bluuebunny/crossref_metadata_2025 huggingface dataset:
Performance and intrusion errors on challenging cognitive assessments associate with subjective cognitive decline
Authors: Joyce Jillian L. , Chapman Silvia , Barker Megan S. , Rizer Sandra , Sunderaraman Preeti , Charles Kreisl William , Cosentino Stephanie
Published: December 2020

Background

Subjective cognitive decline (SCD) in ostensibly cognitively normal older adults has been proposed to reflect preclinical Alzheimer’s disease (AD). Yet traditional neuropsychological tests have inconsistently linked SCD and cognitive performance, possibly reflecting the lack of sensitivity and specificity in such tests to capture subtle cognitive changes. Indeed, novel cognitive tests as well as intrusion errors appear to be more closely associated with preclinical AD biomarkers. However, there is limited investigation into the association of SCD with these cognitive outcomes. This study examines SCD in relation to the main outcomes and intrusion errors on two novel challenging cognitive tasks, and a traditional neuropsychological test.

Method

94 healthy older adults with a mean age of 73 years (SD=7.36), and education of 17 years (SD=2.34) were recruited for this study. Participants completed three SCD questionnaires regarding common cognitive difficulties in memory, language, attention and executive functioning. A single factor score was derived as main outcome for SCD. Cognitive assessment included the Loewenstein‐Acevedo Scale for Semantic Interference and Learning (LASSI‐L), the Face‐Name Associative Memory Exam (FNAME) task, and the Selective Reminding Test (SRT). Main outcomes for each measure included: SRT (total and delayed recall and intrusion errors); LASSI‐L (recovery from semantic interference, percentage of intrusions errors, total semantically related intrusions (SRI) and competing item intrusions (CII)); FNAME (total names recalled, SRI and CII). Demographically adjusted linear regressions were conducted to examine the unique contribution of performance and intrusion errors on each measure to SCD.

Result

Both FNAME names recall (β=‐.24, p=.027) and SRI (β=.25, p=.015) were independently associated with SCD, while overall intrusions and CII were not (p>.05). The LASSI‐L overall intrusions (β=‐ .30, p=.009) and CII (β=‐ .29, p=.014) were also associated with SCD, while SRI and recovery from semantic interference were not. (p>.05). No SRT outcomes were associated with SCD (p>.05)

Conclusion

SCD appears to capture subtle changes on sensitive cognitive measures proposed to be indicative of preclinical AD. Results support the use of both main outcomes and intrusion errors on these cognitive tests, as they may each reveal sensitive information regarding various mechanisms that can breakdown in early AD.
Genome‐wide interaction study of smoking in Alzheimer’s disease
Authors: Moore Mackenzie R. , Chung Jaeyoon , Rosenthaler Max , Uretsky Madeline , Abdolmohammadi Bobak , Raghavan Neha S. , Farrell John , Bennett David A. , Crane Paul K. , Kamboh M. Ilyas , Kukull Walter A. , Larson Eric B , Haines Jonathan L. , Pericak‐Vance Margaret A , Schellenberg Gerard D , Mayeux Richard , Lunetta Kathryn L , Farrer Lindsay A. , Mez Jesse ,   Alzheimer’s Disease Genetic Consortium
Published: December 2020

Background

Genome‐wide association studies (GWAS) have identified approximately 40 risk loci associated with Alzheimer’s disease (AD). However, only a fraction of heritability has been explained. In large meta‐analysis, smoking was associated with AD dementia. In this study, we sought to identify interactions between smoking and single‐nucleotide polymorphisms (SNPs) to further characterize AD genetic architecture.

Method

We used a subset of datasets of individuals of European ancestry from the Alzheimer’s Disease Genetic Consortium (ADGC) that had smoking information available from parent studies. The presence of any past or current smoking habit was considered to be positive smoking exposure. In each dataset, we ran a genome‐wide case‐control analysis including SNP and smoking main terms, and a SNP‐smoking interaction term. Models were adjusted for age, sex, and principal components of population substructure. Results from each dataset were meta‐analyzed using the inverse variance method. Pathway analysis of top SNPs was run using Ingenuity.

Result

The sample included 6,916 total individuals, including 2,862 AD cases and 4,054 controls. Although no interaction terms reached genome‐wide significance, there were two suggestive loci: top SNP rs3734416 [minor (C) allele frequency (MAF) = 0.27; interaction P = 7.2 × 10−6; OR for C allele in smokers = 1.23; OR for C allele in non‐smokers = 0.86] on chromosome 6 within the gene MTHFD1L and 95kb downstream of PLEKHG1, and top SNP rs693951 [MAF (G) = 0.27; interaction P = 1.3 × 10−6; OR for major A allele in smokers = 1.31; OR for A allele in non‐smokers = 0.83] on chromosome 8, 70kb upstream of ANGPT1. Pathway analysis implicated cellular development, cellular growth and proliferation and nervous system development and function. MTHFD1L has been implicated in candidate gene studies of AD and PLEKHG1 has been implicated in a GWAS of white matter hyperintensities. ANGPT1 has been implicated in recovery after ischemic stroke in candidate gene, transcriptomic and blood‐based biomarker studies.

Conclusion

We found suggestive evidence of a smoking‐SNP interaction associated with AD risk at 2 loci previously linked with AD and cerebrovascular disease, but that were not identified in the largest AD GWAS to date. Expansion of the sample and replication are underway.
A study of prevalence and factors related to cognitive impairment in Thai patients with neuromyelitis optica
Authors: Rattanabannakit Chatchawan , Lerttanatum Chompoonuch , Maethasith Inthiporn , Siritho Sasithorn , Jitpapaikulsarn Jiraporn , Prayoonwiwat Naraporn , Senanarong Vorapun
Published: December 2020

Background

Neuromyelitis Optica (NMO) is a demyelinating disease caused by an autoimmune process that attacks the central nervous system resulting in a neurological deficit. Previous studies showed cognitive problems in these patients, especially the decline in processing speed, episodic memory, executive function, and attention. We aimed to study the prevalence and the factors related to cognitive impairment in Thai patients with NMO.

