bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of plasma abeta and tau levels in relation to cognition and brain structure in a diverse community
Authors: DeCarli Charles , Erickson Kelsey , Farias Sarah Tomaszewski , Olichney John M , Johnson David K , Dugger Brittany N , Mungas Dan M , Fletcher Evan , Maillard Pauline , Maezawa Izumi , Jin Lee‐Way
Published: December 2020

Background

Early studies of mostly non‐Hispanic White groups suggest that plasma tau and abeta levels are associated with clinically relevant cognitive impairment. Given limited studies of more ethnically diverse communities, we chose to study 402 subjects from the UC Davis Alzheimer’s Disease Center.

Method

The subjects were diverse (14% White, 45% Black and 41% Hispanic), 61% women, average age of 76 + 7.3 years with 12 + 5 years of education with a spectrum of cognitive ability (66% cognitively normal, 19% MCI and 15% demented). Plasma samples were obtained within 0.3 + 0.8 years of cognitive and MRI assessments. Duplicate plasma samples were measured for tau, abeta 40 and 42 on a Quanterix SRX using SIMOA technology. Subjects with CV >20% or extreme values (>5 SD) were excluded. Analyses compared cross‐sectional associations between plasma abeta and tau levels and diagnosis adjusting for age, sex, race/ethnicity and education as well as associations with memory, executive function and structural MRI measures.

Result

The table summarizes mean values for Tau, abeta 40, 42 and the 42/40 ratio across diagnoses and race/ethnicity. Both abeta 42 and the 42/40 ratio differed significantly by clinical diagnosis. The abeta 42/40 ratio was significantly lower for non‐Hispanic whites than Blacks and Hispanics (Tukey HSD, p <0.05). Higher plasma tau levels were weakly negatively associated (beta =‐0.04 + 0.02, <0.05) whereas higher abeta 42/40 ratios were significantly positively associated (beta = 6.6 + 2.9, p =0.02) with executive function. Higher abeta 42/40 ratios were also significantly positively associated (beta = 7.1 + 3.4, p <0.05) with hippocampal and temporal lobe gray matter (beta = 146 + 46, p =0.002) volumes. Logistic regression predicting diagnostic category found that the abeta 42/40 ratio significantly differentiated the groups (chi sqr =17, p = 0.0002).

Conclusion

In this study of diverse, community recruited individuals, plasma abeta 42 and the abeta 42/40 ratio were significant predictors of clinical diagnosis, cognition and MRI measures, indication that plasma levels of abeta measured have clinical implications in a diverse cohort where mixed pathologies are known to be common1. Reference: 1.Filshtein TJ, Dugger BN, Jin LW, et al. J Alzheimers Dis 2019.
Xerogenic medications as a predictor for dental health intervention in people with dementia
Authors: Tan Edwin CK , Lexomboon Duangjai , Häbel Henrike , Fastbom Johan , Eriksdotter Maria , Johnell Kristina , Sandborgh‐Englund Gunilla
Published: December 2020

Background

Older people with dementia often have poor oral health. Chronic use of xerogenic medications may contribute to adverse dental outcomes. The aim of our study was to investigate the impact of xerogenic medication classes on the predicted risk for dental health interventions in people with dementia.

Method

This was a population‐based register study involving the Swedish Dementia Registry (SveDem), the Swedish Prescribed Drug Register, the Swedish National Patient Register, and the Dental Health Register. Participants were persons with dementia who were registered in the SveDem at the time of their dementia diagnosis. The exposure was xerogenic medication classes used over the 3‐year period immediately preceding the date of dementia diagnosis (baseline). The primary outcome was the composite of number of tooth extractions and dental restorations during the 3‐year period after baseline. Secondary outcomes included the number of tooth extractions and number of dental restorations. Poisson regression models were used to estimate incidence rate ratios (IRRs) and 95% confidence intervals (CIs) for the association between the exposure and outcomes. Analyses were adjusted for age, gender, Mini‐Mental State Examination, living arrangement, dementia disorder, average number of medications, Charlson’s comorbidity index, number of dental visits and number of teeth.

Result

A total of 30955 people were included in the analysis. After adjusting for potential covariates, the use of urological drugs (IRR 1.16, 95% CI 1.04 – 1.28), proton pump inhibitors (IRR 1.13, 95% CI 1.04 – 1.23) and opioids (IRR 1.19, 95% CI 1.06 – 1.34) were significantly associated with the primary composite outcome.

Conclusion

The use of specific classes of xerogenic medications was associated with an increased risk for tooth extractions and restorations in people with dementia. The risks and benefits of xerogenic medications, in the context of oral health, should be carefully assessed in this vulnerable population.
Accumulating and heterogeneous network‐knockout profiles in amnestic mild cognitive impairment and Alzheimer’s disease dementia
Authors: Nestor Sean M , Bratislav Misic , Ramirez Joel , Graham Simon J , Verhoeff Nicolaas Paul L.G. , Stuss Donald T , Masellis Mario , Black Sandra E ,   Alzheimer's Disease Neuroimaging Initiative
Published: December 2020

Background

Large‐scale brain networks are disrupted in Alzheimer’s disease (AD). We posit that network disruption may be explained by additive and multifactor knockout of multiple networks (functional and structural) as opposed to a single system or set of subsystems. Here we test this hypothesis using a data‐driven structural covariance network analysis.

