bluuebunny/crossref_metadata_2025 huggingface dataset:
Elevated plasma neurofilament light (NfL) is associated with incident Alzheimer’s disease and accelerated cognitive decline in adults with Down syndrome
Authors: Dang Lam‐Ha T. , Krinsky‐McHale Sharon J. , O'Bryant Sid , Pang Deborah , Zigman Warren B , Silverman Wayne , Schupf Nicole , Lee Joseph H.
Published: December 2020

Background

The value of plasma neurofilament light (NfL), a marker of neurodegeneration, in Alzheimer’s Disease (AD) has been reported in the general population. However, evidence for NfL as a predictive marker of neurodegeneration in adults with Down Syndrome (DS) is limited. The small number of longitudinal studies have short follow‐up periods. Thus, the value of NfL as a prognostic indicator of AD is still unknown. To date, no study has examined whether levels of NfL predict the trajectories of cognitive decline in adults with DS. In this study, we will examine the association of NfL with incident AD and trajectories of cognitive decline.

Method

We studied 271 adults with DS who were dementia‐free at the baseline and were assessed at 14‐ to 18‐month intervals for up to 5‐cycles. Baseline plasma NfL was measured using the Simoa platform. Neuropsychological tests assessing various cognitive domains were administered at each follow‐up visit and AD status was determined by consensus diagnosis. Cox proportional hazards models were used to assess the association between baseline NfL and incident AD. Linear mixed modeling was used to evaluate the relations between NfL and changes in neuropsychological measures over time. Estimates were adjusted for age at blood collection, sex, presence of APOE ε4 allele, and level of premorbid intellectual functioning.

Result

Over the follow‐up period, 54 (21%) individuals developed AD with the mean follow‐up of 4.7 years. Elevated plasma NfL levels were significantly associated with incident dementia (p < 0.001); the risk of AD increases by 34% per 10 pg/mL increase in NfL. Participants who were in the highest quartile of NfL (41‐120 pg/mL) were 8 times (95% CI: 2.5‐25.3) more likely to develop AD, compared to those in the lowest quartile. Moreover, elevated NfL levels were significantly associated with faster declines in various neuropsychological domains (i.e., mental status, episodic memory, visuospatial organization), but not verbal fluency and construction.

Conclusion

Elevated baseline plasma NfL is a prognostic marker of accelerated cognitive decline and subsequent incident dementia in adults with DS. Our findings suggest that NfL may have utility for use in routine disease monitoring and clinical trial screening.
Prevalent skin cancer and conservative faith may be linked with cognitive impairment in Ashkenazi Jewish exceptionally long‐lived individuals
Authors: Rivkin Elina , Weinstein Galit , Barzilai Nir , Atzmon Gil
Published: December 2020

Background

Exceptional long‐lived individuals (ELLI) are known for their improved health status and independence regardless of life‐style and health behaviors. Yet, little is known about their cognitive function correlates. The aim of the present study was to assess the correlation between social, clinical, behavioral and personality factors and cognitive impairment in a sample of Ashkenazi Jews (AJ) ELLIs.

Method

The study sample included 401 AJ participants, aged 95 years or older, of the Longevity Genes Project at Einstein, who were residents of the northeastern United States and lived independently in the community. Socio‐demographic, medical history data and life‐style factors were collected via mailed questionnaires, telephone calls, or in‐person visits. Personality was assessed through the Personality Outlook Profile Scale. In the event that participants had difficulty responding to questions in a reliable manner, their children or legal guardian assisted them. Cognitive status was assessed using the Mini Mental State Exam (MMSE) with a score of 24 or lower considered as cognitive impairment. Cross‐sectional associations of medical, social, life‐style and personality characteristics with odds for cognitive impairment were assessed using logistic regression models while adjusting for potential confounders.

Result

Of the total sample (mean age=97.72.8 years, 84% women), 178 (44%) were cognitively impaired. Following adjustment for age, sex and education, prevalent skin cancer (OR, 95% CI: 0.40, 0.22‐0.74) as well as being conservative religious (OR, 95% CI: 0.18, 0.03‐0.97) and attending temple in Holidays only (OR, 95% CI=0.25, 0.07‐0.88) and weekly (OR, 95% CI: 0.25, 0.06‐0.97) at age ∼70 years were associated with lower odds for cognitive impairment.

Conclusion

Cognitive impairment correlates in ELLI may differ from those in the general population. Future studies are warranted to explore the role of religious involvement in brain aging. Furthermore, the strong link between a history of skin cancer and cognition in the oldest‐old should be examined.
Assessing the relationship between cognitive dysfunction and brain atrophy in Alzheimer's disease
Authors: Edison Paul , Femminella Grazia Daniela , Nowell Joseph , Raza Sanara , Livingston Nicholas R , Blunt Eleanor G , Carver Stefan , Holmes Clive , Ritchie Craig W , Lawrence Robert M , McFarlane Brady , Tadros George , Ridha Basil H , Bannister Carol , Walker Zuzana , Archer Hilary , Coulthard Elizabeth , Underwood Ben , Prasanna Aparna , Koranteng Paul , Karim Salman , Junaid Kehinde , McGuinness Bernadette , Nilforooshan Ramin , Macharouthu Ajayverma , Donaldson Andrew , Thacker Simon , Russell Gregor , Malik Naghma , Mate Vandana , Knight Lucy , Kshemendran Sajeev , Harrison John E , Brooks David J , Passmore Anthony Peter , Ballard Clive
Published: December 2020

Background

Brain atrophy can be reliably measured through volumetric analysis of structural MRI and is a valid biomarker of neurodegeneration in Alzheimer’s disease (AD) pathology1. The Alzheimer’s Disease Assessment Scale‐Cognitive subscale (ADAS‐Cog12) is a neuropsychological test designed to assess the level of cognitive dysfunction in AD within cognitive domains such as memory2. This study aimed to assess the relationship between brain atrophy and ADAS‐Cog12 score in patients with AD.

