bluuebunny/crossref_metadata_2025 huggingface dataset:
The etiology of long‐term stable mild cognitive impairment
Authors: Sharma Manu J. , Callahan Brandy L.
Published: December 2020

Background

Of those diagnosed with mild cognitive impairment (MCI), 5‐10% convert annually to dementia (Mitchell & Shiri‐Feshki, 2009). However, 5‐30% can remain cognitively stable (sMCI) for up to 10 years (Alves et al., 2018), suggesting a non‐neurodegenerative etiology in these patients. This study aims to examine the etiological underpinnings of those who remain cognitively stable versus those who decline over time.

Method

Participants from the National Alzheimer’s Coordinating Center were selected if they were nondemented at baseline, had available clinical data ≥5 years following baseline, and had available autopsy data <1.5 years following last visit. They were defined as stable normal controls (sNC; n = 106) or sMCI (n = 28) if cognitive status was unchanged between first and last visit (≥5 years later); declined normal controls (dNC; n = 128) if cognitive status at first visit was normal and MCI or demented by last visit; or declined MCI (dMCI; n = 139) if cognitive status was MCI at first visit and demented by last visit. Neuropathological features were dichotomized to reflect clinically significant levels (≥moderate neuritic plaque density; Braak neurofibrillary degeneration stage ≥4; Thal amyloid plaque phase ≥3; any Lewy bodies; ≥1 large arterial infarct; ≥1 lacune; ≥1 microbleed; ≥1 hemorrhage). Baseline psychiatric symptoms were quantified using the Geriatric Depression Scale (GDS; ≥6 considered clinically significant) and the Neuropsychiatric Inventory Questionnaire (NPI‐Q; grouped into ‘mood’, ‘agitation’ and ‘psychosis’ factors based on previous factor analysis: Aalten et al., 2003, Siafarikas et al., 2018). The groups were compared on frequencies of neuropathological features at autopsy and baseline psychiatric symptoms using chi‐square (χ
2).

Result

Demographics are presented in Table 1, with main analysis results in Table 2. Relative to other groups, sMCI had significantly fewer amyloid plaques (χ
2 = 44.2, p < 0.001) and more microinfarcts (χ
2 = 9.9, p = .019). GDS and NPI‐Q showed no significant relationship with sMCI.

Conclusion

Previous research indicates microinfarcts are independent of neurodegenerative disease (Launer et al., 2011). In line with this, our results suggest that sMCI may be caused by microinfarcts, rather than frank neurodegenerative disease. This study was limited as only neuropsychiatric symptoms were reported, and future studies should examine sMCI in relation to diagnosed psychiatric disorders.
Acoustic measures in natural speech of progressive supranuclear palsy and corticobasal spectrum disorders
Authors: Parjane Natalia , Ash Sharon , Cho Sunghye , Shellikeri Sanjana , Liberman Mark Y. , Grossman Murray , Nevler Naomi
Published: December 2020

Background

Progressive supranuclear palsy and corticobasal syndrome (PSP‐CBS) are neurodegenerative disorders involving motor and cognitive deficits. These patients may have slowed and dysfluent speech. However, few studies have investigated specific speech and language deficits in these disorders, although some patients may have non‐fluent/agrammatic primary progressive aphasia (naPPA). In our study, we used novel, automated speech analysis methods to quantify acoustic properties of natural speech in PSP‐CBS. We hypothesized patients would exhibit slowed speech and longer pauses, and predicted that prosodic changes would be related to underlying cognitive and motor impairments. Because PSP and CBS are tauopathies, we related their acoustic performance to cerebrospinal fluid (CSF) analytes associated with Tau pathology.

Method

We obtained digitized samples of natural speech with the Cookie Theft picture description task from PSP‐CBS patients (n = 95), naPPA patients (n = 25) and healthy controls (HC, n = 41). Eight PSP‐CBS patients had concomitant naPPA (PSP‐CBS+naPPA). The groups were matched for age, sex, education, and disease duration. A speech activity detector program automatically segmented the acoustic signal into speech and silent pause segments. We automatically calculated the pitch range by measuring fundamental frequency (f0, semitones), total speech duration, mean speech and pause segment durations, and pause rate (pauses per minute). In a subset of patients with available CSF analytes, we related acoustic markers with levels of phosphorylated tau (pTau).