Method

We recruited 83 participants diagnosed with NMO by the 2015 international consensus diagnostic criteria for NMO spectrum disorder who visited the Demyelinating Disease Clinic at Siriraj Hospital. Participants with the last clinical relapse within 3 months or those who could not perform cognitive tests due to disability were excluded. Cognitive functions were assessed by using the Montreal Cognitive Assessment – Thai version (MoCA‐T) and Frontal Assessment Battery (FAB). The subjective reports of any cognitive problem by interviewing participants and their informants were also collected. Demographic data, cognitive performance, and factors related to the MoCA‐T score were analyzed.

Result

The mean MoCA‐T score in patients with NMO was 22.96 ± 3.82, and the mean FAB score was 15.27 ± 2.47. The majority (54%) of them had cognitive impairment according to the cut‐off of the MoCA‐T score of less than 25. Participants with cognitive impairment had significantly less education than those without cognitive impairment (9.9 4.3 and 14.6 3.6 years, p < 0.001), and they used more time to complete the MoCA‐T (p < 0.001). The disease severity evaluated by the Expanded Disability Severity Scale was associated with the MoCA‐T score (r = ‐0.29, p = 0.008). Age, the annual relapse rate in the first five years, duration of disease, and Aquaporin‐4 antibody status were not associated with cognitive impairment (all p > 0.5). Interestingly, the informant‐report of cognitive decline in NMO patients was associated with the less MoCA‐T performance (p = 0.032), but not the self‐report (p = 0.397).

Conclusion

Most of the Thai patients with NMO had cognitive impairment, which related to education, disease severity, and also the perception of their relatives. Future studies that included more comprehensive neuropsychological evaluations and neuroimaging findings are needed in these patients.
Defining the role of gut microbiota‐derived ketamine metabolites in Alzheimer’s disease
Authors: Pasinetti Giulio Maria , Naughton Sean X. , Trageser Kyle J. , Harary Joyce M. , Westfall Susan
Published: December 2020

Background

Ketamine, typically used for providing pain relief and sedation prior to surgical procedures, has recently been recognized as a potential therapy for disorders rooted in neuroinflammation such as major depression. Ketamine undergoes extensive metabolism and characterizing these metabolites is essential to understand the therapeutic efficacy and long‐term effects of ketamine treatment for neuroinflammation. Further, specific enantiomers of ketamine have been shown to specifically alter the composition of the gut microbiota, which through gut‐brain‐axis mechanisms, may contribute to its anti‐inflammatory activity. The objective of this study is to characterize the impact of the gut microbiota on ketamine metabolism and using these metabolites understand how ketamine can be used as a therapeutic for neuroinflammation associated with Alzheimer’s disease (AD).

Method

Using an in vitro model of the human gastrointestinal tract, EBIOME we are exploring the impact of ketamine on the human microbiome with metagenomic quantification of gut microbiome species and quantification of ketamine metabolites with UPLC‐MS/MS technology platforms. Ketamine is known to undergo extensive metabolism by liver P450 enzymes, which will interact with the gut microbiome derived metabolites. Hence, following validation in vitro, in ongoing studies ketamine will be chronically dosed into wildtype mice to understand how the gut microbiota‐derived metabolites affect the known liver‐derived secondary metabolites including norketamine and its hydroxylated isomers and dehydrogenated forms.

Result

We have evidence in rodents, that ketamine amplifies Lactobacillus, Turicibacter and Sarcina spp. while reducing populations of the opportunistic pathogens Mucispirillim and Ruminococcus indicating that there is a species‐dependent metabolism of ketamine. Bioavailability and acute over chronic pharmacokinetics of these metabolites will be determined in the gut, blood and brain to understand how the gut‐liver metabolic interactions affect chronic ketamine dosing towards understanding the long‐term safety of ketamine.

Conclusion

With an understanding of ketamine metabolism, ketamine chronically dosed into 5xFAD AD mouse models we will understand the brain‐bioavailable ketamine metabolites on neuroinflammatory pathophysiologies of AD. Ultimately these studies will help to asses microglia inflammatory activation and Alzheimer’ disease neuropathology.
Beers criteria medications administered intraoperatively to older surgical patients with cognitive impairment
Authors: Schenning Katie J , Navales Andres Tirado , Tekkali Praveen , Quinn Joseph F
Published: December 2020

Background

The American Geriatrics Society maintains a list of drugs that are not recommended for geriatric patients with dementia or cognitive impairment (i.e. Beers Criteria) due to increased risk of delirium. Several drugs from this list are commonly used in the perioperative period, including benzodiazepines and drugs with anticholinergic properties. Our objective was to determine the prevalence of potentially inappropriate medication (PIM) administration intraoperatively in geriatric surgical patients who screened positive for cognitive impairment.

Method

This was a retrospective evaluation of 2,410 older adults (at least 65 years) who presented for elective, inpatient surgery between February, 2018, and January, 2020, in a large tertiary teaching hospital. Patients were screened preoperatively for cognitive impairment using the Mini‐Cog. Mini‐Cog scores 0‐2 were considered positive for cognitive impairment. Charts were reviewed to analyze which 2019 Beers Criteria medications were administered intraoperatively by the anesthesiology team. An unpaired t‐test was performed to determine whether there was a difference in PIM administration in patients who screened positive vs negative for cognitive impairment.