Methods

172 patients with mild‐to‐moderate Alzheimer’s disease (Age range 51‐58, Mean=71, SD=+/‐8) underwent a T1‐weighted MPRAGE MRI scan and neuropsychological testing using the ADAS‐Cog12. Volumetric MRI measures extracted using Freesurfer for the hippocampus, medial temporal lobe, temporal lobe and total grey matter were individually correlated with each patient’s ADAS‐Cog12 score using Pearson’s correlation coefficient following removal of outliers in each data set (+/‐ 2SD from the mean).

Results

Increasing ADAS‐Cog12 score was significantly correlated with decreasing volume of the hippocampus (r=‐0.280, p<0.001), medial temporal lobe (r=‐0.246, p=0.001), temporal lobe (r=‐0.300, p<0.001) and total grey matter (r=‐0.236, p=0.002).

Conclusions

This study demonstrated that the ADAS‐Cog12 correlated with AD‐related regional brain atrophy, suggesting that ADAS‐Cog could be used as an outcome measure in AD trials and reflects underlying neuronal damage along with cognitive function.
Olfaction, the ‘Olfactory Stress Test’ and correlates in a sample of elders
Authors: Bukajumbe Emmanuel , Attia John , McEvoy Mark , Jones Alison L , Schofield Peter W.
Published: December 2020

Background

Previously, we investigated the potential of an atropine challenge procedure (‘the Olfactory Stress Test’ (OST)) to detect early AD. Olfaction was tested with 20 items of the University of Pennsylvania Smell Identification test (UPSIT)) before, and with the remaining 20 items after, a unilateral intranasal spray of atropine. In that small study of individuals with normal cognition, cognitive impairment and probable AD, the change in olfaction after atropine (the ‘atropine effect’ (AE)) was significantly correlated with cognition, hippocampal volume and ApoE‐ε4 allele status. In the present study, we administered the OST to a larger sample of mainly cognitively normal elders.

Method

295 community‐dwelling elders (mean age of 72.63, SD=5.81 years) underwent olfactory testing as described above. Participants were administered the Audio Recorded Cognitive Screen (ARCS)), the Hyposmia Rating Scale (HRS), were genotyped for APOE, and a subsample underwent brain MRI. Linear regression analyses were undertaken seeking associations of olfactory measures, or the HRS, with cognition, hippocampal volume and APOE genotype.

Result

Mean post atropine UPSIT scores were lower than pre‐atropine UPSIT scores (‘preup’) (Student’s paired t‐test = 9.155, p<0.001). After controlling for sociodemographic and health factors, preup and AE were associated with ARCS (β=1.225 (0.621 – 1.889, p<0.001) and β = ‐0.598 (‐8.731 – ‐0.172, p=0.095)), respectively. Compared to preup scores ≥15, scores <15 were associated with a mean ARCS less by 6.509 (β = ‐6.509 (‐10.805 – ‐2.212, p=0.003)). Using a dichotomised AE, AE≥0 was associated with mean ARCS score less than AE<0 by 4.452 (β = ‐4.452 (‐8.731 – ‐0.172, p=0.042)). Preup (but not AE or HRS) was associated with hippocampal volume. HRS was negatively associated with ARCS (β = ‐0.672 (‐1.238 – ‐0.106, p=0.020)). None of the predictors were associated with APOE genotype.

Conclusion

This study confirms previously reported associations of conventional olfaction tests with cognition. By contrast with our previous study, olfactory score change after atropine was more weakly, and negatively, associated with cognition. The current study failed to replicate our previous findings.
Effects of levetiracetam treatment on cognitive and noncognitive impairments in a mouse model of tauopathy
Authors: Joly‐Amado Aurélie , Novoa Michelle , Alvarez Luis , Chan Deanna , Paek Hyeonji , Willman Jonathan , Willman Matthew , Nash Kevin
Published: December 2020

Background

Alzheimer’s disease (AD) is characterized clinically by progressive cognitive decline, eventually resulting in death, usually within 10 years of diagnosis. Abnormal tau hyperphosphorylation and its accumulation into neurofibrillary tangles are linked to neurodegeneration in Alzheimer’s disease and similar tauopathies. Aberrant motor behaviors such as pacing/wandering are common in AD. Some AD cases have metabolic changes resulting in weight loss in spite of increased food consumption. Tg4510 mice are characterized by tau deposition in the brain together with cognitive and non‐cognitive impairments that resemble those seen in patients. Leviteracetam is an FDA approved drug that has shown cognitive improvements in mice models of amyloid deposition. The aim of this study was to test the effects of a Leviteracetam diet on cognitive and non‐cognitive impairments in a mouse model of tauopathy, the Tg4510 mice.

Method

Three‐month old Tg4510 transgenic and non‐transgenic littermate mice were equally randomly assigned to treated (food containing 240mg/kg Levetiracetam) or placebo (normal diet) groups (n=10, 5F & 5M). All mice were single housed, and food intake and mice body weight were recorded once a week for 3 months. During the last 2 weeks before tissue collection the following behavioral tests were performed: open field, Y‐maze, marble burying, RAWM with reversal, rotarod, novel object recognition (NOR) and fear conditioning. On the last day, the brain was dissected, blood sample was collected, and muscle mass, white fat, and brown fat were weighed.

