Life History Mail Survey (LHMS) and additional cognitive and demographic variables, all of which came from the Health and Retirement Study (HRS).

Method

A complete‐case analysis was conducted from a subset of respondents in the HRS aged 50+ (N = 1,872, M = 66.5, SD = 10.1) who completed cognitive testing during 2010 and completed the ten‐item retrospective survey in the LHMS on enriching activities performed during adolescence. Univariate and multivariate linear regression models were used to assess the relationship between EELAs in adolescence and cognition in later‐life.

Result

Engaging in EELAs was positively associated with late‐life cognition after adjusting for age, gender, race, mother's and father’s education, birth cohort, income, and various health behaviors (e.g., smoking, diabetes, hypertension). After incorporating one’s level of education into the model, this association was no longer significant.

Conclusion

These results suggest that engaging in enriching activities in adolescence may be protective against cognitive decline in later‐life. Providing programs that promote EELAs (e.g., after‐school programs, extracurricular activities, etc.) during adolescence may be a key modifiable factor to buffer the effects of cognitive decline in later‐life. Future studies should incorporate additional in‐depth questions about EELAs to further investigate the relationship between these activities in early‐life and cognition in later‐life.
ICA‐derived sources of synaptic density PET ([11C]UCB‐J) relate to cognitive impairment severity in Alzheimer’s disease
Authors: Fang Xiaotian T. , Mecca Adam P. , Naganawa Mika , O'Dell Ryan S. , Chen Ming‐Kai , van Dyck Christopher H. , Carson Richard E.
Published: December 2020

Background

Synaptic loss is a primary pathology in Alzheimer's disease (AD) and correlates best with cognitive impairment as found in postmortem studies. Previously, we observed in vivo synaptic density loss with [11C]UCB‐J PET (radiotracer for synaptic vesicle protein 2A, SV2A) in hippocampus and throughout the cortex. Here, we used independent component analysis (ICA), a data‐driven method that identifies independent sources (networks) by linearly unmixing the observed signal into maximally independent components. The aim is to apply ICA, which does not use subject group information, to synaptic density PET data to identify brain networks associated with cognitive deficits in AD.

Method

[11C]PIB PET was performed to determine brain amyloid status. A structural T1‐weighted MR was acquired to exclude structural abnormalities and for PET co‐registration and analysis. [11C]UCB‐J binding to SV2A was measured in 38 AD (24 dementia, 14 mild cognitive impairment) and 19 cognitively normal (CN) participants. [11C]UCB‐J distribution volume ratio values were calculated using SRTM2 (population‐fixed k2') with whole cerebellum as reference, registered into MNI space and smoothed (8‐mm Gaussian). Based on previous SV2A ICA, 18 independent components (IC) were extracted. Subject loadings per IC were compared between groups using unpaired t‐tests. Pearson's correlations were used to assess relationships between loading weights and cognitive measures: logical memory II (LMII), Rey auditory verbal learning test (RAVLT‐delay), clinical dementia rating sum of boxes (CDR‐sob), mini‐mental state examination (MMSE).

Result

For 8 ICs, we observed significant differences in loading weights between CN and AD groups, including a component (IC01) located in hippocampus and temporal lobe (Figure 1). Within the AD/MCI group, loading weights for IC02, located in the right parietal‐temporal lobe (Figure 2), correlated with LMII (R2: 0.13, p=0.025), and RAVTL‐delay (R2: 0.13, p=0.027). For IC03, located in the left parietal hemisphere (Figure 3), loading weights correlated with CDR‐sob (R2: 0.23, p=0.0028) and MMSE (R2: 0.13, p=0.024).

Conclusion

We demonstrated that ICA could define coherent spatial patterns of synaptic density. Furthermore, commonly used cognitive measures correlate significantly with loading weights for two of such networks within only the AD/MCI group. Further studies will explore whether ICA‐based networks might be more sensitive than conventional ROI‐based analysis.
Web‐based assessment of cardiovascular risk factors and cognition in older adults: Findings from the Brain eHealth feasibility study
Authors: Yaffe Kristine , Kaup Allison R , Bahorik Amber L , Butcher Xochitl , Attarha Mouna , Marcus Gregory M , Pletcher Mark J , Olgin Jeffrey E
Published: December 2020

Background

Cardiovascular risk factors (CVRFs) are linked to cognitive aging. Most studies rely on lengthy in‐person assessments, and it is unclear if web‐based platforms can be used to detect the contribution of risk factors, including CVRFs, to cognitive aging offering a more pragmatic and low cost approach.