Methods

Demographic, imaging and available biomarker data were downloaded from 77 normal controls (NC) (age= 72±6, M/F=33/44), 106 persons with amnestic mild cognitive impairment (MCI) (age= 73±8, M/F=70/36) and 42 persons with Alzheimer’s dementia (age=75±9, M/F=25/17) that participated in the Alzheimer’s Disease Neuroimaging Initiative 2.0. We used a multivariate covariance technique to isolate large‐scale grey matter networks that relate fiber tract microstructure derived at different stages of injury to vertex‐based cortical thickness maps. Cortical thickness was computed from 3.0 Telsa T1‐weighted MRI and tract‐based white matter microstructural measures were performed using diffusion tensor imaging; these data were submitted to a multivariate data‐driven analysis. Measures of network integrity (NII) were computed for each significant covariance network for all participants. Univariate models assessed the relationship between biomarkers, demographic variables and NIIs for each network. Network knockouts were defined as an NII <1.5 SD below the NC group average for a given network. Knockout combinations were characterized across individuals and average knockout numbers were compared between groups.

Results

Eight network ensembles related to tract‐based connectivity or recapitulated functional network architecture. Degradation of these systems was additively and differentially linked to increased age, APOE e4 genotype and unique combinations of white matter hyperintensity volume, CSF markers (CSF amyloid and Tau protein levels) and hippocampal volume in MCI. Knockouts exponentially and significantly increased across groups: NC>MCI>AD (P<0.01). There were 64 unique network knockout combinations across all participants.

Conclusion

Heterogeneous pathological exposures may additively and differentially disrupt large‐scale networks, leading to many possible network knockout sequences that accumulate exponentially from MCI to AD. These findings may partially explain the endophenotypic heterogeneity in AD and should be assessed in other cohort samples.
The Alzheimer’s prevention initiative Generation program: A global perspective on best practices for site support and engagement to accelerate participant recruitment
Authors: Walsh Trisha L. , Riviere Marie‐Emmanuelle , Tariot Pierre N. , Alred Melody , Doak Karen , Liu Fonda , Ricart Javier , Scholten Ingo , Arbuckle Julian , Quinn Matt , Duff Laurie , Smith Molly , Graf Ana , Langbaum Jessica B.
Published: December 2020

Background

The API Generation Program consists of two trials: Generation Studies 1 and 2. Generation Study 1 enrolled cognitively unimpaired APOE4 homozygotes (HMs) ages 60‐75; Generation Study 2 enrolled cognitively unimpaired APOE4 carriers (HMs and heterozygotes (HTs), HTs had to have elevated brain amyloid). To address the unique challenges with recruitment of this population, we developed a multifaceted approach to maintaining engagement with sites and sharing best practices for recruitment among study site teams.

Method

We designed a flexible menu of novel recruitment tactics and implemented strategies, some of which were country‐specific, and collaborated with site teams on a regular basis. We conducted individualized “recruitment planning and implementation” calls with sites soon after they were activated, traveled to sites for in‐person meetings, held regional and country‐wide workshops and roundtable meetings, bi‐monthly study coordinator calls, and monthly media training calls. In addition, we developed an online recruitment and retention toolkit to provide a one‐stop shop for sites to review available, IRB approved materials that could be ordered and customized to meet their site‐specific needs. In the US, we consulted with UsA2 for cultural competency to develop a tip sheet for minority community engagement, postcards, ads, and brochures specific to the Latino and African American communities near study sites.

Result

Recruitment was terminated in July 2019 after an early signal of mild worsening in some measures of cognitive function with umibecestat. At the time the program closed, 35,333 participants had come to a study site for genetic testing, 9,623 screened and 1,626 were randomized. 50% of activated sites had enrolled at least five participants between both studies. Despite the unprecedented challenges for recruitment of cognitively normal APOE4 HMs and HTs, we were on target to complete enrollment by end of 2019. Results from specific engagement and recruitment strategies, along with characteristics of high enrolling sites, will be presented.

Conclusion

Collaboration between study sponsor and site teams and the development of flexible recruitment plans and materials that can be adapted to meet sites’ needs played a crucial role in the successful recruitment, enrollment, and retention of participants for the API Generation Program.
The dual GLP‐1/GIP receptor agonist DA4‐JC shows superior protective properties in the APP/PS1 mouse model of Alzheimer’s disease
Authors: Maskery Mark , Gengler Simon , Goulding Elizabeth Mary , Melchiorsen Josefine Ulrikke , Rosenkilde Mette M. , Edison Paul , Holscher Christian
Published: December 2020

Background

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder for which there is no cure. Type II diabetes is a risk factor for developing AD, and drugs that initially have been developed to treat diabetes have shown good neuroprotective effects in animal models of AD. We have tested the agonist of glucagon‐like peptide 1 (GLP‐1) liraglutide in patients with Alzheimer’s disease and present the results at this meeting. In addition, GLP‐1 analogues and Glucose‐dependent insulinotropic polypeptide (GIP) analogues have shown good effects in animal models of AD.

Method

Here, we test a dual GLP‐1/GIP receptor agonist (DA4‐JC) that has a cell penetrating sequence added to enhance blood‐brain barrier penetration. We test the receptor activation properties in cell culture measuring cAMP levels and test liraglutide and DA4‐JC head‐to‐head in the APP/PS1 transgenic mouse model of AD. Memory formation in the water maze, synaptic plasticity (LTP) in the hippocampus, amyloid plaque load, and chronic inflammation was evaluated.