Result

PSP‐CBS without naPPA had shorter mean speech segments (1.42 ± 0.48 sec), shorter total speech durations (31.77 ± 14.66 sec), longer mean pause segments (1.82 ± 1.01 sec) and higher pause rates (45.10 ± 13.43 pauses per minute) compared to HC (2.00 ± 0.57 sec, p < .001; 51.08 ± 21.30 sec, p < .001; 0.93 ± 0.44 sec, p < .001; 31.61 ± 9.51 ppm, p < .001, respectively). PSP‐CBS only differed from naPPA for pause rate (PSP‐CBS, 45.10 ± 13.43 ppm; naPPA, 57.81 ± 19.95 ppm; p = .026). PSP‐CBS+naPPA patients were most impaired for f0 range (3.56 ± 1.21 ST) compared to HC (5.87 ± 1.94 ST, p = .021), paralleling naPPA patients, who had reduced f0 range compared to HC (4.30 ± 1.59 ST, p = .02). f0 range was associated with pTau levels in all patients (r = ‐0.43, p = .004).

Conclusion

Patients with PSP‐CBS have impaired speech as quantified by automated analysis of acoustic measures of speech. These measures are related to pTau, a marker of likely pathology.
Rural–urban differences in the prevalence and characteristics of mild cognitive impairment in independent community‐dwelling older adults in Taiwan
Authors: Chuang Yi‐Fang , Liu Yi‐Chien , Tseng Hsin‐Yi , Chiu Yen‐Ling , Kuan‐Chia Lin , Shih Ming‐Hsiung
Published: December 2020

Background

Taiwan is among one of rapidly aging countries and cognitive impairment increases exponentially with age among older adults. Mild Cognitive Impairment (MCI) bears an increased risk of developing dementia later and may represent an early disease stage that is amenable to preventive strategies. There is currently no epidemiological data about the prevalence of MCI in Taiwan.

Method

The data was from the baseline assessment of a community‐based prospective cohort study conducted in one rural and one urban areas of New Taipei City in Taiwan between 2017‐2019. Four hundred and seventy individuals aged 65 years and older, independently living in the community, were recruited and underwent a battery of neuropsychological tests assessing cognitive domains of attention, memory and executive function. Diagnosis of MCI was ascertained through an expert consensus panel based on 2011 NIA‐AA criteria.

Result

Mean age of participants was 71.1± 5.5 years. Participants from the rural area were older (72.6 vs. 70.6 years), had poorer education (5.5 vs. 8.7 years), higher body mass index (25. 9 vs. 24.6 kg/m2), and higher percentage of hypertension (54.5 vs. 43.6%) The prevalence of MCI was 45/122 (36.6 %) in the rural area and 40/348 (11.5 %) in the urban areas, for a overall 85/470 (18.1 %). The rural area had a significantly higher prevalence of MCI (age‐ ,sex‐, and education‐adjusted odds ratio [OR] = 2.86, 95 % CI: 1.68–4.86) than the urban area. There was no differences in the distribution of subtypes of MCI in two areas. In the rural area, only poorer education was associated higher prevalence OR of MCI whereas in the urban area, being male, poorer education, and higher geriatric depressive scale were associated higher prevalence OR of MCI.

Conclusion

The prevalence of MCI was much higher in the rural area relative to the urban area. Different factors were associated with the prevalence of MCI in the rural and urban areas. This regional difference suggests preventive strategies or programs against cognitive impairment should be tailored and modified according to the urbanicity of an area.
Presenilin 1 and APP gene mutations in early‐onset AD families from a southeast region of China
Authors: Peng Guoping
Published: December 2020

Background

Early‐onset familial Alzheimer’s disease (EOFAD) has been reported to be associated with presenilin 1 (PSEN1), presenilin 2 (PSEN2), and amyloid precursor protein (APP) genes. The spectrum of mutations in Chinese patients with EOFAD was rarely investigated. Thus, this study intends to investigate the spectrum of mutations in patients with EOFAD in Chinese population.

Method

We performed a whole‐exome sequencing and described relevant clinical features in a total of 67 patients from 3 families with EOFAD.

Result

A splice mutation (p.S290C) in PSEN1 and a missense mutation (p.V717I) in APP were identified.

Conclusion

The variant p. S290C (c.869‐2>G) in PSEN1 in Chinese EOAD family revealed different clinical phenotype when compared with that of European.
Predicting activities of daily living in people with dementia of Alzheimer’s type using neurocognitive measures
Authors: Rai Pooja , Singh Tara , Singh Indramani L. , Tiwari Trayambak , Joshi Deepika
Published: December 2020

Background

Cognitive deterioration in neurodegenerative disorders like dementia of Alzheimer’s type affects the overall functioning of daily life activities of a person. Till date, numerous studies have shown correlation between performance on cognitive task and activities of daily living (ADL). Among all the cognitive domains attentional functioning has been the main focus in DAT as it has been the first cognitive domain to be affected.

Method

The present study has an attempt to associate the cognitive functions especially attentional functioning in predicting ADLs in people with DAT. The different ADLs which mainly categories into basic and instrumental ADL have been studied meta‐anatically in relation to its relationship with cognitive functioning in people with DAT. The keywords related with study have been selected and searched on different platforms like Google Scholar, Pubmed etc. The lack of research works in this field narrows the studies related with predictive value of cognitive ability.