Method

We recruited 239 adults who were enrolled in the Health eHeart project in order to conduct the Brain eHealth study, a mobile health feasibility study of web‐based measurement tools in adults age ≥50. CVRFs were identified based on health surveys from the Health eHeart study using the Eureka Research platform between March 2013, and February 2019, and included hypertension, high cholesterol, diabetes, and atrial fibrillation. After an average of 3 years participants completed a web‐based cognitive assessment with the BrainHQ platform (POSIT Science) that assessed 3 cognitive domains: episodic memory, working memory, and executive function. We used linear regression models to examine the association between CVRFs and cognitive function.

Result

Among the 239 participants (mean age, 62.7±8.8, 43% female, 89% white), CVRF prevalence was 54% for high cholesterol, 44% for hypertension, 12% for atrial fibrillation, and 7% for diabetes. In multivariable models adjusted for age, race/ethnicity, and sex, atrial fibrillation was associated with poor working memory (β = ‐0.52, 95%CI ‐0.92,‐0.11) and worse episodic memory (β = ‐0.26, 95%CI ‐0.42,‐0.08), and hypertension was associated with worse episodic memory (β = ‐0.25, 95%CI ‐0.42, ‐0.08). There was no association for diabetes or high cholesterol. In a sensitivity analysis, we further adjusted for motor speed processing, which led to similar results.

Conclusion

Results of this feasibility study suggest that web‐based tools may be used to detect the contribution of CVRFs, especially atrial fibrillation and hypertension to cognitive function in older adults. The potential of these mobile measurement tools to track the relationship between older adults’ cardiovascular health and cognitive aging should be further investigated in a larger study.
Associations between amyloid‐β, white matter disease, functional brain networks, and mobility function: Possible indicators of reserve and resilience
Authors: Neyland Blake R. , Hugenschmidt Christina E. , Lockhart Samuel N. , Okonmah‐Obazee Stephanie , Sai Kiran Solingapuram , Baker Laura D. , Craft Suzanne , Miller Michael E. , Laurienti Paul J. , Kritchevsky Stephen B.
Published: December 2020

Background

Undetected AD pathology in cognitively normal older adults may increase risk for mobility decline by both increasing white matter pathology and directly interfering with functional networks through Aβ deposition.

Methods

Thirty‐one cognitively normal older adults (75.01 ± 4.15 y, 35.5% female) enrolled in the Brain Networks and Mobility Function (B‐NET) study received PiB PET and MRI. A global cortical PiB average for each participant was calculated by coregistering PET to MRI using Freesurfer v5.6 to generate masks and thresholding at 1.21 to create PiB positivity groups (PiB‐ = 16, PiB+ = 15). White matter hyperintensity (WMH) volume was calculated with the Lesion Segmentation Toolbox (LST) implemented in SPM12. Mobility function was assessed using the expanded Short Physical Performance Battery (eSPPB), a 4‐meter walk, and a 400‐meter walk. Cognitive measures included the Montreal Cognitive Assessment (MOCA) and Digit Symbol Substitution Task (DSST). Associations were explored using linear regression, correcting for age, sex, and BMI in the fully adjusted mobility model while age, sex, and education were used in the fully adjusted cognition and WMH model.

Results

PiB+ individuals had significantly faster 4‐meter gait speed (p<0.05) and a trend for higher DSST (p=0.052). These associations were independent of WMH volume. PiB+ individuals also had significantly higher total (p<0.05) and motor WMH (p<0.05).

Conclusions

The observation that PiB+ individuals had better physical function than PiB‐ was unexpected given existing literature showing associations between regional Aβ volume and slower gait speed. It was also unexpected given that the PiB+ group had higher WMH volume, which is associated with slower gait speed. The current sample, which includes primarily individuals with good physical and cognitive function, may represent a resilient phenotype. Continued recruitment of more diverse participants with lower physical function will be an important addition to this sample. Future analyses will allow for the inclusion of APOE and an increased sample size. Whole‐brain functional connectivity will also be assessed in this cohort using graph‐theory based methods.
Differentiating Aβ40 and Aβ42 with a small‐molecule fluorescence probe
Authors: Ran Chongzhao , Wang Peng , Yang Jing , Zhu Biyue
Published: December 2020