Result

We show in a receptor activation study that when measuring cAMP levels, DA4‐JC has balanced activity on both GLP‐1 and GIP receptors but not on GLP‐2 or Glucagon receptors. A dose‐response study in the APP/PS1 mouse model of AD showed a dose‐dependent drug effect on both the chronic inflammation response and the reduction of amyloid plaques in the brain. When comparing DA4‐JC with the GLP‐1 analogue liraglutide at equal doses of 10nmol/kg bw ip. once‐daily for 8 weeks, DA4‐JC was more effective in reversing memory loss, enhancing synaptic plasticity (LTP) in the hippocampus, reducing amyloid plaque load in the cortex, and reducing the number of activated microglia and astroglia and lowering pro‐inflammatory cytokine levels in the brain.

Conclusion

The results show good neuroprotective effects of liraglutide and DA4‐JC, and suggest that the dual GLP‐1/GIP receptor agonist DA4‐JC may be more effective in treating AD than a single GLP‐1 receptor agonist. Funded in part by the Alzheimer Society UK.
Strategies to improve dementia clinical research participation at the local level
Authors: Bouranis Nicole , Gelmon Sherril B , Lindauer Allison , Waddell Elizabeth N , Richardson Dawn M , Woo Hyeyoung
Published: December 2020

Background

The National Institute on Aging’s 2018 National Strategy for Recruitment and Participation in Alzheimer’s and Related Dementias Clinical Research emphasizes local community collaboration. Current literature focuses on national factors affecting a person with dementia’s decision to participate in research. Although these factors affect local dementia research efforts, they do not speak to specific state or local factors nor the effects of local efforts. This study aimed to develop strategies to improve dementia research participation in the Portland, OR metropolitan area.

Method

A community advisory board (CAB) comprised of clinicians, researchers, advocates, people with dementia, family caregivers, and older African Americans was established for this project. Thirty‐three interviewees were conducted with clinicians, researchers, advocates, people with ADRD, and family caregivers. An inductive approach was used to allow themes to emerge from the data organically and mitigate the possibility of coding themes based on current literature rather than the interviews. The investigator was the single coder and the CAB interpreted findings by identifying what was most important, surprising, or missing in the interviews.

Result

The Robert Wood Johnson Foundation’s Culture of Health Action Framework was used to conceptualize motivation strategies and reflect elements that describe research participation among people with dementia. Six strategies were identified to improve dementia clinical research participation: 1) Identify and promote local champions for ADRD clinical research participation; 2) Promote policies and processes the incentive cross‐sector collaboration; 3) Recognize caregivers as full research participants; 4) Include people with ADRD and caregivers in the research design process; 5) Offer alternative options to reduce participation burden; 6) Evaluate and improve relationships between healthcare/research staff and patients/participants.

Conclusion

These six strategies can be used in conjunction with the Culture of Health Action Framework as a roadmap to form organization‐community partnerships, facilitate motivation and empowerment, give back decision‐making power to people with ADRD and promote a culture of research at the local level. Implemented strategies should be routinely evaluated to determine their feasibility and effectiveness. This study should be conducted in a larger context or as pilots in other communities to determine contextual relevance and generalizability for other areas.
Dementia in Vietnam: A situational analysis
Authors: Nguyen Tuan Anh , Dang Thu Ha , Tran Kham , Kim Giang Bao , Brodaty Henry , Pham Thang , Pham Tuan Le , Crotty Maria , Kurrle Susan , Hinton Ladson , Esterman Adrian , Nguyen Trung Anh , Roughead Elizabeth E
Published: December 2020

Background

Vietnam has decided to develop an integrated national action plan that integrates dementia into existing non‐communicable diseases (NCD) initiatives. Prior to formulating an effective plan, however, reliable information on current situation of dementia care, treatment and support in Vietnam is needed. This study was conducted to better understand the context, barriers and opportunities for improving dementia care, treatment and support in Vietnam and guide the plan development.

Method

A desk review was conducted using the Situational Analysis Desk Review Topic guide developed by the Strengthening responses to dementia in developing countries (STRiDE) project. Key WHO Global Dementia Observatory (GDO) indicators were collected, focusing on Policy, Service Delivery and Epidemiological assessments.

Result

Vietnam has a high level institutional and policy framework on aging, NCD, mental health and disability including the 2009 Law on the Elderly, which provides the legal umbrella for policies on older people. However, no dementia‐specific policy exists and policies to promote healthy brain remain weak. Rapid aging significantly contributes to the explosion of NCD including dementia in Vietnam. There are 660000 Vietnamese people estimated to be living with dementia, with resultant dementia related costs of US$ 960 million. The healthcare system is not yet prepared for the shift to NCD from an acute, communicable disease burden in the past. Health service delivery is hospital‐centric, with over‐reliance on hospitals and under‐utilization of primary care system that in turn is fragmented and poorly prepared to address the rising challenge of dementia. Social care and support specific for dementia is lacking although there is an impressive grassroots organisation of older people with nearly 100,000 branches.