Result

The study revealed that out of 11 studies, 7 were related to the assessment of cognitive functioning with ADLs. Out of which 4 were concerning about the cognitive domain related with ADLs whereas 3 studies have shown domains other than attention like visuospatial ability, immediate memory and executive functioning as a predictor to the ADLs in DAT.

Conclusion

The relevance of conducting the present study is the emerging life problems of elderly with cognitive impairment. The study suggests how the present approach can be applied to address research issues related with diagnosis and rehabilitation technique for people with DAT.
Physical activity for people with Alzheimer's disease: Are we doing enough?
Authors: Feter Natan , Cassuriaga Júlia , Leite Jayne S , Rombaldi Airton ,   NeuroLaBFEx
Published: December 2020

Background

National Alzheimer disease (AD) associations are the primary resource of information for AD patients and their caregivers. Physical activity (PA) (i.e. walking) improve quality of life and functional capacity, and preserve cognitive function in patients with AD. We aimed to verify if national AD associations and dementia control plans worldwide recommend PA for this population.

Method

We search for PA mention and recommendation on national dementia control plan in each country in the world. Further, we contacted national Alzheimer’s associations worldwide to verify if it had any mention or recommendation of PA for people with AD

Result

From 224 countries and territories analyzed, 123 had either a national AD association or a national dementia control plan. The sample was compound by 112 countries (loss/refuses: 8.9%). About 50% mentioned PA as a protective factor against AD. Only 19% provided some type of recommendation (i.e. frequency, type, time, intensity) of PA for people with AD. However, all those countries were classified as upper‐middle or high income countries.

Conclusion

Dissemination of benefit from PA for people with AD should be encouraged especially in low and lower‐middle income.
Association of an index of lifespan cognitive reserve with the risk of mild cognitive impairment and its progression to dementia
Authors: Xu Hui , Yang Rongrong , Dintica Christina S , Qi Xiuying , Song Ruixue , Bennett David A , Xu Weili
Published: December 2020

Background

The effect of lifespan cognitive reserve (CR) on mild cognitive impairment (MCI) and its progression to dementia remains controversial.

Method

Within the Rush Memory and Aging Project, a community‐based cohort study (mean age, 79 years) with annual follow‐up (median, 5.16 years; maximum, 20 years), a cognitively intact group (n=1182) and an MCI group (n=420) were identified at baseline. During the follow‐up, 611 participants died and underwent autopsies. Neuropathologic evaluations for Alzheimer’s disease (AD) and infarcts were performed in autopsied participants. CR indicator encompassing education, early‐ to late‐life cognitive and social activities was obtained and tertiled.

Result

Compared to the lowest CR, the multi‐adjusted hazards ratios (HRs, 95% CI) of the highest CR was 0.78 (0.63–0.98) for incident MCI in the cognitively intact group, and 0.66 (0.45–0.97) for dementia in the MCI group. Among MCI participants with high brain pathologies (including global AD pathology or gross infarcts), the adjusted incident rate of dementia was about 50‐65% lower in people with highest CR compared to lowest CR.

Conclusion

High lifespan CR indicator reduces risk of MCI, and delays its progression to dementia, in the presence of brain pathologies.
Transcranial pulse stimulation in Chinese patients with Alzheimer’s disease
Authors: Au Lisa W.C. , Kwan Pauline , Mok Vincent C.T.
Published: December 2020

Background

Low‐intensity extracorporeal shock wave therapy (Li‐ESWT) has been used for years to treat musculoskeletal disorders through promoting tissue regeneration. Recently, transcranial pulse stimulation (TPS) with ultrasound, which is a form of Li‐ESWT, was applied to patients with Alzheimer’s disease (AD). The pivotal study using a newly developed TPS system NEUROLITH® showed promising effects on AD. The aim of this study was to investigate the safety and tolerability of TPS in Chinese patients with AD.

Method

Clinically stable patients with mild cognitive impairment due to Alzheimer’s disease as defined by National Institute on Aging‐Alzheimer’s Association (NIA‐AA) criteria, who had documented abnormal biomarkers including amyloid and tau on positron emission tomography (PET) brain imaging were recruited from an outpatient cognitive neurology clinic in Hong Kong. TPS was performed using NEUROLITH® by trained staffs. Each therapeutic session comprised 6000 shocks at an energy flux density of 0.2 mJ/mm2and pulse repetition frequency of 5 Hz. Stimulation targets include bilateral frontal cortex, bilateral lateral parietal cortex and extended precuneus cortex. The treatment comprised 6 sessions within two weeks. Participants were closely monitored during treatment. Patient’s experience and any adverse reactions were documented. The Clinical Global Impression of Change scale (CGIC) was administered at 4 weeks after treatment.