Background

Amyloid beta (Aβ) plaque, one of the characteristic biomarkers for Alzheimer’s disease (AD), has been discovered more than 100 years in the postmortem brains of AD patients. However, the role of Aβ plaques in the pathology of AD has still been heavily debated, because the correlation between plaque burdens (numbers and areas) and the severity of AD is poor [2]. In the plaques, Aβ40 and Aβ42 peptides are major constituents. Nonetheless, unlike the role of plaque, there is nearly no argument that Aβ42 has much higher neurotoxicity than Aβ40 does. Conceivably, differentiating Aβ40 and Aβ42 can considerably clarify the role of plaque in AD pathology. Unfortunately, small‐molecule probes with such capacity are scarce. Due to the small difference of amino acid sequence of the peptides, discovering small‐molecule probes capable of differentiating Aβ40 and Aβ42 has been considered as an impossible mission.

Method

Based on recently published structures of Aβ fibrils, we designed iminocoumarin‐thiazole (ICT) fluorescence probes to differentiate Aβ40 and Aβ42, among which Aβ42 has been considered to be much higher neurotoxic.

Result

We demonstrated that ICTAD‐1 robustly respond to Aβ fibrils, evidenced by turn‐on fluorescence intensity and red‐shifting of emission peaks. Remarkably, ICTAD‐1 showed different spectra towards Aβ40 and Aβ42 fibrils. In vitro results demonstrated that ICTAD‐1 could be used to differentiate Aβ40/42 in solutions. Moreover, our data revealed that ICTAD‐1 could be used to separate Aβ40/42 components in plaques of AD mouse brain slides. In addition, two‐photon imaging suggested that ICTAD‐1 was able to cross BBB and label plaques in vivo. Interestingly, we observed that ICTAD‐1 was specific toward plaques, but not cerebral amyloid angiopathy (CAA) on brain blood vessels.

Conclusion

In summary, we demonstrated that ICTAD‐1 is the first probe of its kind for differentiating Aβ40/42. ICTAD‐1 has the potential to dissect the toxicity contributions of Aβ40 and Aβ42, and could be considered as a lead compound for developing Aβ42 specific PET tracers.
Monoclonal GW‐23B7 removes Aβ‐pathologic oligomers and produces cognitive rescue without toxicity in old TGSWDI AD model mice with advanced pathology
Authors: Goni Fernando , Pires Geoffrey , Genovese Thomas S. , Wisniewski Thomas
Published: December 2020

Background

We have previously demonstrated that a monoclonal antibody (GW‐23B7) which targets specific β‐sheet secondary structure present in all AD pathologic oligomers produces significant cognitive rescue linked to lowering of both Aβ and Tau oligomers in APP/PS1 and 3xTg mouse models. We have now tested the efficacy and safety of GW‐23B7 in a cerebral amyloid angiopathy (CAA) TgSwDI model.

Method

Two groups of 15 months old TgSwDI AD animals were used for the preclinical trial. One group was inoculated i.p. weekly for two months with 100 µg/animal of GW‐23B7 in sterile saline (IgM) or sterile saline vehicle alone. The animals then underwent locomotor and cognitive testing followed by the brains being harvested for immunohistochemical and biochemical analysis.

Result

The intact GW‐23B7 (IgM) interacted with the brain vasculature and penetrated the BBB in the treated group without inducing microhemorrhages as determined by Prussian Blue staining. Moreover, the treated group showed significant cognitive rescue compared to controls on the Barnes Maze, which correlated with a significant decrease of soluble aggregated Aβ in specific ELISA tests, and a significant decrease of vascular and parenchymal Aβ pathology, with a reduction of activated glia shown by ABl1, GFAP and CD‐45 immunohistochemistry.

Conclusion

We have shown that peripherally infused GW‐23B7‐IgM that only targets Aβ pathologic oligomers, reduces soluble oligomeric and deposited vascular and parenchymal pathology by an Aβ‐sequence independent mechanism avoiding ADCC induced microhemorrhages or inflammation. Our preclinical data testing GW‐23B7‐IgM in multiple AD models suggests that it could be safely translated to human AD clinical trials with a minimal possibility of ARIA or autoimmune toxicity complications.
Rehabilitation of persons living with dementia: Using technology to improve participation
Authors: Chiusano Carrie , Zarit Steven H. , Krause Christopher , Sewell Lynne , Harrison Aime S. , Liu Yin
Published: December 2020

Background

Rehabilitation following an illness or injury can improve functioning for persons living with dementia (PLWD) and help them remain as independent in daily life as possible. Gains, however, may be limited, because PLWD are often not able to engage fully in treatment. This study examined how a technology system, “It’s Never 2 Late” (iN2L), may help augment traditional rehabilitation approaches for PLWD by improving engagement in therapy sessions and achieving better functional outcomes.