Result

Among 2,410 geriatric surgical patients with a mean age of 73 years, 1,817 (75.4%) had at least one PIM administered during surgery/anesthesia. The most commonly administered medications were steroids (n=1096, 45.5%), medications with anticholinergic properties (n=930, 38.6%), and benzodiazepines (n=852, 35.4%). (Table 1) Patients who screened positive for cognitive impairment received fewer PIMs on average than patients who had a negative cognitive screening test. (mean ± SEM, 1.03±0.05 vs. 1.24±0.02 PIM, p<0.001). (Table 2)

Conclusion

There is a high prevalence of PIM used in geriatric surgical patients, including patients who have screened positively for preexisting cognitive impairment.
Dementia is strongly associated with atrophy of medial temporal lobe structures even after accounting for neuropathologies
Authors: Woodworth Davis C. , Sheikh‐Bahaei Nasim , Scambray Kiana Alexis , Phelan Michael , Corrada Maria M.M. , Kawas Claudia H. , Sajjadi S. Ahmad
Published: December 2020

Background

Brain atrophy is associated with various neuropathologies as well as clinical status of dementia. However, few studies have examined if dementia has an independent effect on brain atrophy. In this study, we examined the pattern of atrophy associated with dementia while accounting for the most common dementia‐related neuropathologies.

Method

We used data from the National Alzheimer’s Coordinating Center (NACC) (09/2005‐03/2017) and identified 129 participants with suitable 3D‐T1w MRI and autopsy data. We determined dementia status at visit closest to MRI. We used the following dichotomized neuropathological variables in our analysis: Alzheimer’s disease neuropathology, hippocampal sclerosis, Lewy Bodies, cerebral amyloid angiopathy, atherosclerosis, gross infarcts, microinfarcts, and micro/macro hemorrhages. We used the Computational Anatomy Toolbox (CAT12) to segment the T1w scans into tissue types and generate gray matter density maps. First, we performed a voxel‐based morphometry (VBM) analysis to identify regions associated with dementia. We further explored this relationship by analyzing the volumes of the identified regions of interest (ROI). Also, to examine the association of dementia with global measures of atrophy, we assessed the relation of dementia with total gray matter, white matter, and cerebrospinal fluid. We used multiple linear regression models of density/volumes in relation to dementia while adjusting for neuropathologies, sex, age, education, years from MRI to death, and intracranial volume.

Result

Table‐1 summarizes participant characteristics. VBM showed that grey matter atrophy of hippocampus and surrounding structures had the strongest association with dementia (Figure‐1). Therefore, we selected the hippocampus, amygdala, and medial temporal cortex for ROI analysis. We found strong associations with dementia for volumes of the hippocampus, amygdala, and medial temporal cortex (P<0.0001 and semi‐partial correlations≥0.25 for each, Table‐2). Dementia status accounted for more variance in atrophy in these structures (∼8%) compared with all demographic and neuropathological variables; the only exception was hippocampal sclerosis which accounted for more variance in hippocampal atrophy (10%, Table‐3).

Conclusion

Even after accounting for the most common neuropathologies, dementia still had the strongest association with atrophy of medial temporal lobe structures. This suggests that atrophy of the hippocampus and medial temporal lobe is most related to clinical dementia as opposed to Alzheimer's disease neuropathology.
Comorbidity burden in Alzheimer’s disease clinical trials
Authors: Fowler Mackenzie E. , Murchison Charles F. , Cutter Gary R. , Schneider Lon , Kennedy Richard
Published: December 2020

Background

Individuals with AD may be healthier than the general older adult population. Clinical trials for AD have been known to enroll individuals who are not representative of the general population, but it is unclear to what extent comorbidity affects cognitive outcomes in clinical trials.

Methods

We included 10 studies with 4,002 subjects with AD from our meta‐database of 18 ADCS studies and ADNI. Comorbidity was measured using the RxRisk‐V, which provides a count of the total number of comorbid conditions based on medication data. Cognition was measured using the Alzheimer’s Disease Assessment Scale‐Cognitive Subscale (ADAS‐Cog). We used linear mixed effects models to examine the rate of cognitive decline by total comorbidity count, by individual disorders, and by presence of hypertension plus diabetes as known AD risk factors.

Results

Across all participants, the mean RxRisk comorbidity score was 1.90 (SD 2.04). Approximately 27% had 0 comorbidities, 27% had 1 comorbidity, and 46% had 2+ comorbidities. Across all studies, for each additional comorbidity, the rate of progression on the ADAS‐cog increased by 0.11 point/year (95% CI ‐0.05, 0.26), reflecting a non‐significant worsening of cognition (Figure). After adjusting for other comorbidities, the rate of progression was not significant for congestive heart failure (‐0.5 point/year, 95% CI ‐1.3, 0.3), COPD (‐0.1 point/year, 95% CI ‐1.6, 1.3), diabetes (‐1.2 point/year, 95% CI ‐2.5, 0.1), hypertension (0.7 point/year, 95% CI ‐0.1, 1.6), or ischemic heart disease (‐0.3 point/year, 95% ‐0.9, 0.4). The rate of progression was also not significant for the combination of hypertension plus diabetes (0.1 point/year, 95% ‐0.7, 0.9).