Result

Treatment with Leviteracetam did not improve cognition or activity in Tg4510 during RAWM, open field, and fear conditioning tests. Although Leviteracetam improved performance during rotarod and reduced body weight in non‐transgenic littermates, such effects were not seen in Tg4510 mice.

Conclusion

There were no significant improvements in cognitive and non‐cognitive deficits in Tg4510 mice treated with Levetiracetam. Interestingly, Leviteracetam diet resulted in a decrease in body weight together with improvement in rotarod in non‐transgenic littermates when compared to chow diet, whereas no effects were observed in Tg4510 mice treated with leviteracetam. Biochemical and histochemical analysis will be performed in brain tissue to know if treatment with Levetiracetam had an effect on tau pathology.
The relation between accelerometer‐derived physical activity and brain structure: Findings from the Rhineland Study
Authors: Fox Fabienne A.U. , Reuter Martin , Breteler Monique M.B. , Aziz N. Ahmad
Published: December 2020

Background

Physical activity is associated with a reduced risk of dementia. Although physical activity induces potent neuroprotective effects in animals, human studies assessing its effects on brain structure are sparse and inconclusive. The discrepancies in human studies may have been due to application of subjective physical activity measures, low spatial‐resolution imaging or small sample sizes. Therefore, we aimed to assess whether objectively quantified physical activity levels are associated with detailed measures of brain structure in a large cohort study.

Method

Our analyses were based on data of the first 4,000 participants (56.6% female, mean age: 55.2 years (range 30 – 95 years)) of the Rhineland Study, a population‐based prospective cohort study in Bonn, Germany. Free‐living physical activity over seven days was continuously measured using the ActivPAL™ accelerometer. Average daily physical activity measures included metabolic equivalent (MET)‐hours, total step count, as well as minutes spent stepping or performing light and moderate‐to‐vigorous physical activities. Grey matter (GM), white matter (WM) and total brain volume (TBV) estimates were obtained from 3T MRI scans using FreeSurfer. Multivariable regression models were used to examine the association between physical activity and brain structure, with physical activity levels as independent and brain structure measures as dependent variables, while adjusting for age, sex, intracranial volume, education and smoking status.

Result

Daily MET‐hours were associated with all volumetric measures of brain structure (effect estimates [in cm3/hour] for TBV: ß=2.36, 95% CI: 1.05 – 3.67; GM: ß=0.82, 95% CI: 0.15 – 1.50; WM: ß=0.97, 95% CI: 0.08 – 1.85). Importantly, we found a significant interaction between the effects of MET‐hours and age on TBV: in participants below median age the effect of MET‐hours on TBV was 0.28 cm3/hour (95% CI: ‐1.40 – 1.97), while in those above median age the effect was 2.01 cm3/hour (95% CI: 0.08–3.94). Overall, we obtained comparable findings for other physical activity measures as well (data not shown).

Conclusion

Physical activity was consistently associated with grey matter, white matter and total brain volumes in a large cohort of individuals from the general population. These findings suggest that promoting physical activity could be critical in the prevention of age‐associated brain atrophy.
Predicting the time to tau onset in Down syndrome using amyloid chronicity
Authors: Zammit Matthew D , Laymon Charles M , Koscik Rebecca L. , Tudorascu Dana L , Betthauser Tobey J , Ellison Paul , Cohen Ann , Minhas Davneet S , Zaman Shahid , Ances Beau M , Mathis Chester , Johnson Sterling C. , Klunk William E , Handen Benjamin L , Christian Bradley T
Published: December 2020

Background

Adults with Down syndrome (DS) are predisposed to Alzheimer’s disease (AD) with the majority developing clinical dementia by their 60s. This study aims to estimate the time to tau onset in DS using the metric of Aβ chronicity (estimated duration of Aβ(+)) as a predictor.

Method

N=140 adults with DS (age=39.3±8.4 years) were evaluated for Aβ and tau using [C‐11]PiB and [F‐18]AV‐1451 PET, respectively. 50‐70 minute PiB SUVr and 80‐100 minute AV‐1451 SUVr images were created (cerebellar gray matter reference region). Longitudinal PiB scans were conducted for n=68 (3.0±0.7 scans; 2.4±0.6 years apart). The Amyloid Load (AβL), calculated from PiB SUVr images, indicates global Aβ burden. Group‐based trajectory modeling (GBTM) was applied across longitudinal AβL data to identify Aβ accumulation groups. The trajectories with the lowest BIC were solved to determine the estimated age of Aβ(+) onset (AβL cutoff: 20.0% (Zammit, DADM 2020)) and Aβ chronicity was calculated as chronological age minus estimated Aβ(+) age (Koscik and Betthauser, DADM 2020). Regional AV‐1451 SUVr values were extracted based on ROIs encompassing the Braak staging of NFT pathology. Preliminary thresholds for elevated tau (tau(+)) were determined for each Braak composite region using k‐means clustering with resampling. Linear regression models were performed between Aβ chronicity and AV‐1451 SUVr. The functional form of the regression fit was solved to estimate average Aβ(+) chronicity at tau(+) in each Braak region.

Result

GBTM identified two Aβ accumulator groups in our DS cohort with estimated ages of Aβ(+) onset of 32 and 49 years (Figure 1). Of the early accumulators, only n=2 carried the APOE E4 allele. Aβ chronicity and AV‐1451 SUVr displayed a linear relationship for Braak regions 1‐2, and a quadratic relationship for Braak regions 3‐6 (Figure 2). The pattern of tau deposition in DS followed the conventional Braak NFT staging observed in late‐onset AD. Estimated Aβ(+) chronicity at tau(+) onset increased as tau pathology progressed through each Braak stage (Table 1).