Method

The study used a two group quasi‐experimental design. Older adults living with dementia (N= 96) were recruited from two rehabilitation departments housed within residential care communities operated by the same organization. Participants received daily occupational and physical therapy sessions using treatment as usual (TAU) at one site (n = 49) or treatment augmented with iN2L (n = 47) at the other site. A goal attainment approach was used to assess functional outcomes. As part of standard procedures at each site, initial and final functioning was assessed across 23 measures of functioning, mobility, and activities of daily living. Therapists selected goals from these items and specified levels of function that would indicate goal attainment. Goal attainment was scored comparing functioning at completion of treatment against initial goals. Engagement was rated from observations of treatment sessions by research assistants using the Pittsburgh Rehabilitation Participation Scale. It was hypothesized that patients at the iN2L site will show greater attainment of therapy goals and greater engagement during therapy sessions than patients receiving TAU and that improvement in engagement will mediate the association of treatment type (iN2L or TAU) with greater goal attainment.

Result

Participants in the iN2L treatment had significantly higher goal attainment than TAU, significantly higher levels of engagement at baseline, and significantly steeper increases in engagement over the course of therapy. A multilevel regression model in MPLUS was used to estimate total and indirect (i.e. mediation) effects. Results showed that the effects of treatment on goal attainment was significantly mediated by increases in engagement.

Conclusion

Findings suggest that iN2L technology has the potential to increase treatment engagement and enhance rehabilitation outcomes among older adults living with dementia.
From source to bedside: Translational studies of centella asiatica for Alzheimer's disease
Authors: Wright Kirsten M. , Magana Armando Alcazar , Bollen Melissa , Caruso Maya , Gray Nora E. , Matthews Donald G , David Jason C. , Mepham Brigitte , Stevens Jan F. , Maier Claudia S. , Quinn Joseph F. , Soumyanath Amala
Published: December 2020

Background

Centella asiatica (CA) is a botanical from Eastern medicine reputed to enhance cognition. Preclinical studies on CA and its bioactive components (triterpenoids and caffeoylquinic acids) strongly support its potential as a phytotherapeutic agent for aging, cognitive decline, and Alzheimer’s disease (AD) through influences on antioxidant response, mitochondrial activity, tau phosphorylation, and synaptic density. Translation from preclinical models to humans, and developing an optimized, reproducible product for use in aging and AD clinical trials, present particular challenges for phytotherapeutic agents compared to single chemical entities.

Method

To perform translational studies, a comprehensive scientific approach was developed including: identifying an optimal dose range for clinical evaluation, analysis and characterization of phytochemical variability, assessment for contamination and adulteration of raw material, formulation and manufacture of a stable botanical intervention and matching placebo, and application to a human pharmacokinetic trial (NCT03929250). Two doses of a custom made CA water extract product (2g and 4g) were administered orally to eight healthy elders (n=4 female, n=4 male) on two separate days. Plasma was collected over 12 hours to determine bioavailability and analyzed using reversed phase liquid chromatography‐tandem mass spectrometry.

Result

The maximum plasma concentration (Cmax) of the bioactive triterpenoids (1‐1.6µM) occurred at two hours (Tmax) after oral administration.

Conclusion

A robust scientific approach is necessary to address the complexity and variability of raw botanicals and botanical extracts for AD. Triterpenoids from CA water extract are orally bioavailable in humans.
The association between memory and hippocampal volumes differs in young‐old versus very old patients
Authors: Wong Christina G. , Caldwell Jessica Z.K. , Miller Justin B.
Published: December 2020

Background

Hippocampal atrophy and declines in episodic memory are hallmark features of Alzheimer’s disease (AD). A positive association between hippocampal volumes (HCV) and memory test performance has been demonstrated; however, this relationship may not hold true in Very‐Old individuals. Relationships between other AD biomarkers and dementia severity seen in Young‐Old groups have not been found in Very‐Old groups. This study compared the associations between memory test performance and HCV in Young‐Old and Very‐Old patients in a memory disorders clinic setting.