Result

Two patients underwent TPS treatment using NEUROLITH®. Both were female Chinese patients aged 71 years. Both patients reported satisfactory treatment experience with no adverse reactions. One patient completed follow up at 4 weeks with CGIC showed improvement in behavior/ mood with less agitation.

Conclusion

Transcranial pulse stimulation is a safe and well‐tolerated treatment for Alzheimer’s disease patients in Hong Kong. Further studies are required to assess the long‐term efficacy of TPS on cognitive, behavioral and psychological symptoms of Alzheimer’s disease patients.
Towards cross‐cohort estimation of cognitive decline in neurodegenerative diseases
Authors: Maheux Etienne , Koval Igor , Archetti Damiano , Redolfi Alberto , Durrleman Stanley
Published: December 2020

Background

Heterogeneity of cohorts, in terms of inclusion criteria, design of follow‐up visits and batteries of cognitive assessments, hinders any thorough comparisons between them. For that reason, we build a cross‐cohort model of cognitive decline that can be personalized to any patient, allowing to impute partially or totally missing scores. This enables to compare the subjects’ progression across cohorts thanks to common cognitive assessments.

Method

Based on a generic framework of disease progression that handles longitudinal data (Schiratti et al. 2015, NIPS) and implemented in the Leaspy Python package, we first estimate the joint progression of a large set of cognitive scores from the ADNI database along a common disease timeline. This group‐average progression is then personalized to individual trajectories of patients from the PharmaCog and AIBL cohorts. In particular, all individuals are characterized by a relative pace of progression and onset age that can be compared across cohorts. To validate our model, we impute missing values of a given score, based on its past and future values together with the dynamics of concurrent scores and compare errors to constant predictions and linear regressions. We finally go further by simulating purposely concealed scores thanks to the progression of the remaining features so to mock reconstruction of scores that are entirely missing in a particular cohort.

Results

Figure 1 shows the relative positioning of all subjects from the 3 cohorts based on their individual pace of progression and their age at disease onset. Such characterization enables to impute missing values of the MMSE or the Immediate/Delayed Logical Memory better than imputing the last known value or fitting a linear regression [Figure 2]. Furthermore, from the multiple measurements of a single score, the model is able to reconstruct the individual progression of the other scores at the corresponding visits [Figure 3], with a controlled error rate.

Conclusion

Our model enables comparison of patients trajectories from different cohorts. It permits to lessen imputation errors of most cognitive scores in new cohorts and demonstrates a new way to simulate, at any individual visit, scores that have not been measured in practice.
Neurovascular uncoupling of cerebral blood flow and glucose metabolism in APOE4, TREM2, and APOE4.TREM2 mice
Authors: Territo Paul R. , Lin Peter B. , Persohn Scott C. , Bedwell Amanda A. , Eldridge Kierra , Speedy Rachael , Kotredes Kevin P. , Pandey Ravi S. , Oblak Adrian L. , Sasner Michael , Carter Gregory W. , Lamb Bruce T. , Howell Gareth
Published: December 2020

Background

Alzheimer’s disease (AD) is the most common cause of dementia in the United States, with approximately 95% of patients exhibiting sporadic Late‐Onset AD (LOAD), which lacks an inheritance pattern. Therefore, identifying phenotypic patterns are critical for understanding disease progression. Apolipoprotein E4 (APOE4), the strongest genetic risk factor of LOAD, increases AD risk by 3‐12 fold depending on copy number. Recent GWAS analysis elucidated the LOAD‐associated loci on the triggering receptor expressed on myeloid cell 2 (TREM2). APOE is a known ligand to the TREM2 receptor, and the R47H variant could increase the AD risk by 2‐3 fold. Preclinical studies of these risk alleles and their phenotypes are underway by MODEL‐AD.

Methods

Using PET/MRI and a novel analytical scheme, we established the perfusion‐metabolism profiles across 27 brain regions in both sexes by using 64Cu‐PTSM and 18F‐FDG in the APOE4 (APOE
E4/E4), TREM2 (TREM2
R47H), and double (APOE
E4/E4.TREM2
R47H) knockin (KI) mice, and compared these to blood chemistry and nanoString transcriptomic analysis.

Results

Longitudinal analysis comparing 12mo to 4mo time point revealed that male APOE4 mice and both sexes of TREM2 had hypo‐ perfusion and metabolism, while female APOE4 mice showed an uncoupled hyper‐perfusion and hypo‐metabolism phenotype, and was correlated to human AD pathology. In double KI mice, perfusion and metabolism showed a mixed phenotype which was region dependent. Cross‐sectional analysis of KI compared to C57BL/6J mice at 12mo showed an overall reduced glucose metabolism. Intriguingly, male APOE4, TREM2, and double mice showed hypo‐perfusion and metabolism, while female double mice showed metabolic uncoupling compared to C57BL/6J. Analysis of blood biochemistry in non‐fasted mice revealed no significant difference between genotypes in blood glucose with age. However, APOE4 decreased the blood cholesterol level (LDL, and HDL). RNAseq and immunohistology was peformed, and key genes involved in the regulation of cerebral perfusion, glucose transportation, and metabolism were altered.