Conclusion

These preliminary findings reveal insight on the time course of tau deposition relative to Aβ in DS. Longitudinal AV‐1451 scans are currently underway to further refine the model and characterize tau progression in this population.
Characterization of mRNA isoform diversity in a transgenic model of tau pathology using targeted long‐read sequencing
Authors: Leung Szi Kay , Jeffries Aaron , Hannon Eilis , Castanho Isabel , Moore Karen , Murray Tracey K. , Ahmed Zeshan , Collier David A. , Mill Jonathan
Published: December 2020

Background

An increasing number of studies implicate a role for alternative splicing in the development and neuropathology of Alzheimer’s disease (AD). However, it has been historically challenging to characterise splicing events, due to the limitations of short‐read RNA‐sequencing (RNA‐Seq) for the capture full‐length transcripts critical for transcriptome assembly. In this study, we used Pacific Biosciences long‐read isoform sequencing (Iso‐Seq) to enrich and comprehensively characterise isoform diversity for AD‐associated genes in entorhinal cortex samples from a well‐validated AD transgenic mouse model.

Method

We used Pacific Biosciences Targeted Iso‐Seq to investigate splicing of 20 AD‐associated genes (including TREM2, BIN1, and APOE) in entorhinal cortex of a well‐characterised mouse model of tau pathology, rTg4510. Sequence data was processed using the Iso‐Seq3 pipeline, followed by downstream analysis using other publically available resources and customised scripts. The same samples have additionally been sequenced using whole transcriptome Iso‐Seq and RNA‐Seq as validation.

Result

We obtained deep sequencing coverage of full‐length transcripts for each of the AD genes, revealing complex usage of alternative start sites and splicing events, as well as many novel 5′starts and 3’ends not previously annotated in existing genomic datasets. We identified differential transcript expression and isoform usage between transgenic and wild‐type mice, with highly‐correlated gene expression between Iso‐Seq and short‐read RNA‐seq data.

Conclusion

This study highlights the application of long‐read sequencing approaches to assess splicing variation and isoform diversity in AD by selective gene enrichment. Results suggest differential splicing events associated with AD pathology, supporting a role for transcriptomic dysregulation in development of AD. Further work will be undertaken to characterise other AD‐associated genes, and to extend these analyses to human post‐mortem brain samples.
Change in 12‐month health care utilization patterns among persons living with dementia who received a comprehensive home‐based dementia care coordination program: Mind at home
Authors: Samus Quincy M , Amjad Halima , Huang Jin , Leoutsakos Jeannie‐Marie S , Lyketsos Constantine , Johnston Deirdre
Published: December 2020

Background

MIND at Home, a value‐based innovation, is a comprehensive, home‐based care coordination program for people with dementia and their carers to identify and address a broad set of health determinants to improve health, clinical outcomes, and reduce costs. We present pooled trial data evaluate change in 12‐month health care utilization patterns among a racially and cognitively diverse group of persons living with dementia who received MIND at Home.

Method

Pre‐post, adjusted Poisson regression models were used to evaluate health care utilization patterns for a pooled sample of persons with dementia receiving MIND at Home (n=391) in the 12 month period after enrollment in the program with the 12 month period prior to enrollment. Hospitalizations, ED visits, outpatient visits, home and community‐based services (HCBS) were ascertained via proxy‐report from carers.

Result

The mean number of hospital admissions decreased by 27% in the one year period after baseline (95% CI: 6%, 44%, p=0.01) compared with the year prior. Adjusted rates of one or more hospitalizations declined from 36.8% to 32.5%, with a crude rate reduction of 11.6% (unadjusted) between pre‐and post‐periods. Mean number of HCBS services used increased by 70% (95% CI: 54%, 88%, p<0.01) and mean number of outpatient specialties seen in the post period increased by 52% (95% CI: 43%, 62%, p<0.01) compared with the year before baseline. Average number of outpatient provider visits remained the same (p=0.76). Mean number of ER visits decreased by 16% (95% CI: ‐8%, 34%) but was not statistically significant (p=0.18).

Conclusion

Results provide compelling new quasi‐experimental data that supports the impact of the MIND at Home program on changing health care utilization patterns and is in line with our prior findings. Persons who received MIND at Home were less likely to use high cost acute health services (inpatient) and more likely to use more cost‐efficient services like home and community based services and physician services in the year after enrollment compared to the year prior. These data imply a potential cost benefit of the MIND at Home dementia care coordination program.
Development and implementation of a training program to facilitate community partnerships in the Indigenous Cultural Understandings of Alzheimer’s Disease and Related Dementias – Research and Engagement (ICARE) project
Authors: Blind Melissa J , Pitawanakwat Karen , Koski Jessica , Lambrou Nickolas H , Lemieux Andrine , Jacklin Kristen , Warry Wayne
Published: December 2020

Background

Indigenous Cultural‐understandings of Alzheimer’s – Research and Engagement (ICARE) is a program of research investigating the lived experiences of family and professional care providers for Indigenous people with dementia involving three diverse sites in Canada and the United States. We employ a community‐based participatory research (CBPR) approach that includes hiring Indigenous community‐based researchers to assist with community engagement, subject recruitment, data collection, analysis, and dissemination. This poster describes the development and deployment of a training program designed to build capacity and support community participation in the ICARE project.

Method

The goal was to design culturally safe training that would support community participation in the study, build research capacity in local community members, and improve standardization of protocols across the sites. The training objectives were to teach the basics of CBPR, administrative tasks, basics of qualitative research, protocols of the study, including research ethics and compliance. To accomplish this, we used a Two‐Eyed seeing approach and cultural safety lens. The training encompasses four modules, with online active and reflective learning, mandatory readings, and videotaped interviews. Five community researchers completed the training. Post‐training debriefing interviews and written review of lessons learned were conducted four months after the training was completed.