Method

126 Young‐Old (Age: range=65‐75, M=70.02, SD=3.18) and 57 Very‐Old (Age: range =76‐90, M=79.98, SD=3.54) patients who had neuropsychological assessment and magnetic resonance imaging (MRI) within 6 months of each other were included. Memory measures included immediate and delayed recall raw scores from WMS‐IV Logical Memory (LM), Hopkins Verbal Learning Test‐Revised (HVLT‐R), and Brief Visuospatial Memory Test‐Revised (BVMT‐R). Left HCV, right HCV, and total intracranial volume (TIV) were computed with FreeSurfer volumetric analysis and underwent a quality assessment process. Partial correlations, accounting for age, education, and TIV, were conducted to determine the relationship between memory performance and HCV in each group separately.

Result

In the Young‐Old, significant positive correlations were found between all memory scores and HCV (r=.37 to .57, p’s<.001), indicating greater memory impairment with decreased HCV. In contrast, in the Very‐Old, only LM immediate recall was significantly correlated with HCV (left r=.37, p=.006, right r=.29, p=.032); HVLT‐R and BVMT‐R were not significantly associated with HCV in the Very‐Old (r=‐.02 to .24, p’s>.05). Fisher’s r‐to‐z transformation indicated significant differences in the magnitude of correlations between most memory scores and HCV as a function of age group.

Conclusion

Expected relationships between memory test performance and hippocampal volumes were found in Young‐Old patients, but these correlations were reduced and largely not significant in Very‐Old patients. Logical Memory was the one test associated with hippocampal volumes in the Very‐Old, which supports its inclusion in neuropsychological evaluations for this age group. Mechanisms associated with cognitive decline likely differ in advanced age and more research in this growing portion of the population is need.
Omega‐3 fatty acid add‐on nutritional immunotherapy delays progression to dementia in MCI patients on cholinesterase therapy
Authors: Fiala Milan
Published: December 2020

Background

Cholinesterase inhibitor (CI) drugs have cognitive benefits for one year but are not disease modifying. Omega‐3 fatty acids (omega‐3) with anti‐oxidants and resveratrol increase transcription of energy molecules, enhance phagocytosis of amyloid‐β (Aβ), increase monocyte/macrophages (MM) clearance of Aβ in the AD brain, and may be disease modifying.

Method

We test cognition by MMSE, energy in peripheral blood mononuclear cells (PBMC) and macrophages using a) single cell RNA‐seq, b) respirometry in the Seahorse Analyzer; c) phagocytosis of fluorescent Aβ and P‐tau. We study glycans in PBMC using nanoLC/ESI‐QTOF‐MS system.

Result

We enrolled into the study patients with cognitive problems who had been failing CI therapy according to neurologists and caregivers. We diagnosed study patients by neurological testing and imaging: 8 as subjective cognitive impairment (SCI), 7 as MCI, 1 as fronto‐temporal dementia (FTD), 2 as vascular cognitive impairment (VCI), and 3 as dementia with Lewy bodies (DLB). In the study, the patients added supplementation by omega‐3 fatty acid drink with anti‐oxidants and resveratrol (Smartfish) to CI. On these therapies, MCI patients maintained MCI status for >1 to 4.5 years and all improved Aβ immunity and activities of daily living in short term. The ω‐3 –supplemented MCI patients up regulated in vivo and in vitro glycolytic and TCA cycle enzymes and NAD synthesis enzyme NAMPT and increased Aβ phagocytosis. DLB and FTD patients progressed to dementia in 1 to 2 years, despite omega‐3.

Conclusion

MCI patients have energy deficiency in macrophages and other immune cells. Omega‐3 provide ox‐phos energy for immune clearance of Aβ and neuronal homeostasis around the clock, thereby delaying progression to dementia.
Short‐ and long‐term signatures of motherhood in the hippocampus: Implications for brain aging and dementia risk
Authors: Duarte‐Guterman Paula , Skandalis Dimitri A. , Lieblich Stephanie E. , Eid Rand S. , Galea Liisa A.
Published: December 2020

Background

Diagnosis rates of Alzheimer’s disease (AD) are greater in women than men, who also show greater cognitive decline and AD neuropathology. Increasing parity (pregnancy and motherhood experience) is associated with reduced grey matter volume in the brain and in the long term greater risk of dementia, earlier age of AD onset, and AD neuropathology. This suggests that parity and AD are linked. The hippocampus is one of the first areas to be affected by AD. Here, we examine the short‐ and long‐term effects of parity on neuroplasticity and neuroinflammation to assess changes in hippocampal function, and apply transcriptomics to identify novel effects of parity on hippocampal physiology.