Conclusions

These data suggest that the new perfusion‐metabolism strategy may be able to identify AD‐related patterns. Moreover, they replicate clinical manifestations of subjects with the same variants, suggesting additional mechanistic studies are needed to elucidate the mechanisms and etiology of this uncoupling phenomenon.
Brain imaging and neuropsychiatric profiles associated with plasma cortisol level among nondemented older adults
Authors: Oh Hwamee , Leung Hoi‐Chung , Canli Turhan , Slifstein Mark
Published: December 2020

Background

A predisposition to stress or expression of chronic stress‐related symptoms has been considered as a risk factor for Alzheimer’s disease (AD). To elucidate a neural mechanism underlying the risk of AD, we examined the relationship between glucocorticoids, glucose metabolism, hippocampal volume, and subsequent amyloid deposition among nondemented older adults.

Method

We assessed plasma cortisol level (cortisol), FDG counts in AD signature cortical regions, adjusted hippocampal volume, cognitive and neuropsychiatric measures and subsequent amyloid accumulation in 58 cognitively normal older adults (CNs) and 396 participants with mild cognitive impairment (MCIs) in the Alzheimer’s Disease Neuroimaging Initiative. Multiple regression models were applied to assess the relationships between these measures across all groups, followed by within‐group analyses. For psychological measures, neuropsychiatric inventory (NPI) scale total scores were assessed in relation with cortisol and neuroimaging measures.

Result

Higher cortisol was associated with smaller adjusted hippocampal volume and greater NPI scores. With glucosemetabolic rates in AD signature regions, higher cortisol was associated with lower glucose metabolism in the MCI group, but with increased glucose metabolism in the CN group. Smaller hippocampal volume, but not higher cortisol, at baseline, was related to higher brain amyloid burden over time.

Conclusion

Individuals’ susceptibility to stress as measured by plasma cortisol levels may confer risk for neurodegeneration and the development of AD pathology among nondemented older adults.
Brain network dysfunction associated with blood neurofilament light chain in autosomal dominant Alzheimer disease
Authors: Wheelock Muriah D. , Strain Jeremy F. , Ances Beau M. , Preische Oliver , Morris John C. , Bateman Randall J. , Jucker Mathias , Benzinger Tammie L.S. , Eggebrecht Adam T. , Gordon Brian A. ,   Dominantly Inherited Alzheimer Network
Published: December 2020

Background

Alzheimer disease is characterized by accrual of amyloid‐b and tau, cortical thinning, and disruptions in brain connectivity. Recent reports suggest neurofilament light chain (NfL), a measure of brain damage and atrophy, is measurable in the blood and is predictive of presymptomatic cognitive decline in individuals with autosomal dominant Alzheimer Disease. We sought to investigate the relationship between serum blood estimates of NfL and functional brain connectivity. We hypothesized that increasing NfL levels would be associated with increasing disruption of within and between network connectivity.

Method

We performed neuroimaging and blood serum NfL assessments in a longitudinal sample of 78 mutation non‐carriers (NC) and 112 mutation carriers (MC) age 20‐65 enrolled in the Dominantly Inherited Alzheimer Network. Serum blood samples were collected and assayed in duplicate for NfL. Resting state‐functional MRI (rs‐fMRI) data were acquired on 3T Siemens scanners. For each subject, five minutes of low‐motion rs‐fMRI data were included (scrubbing with FD <0.2 mm). Functional connectivity (FC) was estimated using zero‐lag Pearson correlations calculated between 246 regions of interest (Figure 1A). NfL values were compared between mutation carriers and non‐carriers using non‐parametric Mann‐Whitney U tests (Figure 1B). We examined associations between FC and NfL using a Network Level Analysis (NLA) approach. Briefly, NLA uses non‐parametric test statistics and permutation testing to determine FC networks associated with NfL scores (Figure 1A).

Result

NfL was correlated with a wide‐range of within and between‐network connectivity in MC but not NC subjects (Figure 2A). The five strongest associations with NfL were within the DMN, cingulo opercular (CO) and dorsal attention (DAN) networks. Specifically, greater levels of NfL were associated with reduced magnitude of within‐ and between‐network connectivity (Figure 2D&E).