Conclusions

Comorbidity did not have a significant effect on rate of cognitive decline across AD clinical trials. As several comorbidities are known to affect the rate of AD progression, these findings suggest that AD clinical trials enroll participants with less severe comorbidities that do not affect cognitive decline. Further study of the effects of comorbidities on AD clinical trial outcomes are warranted, particularly study of severity of comorbidities.
Signatures of disrupted synaptic maintenance in the entorhinal cortex of both pathology‐free APOE4 carriers and aged APOE4 mice
Authors: Arain Hirra A. , Kumar Gautam , Figueroa Helen Y. , Cookson Mark R. , Mathews Paul , Duff Karen E. , Nuriel Tal
Published: December 2020

Background

The greatest genetic risk factor for late‐onset Alzheimer’s disease (AD) is the possession of the apolipoprotein E4 (APOE4) variant. Yet the mechanism by which APOE4 increases AD susceptibility is unclear. The entorhinal cortex (EC) is one of the first region of the brain to succumb to AD pathology, and previous studies in our lab have revealed unique APOE4‐assocated effects on the regulation of important biological processes in the EC of aged APOE4 mice. In this study, we further elucidated APOE4‐associated vulnerability in the EC by investigating such alterations in AD pathology‐free brain tissues from human APOE4 carriers.

Method

Using both confirmed pathology‐free human brain tissue genotyped for APOE status and brain tissue from aged APOE targeted replacement mice, we investigated the effects of APOE4 expression in the EC using a combination of transcriptomic analysis, immunohistochemistry and biochemical assays.

Result

Differentially expressed genes present in both human and mouse samples revealed APOE4‐associated alteration of transcripts in the EC related to both the maintenance and the structural integrity of synapses. Follow up studies have elucidated the ways in which the alterations of these transcripts affects synapse integrity and causes dysregulation of vital biological processes in the EC. Additional studies are currently underway to understand how such pathway dysregulations are related to one another and how they are instrumental in the AD pathology that accumulates early on in the EC.

Conclusion

Our studies reveal novel insights into the ways in which APOE4 expression may increase AD risk by revealing region‐specific alterations in vital biological processes present in both humans and mice that possess the APOE4 allele. We believe that these results will point to novel ways in which AD can be slowed or prevented, especially among APOE4 carriers.
Artificial intelligence‐led decision support services to reduce caregiver load related to persons with cognitive impairment
Authors: Dorai Chitra , Stern Edith
Published: December 2020

Background

The number of people in the US living with cognitive impairment (including Alzheimer’s Disease and other dementia) is over 5.8M today, and is expected to increase to nearly 14M by 2050 [c.f. alz.org]. The rapidly growing population of informal caregivers is subject to high stress due to patient behavioral symptoms, increased demands on caregiver time, and lack of knowledge about new care giving tasks. Many of these tasks are complex and time consuming such as determining and coordinating services/resources for the patients, seeking information and talking with the clinical team about patient conditions and care plans, and arranging for someone to care for their charge.

Method

We hypothesize that the power of artificial intelligence (AI) technology can be harnessed to meaningfully support caregivers in time consuming, complex tasks encountered in care giving and thereby reduce their load before, during and after diagnosis. We have developed a set of ARTful (accountable, responsible, and transparent) AI services to support informal caregivers of patients with mild cognitive impairment who are being diagnosed and treated at a hospital Memory Clinic. Barriers to adoption of AI technology services include usability (as defined in the System Usability Scale), acceptability (fear of AI) and experience (digitally unprepared) on the part of patient/caregiver pairs.

Result

In this paper, we present case studies covering service onboarding, caregiver exploration and patterns of use of the AI technology, and initial assessment of its impact on adherence to care plans and on caregiver burden. Preliminary findings indicate that well‐thought out AI‐led solutions can reduce caregiver load and increase care plan adherence. A double‐blind study is planned to quantitatively assess impact as measured by scores on the Oberst Caregiver Burden Scale.

Conclusion

A demonstration of the effectiveness of this technology in reducing caregiver load will lead to a scalable, cost‐effective solution that raises the standard of current practices in neurodegenerative care, and leads to improved health outcomes.
Effects of a high‐fat diet on the brain in FRGN mice with humanized livers
Authors: Edlund Anna K. , Giannisis Andreas , Patra Kalicharan , Morrema Tjado H.J. , Hoozemans Jeroen J.M. , Bial Greg , Foquet Lander , Nielsen Henrietta M.
Published: December 2020

Background

Diets rich in fat lead to high levels of circulating free fatty acids that induce systemic inflammation, which contribute to systemic insulin resistance and consequently impaired glycemic control. Both of these conditions are associated with brain glucose hypometabolism [1, 2] and an increased risk of neurodegenerative dementias such as Alzheimer’s disease. Mice on a high‐fat diet (HFD) were reported to show signs of brain insulin resistance with coinciding cognitive impairment [3]. Due to the significant difference in lipid metabolism between mouse and man, its poorly understood how the effects of a HFD on mice brains translate to human brain. We therefore employ a mouse model with humanized livers resulting in a more human‐like peripheral lipid profile [4] to study the effects of a HFD on the mice brain.

Method

FRGN mice with humanized livers were fed either normal chow or a 12‐week HFD. Brains were harvested and divided with a sagittal cut. The right hemispheres were used for immunohistochemical analysis and the left hemisphere was macro‐dissected to retrieve the hippocampus and the cortex which were fractionated into nuclei‐ and synaptosome enriched as well as synaptosome‐depleted tissue fractions using an established differential centrifugation protocol. Tissue fractions were used for western blotting assessment of various markers relevant to insulin signalling, glucose uptake, synaptic integrity and neuroinflammation.

Result

Initial results from the immunohistochemical analysis of the cortex reveal near‐abolished levels of the microglial marker IBA1 (model effect) and increased accumulation of reactive astrocytes around blood vessels in FRGN mice compared to WT mice. The GFAP signals were slightly reduced in FRGN mice with humanized livers. Both observations were unrelated to the HFD.