Conclusion

To allow for a more harmonized response across the health sector and more effective use of limited resources, an integrated national action plan for dementia is sensible. However, Vietnam should take into consideration the potential for fragmentation and lack of dedicated resources being allocated to dementia. A new, integrated model of care focusing on a stronger primary healthcare system, community‐based social care and a healthy aging approach is needed to improve dementia prevention, care, treatment and support in Vietnam.
Distribution of isomerized and racemized amyloid β isoforms in sporadic Alzheimer’s disease using ion‐mobility mass spectrometry
Authors: Mukherjee Soumya , Perez Keyla , Lago Larissa Cristina , Klatt Stephan , Birchall Ian , Barnham Kevin J. , Masters Colin L. , Roberts Blaine Russell
Published: December 2020

Background

Extracellular amyloid plaques and intracellular neurofibrillary tangles are the pathological hallmarks of Alzheimer’s Disease (AD). It takes on average 19 years for amyloid β (Aβ) peptides to deposit as insoluble plaques from onset to clinical dementia symptoms in AD. Such long‐lived nature of amyloidosis predisposes the polypeptide chains to undergo multiple spontaneous and non‐enzymatic post‐translational modifications (PTMs), which can render them resistant to normal cellular proteolysis mechanisms. Several biochemical approaches have estimated very high degree of isomerization and racemization of Asp and Ser residues in Aβ purified from the insoluble plaques. This goes along with a sequential loss of N‐terminal amino acids. However, comprehensive characterisation of these isomers as well as their quantitative estimation is yet to be done.

Method

Freshly frozen post‐mortem frontal temporal cortex samples from non‐demented brains (n=10) and AD brains (n=11) were homogenised and fractionated into distinct soluble, vesicular, membranous and insoluble/aggregated biological pools of Aβ. The Aβ rich pools were enzymatically digested and separated on UHPLC coupled to ESI‐drift tube ion mobility (DTIM) mass spectrometer (Agilent Technologies, Santa Clara, USA). Stable isotope labeled peptides (SIS) were spiked in these brain homogenates to quantify the amount of these isomers/racemers in the different fractionated biochemical pools of the temporal cortex grey matter of human AD and control brains.

Result

We have characterised and quantified the most relevant Aβ isomers (stereoisomers of the N‐terminus) from AD brains by using their SIS peptides. Isomer separation was achieved by LC and their collisional cross section (DTCCSN2) values. Significant isomerization was observed in AD compared to controls brains. Moreover, the amount of these isomerized and racemized peptides differed from lower levels in the soluble/peripheral membranous to higher levels in the insoluble/aggregated debris in AD brain. These findings have implications in Aβ neurotoxicity, oligomerization, structures of amyloid fibrils present in the AD brain.

Conclusion

The results show that isomerized/racemized Aβ peptides are intricately associated with the accumulation and deposition of amyloid in the brain, allowing distinct differentiation between old plaques and freshly generated Aβ. Specifically targeting these long‐lived isomers for enhanced clearance from the CNS would be crucial in developing any therapeutics targeting Aβ.
Development of the elderly lifestyle profile: A Delphi survey of multidisciplinary health care experts
Authors: Park Kang‐Hyun , Park Ji‐Hyuk
Published: December 2020

Background

Lifestyle has been considered as a crucial key factor which effect on one's health and quality of life and it has become a focus of increasing research interest worldwide. As research shown that lifestyle is reconsidered an important health determinant in preventive health care. However, lifestyle is a multifaceted construct and there was a limited evident regarding lifestyle assessment which is able to evaluate individual's multi‐domain lifestyle factors. This study attempt to develop evaluation items used to measure a multifaceted lifestyle profile for community‐dwelling elders in order to prevent chronic disease and improve their health and quality of life.

Method

Opinions from 21 Delphi panels who have experience with elderly and lifestyle research were collected from December 2019 to January 2020. A Delphi survey was carried out three times, and based on previous research. The first Delphi survey gathered opinions using a mix of open‐ended questions and closed‐ended questions reconstructed regarding the evaluation items of elderly's multifaceted lifestyle profile. The second Delphi survey was conducted after the processes of deleting and modifying several items based on the first Delphi survey. In the third Delphi survey after the results of second Delphi survey were presented to expert panels, final opinions from experts were converged. Ethics approval was granted by the Yonsei University(YUWIRB‐1041849‐201901‐BM‐012‐01)

Result

65 items were selected as the first Delphi results, and as the second Delphi result, 62 items were analyzed after the processes of deleting and modifying the values below a content validity ratio of .42. Finally, in the third Delphi survey, 62 items were analyzed as appropriate items. The average content validity ratio of the final Delphi survey was .92 stability .18, and consensus .80, which were high

Conclusion

This study verified the content validity of the evaluation items for community‐dwelling older' multifaceted lifestyle profile. In the future, it is expected that through verifying validity and reliability, there will be used as a standardized assessment tool in the clinical environment.
Masupirdine (SUVN‐502) in combination with donepezil and memantine in moderate Alzheimer's disease: Effect of AD duration since diagnosis and patient’s age on efficacy endpoints
Authors: Nirogi Ramakrishna , Shinde Anil K , Benade Vijay , Subramanian Ramkumar , Bhyrapuneni Gopinadh , Ravulu Jyothsna , Jetta Satish , Rasheed Mohammed Abdul , Badange Rajesh Kumar , Jasti Venkat
Published: December 2020

Background

Masupirdine (SUVN‐502), a selective 5‐hydroxytryptamine‐6 (5‐HT6) receptor antagonist is in clinical development for the treatment of moderate Alzheimer’s disease (AD). Masupirdine was studied in a phase 2 POC, multicenter, randomized, double‐blind, parallel group, 26‐week, placebo‐controlled proof‐of‐concept study in patients with moderate AD receiving stable doses of donepezil and memantine.