Conclusion

Only in the MC group was NfL correlated with deterioration of the DMN and reduced connectivity between the DMN and other brain systems. Reduced connectivity between DMN and CO and DAN with increasing atrophy may be associated with executive and cognitive decline following full progression to Alzheimer’s disease. The present study suggests that indirect measurement of cell death and brain atrophy with serum NfL corresponds to reduced functional connectivity in presymptomatic Alzheimer’s disease.
Care ecosystem training: Developing a free online dementia course for a growing lay health workforce
Authors: Dulaney Sarah , Allawala Mahnoor , Thoma Mark , Merrilees Jennifer , Lynch Shalini , Chodos Anna H , Huffman Sara , Chiong Winston , Hooper Sarah M , Possin Kate L
Published: December 2020

Background

The Care Ecosystem is a telephone‐based dementia care program that is delivered by trained lay heath workers called Care Team Navigators (CTNs) who are supported and supervised by a clinical team with expertise in dementia (Possin, et.al., 2019). We hypothesized that health systems interested in implementing the Care Ecosystem would benefit from an asynchronous online training course to help prepare a dementia‐capable workforce.

Method

With a grant from the Merck Foundation, faculty and staff from the UCSF Memory and Aging Center and UC Hastings College of Law developed a series of brief videos (∼10min). Content was adapted for a lay, adult‐learner audience. Multiple choice post‐test questions were written to reinforce content. A Likert scale and an open‐ended question were used to collect feedback for each video. Presentations and quizzes were reviewed by our multidisciplinary team in monthly meetings and over email. Audio was recorded using a smartphone application and spliced with slides into an mp4 video using basic movie editing software. The Canvas Network platform was selected for ease of use, broad availability, and free user account options.

Result

The Care Ecosystem Training was released in September 2019 with a link embedded on the Care Ecosystem website (memory.ucsf.edu/care‐ecosystem) and email distribution to three implementation sites. By January 2020, 44 students enrolled in the course, 130 quizzes on 34 topics were completed with an average quality rating of 4.6 (out of 5).

Conclusion

The Care Ecosystem Training demonstrates that simple, broadly available technology can be used to increase access to dementia care training. A peer review process helps tailor content for a lay health workforce. The Care Ecosystem Training is designed to be used with the Care Ecosystem Toolkit, and supplemented by clinical observation and case discussions with local clinicians. By prioritizing ease of access for users, the ability to collect user data may be limited. Feedback from quizzes will be used to improve the course.
MRI measures of neurodegeneration in the LEADS cohort
Authors: Dickerson Brad C.
Published: December 2020

Background

Although early‐onset AD (EOAD) and late‐onset AD (LOAD) share the same pathologic substrate, there are notable differences in their atrophy patterns compared with LOAD. EOAD is associated with greater baseline cortical atrophy, less medial temporal lobe involvement and often more severe AD pathology than LOAD. In addition, MRI measures can be informative about likely etiology in patients with a clinical phenotype suggestive of EOAD who turn out to have biomarkers not consistent with EOAD.

Method

In LEADS, the goals of the MRI core are to 1) collect and perform quality control procedures using the ADNI 3 protocol; 2) collect and analyze T1‐ and T2‐weighted MRI data to obtain measures of atrophy (neurodegeneration) and white matter signal abnormalities; 3) collect and analyze advanced diffusion, perfusion, resting‐state functional MRI, and high‐resolution medial temporal lobe sequences. At present, we are focusing on the Freesurfer‐based analysis of T1‐weighted MRI data for the purposes of evaluating atrophy patterns to compare patients with elevated amyloid vs. those with low amyloid, and furthermore to try to identify patterns suggestive of non‐AD pathologies. Furthermore, we are comparing several methods for defining neurodegeneration from T1‐weighted MRI scans, including whole brain volume, hippocampal volume, average cortical thickness, and AD‐signature cortical thickness.

Result

As a group, the T1‐derived atrophy pattern relative to controls from patients with elevated amyloid show prominent lateral temporoparietal and posterior cingulate/precuneus atrophy. The low‐amyloid group do not show a clear pattern of atrophy, as a group. AD‐signature cortical thickness differs between EOAD and controls but not between EO‐nonAD and controls, while hippocampal volume differs between both patient groups and controls. In some patients with low amyloid, atrophy patterns are suggestive of likely FTLD pathology.

Conclusion

The initial MRI data from LEADS support the observations reported from smaller studies of EOAD. Analyses are ongoing to determine whether MRI‐based definitions of neurodegeneration previously developed in LOAD are generalizable to EOAD.
MAPT mutations cause rapid progressive frontal temporal dementia: A case report
Authors: Mao Chenhui , Li Jie , Zhou Liangrui , Huang Xinying , Lei Dan , Liu Caiyan , Dong Liling , Gao Jing
Published: December 2020

Background

Frontal temporal dementia (FTD) was a heterogeneous disease entity which was divided into behavior variant FTD (bvFTD), semantic dementia and none fluent progressive aphasia. The pathologic and genetic mechanism was much more complicated and intercrossed. Mutations in the microtubule‐associated protein tau (MAPT) gene were the first to be associated with inherited FTD and the clinicopathological phenotypes depended on tau isoform composition, relative disposition of abnormal tau in neurons and glia, as well as different anatomic distribution of tau pathology and neuronal loss.