Conclusion

Initial results from our immunohistochemical evaluation of the cortex suggest a model‐specific decrease in microglial cells in the FRGN mice, and modest changes in the presence of astrocytes in FRGN mice with humanized livers that appeared unaffected by a HFD. References: (1) Burns, C.M., et al.,Neurology, 2013. 80(17): p. 1557‐64. (2) Baker, L.D., et al., Arch Neurol, 2011. 68(1): p. 51‐7. (3) Kothari, V., et al., Biochim Biophys Acta Mol Basis Dis, 2017. 1863(2): p. 499‐508. (4) Ellis, E.C., et al., PLoS One, 2013. 8(11): p. e78550.
Soccer heading and cognitive performance in professional soccer players: One‐year longitudinal data
Authors: Caramelli Paulo , Lima Mariana D. M. , Palma Giovanni B. , Furtado Celso , Lasmar Rodrigo P. , Rodrigues Ana Carolina O.
Published: December 2020

Background

Soccer is the most popular sport worldwide and the only sport in which participants purposely hit the ball with their head. Although researchers have focused on the effects of concussions in contact sports, the role of sub‐concussive impacts (e.g. heading), has gained attention. The aim of this ongoing longitudinal study is to investigate the effects of soccer heading on cognitive functioning in active soccer players.

Method

Male professional soccer players (n=22), from two teams playing in the Brazilian championship, and non‐athletes (n=37), matched by age and education, were submitted to computerized (E‐Prime software) and conventional (NEUPSILIN battery) cognitive assessment. All subjects were tested on two occasions – T0 and T1 – separated by a one‐year interval.

Result

In T0, players performed better than controls on three variables of computerized testing – reaction time and accuracy in executive functioning tests – and on two variables of NEUPSILIN battery – scores in memory and arithmetic abilities tests. In T1, soccer players outperformed controls on three variables of the computerized testing – reaction time in general motor coordination test and accuracy in executive functioning tests – and on one variable of the NEUPSILIN battery – score in arithmetic abilities test. Intragroup analyses revealed that while controls improved their performance on three variables from T0 to T1 – reaction time in attention test, accuracy in executive functioning test and score in memory test – no improvement was observed among soccer players. However, a comparison involving variation in performance between T0 and T1 showed no significant differences between groups. Among soccer players, no significant correlations were found between self‐reported number of headings per game and cognitive performance in T0 and T1, controlling for concussion history.

Conclusion

There was no evidence of cognitive impairment in soccer players, compared to non‐athletes, in T0 and T1. Soccer players even outperformed controls on some tests. The change in cognitive performance from T0 to T1 was similar between groups. Moreover, estimate of exposure to heading did not correlate with performance of soccer players in tests. Further longitudinal investigations are needed to clarify the relationship between soccer heading and cognition.
Frequency of familial Alzheimer’s disease gene mutations within the Alzheimer Disease Sequencing Project (ADSP)
Authors: Scalici Alexandra , Peloso Gina M. , Wang Yanbing , Lin Honghuang , Sarnowski Chloé , Pitsillides Achilleas N. , Dupuis Josée , Seshadri Sudha , Destefano Anita L. ,   CHARGE ADSP FUS Group
Published: December 2020

Background

Mutations within the amyloid precursor protein (APP), presenilin‐1 (PSEN1), and presenilin‐2 (PSEN2) genes are known to cause familial Alzheimer’s disease (AD). Our goal is to examine the distribution of clinical variants in these genes within the ethnically diverse participants in the Alzheimer Disease Sequencing Project (ADSP) whole genome sequence (N = 4789) and whole exome sequencing (N = 20,158) data.

Method

We aggregated mutations reported in APP, PSEN1, and PSEN2 from the Alzheimer’s disease and Frontotemporal Dementia Mutation Database, ClinVar, and the Online Mendelian Inheritance in Man, and selected rare variants (minor allele frequency < 1%) described as pathogenic and related to AD or dementia yielding 304 variants (53 in APP, 233 in PSEN1, 18 in PSEN2). We counted the presence of these clinically implicated variants in the currently available ADSP data.

Result

Among 22,558 ADSP subjects passing quality control filters we observed 16 PSEN1, 5 PSEN2 and 6 APP variants. We identified 48 individuals (13 controls, 30 AD cases, 5 missing AD diagnosis) that were heterozygous for one of these variants. An additional AD case was a compound heterozygote for two APP variants. Out of the total sample, 0.06% of African Americans (AA), 0.21% of whites (non‐Hispanic white or white with ethnicity unknown), and 0.33% of Hispanics (HI) were carriers. In contrast, AA, white, and HI represented 21%, 63%, and 15% of the sample, respectively. The carriers included two pairs of second‐degree relatives: one Hispanic pair and one pair consisting of one Hispanic and one white/ethnicity unknown individual.

Conclusion

A reported mutation in APP, PSEN1 or PSEN2 was observed in 0.22% of ADSP participants, with the lowest carrier rate in AA. Studies in other diseases indicate that disparities in inclusion in genomic sequencing may result in misclassification or higher rate of uncertain significance for patients in underrepresented populations (e.g. Manrai et.al. 2016, Spratt et.al. 2016). It is unknown if the current difference in observed carrier rate by ancestry reflects study design, a true difference in frequency of AD causal APP, PSEN1, and PSEN2 mutations across populations, or limitations in identified pathogenic mutations due to populations historically included in genetic studies of AD.
A preliminary assessment of longitudinal amyloid status in the ongoing open‐label extension phase in subjects with early Alzheimer’s disease
Authors: Swanson Chad J. , Zhang Yong , Dhadda Shobha , Wang Jinping , Kaplow June , Bradley Heather , Rabe Martin , Lai Robert Y.K. , Gordon Robert , Kramer Lynn D.
Published: December 2020

Background

BAN2401 is a humanized IgG1 monoclonal antibody that selectively binds large soluble Aβ aggregates over monomers and fibrils. We have previously shown that amyloid reduction over 18 months of BAN2401 treatment at 10 mg/kg‐biweekly persists at baseline in an open label extension (OLE) following long‐term withdrawal from BAN2401. Here, we present preliminary data on the early longitudinal effects of BAN2401 on brain amyloid in the OLE of BAN2401‐G000‐201.