Method

A total of 564 moderate AD patients with MMSE scores between 12 ‐ 20 were randomized (1:1:1) to receive either 50 mg or 100 mg of masupirdine or placebo once daily for 26 weeks. The study recruited patients in the age range of 50‐85 years, both inclusive and AD duration since diagnosis of 1 year or more. The primary efficacy endpoint was change from baseline in the Alzheimer's Disease Assessment Scale ‐ Cognitive Subscale (ADAS‐Cog 11). In subgroup analyses, impact of AD duration since diagnosis and patient’s age on the effects of masupirdine on the clinical functions were assessed using primary and secondary endpoints. To evaluate the effect of AD duration, subgroup analysis of different diagnosis durations at screening visit were performed. To evaluate the effect of patient’s age, subgroup analysis of 50‐70 years and 71‐85 years of age at the screening visit, both inclusive were performed. Further stratification was carried out based on memantine plasma concentrations at week 26 in both the subgroups. Safety was assessed throughout the study.

Result

Masupirdine slowed down the cognitive decline in patients with AD diagnosis duration of >3 years. Beneficial effects of masupirdine increased with increasing disease duration; longer the AD duration, better the effect. Patients aged 50 ‐ 70 years had better improvement with masupirdine treatment on efficacy endpoints (ADAS‐Cog 11, CDR‐SB, MMSE) compared to placebo; difference reached to the level of minimum clinically important difference for cognitive endpoints. Subgroup analyses suggest further exploration of masupirdine as a treatment option in patients where current therapy is not responding.

Conclusion

Together with the safety profile of masupirdine, the outcome from these subgroup analyses supports the potential clinical utility of masupirdine in patients with AD.
Selective upregulation of FynT tyrosine kinase in neurodegenerative dementia correlates well with tau pathology and neuroinflammation
Authors: Lim Frances Ting Wei , Low Clara Ying Bei , Lee Jasinda , Lee Chingli , Francis Paul T. , Lai Mitchell Kim Peng , Tan Michelle Guet Khim
Published: December 2020

Background

Fyn tyrosine kinase is involved in the disease progression of Alzheimer’s disease (AD). Our lab has previously reported an isoform‐specific role of FynT tyrosine kinase in AD brain which is associated with neurodegeneration and reactive astrogliosis [Lee et al., 2016]. In view of AD‐related neuropathology and neuroinflammation were not exclusively found in AD, the objective of the study is to investigate whether differential alternative splicing of Fyn to favour FynT expression could also be detected in other neurodegenerative dementias including dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD).

Method

Post‐mortem human brain tissues (prefrontal cortex Brodmann area 9 (BA9) and temporal cortex (BA21) derived from subjects diagnosed with AD, DLB, PDD, as well as controls (CTRL) without neurological or psychiatric diseases were provided by the Brains for Dementia Research (BDR). The brain tissues were recorded for Mini‐Mental State Examination (MMSE) and Braak staging. The brain tissues were processed accordingly for ELISA, real‐time PCR, capillary electrophoresis and HTA array studies.

Result

Selective and significant up‐regulation of FynT isoform expression in prefrontal and temporal cortex of AD, DLB and PDD when compared with CTRL was observed to significantly correlate with cognitive impairment and neuropathological characteristics. FynT induction in AD, DLB and PDD was associated with neuroinflammatory markers. Synaptic dysfunction could be the adverse impacts of FynT induction in neurodegenerative dementias.

Conclusion

Using an independent cohort, we reported that FynT induction was not exclusive to AD, but also detected in neurodegenerative dementia including DLB and PDD. FynT induction was closely associated with tau pathology and neuroinflammation, which likely contributed to synaptic dysfunction and cognitive impairment. Potential therapeutic treatment should specifically target the disease‐associated isoform of Fyn.
Dual‐task gait as a differential marker of dementia disease subtype: Considering a declarative memory task
Authors: Ardle Ríona Mc , Galna Brook , Thomas Alan J , Rochester Lynn
Published: December 2020

Background

Dual‐task (DT) gait involves walking while concurrently engaging with a cognitively‐demanding task. It may be useful to identify dementia and differentiate cognitive subtypes [Montero‐Odasso etal., 2019]. Gait performance deteriorates under DT conditions due to added attentional demand. The majority of studies employ attentional DTs, limiting our understanding of the impact of alternative cognitive domains (e.g. memory or visuospatial abilities). Different dementia subtypes have unique cognitive profiles. Applying cognitive DTs related to these discrete profiles may improve the discriminatory ability of DT gait. This study aimed to assess the feasibility and efficacy of employing a concurrent declarative memory test on gait performance to differentiate Alzheimer’s disease (AD) and Lewy body disease (LBD).