Result

At completion of the training, community researchers could define the key tenets and methodological procedures used in CBPR, including the unique ethical considerations for completing research related to dementia within Indigenous communities, the administrative duties required to produce reliable data, and demonstrate key qualitative research. Trainees reported the videotaped interviews conducted with a senior community were the most important to their learning, as the videos gave concrete examples of what to expect in conducting research within their own communities. They wished we had more content and videos on accessing and using the technology associated with the administrative tasks.

Conclusion

Hiring and training community‐based researchers is considered best practice in Indigenous Health research, yet there are few guidelines on how to develop local capacity to fill these roles. The ICARE training provided community‐based researchers with critical skills to facilitate community involvement in the research process and grounding in academic protocols and methods.
Diagnostic differentiation by NIH Toolbox‐Cognition (iPAD) for Alzheimer’s disease, mild cognitive impairment (MCI), and healthy control participants
Authors: Bhaumik Arijit K. , Reader Jonathan M. , Rahman‐Filipiak Annalise , Kairys Anson , Duda Bryant , Heidebrink Judith L. , Hampstead Benjamin M. , Paulson Henry L. , Giordani Bruno
Published: December 2020

Background

Age‐associated impairment among older adults is a significant public health concern. The NIH Toolbox for Assessment of Neurological and Behavioral Function® (NIHTB) was developed for use in studies for which standardized, computer‐based measurement of cognitive, motor, sensory, and behavioral processes is of importance. The NIH Toolbox–Cognition battery measures both crystallized and fluid cognitive functions. The goal of this study was to compare performance of the newly available tablet‐version of the Cognition battery across healthy and impaired older adults and to analyze if race and gender effects would be evident even when using NIHTB fully‐adjusted T‐scores.

Method

A total of 104 individuals (28 men, 56 women; 45% African American) completed the NIH Toolbox–Cognition as part of a National Alzheimer’s Disease Coordinating Center (NACC) longitudinal study of memory and aging through the Michigan Alzheimer’s Disease Research Center (Michigan ADRC). All participants received the Unified Data Set (UDS) and consensus diagnosis of normal cognition (NL), amnestic mild cognitive impairment (aMCI), or Alzheimer’s dementia (AD). Univariate analyses of variance with post‐hoc comparisons were used to compare fully adjusted (age, gender, race/ethnicity, education) Toolbox T‐Score performance across the groups.

Results

Univariate ANOVAs revealed significant findings for the Total and Fluid composites (both p<0.001) and Crystallized Composite (p<0.05). For Crystallized subtests, only Oral Reading demonstrated group differences, with NL>AD. Though NL and aMCI groups performed similarly, both groups outperformed AD on Dimensional Card Sort, Flanker, and Pattern Comparison Fluid subtests. NL>aMCI>AD on List Sorting Working Memory and Picture Sequence Memory. Main effects for race or gender were not seen for comparisons of NL to aMCI, but some group sizes were too small for adequate testing in the AD participants.

Conclusions

As expected, NL, aMCI, and AD demonstrated significant performance differences on NIH Toolbox—Cognition composite and scale scores. As expected, Crystallized tasks were least effective, traditionally representing cognitive areas least sensitive to neurologic dysfunction. Fluid tasks were noticeably more effective, with the working memory and learning measures showing a significant tiered difference, with NL highest and AD lowest. The fully adjusted scores were successful in accounting for demographic variables.
Distinct patterns of gray matter atrophy in hippocampal sclerosis of aging and Alzheimer’s disease neuropathology
Authors: Woodworth Davis C. , Scambray Kiana Alexis , Phelan Michael , Corrada Maria M.M. , Kawas Claudia H. , Sajjadi S. Ahmad
Published: December 2020

Background

Hippocampal sclerosis of aging (HS) and Alzheimer’s Disease Neuropathology (ADNP) both contribute to dementia in the elderly but are difficult to distinguish in vivo. Currently, there are no established biomarkers for HS, and few studies have investigated the distinction between HS‐ and ADNP‐related patterns of brain atrophy. We hypothesized that HS‐related atrophy would be restricted to the hippocampus and surrounding structures, while ADNP‐related atrophy would be most pronounced in the lateral temporal and parietal lobes.

Method

We used data from the National Alzheimer’s Coordinating Center (NACC) (09/2005‐03/2017) and identified 134 participants with suitable 3D T1w MRI and autopsy data. HS pathology was available as present/absent and we defined ADNP as present by a combination of high Braak stage (V/VI) and CERAD neuritic plaque score (3). We used the Computational Anatomy Toolbox (CAT12) to segment the MRI scans into tissue types and generate gray matter density maps. We examined the following regions of interest (ROIs): hippocampus, parahippocampus, amygdala, temporal and parietal regions, and global tissues measures. Additionally, we performed a voxel‐based morphometry (VBM) analysis. We studied the relationship between volumes/densities and neuropathologies using multiple linear regression models while adjusting for sex, age, education, dementia status, years from MRI to death, and intracranial volume.

Result

Table 1 depicts participant characteristics. We found that HS, but not ADNP, was associated with the volumes of the hippocampus (HS P<0.001, ADNP P=0.4), parahippocampus (anterior only, HS P=0.007, ADNP P=0.8), and amygdala (HS P=0.009, ADNP=0.2, Table 2). ADNP was significantly associated with lateral temporal lobe volumes, most strongly the inferior/middle temporal gyri. We found a trend of association between ADNP and gray matter atrophy (P=0.051). HS was significantly associated with white matter atrophy (P=0.001). We display the VBM results in Figure 1, which largely confirm the ROI results. Additionally, we found HS was associated with bilateral thalamic and insular regions and ADNP with the left amygdala and hippocampal tail atrophy.