Methods

Subjects who fulfilled OLE inclusion/exclusion criteria were eligible. Amyloid positivity was required at baseline of the core Phase 2 study. Amyloid PET status was determined by visual read using an identical approach to that conducted at baseline in the core. The OLE was initiated after analysis of the core study showed clinical potential for BAN2401, thus, individuals were off drug for variable periods of time prior to entering the OLE. All subjects received 10 mg/kg biweekly in the OLE. Data for longitudinal PET standard uptake value ratio (SUVr) were collected in subjects at either 3mo and 6mo assessment. Piecewise regression was used to predict change from OLE baseline over 6mo.

Results

A total of 105 subjects from the core study have undergone an amyloid PET at OLE baseline with florbetatpir (mean duration off drug: ∼24mo; min=9.2mo; max=59.7mo). OLE baseline SUVr for those with longitudinal OLE assessments in the core phase for placebo, 10mg/kg‐monthly, and 10mg/kg‐biweekly were 1.46 (N=5), 1.21 (N=7), and 1.09 (N=8), respectively. Mean PET SUVr change from OLE baseline at 6mo was ‐0.26 (N=5), ‐0.09 (N=7), and ‐0.01 (N=8), with predicted slopes for 6 mo change of ‐0.042, ‐0.012, and ‐0.005 for subjects treated in the core phase with placebo, 10mg/kg‐monthly, and 10mg/kg‐biweekly, respectively. Three (3) of 5 subjects in the core placebo group became amyloid negative by visual read at 3mo treatment in OLE, with 5/5 subjects amyloid negative at 6mo.

Conclusions

In this preliminary analysis, 10 mg/kg‐biweekly BAN2401‐mediated amyloid reduction in the OLE was dependent on core treatment/SUVr at OLE baseline, and was apparent by 3mo with amyloid negativity achieved at 6mo (visual read) in placebo‐treated subjects from the core. Updated data will be presented as available.
Quantitative susceptibility mapping of substantia nigra in dementia with Lewy bodies
Authors: Chen Qin , Boeve Bradley F. , Arani Arvin , Senjem Matthew L. , Jack Clifford R. , Przybelski Scott A. , Lesnick Timothy G. , Fields Julie A. , Schwarz Christopher G. , Gunter Jeffrey L. , Graff‐Radford Jonathan , Savica Rodolfo , Knopman David S. , Ferman Tanis J. , Graff‐Radford Neill R. , Petersen Ronald C. , Kantarci Kejal
Published: December 2020

Background

Neurodegeneration of the substantia nigra in dementia with Lewy bodies is associated with iron deposition, which increases the magnetic susceptibility of the substantia nigra on MRI. The objective of this study was to measure the magnetic susceptibility of the substantia nigra in patients with dementia with Lewy bodies (DLB) and patients with mild cognitive impairment with at least one core feature of DLB (MCI‐DLB) compared to cognitively unimpaired controls (CU) by quantitative susceptibility mapping (QSM).

Method

We studied clinically diagnosed patients with DLB (n=36), patients with MCI‐DLB (n=16), and age‐, gender‐matched CU (n=104) in a case‐control study. MR images used for QSM were performed on 3T MRI with a multi‐echo (5 echoes) 3D gradient recalled echo sequence with a bipolar‐readout. Three‐dimensional regions of interest (ROIs) of bilateral substantia nigra, based on the DISTAL atlas, were propagated from the Mayo Clinic Adult Lifespan Template (MCALT) to each subject’s T1 image using ANTs nonlinear registration. The mean susceptibility values of the substantia nigra were extracted by aligning each subjects QSM image to their T1 image and corresponding ROIs with a 6 DOF rigid registration.

Result

The mean susceptibility values of the substantia nigra bilaterally was 0.110 ± 0.026 for DLB, 0.099 ± 0.028 for MCI‐DLB and 0.091 ± 0.025 for controls (Figure 1). No difference was found across the mean susceptibility from left, right and combined bilateral substantia nigra. Compared to controls, patients with DLB had higher susceptibility in the substantia nigra (p<0.001). The susceptibility of substantia nigra showed an increasing trend from controls to MCI‐DLB and to DLB (p<0.001). There was no correlation between the Unified Parkinson's Disease Rating Scale (UPDRS) and the mean susceptibility in the substantia nigra in patients with MCI‐DLB and DLB (r=0.03; p=0.82).

Conclusion

Quantitative susceptibility mapping is sensitive to the increased magnetic susceptibility due to higher iron content in the substantia nigra in DLB. The trend of increasing susceptibility from CU to MCI‐DLB and to DLB suggests that iron deposition in the substantia nigra starts to increase as early as the prodromal stage in DLB and continues to increase as the disease progresses independent of the severity of Parkinsonism.
Computer device and phone utilization trends among a cohort of older adults
Authors: Bouranis Nicole , Gothard Sarah , Mattek Nora , Kaye Jeffrey
Published: December 2020

Background

Surveys assessing rates of technology adaptation among older adults are cross‐sectional in nature, but few studies assess usage among a single older adult cohort. This study analyzes rates of computer device utilization among community‐dwelling older adults age 62 and older who are enrolled in longitudinal technology studies at the Oregon Center for Aging and Technology in Portland, Oregon.