Method

110 participants were recruited. This included 29 people with cognitive impairment due to AD (Age:77±9; sMMSE:24±4), 31 due to LBD (Age:75±6; sMMSE:25±3) and 29 similarly‐aged controls (Age:74±9; sMMSE:29±1). Gait was assessed using an instrumented walkway (GAITRite) under single‐task (ST) and DT conditions (performing a story recall task). Gait outcomes in ST and DT conditions included measures of pace, variability, rhythm, asymmetry and postural control. Kruskall Wallis tests with Mann Whiney U post‐hocs assessed group differences.

Result

89 participants successfully completed both conditions. The declarative task was too difficult for 21 participants (AD:7; LBD:14). There were no differences in gait performance between disease groups during the DT. During ST, the LBD group showed greater step length variability (p=.035) and stance time asymmetry (p=.037) compared to AD. Both disease groups demonstrated impaired gait compared to controls (p≤.05) in both conditions. There were no significant differences between disease groups on performance of the story recall task in either condition, but performance was significantly worse (p≤.001) compared to controls.

Conclusion

This study demonstrated limited feasibility for people with cognitive impairment to complete a declarative memory DT. This particular DT was not as useful as ST gait for differentiating dementia subtypes. It is important to understand how feasible and effective different cognitive tasks are when using DT gait as a clinical tool. Future research should consider the efficacy of this task to predict dementia in “at‐risk” groups, such as those with genetic risk factors.
Effect of occupational complexity on cognitive change during a multidomain lifestyle intervention: The FINGER trial
Authors: Rydström Anders , Darin‐Mattsson Alexander , Kåreholt Ingemar , Ngandu Tiia , Solomon Alina , Lehtisalo Jenni , Antikainen Riitta , Bäckman Lars , Hänninen Tuomo , Laatikainen Tiina , Levälahti Esko , Lindstrom Jaana , Paajanen Teemu , Havulinna Satu , Peltonen Markku , Soininen Hilkka , Neely Anna Stigsdotter , Strandberg Timo , Tuomilehto Jaakko , Kivipelto Miia , Mangialsche Francesca
Published: December 2020

Background

Life‐long mental stimulation through occupational complexity has been associated with late‐life cognition and might affect the rate of cognitive changes in randomized controlled trials (RCTs) testing preventive interventions for dementia. The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER, ClinicalTrials.gov NCT01041989) is a landmark RCT that tested a lifestyle‐based multidomain intervention in 1260 community‐dwellers aged 60‐77 years at increased risk of dementia. Participants were randomized to either a group that received general health advice, or a 2‐year multidomain intervention that incorporated dietary counselling, exercise, cognitive training, and vascular/metabolic risk monitoring. The intervention improved global cognition (primary outcome) and cognitive sub‐domains including executive function, processing speed, and memory. This study aimed to test if the cognitive benefits of the 2‐year multimodal intervention were linked to baseline levels of occupational complexity.

Method

Study participants: all randomized FINGER participants with at least one cognitive outcome assessment after the baseline visit (modified intention‐to treat population), available data on last held occupation, and who were retired (N: 1026). Occupational complexity was assessed through a validated rating system, identifying three domains: complexity with data; complexity with people; and substantive complexity. Cognition was assessed at baseline, 1‐year and 2‐year with the Neuropsychological Test Battery (NTB). The following cognitive outcomes were considered: global cognition, executive function, processing speed, and memory. Data analysis: Mixed‐model repeated‐measures analyses with maximum likelihood estimation were used to analyse change in cognitive scores as a function of randomization group, time, levels of occupational complexity (standardized Z‐scores), their interaction (randomization group × time × occupational complexity), age, sex, education, study site.

Result

Subjects with higher levels of occupational complexity with data (i.e., occupations more mentally demanding) benefitted most in terms of improvement in executive function (interaction coefficient group × time × occupational complexity: ß[SE]: .03 (.01), p= .044) and global cognition (ß[SE]: .02 (.01), p= .060).

Conclusion

The cognitive change in a multidomain preventive intervention can be affected by previous occupational complexity. This facet of mental stimulation should be further investigated within RCTs for cognitive impairment.
Association of obesity and diabetes in sex‐related differences in cognitive function: Findings from the Cocoa Supplement and Multivitamin Outcomes Study for the Mind (COSMOS‐Mind)
Authors: Espeland Mark A , Rapp Stephen R , Manson JoAnn E , Gaussoin Sarah A , Hayden Kathleen M , Shumaker Sally A , Sesso Howard D , Banack Hailey R
Published: December 2020

Background

Type 2 diabetes and mid‐life obesity increase the risk for cognitive decline and cognitive impairment in men and women. Studies disagree, however, on whether the associations diabetes and obesity have with cognitive function vary by sex.

Method

We analyzed data from the COSMOS clinical trial and its COSMOS‐Mind ancillary study of cocoa extract (including 600 mg/d cocoa flavanols) and a multivitamin to reduce risks for major cardiovascular events and total invasive cancer (COSMOS), and cognitive decline (COSMOS‐Mind). In COSMOS‐Mind we administered a standardized telephone‐based cognitive battery to assess episodic memory, executive function and global cognition in 2,262 adults, age>65 (mean=73) years, 58% women, 33% obese (body mass index >30 kg/m2), and 10% diabetes. Individuals with histories of myocardial infarction, stroke, or cancer (excluding non‐melanoma skin cancer) were excluded. Sex, obesity, and diabetes were based on self‐report. Multiple regression analyses were used to compare cross‐sectional associations between cognitive function and age for women and men grouped by obesity and diabetes, with adjustments for education and race/ethnicity.