Conclusion

While HS is strongly associated with atrophy of the hippocampus and surrounding structures, ADNP is associated with atrophy of lateral temporal lobe regions. These diverging atrophy patterns are potential biomarkers for differentiating these two clinically indistinguishable conditions during life.
Lithium protects against lipopolysaccharide‐induced cytotoxicity in SH‐SY5Y cells expressing Alzheimer’s presenilin 1 mutation by ameliorating calcium dysregulation
Authors: Sun Liang , Liang Ge , Wei Huafeng
Published: December 2020

Background

Lipopolysaccharide is a crucial mediator of neuroinflammation in sepsis. Neuroinflammation is implicated in normal brain aging and neurodegeneration in various neurodegenerative disorders including Alzheimer's disease. We examined the effect and mechanisms of lithium protection against lipopolysaccharide‐induced cytotoxicity in human neuroblastoma SH‐SY5Y cells expressing familial Alzheimer’s disease mutant presenilin‐1 (PS1) and compared to wide type control.

Method

Human neuroblastoma SH‐SY5Y cells transfected with human wild type or point mutant PS1 (M146L) were pretreated with lithium chloride (1 mM) for 1 week, and then challenged with lipopolysaccharide for 24 h. Cell viability was determined by the 3‐(4,5‐dimethylthiazol‐2yl)‐2,5‐diphenyltetrazolium bromide (MTT) reduction assay. Alterations of cytosolic Ca2+ concentrations were measured using jellyfish specific photo protein aequorin‐based probes.

Result

Lipopolysaccharide resulted in a dose‐dependent cytotoxic effects (starting from the concentration of 400 μg/ml) in both types of cells. Moreover, lipopolysaccharide (400 μg/ml) caused significantly more cytotoxicity in M146L than its corresponding wild type control cells, which could be inhibited significantly by lithium (1 mM) pretreatment. Lipopolysaccharide induced significantly more elevation of peak cytosolic Ca2+ concentrations in M146L cells than in wide type control cells, which could be abolished by lithium (1 mM) pretreatment.

Conclusions

Our results suggest that lithium pretreatment at clinically relevant concentrations could effectively mitigates lipopolysaccharide mediated cytotoxicity, especially in Alzheimer’s PS 1 mutated cells, possibly by ameliorating the abnormally elevated cytosolic Ca2+ concentration.
Neuropathology and immune biomarker discovery in a rat model of Alzheimer's disease, TgF344‐AD, with controlled cortical injury model of traumatic brain injury
Authors: Wang Athena Ching‐Jung , Adame Vanesa , Markham Neil , Potter Huntington , Boyd Timothy
Published: December 2020

Background

Individuals with a history of traumatic brain injury (TBI) have a higher risk of developing Alzheimer’s disease (AD) and AD‐related dementias (ADRD), such as chronic traumatic encephalopathy (CTE). However, the relationship(s) between TBI, AD, and CTE remain poorly understood and markedly understudied. Because transgenic mouse models of AD that develop amyloidosis do not readily develop pathological tauopathy that is commonly found in ADRD, we used the TgF344‐AD transgenic rat model of AD in which amyloid deposition drives endogenous tauopathy and neurodegeneration for our TBI studies.

Method

We used the closed‐head controlled cortical impact (CCI) model of TBI, performed either once (1X‐CCI) or twice over two weeks (2X‐CCI) in both 6‐ and 12‐month‐old TgF344‐AD and wild‐type (F344) rats to investigate the effects of TBI on acute and chronic neuroinflammation, on blood brain barrier (BBB) integrity, and on ADRD‐associated neuropathology. Whole brains and terminal blood draws were collected at different time points following the 1X‐ or 2X‐CCI TBI procedures at 3, 15, 30, 60, and 120 days after the final CCI procedure. Thus, the tissue collection ages of animals across the project allow for TBI‐induced ADRD‐related pathological analyses at 6, 7, 8, 10, 12, 13, 14, and 16 months of age. MRI scans were conducted at 30‐days post‐CCI to examine BBB leakage and chronic inflammation, with subsequent post‐mortem histochemical confirmation. Terminal blood draw samples were used for complete blood cell counts with differential and multiple biomarker analyses.

Result

This project is ongoing, but interim analyses reveal chronic neutrophil percentages remaining consistent in both TgF344‐AD and wild‐type 12‐month‐old cohorts undergoing either 1X‐ or 2X‐CCI at all post‐injury time points. Also, the upright time for the animals does not appear to differ based on impact type or genotype so far. However, histochemical pathological analyses of the 12‐month‐old AD rats have demonstrated changes in Aβ pathology and astrogliosis markers. MRI analyses have not yet been completed.

Conclusion

We are continuing to carry out detailed analyses of changes in ADRD‐related pathology and blood biomarkers. These animal models should help provide an increased understanding of chronic neuroinflammation and other pathological mechanisms associated with TBI and risk for ADRD.
iPSC‐derived neurons and microglia with an African‐specific ABCA7 frameshift deletion have impaired function
Authors: Cukier Holly N. , Laverde‐Paz Juliana , Ramirez Juliana , Adams Larry D. , Starks Takiyah D. , Vance Jeffery M. , Cuccaro Michael L. , Blurton‐Jones Mathew , Haines Jonathan L. , Byrd Goldie S. , Pericak‐Vance Margaret A , Dykxhoorn Derek M.
Published: December 2020

Background

The ATP‐binding cassette, sub‐family A (ABC1), member 7 (ABCA7) gene has been implicated as a risk factor in Alzheimer’s disease (AD) across populations. However, the risk effect of ABCA7 in African Americans (AAs) is stronger than in non‐Hispanic white (NHW) populations. We identified a 44 base pair deletion in AA significantly associated with disease (cases = 15.2%, controls = 9.74%, p = 1.414 × 10−5, Cukier, et al, 2016). The deleted allele is predicted to produce a frameshift mutation (p.Arg578Alafs), resulting in a truncated protein that may interfere with its normal functions, including APP processing and Aβ clearance.