Method

We reported a proven case of rapid progressive FTD with detail clinical description, neuroimaging, neuropathology and genetic data. Then we discussed the diagnosis and differential diagnosis thoughts.

Result

It was a 31 years old female patient admitted with behavior and psychiatric symptoms as well as rapid progressive dementia for 10 months. The onset symptoms included abnormal behavior, changed personality and apathy. Then she had cognitive disorder, declined memory, however, the ability of housekeeping, taking care of herself and daily life was kept. About 4 months later, she got dysarthria. No family history was found. Encephalitis was suspected. Brain MRI showed unilateral atrophy of right frontal and temporal lobe with white matter lesions. Lumber puncture revealed no inflammation reactions. Systemic screening for antibodies, abnormal metabolites, tumors was negative. Brain biopsy of right frontal lobe revealed severe loss and degeneration of neurons with extensive proliferation of glial cells. No active inflammation or necrosis was seen. Neurodegeneration was suspected. Genetic sequencing suggested MAPT (NM_005910.5) exon8 c.796C>G p.leu266val, which was a definite pathogenic mutation. The final diagnosis was MAPT related FTD.

Conclusion

We reported an atypical case of bvFTD caused by MAPT mutation which was difficult in the diagnosis process, because of the short and rapid course and atypical neuroimaging manifestation.
Automated hippocampal segmentation improved by convolutional neural network approach in participants with a history of cerebrovascular accident
Authors: Zavaliangos‐Petropul Artemis , Tubi Meral A , Zhu Alyssa , Haddad Elizabeth , Jahanshad Neda , Thompson Paul M , Liew Sook‐Lei
Published: December 2020

Background

Cerebrovascular accidents (CVA) are risk factors for dementia, including Alzheimer’s disease (AD; Arvanitakis et al., 2016). Hippocampal atrophy is observed in both CVA (Gemmel et al., 2012) and AD (Braak & Braak, 1991) patients. Thus, the hippocampus may be an important biomarker for CVA patients with high AD‐risk. FreeSurfer, a commonly used automated hippocampal segmentation method to study post‐CVA hippocampal volume (Khlif et al., 2019), uses an atlas‐based approach, making it more likely to fail in the presence of CVA lesions (Yang et al., 2016). Two recent convolutional neural network‐based (CNN) hippocampal segmentation algorithms, Hippodeep (Thyreau et al., 2018) and Hippmapp3r (Goubran et al., 2019), are more flexible for post‐CVA anatomical changes since they do not rely on a single atlas. However, they have not been widely tested in CVA populations. Here, we compare the segmentation accuracy of FreeSurfer, Hippodeep, and Hippmapp3r in participants with a history of CVA.

Method

30 T1‐weighted structural brain MRIs from CVA participants with varying lesion sizes (0.43‐181.5 cc) in the Anatomical Tracings of Lesions After Stroke dataset (Liew et al., 2018) were used to compare FreeSurfer, Hippodeep, and Hippmapp3r to manual segmentations. Accuracy was measured as spatial overlap between each automated and manual segmentation using the Dice Coefficient (DC). An ANOVA was used to test for DC differences across methods.

Result

DC significantly differed by segmentation method (F‐value=178.3;p‐value<2.10x‐16). Ipsilesional results: Hippodeep DC was significantly greater than FreeSurfer DC (p‐value=1.03x10‐17;t‐value=18.7) but not significantly different from Hippmapp3r DC. Contralesional results: Hippmapp3r DC was significantly greater than both Hippodeep (p‐value=9.53x10‐4;t‐value=4.52) and FreeSurfer (p‐value=4.68x10‐21;t‐value=24.8;Figure 1).

Conclusion

Hippodeep and Hippmapp3r segmentations had significantly better accuracy than FreeSurfer, although all methods had a DC >0.7 (recommended threshold for good segmentation overlap; Zou et al., 2004). For ipsilesional segmentation accuracy, the two CNN methods did not significantly differ, while for contralesional segmentations, Hippmapp3r performed best. Future studies may benefit from using CNN approaches to more accurately estimate hippocampal volumes in patients with CVA with high AD risk.
Tau microtubule binding region in cerebrospinal fluid as a biomarker to differentiate tau pathology in Alzheimer’s disease
Authors: Horie Kanta , Barthelemy Nicolas R , Sato Chihiro , Bateman Randall J
Published: December 2020

Background

Tau deposition in brain is a pathological hallmark of some neurodegenerative disorders including Alzheimer’s disease (AD). Braak staging of post‐mortem tissue suggests pathological tau spreads through the brain via synaptically connected pathways, and specific tau isoforms containing the microtubule binding region (MTBR) are thought to be essential to form extracellular seeds that propagate pathology. Tau is cleaved at the mid‐domain and the N‐ter to mid‐domain species are actively secreted extracellularly, whereas MTBR‐tau show faster turn‐over and deposition in brain. Recently, we identified the MTBR regions (residues 299‐317 (HVPG) and 354‐369 (IGSL)) and the nearby region (residue 243‐254 (LQTA)) were specifically enriched in AD brain aggregates. However, if and how these species change in extracellular spaces under pathophysiogical conditions were not known. This work describes the behavior of the pathological species in extracellular spaces by analyzing human cerebrospinal fluid (CSF) with changes of disease progression.