Result

Women averaged better scores than men for memory (mean+standard error difference=0.42+0.04 SDs), executive function (0.26+0.04 SDs), and global cognitive function (0.30+0.4 SDs), all p<0.001. These differences were evident for individuals both with and without obesity or diabetes (all two‐way interactions p>0.20). Obesity, compared with no obesity, was associated with less steep slopes with greater age among women in all domains (all p<0.04), with no differences seen in men for any domain. This held without and with adjustment for diabetes. For composite cognitive function, the slope of the association with greater age was ‐0.064+0.005 SD/year among women without obesity compared with ‐0.030+0.009 SD/year among those with obesity (p=0.001), and the differences between women and men with obesity increased with age. After adjustment for obesity, diabetes was not associated with steeper slopes with age for any domain in either sex.

Conclusion

In the COSMOS‐Mind cohort of clinical trial volunteers, the difference in cognitive function between women and men with obesity increased with age. However, in these cross‐sectional analyses we cannot rule out potential biases related to self‐report or differential survival.
Genome‐wide association studies for identifying novel genetic variants providing cognitive resilience against AD pathology
Authors: Hohman Timothy J.
Published: December 2020

Background

Alzheimer’s disease neuropathology is common among non‐demented older adults, and 30% meet neuropathological criteria for autopsy‐confirmed AD despite showing no clinical symptoms of disease. Yet, the genetic factors that allow these resilient individuals to remain cognitively normal in the face of substantial neuropathology remains poorly understood. We have performed large‐scale multi‐modal data harmonization to enable deep explorations into the genetic architecture of resilience. We will present comprehensive estimates of heritability of AD resilience phenotypes, describe common genetic variants that contribute to resilience, and provide an overview of gene networks and critical genetic pathways that appear to provide putative protection against the downstream consequences of AD neuropathology.

Method

We harmonized neuroimaging (MRI and PET), neuropsychological, fluid biomarker, and genomic data from 8 longitudinal cohort studies as part of the AD sequencing project phenotype harmonization workgroup. Resilience phenotypes were quantified using an established latent variable model based on better‐than‐predicted cognitive performance and brain volume for an individual’s AD neuropathological burden. We quantified estimates of heritability using the Genome‐wide Complex Trait Analysis (GCTA) software package. Next, we performed genome‐wide association study (GWAS) analyses covarying for age, sex, and population principal components. Summary statistics from GWAS were leveraged to characterize genetic pathways enriched for association with resilience phenotypes. Finally, we quantified gene network associations with resilience phenotypes leveraging RNA sequencing data from brain tissue and replicated leveraging predicted gene expression analyses quantified using GWAS data.

Results

Resilience phenotypes showed heritability estimates that are on par with complex genetic traits ( 0.19< h2< 0.67, p < 0.005), suggesting that genetic variation explains variance in resilience phenotypes. We observed a number of genome‐wide significant variants associated with resilience that replicate across in vivo biomarker datasets and autopsy datasets implicating acetylcholinesterase genes, bile acid homeostasis, and DNA damage repair. Finally, gene network analyses implicated gene modules involved in RNA binding and transcriptional regulation.

Conclusion

We highlight a number of novel genetic variants and genetic pathways that may protect the brain from the downstream consequences of AD neuropathology, highlighting the potential of resilience endophenotypes in the identification of novel therapeutic targets.
A multi‐country, multi‐cohort examination of cortical volume, thickness, and surface area in the motoric cognitive risk (MCR) syndrome
Authors: Blumen Helena M , Schwartz Emily , Allali Gilles , Beauchet Olivier , Callisaya Michele L , Doi Takehiko , Shimada Hiroyuki , Srikanth Velandai K , Verghese Joe
Published: December 2020

Background

The motoric cognitive risk (MCR) syndrome is characterized by slow gait and cognitive complaint, and increases the risk for both Alzheimer’s disease and vascular dementia. Our recently established MCR neuroimaging consortium aims to identify the brain substrates and pathologies in MCR – and consists of > 3,000 MRIs from 6 different older adult cohorts and 5 different countries. The current study examined cortical volume, thickness, and surface area in MCR using a subset of 200 older adults from 4 different cohorts/countries, as a function of image processing methods that involved manual intervention and no manual intervention.

Method

Fifty MRIs from each of the four cohorts were examined (N = 200). FreeSurfer Version 6.0 and general linear statistical models with 1,000 bootstrapped samples (n‐1, with resampling) were used to determine if cortical volume (mm3), thickness (mm) and surface area (mm2) overall and in 34 different cortical regions were associated with MCR – following no manual intervention and manual error correction in the cortical surface. All models were adjusted for age, sex, education, white matter hyperintensities, total intracranial volume, and cohort status.

Result

The mean age was 72.62 years and 33 % met criteria for MCR. Overall cortical thickness – but not cortical volume or surface area – was different in older adults with MCR relative to those without MCR, although a trend in the expected direction was observed in cortical volume (p <.051). Smaller cortical thickness in MCR was pervasive, and included prefrontal (caudal middle frontal, medial orbitofrontal, pars orbitalis, pars opercularis, pars triangularis), insular, cingulate (posterior, isthmus), parietal (inferior parietal, precuneus), temporal (superior temporal, supramarginal) and precentral regions. The relationship between cortical volume, cortical thickness, surface area and MCR did not change following manual interventions (all 95% CIs overlapped).