Method

To further understand the mechanism by which the ABCA7 deletion may be acting, induced pluripotent stem cells (iPSC) lines were developed from the blood of two unrelated AA AD individuals heterozygous for the deletion, as well as age matched cognitively normal individuals. The iPSC lines were differentiated into cortical neurons and microglia, as both cell types endogenously express ABCA7.

Result

Each iPSC line generated was karyotyped and validated for pluripotency through immunocytochemical staining. RNA from the cases demonstrated that a stable RNA transcript is produced from the ABCA7 deletion allele. Preliminary results from iPSC‐derived neurons and microglia identified impaired functions in both cells types. Cortical neurons from patients produced higher levels of Aβ40 and Aβ42 compared to controls. In addition, while the patient‐derived microglia had normal rates of phagocytosis, they were impaired in the uptake and clearance of fibrillar Ab. Furthermore, when exposed to the proinflammatory stimulus lipopolysaccharide (LPS), the patient‐derived microglia had decreased cytokine responses.

Conclusion

This deletion in ABCA7 is an ethnic specific, pathogenic alteration in AD that may result in an increased production of toxic β‐amyloid production in neurons and a depressed ability to clear Ab and impaired responsiveness to proinflammatory signals in microglia.
AL001 restores CSF PGRN levels and normalizes disease‐associated biomarkers in individuals with frontotemporal dementia due to heterozygous mutations in the progranulin gene
Authors: Haynes Beth Ann , Rhinn Herve , Yeh Felix L , Long Hua , Ward Michael , Hagey Mackenzie , Siddiqui Omer , Paul Robert
Published: December 2020

Background

AL001 is a recombinant humanized anti‐Sortilin monoclonal antibody in development for frontotemporal dementia (FTD). Mutations in a single copy of the progranulin gene (GRN) leads to a 50% or greater decrease in the level of circulating progranulin (PGRN) protein levels and are causative of FTD. The disease is associated with increased inflammation and impaired lysosomal function in the brain. The INFRONT Phase 1/1b clinical study AL001‐1 investigated the safety, tolerability, pharmacokinetics and pharmacodynamics of intravenously administered AL001 in healthy volunteers (HV) and participants with a GRN mutation causative of FTD (FTD‐GRN). In addition, the study investigated the effect of AL001 on disease‐associated biomarkers.

Method

A total of 64 participants were enrolled in the AL001‐1 study. In the single dose ascending part of the study, 50 healthy volunteer participants were enrolled with 38 exposed to AL001 and 12 exposed to placebo. The study enrolled 6 asymptomatic FTD‐GRN and 8 symptomatic FTD‐GRN participants. The 8 symptomatic FTD‐GRN participants received 3 doses of 30 mg/kg of AL001 over 4 weeks.

Result

Treatment of symptomatic FTD‐GRN participants with AL001 over 4 weeks restored PGRN levels in the cerebrospinal fluid (CSF) to normal levels for more than 8 weeks. To further investigate the effects of restoring PGRN levels, partial normalization of a FTD disease proteomic signature was observed in the CSF 4 weeks after the last dose in multidose treatment group. Compared to healthy volunteers, AL001 treatment rescued cathepsin B (CTSB), a marker of lysosomal function, by 58%. AL001 treatment also partially normalized markers of inflammation and gliosis, osteopontin (SPP1) and chitotriosidase (CHIT1) by 52% and 22%, respectively. In addition to the reversal of these disease phenotypes, a 14% reduction (n.s.) in plasma neurofilament light chain (NfL), a marker of neuron injury and stress, was observed after 8 weeks after the last dose.

Conclusion

AL001 treatment resulted in a sustained increase in plasma and CSF PGRN in FTD‐GRN mutation carriers. New data showed reduction of NfL and normalization of proteins associated with the disease after one month of dosing. These results have supported progressing AL001 to Phase 2 and pivotal Phase 3 studies.
Why does ARIA‐E appear bright? A quantitative model linking brain tissue composition and T2 FLAIR hyperintensities
Authors: Aldea Roxana , Grimm Hans Peter , Gieschke Ronald , Hofmann Carsten , Klein Gregory , Kunnecke Basil , Piazza Fabrizio , Carare Roxana O , Mazer Norman A
Published: December 2020

Background

Amyloid related imaging abnormalities (ARIA) detected by magnetic resonance imaging (MRI) are associated with a class of therapeutic anti‐amyloid‐β antibodies under investigation in Alzheimer’s disease. ARIA‐E, manifested as bright signals on the T2 fluid attenuated inversion recovery (FLAIR) sequence, are suggestive of parenchymal vasogenic edema and/or sulcal effusions, although, solid experimental support is still missing [1]. By employing a novel voxel‐based model of the MRI signal, we test whether the extravasation of fluid and plasma proteins in the brain tissue and/or sulcal spaces can indeed explain the T2 FLAIR hyperintensities characteristic for ARIA‐E.