Method

We reviewed four years of data (2016‐2019) from a cohort of 113 community‐dwelling individuals age 62 and older and two years of data (2018‐2019) for 158 community‐dwelling low‐income individuals, veterans and spouses of veterans age 62 and older enrolled in a different study. We identified trends in computer device and phone ownership and utilization. Basic descriptive statistics were analyzed.

Result

Among the first cohort there was an increase in the percentage of older adults who own multiple devices (59.7%, up from 37.2%) and a decrease of those who use a desktop computer as their primary device (16.9%, down from 45.2%) between 2016 and 2019. The percentage of participants who own a landline decreased (75.3%, down from 86.7%) while those who own a cell phone increased (84.4%, up from 71.7%). The percentage of participants who do not use a cell phone decreased (8.3%, down from 24.8%). There was an increase in the percentage of participants who own a cell phone with internet access (64.1%, up from 48.1%) and text messaging capabilities (64.1%, up from 43.2%). Among the second cohort, the percentage of people who use desktops, laptop, and smartphones remained constant, but there was an increase in tablet users (37.3%, up from 21.5%) between 2018 and 2019.

Conclusion

These findings indicate a shift from using landlines and desktop computers and an increase in the use of smartphones and tablets among older adults. The majority of older adults own multiple devices and use mobile devices. These findings have implications for communication styles, application development and data collection in studies that analyze computer usage among older adults. Future analyses will include data from the 2020 survey and identify and compare trends among demographic groups, including age, gender, locality, veteran status, and socioeconomic status.
Diesel exhaust particle role on gut microbiome and onset of Alzheimer disease neuroinflammation
Authors: Naughton Sean X , Westfall Susan , Pasinetti Giulio Maria
Published: December 2020

Background

Recent evidence has emerged to show that diesel exhaust particulate (DEP) pollution can double the risk of getting dementia. Evidence suggest that exposure to high levels of air pollution are significantly more likely to develop dementia‐related diseases including Alzheimer’s disease. DEP is primarily composed of polycyclic aromatic hydrocarbons (PAHs) and nitro‐substituted polycyclic aromatic hydrocarbons (n‐PAHs). PAHs have previously been shown to undergo biotransformation through interactions with human colonic microbiota. The goal of the present study is to determine if DEP may influence selective gut microbiota. We will eventually identify gut‐brain‐axis mechanisms associated with DEP mediated neuroinflammatory mechanisms through microbiota dysbiosis.

Method

Using an in vitro model of the human gastrointestinal tract, EBIOME, we are exploring the human gut bacteria exposed to various concentrations of diesel exhaust particulate matter. Bacterial species were quantified over an extended time‐course to monitor log‐scale changes in colony survival and growth. In order to obtain higher resolution of gut microbiome species meta‐genomic analysis will be also conducted.

Result

The current studies have identified concentration dependent changes in microbiome biodiversity. Through ongoing analysis, it is anticipated that altered biodiversity will lead to decreases in the production of brain penetrant metabolites, such as short‐chain fatty acids including butyrate, acetate, and propionate.

Conclusion

Our studies provide novel information regarding the role of the gut‐brain‐axis in neuroinflammation in Alzheimer’s disease and other forms of dementia.
Benefits of a novel highly bioavailable resveratrol formulation, JOTROL, for Alzheimer’s disease
Authors: Volmar Claude‐Henry , Dennison Jessica , Ricciardi Natalie R. , Janczura Karolina J. , Walker Brittni R. , Brown Jonathan M. , Stahl Jack , Hayward Marshall A. , Brothers Shaun P. , Wahlestedt Claes
Published: December 2020

Background

With the recent Alzheimer’s disease (AD) clinical trial shortcomings, we and colleagues agree that an epigenetic approach is needed to address the polygenicity of AD. Recently, a randomized clinical trial with the SIRT1 activator resveratrol (3,5,4’‐trihydroxy‐trans‐stilbene) has shown positive effects in AD patients (Turner et al., 2015; Moussa et al., 2017). However, the high dose needed due to low bioavailability has been reported to cause a GI side effect. To increase bioavailability, JOTROL, a new oral formulation of resveratrol that shows significantly better pharmacokinetic properties than non‐formulated resveratrol, was manufactured by Jupiter Orphan Therapeutics. We hypothesize that equimolar concentrations of JOTROL, compared to non‐formulated resveratrol, will result in greater brain exposure to resveratrol and more efficacious responses on AD biomarkers, allowing for a reduction in dose regimen.

Methods

For acute studies, Sprague Dawley rats or C57B6 mice (n = 3/treatment) were administered a single oral dose of 50 mg/kg JOTROL 30 minutes prior to being euthanized. Blood, buffy coat and brains were harvested. For AD‐related studies, 15‐month‐old male triple‐transgenic (APPSW/PS1M146V/TauP301L; 3xTg‐AD) AD mice were treated by daily oral gavage with 50 mg/kg JOTROL (n = 5) or vehicle (n = 5) for 36 days. Animals were euthanized after behavior tests. The expression of AD‐related genes and proteins in brain, liver and spleen were analyzed using RT‐qPCR, Western blots and ELISAs. Effects on mitochondrial biogenesis were also investigated.

Results

JOTROL (50 mg/kg) increases brain and plasma resveratrol bioavailability in animals, significantly increases both SIRT1 (P<0.0001) and α‐secretase ADAM10 (P<0.0001) gene expression in rat brain, but significantly decreases Tau gene expression (P<0.05). 36‐day treatment of 3xTg‐AD mice with 50 mg/kg JOTROL decreases expression of IL6 (P<0.001 in liver, P<0.05 in spleen) and TNFα (P<0.001 in liver and P<0.01 in spleen), concurrent with a marked decrease of splenomegaly. Increased mitochondrial biogenesis is also observed in the brain (P<0.05) and in the liver (P<0.05) of these mice.