Conclusion

These results suggest that a) cortical thinning in MCR is pervasive and involve regions associated with a number of social, cognitive, affective and motor functions, b) cortical thickness is more sensitive than cortical volume and surface area to the cortical changes observed in MCR, and c) that manual intervention does not influence the relationship between cortical volume, thickness, area and MCR.
Evaluation of patient burden using online social media in mild cognitive impairment
Authors: Monfared Amir Abbas Tahami , Stern Yaakov , Irizarry Michael C , Doogan Stephen , Zhang Quanwu
Published: December 2020

Background

Detection and diagnosis of Mild Cognitive Impairment due to Alzheimer’s Disease (MCI‐AD) can be challenging due to the subtlety of changes in early stages of disease progression. As a result, opportunities to capture the patient burden in MCI‐AD can be limited.

Method

We used Natural Language Processing (NLP) to analyze challenges and issues that were the most frequently reported online by patients living with MCI‐AD and caregivers. Patients’ self‐reports and caregivers’ reports on patients were identified based on online narratives posted between January 1998 and December 2019 across 84 social media sources. The RLytics NLP platform was used in combination with manual curation to codify verbatim symptoms and impairments against standardized medical taxonomies such as WHO‐ICF and MedDRA, and further into the following categorizations: Social, Physical, Emotional, Cognitive, and Role Activity (SPEC‐R).

Result

63,933 narratives from 311 patients with MCI‐AD and 1,454 caregivers were qualified into the sample for analysis. The most frequently reported issues varied between patients and caregivers. Cognitive issues (e.g. memory impairments and comprehension‐related) were the most frequently reported by both groups, however, patients reported at a higher rate. This may suggest a deeper concern with losing cognitive ability felt by patients themselves at the disease stage of MCI. This is further supported by a higher reporting rate of anxiety and depressive disorders among patients relative to caregivers. In contrast, certain role activity, physical and social issues (e.g. driving, fatigue, walking and mobility, relationships with spouse or partner) are reported by caregivers at a higher rate than patients, suggesting that these issues may have a greater impact on the daily lives of caregivers or may be more readily recognizable than cognitive issues.

Conclusion

The SPEC‐R framework helps identify, understand, and prioritize the most pressing concerns at the symptom and functional level by patients and caregivers. It can uncover areas of disease burden in MCI‐AD that are less frequently associated with MCI, particularly in the non‐cognitive domains, that may not be sufficiently captured by early diagnostic processes in the clinical setting.
High fat diet leads to aberrant protein O‐GlcNAcylation and to the development of Alzheimer disease signatures in mice
Authors: Domenico Fabio Di , Zuliani Ilaria , Lanzillotta Chiara , Barone Eugenio , Fusco Salvatore , Grassi Claudio , Tramutola Antonella , Perluigi Marzia
Published: December 2020

Background

High fat diet (HFD) is the most commonly used experimental model of obesity and insulin resistance, resembling the hallmarks of humans metabolic syndromes. It causes detrimental effects on brain function, but the molecular mechanisms involved are still poorly understood. Recent studies show that HFD may lead to the reduction of glucose uptake, which represent an early step in neuronal damage. In this regard, Alzheimer’s disease (AD) was recently proposed to be a form of CD caused by metabolic dys‐homeostasis. Intriguingly, during AD glucose hypometabolism precedes the appearance of clinical symptoms leading to the downregulation of O‐GlcNAcylation, a reversible glucose‐dependent protein PTM, which competes with phosphorylation for Ser or Thr residues. The enzymes (OGT and OGA) regulating the O‐GlcNAcylation cycle rely on brain nutrients through the hexosamine biosynthesis pathway for substrate availability. Recent studies from our lab observed the reduction of O‐GlcNAcylation in the hippocampus of insulin resistant 3xTG‐AD mice supporting a role for this PTMs in the development of CD.

Method

We employed C57 mice fed for 6 weeks with HFD (60% calories from fat) compared with C57 fed with standard diet. Further, we subjected mouse astrocyte to insulin + palmitic acid (IPA) treatment for 24h. The experimental procedures encompassed the analysis of: total and protein specific O‐GlcNAcylation and phosphorylation on Ser and Thr residues, OGT and OGA levels and activity, Tau and APP PTMs and the alteration of metabolic parameters.

Result

We demonstrate that HFD mice show the reduction of protein O‐GlcNAcylation in the hippocampus but not in the liver. Such reduction lead to unbalanced O‐GlcNAcylation/phosphorylation ratio of total proteins and of tau and APP, suggesting its involvement in the development of pathological tau and Aβ. A reduction of OGT protein levels is reported in hippocampal cells supporting a role for this enzyme as metabolic sensor. Similarly, astrocytes treated with IPA show insulin resistance coupled with reduced O‐GlcNAcylation and the progression of AD markers. Intriguingly, altered O‐GlcNAcylation seems to be associated also with mitochondrial defects.

Conclusion

Our data support a key role for aberrant O‐GlcNAcylation in promoting the development of AD markers during diet‐driven brain insulin resistance and glucose hypo metabolism.