Method

Female rats were bred once (primiparous), twice (biparous), or not at all (nulliparous). Hippocampi were collected at 7 months (30 days postpartum) and 13 months (240 days postpartum) to measure synaptic density protein (PSD‐95 electrochemiluminescence assay), numbers of immature neurons (immunohistochemistry of doublecortin expression, DCX), neuroinflammation (IL‐1β, IL‐4, IL‐5, IL‐6, IL‐10, IL‐13, CXCL1, IFN‐γ, and TNF‐α electrochemiluminescence assay), and global gene expression (RNA sequencing).

Results

Synaptic protein PSD‐95 was significantly increased in mothers relative to nulliparous females but was independent of age. In contrast, DCX expression was reduced in mothers only at 7 months, and all groups exhibited significant reductions in DCX expression with age. Neuroinflammatory markers distinguished parity levels; for example, levels of interleukin‐6 (IL‐6) were elevated in biparous females of all ages. Finally, most differentially expressed genes in the transcriptome were associated with aging, but many transcripts were associated with parity exclusively at 7 months. Through gene ontology analysis, we found biological processes enriched during aging were especially involved in synaptic plasticity and neurogenesis, whereas parity involved metabolic processes and recycling of cellular components.

Conclusion

Our work identifies neuroplastic and neuroinflammatory signatures of parity in the hippocampus. The effects of motherhood are identified by short‐term physiological changes that persist through middle‐age. These data contribute to understanding the influence of parity on brain aging and Alzheimer’s risk.
Relationships between oral hypoglycemic drugs and memory decline in people with type 2 diabetes: A stratified longitudinal observational study
Authors: Wu Che‐Yuan , Ouk Michael , Wong Yuen Yan , Anita Natasha , Edwards Jodi D. , Yang Pearl , Shah Baiju R. , Kapral Moira , Herrmann Nathan , Lanctot Krista L. , Macintosh Bradley J. , Rabin Jennifer S. , Black Sandra E. , Swardfager Walter
Published: December 2020

Background

There is increased recognition that diabetes can elevate Alzheimer’s disease (AD) risk and exacerbate memory decline. However, few studies have compared memory decline among patients with diabetes using different oral hypoglycemic drug classes.

Method

Participants using any hypoglycemic medications from 2005 to 2019 were identified from the National Alzheimer's Coordinating Center database. Analyses were conducted separately in elderly with normal cognition (NC), amnestic mild cognitive impairment (aMCI), and dementia due to AD. Drug classes of interest included metformin, sulfonylureas, thiazolidinedione and dipeptidyl peptidase‐4 inhibitors (gliptins). Immediate and delayed recall outcomes were assessed using the Wechsler Memory Scale–Logical Memory test. Linear mixed‐effects models (in NC and aMCI) and mixed‐effects zero‐inflated Poisson or quasi‐Poisson regressions (in AD) were used to examine the associations between drug classes (time‐varying exposures) and memory performance over time. Confounding by indications were corrected by inverse probability treatment weighting. Models were adjusted for covariates including demographics, baseline MMSE, comorbidities and concurrent medications. In post‐hoc analyses, we examined whether ApoE genotype moderated the associations between drug class and memory.

Result

In NC (n=1,201, follow‐up years=3.43±3.27), metformin use was associated with better immediate (β=0.069 [0.011, 0.12]) and delayed (β=0.089 [0.032, 0.15]) memory over time, relative to no metformin use. No oral hypoglycemic drug class exhibited significant associations with memory in aMCI (n=671, follow‐up years=1.50±2.13). In AD (n=807, follow‐up years=1.90±2.21), DPP4 inhibitor use was associated with slower rate of decline in delayed memory (RR=1.22 [1.06, 1.40]), and thiazolidinedione use was associated with a faster rate of decline in immediate memory (RR=0.89 [0.82, 0.97]). In NC, DPP4 inhibitor use was associated with better delayed memory over time specifically among ApoE ε4 carriers (interaction: β=0.038 [0.0039, 0.072]). In AD, ApoE ε4 did not significantly interact with DPP4 inhibitor use, and thiazolidinedione use was associated with a faster rate of decline in immediate memory among non‐ε4 carriers (interaction: RR=1.26 [1.07, 1.47]).