Conclusions

JOTROL has a strong anti‐inflammatory effect in the brain and peripheral organs, promotes non‐amyloidogenic processing of the amyloid precursor protein and increases mitochondrial biogenesis. Further investigation is underway to determine prophylactic effects of JOTROL for AD pathogenesis.
Transcription of nicotinic acetylcholine receptor A7 in monocytic and patient‐derived microglial cell lines
Authors: Torsetnes Silje Bøen , Nordengen Kaja , Wettergreen Marianne , Gisladottir Berglind , Sharma Kulbhushan , Larsen Laila Norrheim , Glover Joel , Christensen Erik , Jaenisch Rudolf , Fladby Tormod
Published: December 2020

Background

Innate immune genetics contribute to Alzheimer’s disease (AD) risk. Innate immune cholinergic activation is implicated in CNS immune regulation, and nicotinic acetylcholine receptor α7 (CHRNA7) activation may alleviate macrophage/monocyte and microglial inflammatory activation. Functional CHRNA7 (“N”) gene‐expression is negatively regulated by transcription or expression of the CHRFAM7‐gene (“M”), which is a uniquely human gene composed of elements from the N genes and FAM7 genes giving rise to truncated and altered α7 N subunits. As polyunsaturated fatty acids are proposed to ameliorate inflammation we hypothesized that docosahexaenoic acid (DHA) in combination with agents for nicotinic activation (positive allosteric modulators; PAMs) might influence N/M transcription patterns.

Method

We investigated the N and M transcription in two innate immune cell models; the human acute monocytic leukemia cell line THP‐1 and AD patient‐derived iPSC microglial cells. The patient‐derived iPSC microglial cells were differentiated according to the Douvaras‐protocol (Douvaras, 2017), and showed ramified morphology, motile processes, the ability to phagocytose amyloid beta (Aβ) 42 and presence of the microglial markers P2Y12, PU.1 and TMEM119. THP‐1 cells were differentiated to macrophages by a 48h treatment of 100 nM TPA (12‐O‐tetradecanoylphorbol‐13‐acetate). The THP‐1 cells were also used for intervention stimulation experiments, and treated with DHA, Aβ40, in addition to type I and type II PAMs and in combinations (see Figure 1). QPCR was performed on the intervention samples after preamplification. Absolute quantification was performed using M and N synthetic oligonucleotides standards. All samples were ran in triplicates.

Result

Roughly similar levels of transcription of both N and M genes are found in both unstimulated microglia and monocytes. However, the stimulation experiments imply that N/M transcription ratio may be altered by intervention through an observed relative increase of N/M by DHA stimulation (N/M ratio>1.2), and a larger increase when combining DHA with either or both Aβ40 and the PAMs (N/M ratios>1.4, see figure).

Conclusion

We show that CHRNA7 and CHRFAM7A subclasses are transcribed in monocytes and patient‐derived iPSC microglia in comparable amounts, and that CHRNA7/CHRFAM7A ratio transcription can be modified by combining DHA with a7‐PAMs. Putatively, this mechanism may be a therapeutically effective way to ameliorate CNS inflammation.
Synbiotic‐derived metabolites reduce neuroinflammatory symptoms of Alzheimer’s disease
Authors: Smith Chad
Published: December 2020

Background

Alzheimer’s disease (AD) is a multifaceted disorder and recent advancements suggest that the gut microbiota and its metabolites play a critical role in the progression and potential treatment of AD. Synbiotics, the combination of probiotics and prebiotics, can be designed to produce specific bioavailable metabolites that penetrate the blood‐brain‐barrier and actively reduce the neuropathologies associated with AD. Recently, we designed an in vitro model of the human gastrointestinal tract that can be used to optimize the production of metabolites from synbiotic formulations using machine learning algorithms that can then be tested in animal models of AD. The objective of this study is to optimize and characterize a synbiotic’s metabolite production using an in vitro bioreactor that could be used as a therapeutic tool against AD. We hypothesize that a synbiotic designed towards the production of specific brain‐bioactive metabolites will synergistically mitigate the neuro‐ and systemic‐pathologies associated with AD.

Method

Using the in vitro model of the human gastrointestinal tract, we have used this optimized combination of polyphenols and tested 15 combinations of 6 probiotic bacteria as a synbiotic to optimize metabolite production using a multivariate regression algorithm (MARS) and found that three probiotic bacteria, Lactobacillus plantarum, Bifidobacterium infantis and L. salivarius together synergistically improve the production of brain bioavailable metabolites including quercetin, kamferin, 4‐hydroxyphenylpyruvic acid and 4‐hydroxyphenylacetic acid.

Result

We have found that two polyphenolic metabolites 3‐hydroxybenzoic acid and 3‐(3’‐hydroxyphenyl) propionic acid derived from a grapeseed polyphenolic extract (GSPE) can penetrate the blood‐brain‐barrier and in vitro,inhibit the aggregation of amyloid plaques and tau fibrils. By increasing the diversity of the polyphenolic pool by adding a concord grape extract and resveratrol to the GSPE, we provided greater protection against cognitive impairment and amyloid aggregation in an AD mouse model than the components alone.

Conclusion

While bioavailability studies have shown that these metabolites cross the blood‐brain‐barrier, in vitro studies have confirmed that these metabolites have potent anti‐inflammatory activity. This synbiotic combining potent grape‐derived polyphenolic precursors with bioactive probiotic bacteria has the potential to slow the progression and treat AD by synergistically targeting multiple of its neuropathologies including inflammation, amyloid aggregation and tau fibril formation.