Method

The modelled MRI voxel consists of myelin (my), intracellular (ic) and extracellular (ec) compartments (Figure 1). The material properties and MRI parameters (T1 and T2 relaxation times) of the physiological system come from experiments on protein solutions and human brain (Table 1). The movement of water molecules between the ic and ec compartments is assumed to be fast and to generate a well‐mixed intra/extra‐cellular (iec) compartment. The net T2 FLAIR signal within the voxel is assumed to result from the water in the my and iec compartments undergoing slow exchange and having independent magnetic relaxation. We assess how expanding the ec space with a protein‐rich fluid affects the T1 and T2 relaxation times of the ec and iec compartments and the total FLAIR signal within the voxel.

Result

Our model predicts that a two‐fold enlargement of the ec space, corresponding to a 12% increase in water volume, can lead to a substantial parenchymal hyperintensity on T2 FLAIR. The presence of a protein‐rich fluid, e.g. plasma, in the ec space cannot yield parenchymal hyperintensities in the absence of ec expansion. Conversely, replacing the cerebrospinal fluid from the sulci (normally appearing dark on T2 FLAIR) with protein‐rich fluid results in a signal comparable to normal grey matter and the apparent loss of sulci (Figure 2).

Conclusion

By linking brain tissue composition to FLAIR signal changes, our model could help unravel the pathophysiological mechanisms of ARIA‐E and, therefore, provide a useful tool for testing other potential mechanisms underpinning brain MRI abnormalities. Reference: (1) van Dyck, Biological Psychiatry, 2018, 83(4):311‐319.
Single nuclei RNA‐seq data analysis identifies glial cell lineages associated with Alzheimer’s disease severity
Authors: Elyanow Rebecca , Green Kevin J. , Greenwood Anna K. , Prater Katherine E. , Melief Erica J. , Valdmanis Paul , Blue Elizabeth E. , Keene C. Dirk , Crane Paul K. , Young Jessica E. , Garden Gwenn A. , Jayadev Suman , Logsdon Benjamin A.
Published: December 2020

Background

Single nucleus RNA sequencing (snRNA‐seq) has the potential to improve our understanding of the cellular‐specific drivers of sporadic Alzheimer’s disease. In this study we re‐analyze published snRNA‐seq data from post‐mortem dorsolateral prefrontal cortex tissue from 48 participants in the Religious Order Study and Memory and Aging Project (ROS/MAP) cohorts (Mathys et al. 2019) and snRNA‐seq data from prefrontal cortex tissue from 9 participants across the Adult Changes in Thought (ACT), University of Washington Alzheimer’s Disease Research Center (UW‐ADRC), and Seattle Longitudinal Study (SLS) cohorts.

Method

All snRNA‐seq data were normalized using scran, with normalized counts pre‐processed in Monocle 3. Pseudotime lineages were learned separately for male and female patients for each cell subtype with Monocle3. Genes with non‐zero counts in fewer than 10 cells in a subtype were discarded.

Result

We reidentified the ROS/MAP disease‐associated microglia subtype (Mic1) from Mathys et al. 2019 in the ACT, UW‐ADRC, and SLS data as determined by Fisher’s exact test overlap of subtype specific gene expression markers (p.adjusted<10−16). Furthermore, we identify a trajectory of cellular state (pseudotime) within the Mic1 population that is disease associated (p.adjusted ≤ 3.4 × 10−11 in females, and p.adjusted ≤ 4.8 × 10−4 in males) in the Mathys et al. data. In female samples in both studies we observed that APOE expression has a positive association with Mic1 pseudotime, which we do not see in males. In males we see MEF2C expression was negatively associated with Mic1 pseudotime. Lastly, we see both activation of similar Mic1 pseudotime expression patterns in a subpopulation of oligodendroglial cells, as well as a loss of oligodendroglial cells in diseased patients.

Conclusion

We provide increasing evidence implicating a specific microglial subpopulation in the etiology of Alzheimer’s disease. Furthermore, we see that this population has heterogeneity in expression of key Alzheimer’s disease risk genes as a function of sex, and that we can define genes that are specific to this microglial subtype lineage for further functional investigation. Finally, we also see evidence of a similar disease‐associated expression signature in oligodendroglial cells, suggesting potentially an interaction between the disease associated microglia populations and oligodendrocytes in diseased patients that warrants further functional investigation.
Can motion‐based technology impact balance, movement confidence, and cognitive function among people with cognitive impairment?
Authors: Dove Erica , Wang Rosalie , Zabjek Karl , Astell Arlene J.
Published: December 2020

Background

Balance, movement confidence, and cognitive function are related to falls among people with cognitive impairment (PwCI; e.g. dementia). Motion‐based technologies (MBT; e.g. Xbox Kinect) are increasingly being explored to encourage exercise participation among PwCI, which can prevent falls. This study is examing the impacts of a group MBT intervention on balance, movement confidence, and cognitive function among PwCI.

Methods

Twenty‐four PwCI played Xbox Kinect bowling twice weekly for ten weeks at four adult day programs. The Mini Balance Evaluation Systems Test (Mini‐BEST) and the Montreal Cognitive Assessment (MoCA) were completed pre‐ and post‐intervention. Video recordings were taken during weeks one, five, and ten used to capture behavioural indicators of movement confidence (e.g. fluency of motion). Quantitative data collected through the Mini‐BEST and MoCA are being compared from pre‐ to post‐test using paired t‐tests. An ANCOVA is also being performed to account for covariates (e.g. number of intervention sessions attended). Count and percentage data are being extracted from coded video recordings to examine movement confidence.

Results

This study will answer questions regarding the potential of a group MBT intervention to impact balance, movement confidence, and cognitive function among PwCI. This could assess the feasibility and potential benefits of using MBT to deliver exercise interventions to PwCI. Finally, this work can be used as the basis for developing specific software and future exercise programs using MBT for PwCI.

Conclusion

The findings will be used to inform future MBT applications to deliver exercise to PwCI.