Conclusion

Associations between memory and particular oral hypoglycemic medications may depend on the presence of AD symptoms. ApoE ε4 may further modify these relationships. Confirmatory analyses in other cohorts, particularly those with more complete clinical data, are required.
Association between clinical and demographic factors on cerebral amyloid angiopathy and Alzheimer dementia
Authors: Mousavi SeyedAli , Hirsch‐Reinshagen Veronica , Mackenzie Ian R. , Ducharme Blake , Chatterjee Atri , Hsiung Ging‐Yuek Robin
Published: December 2020

Background

Cerebral amyloid angiopathy (CAA) is common in age‐related dementia. However, the relationships between severity of CAA and other demographic, and pathological factors are unclear. Therefore, we will examine them in this case series.

Method

We reviewed records of patients with dementia who underwent autopsy at the UBC Hospital Clinic for Alzheimer’s disease between 1994 and 2017 and selected cases in which CAA is identified with AD and compared them to cases with AD pathology only. We excluded cases with other coexisting pathologies (i.e. Lewy Body, TDP‐43). CAA was evaluated with Congo Red stain and rated semi quantitatively. We examined a subset in which APOE genotype was also available. Relevant clinical and pathological characteristics were compared by chi‐square test, ANOVA and logistic regression.

Result

225 cases (120 females) were included: 42 no CAA, 99 mild, 57 moderate, and 27 severe. APOE genotype was available in 70 cases (30 females). There was no significant association between sex (p = 0.316), and APOE genotypes (p = 0.799) with severity of CAA. History of dyslipidemia (p = 0.004), current alcohol intake (p = 0.016) and lower level of education (p = 0.001) were associated with greater severity of CAA. Episodic memory (p = 0.044) and visuospatial problems (p = 0.049) were significantly associated with increased severity of CAA. Diffuse and lobar atrophy (p = 0.013) and ventricular dilatation (p = 0.026) were more prominent in severe CAA cases. There was a positive correlation between deep nuclear atrophy (p < 0.001) and substantia nigra paleness (P = 0.013) with moderate CAA. There were also significant associations between severity of CAA with frequency of the microscopic hemorrhage (p < 0.001), lacunar infarcts (p = 0.011), and arteriosclerosis (p = 0.003).

Conclusion

Greater severity of CAA is associated with certain clinical and pathological factors including dyslipidemia, alcohol intake, lower education, and presence of lacunar infarcts. Sex and APOE genotype do not appear to have any significant influence on the severity of CAA in AD. Further studies will help to confirm these potential modifiable risk factors for CAA in AD.
Midlife cognitive activity moderates the relationship between brain tau deposition and late‐life cognitive decline
Authors: Ko Kang , Yi Dahyun , Byun Min Soo , Lee Jun Ho , Kim Yu Kyeong , Lee Yun‐Sang , Lee Dong Young
Published: December 2020

Background

Cognitive activity (CA), an important modifiable lifestyle factor, has been related to decreased risk of Alzheimer’s disease (AD) dementia, and reduced cerebral beta‐amyloid deposition and neurodegeneration. The relationship between CA and in vivo tau deposition in brain, however, remains still elusive. Hence, we first aim to examine the direct association of CA, midlife CA in particular, with brain tau deposition. We also investigated the modulation effect of midlife CA on the relationship between brain tau deposition and cognitive decline.

Method

One hundred four elderly subjects from the Korean Brain Aging Study for Early Diagnosis and Prediction of AD (KBASE) cohort underwent comprehensive clinical assessment and 18F‐AV‐1451 positron emission tomography (PET). Brain tau deposition in the inferior temporal (IFT) region on the PET imaging was assessed, and participating frequency of midlife CA was evaluated using a structured questionnaire (Wilson et al., 2005). Mini‐Mental State Examination (MMSE) score was used as a cognitive performance measure.

Result

Midlife CA did not show a significant association with IFT tau deposition (Figure 1). We found, however, a significant interaction effect between midlife CA and IFT tau deposition on MMSE score (Table). High midlife CA subgroup showed less steep decline of MMSE score with increase of tau than low CA subgroup (Figure 2).

Conclusion

The findings suggest that midlife CA can attenuate the harmful influence of brain tau deposition on late‐life cognition, while it does not directly change brain deposition of tau pathology.