Method

We established a method to quantify MTBR‐tau in CSF, consisting of chemical extraction followed by tryptic digestion and mass spectrometry analysis. This method was applied to the CSF analysis of AD participants (n=50 amyloid negative with CDR=0‐1, n=50 amyloid positive with CDR=0‐2). A subset of these participants was followed longitudinally (2‐9 years).

Result

Our method revealed that (1) MTBR‐tau were specifically increased in amyloid positive group and HVPG was the most significantly increased even in clinically asymptomatic stages, (2) the increases of HVPG and IGSL were saturated after symptomatic onset, whereas LQTA continued to increase even after the clinical onset, and (3) the concentration of LQTA showed the highest correlation with tau pathology as measured by positron emission tomography (PET) for tau (Pearson r=0.84, n=35) as well as cognitive testing measures.

Conclusion

MTBR‐tau enriched in AD brain aggregates are increased in AD CSF. These findings suggest HVPG and LQTA in CSF could be promising biomarkers to recapitulate amyloid status and tau pathology in AD, respectively. Notably, only LQTA showed the continuous increase along to disease progression in terms of tau‐PET as well as amyloid status and cognitive decline, which suggests the region is key to differentiate tau pathology in AD.
Change in renal biomarkers and in structural MRI outcomes in chronic kidney disease (CKD) patients over three years
Authors: Murray Anne , Vemuri Prashanthi , Davey Cynthia , Reid Robert I. , Wille Samantha M. , Thostenson Kaely , Jack Clifford R. , Knopman David S.
Published: December 2020

Background

We report the associations between change in renal biomarkers in CKD and non‐ CKD participants and change in structural MRI outcomes over 3 years in the BRain IN Kidney disease (BRINK) study MRI cohort. The imaging outcomes were cortical thickness in Alzheimer’s disease signature regions, white matter hyperintensities (WMH), and fractional anisotropy in the corpus callosum (FA CC), an early marker of cerebrovascular disease.

Methods

Participants were ≥ 45 years with CKD (estimated glomerular filtration rate (eGFR) in mL/min/1.73 m2< 60; non‐ dialysis) or non – CKD (eGFR ≥ 60) in Minneapolis/St. Paul. CKD severity was measured by the eGFR and urine albumin creatinine ratio (UACR‐albuminuria, a measure of microvascular disease). Brain images were obtained on a 1.5 T Phillips Ingenia machine at baseline and 3 years. Linear regression models measured the associations between 3 year change in eGFR and UACR, as predictors of change in MRI measures: AD cortical thickness, WMH, and FA CC over 3 years. Adjusted models included age, gender, AA race, education years, cerebrovascular disease risk factor score (CVD RF), smoker/alcohol use, and pulse pressure as covariates, and TIV for change in WMH models.

Results

At baseline, mean age of the 97 participants was 67 years, and mean eGFR was 37 for the CKD group vs. 83.2 for non‐ CKD (Table 1). Mean change in eGFR and UACR in the CKD group were ‐3.6 and +212, respectively compared with ‐ 8.5 and +1.7 in the non‐ CKD group. Mean WMH volume increase (+5.8 cc) and mean FA CC decrease (‐0.012) were significant in CKD (p < 0.001) for both (Table 2). In adjusted models both a 1% decrease and a ≥ 3 unit/year decline in eGFR were associated with a decline in FA CC over 3 years in the CKD group (β (SE) =‐0.020 (0.007); p = 0.004) and ‐0.0097 (0.0042); p = 0.025, respectively). Cortical thickness models were not significant. Unexpectedly, change in UACR was not associated with change in any MRI outcomes.

Conclusions

Decreased eGFR was associated with decreased FA CC in CKD, suggesting that CKD progression exerts its influence largely through cerebrovascular mechanisms.
Hormetic effects of alcohol in an astroglial cellular model and its proteomics signature
Authors: Khorshidi Fatemeh , Poljak Anne , Jayasena Tharusha , Sachdev Perminder S.
Published: December 2020

Background

Hormesis or the adaptive stress response is a biphasic dose response to a factor which has a beneficial effect on cells or an organism at low doses while having a toxic effect at higher doses (1). Alcohol has been considered both a cause and protective factor for dementia (2) and arguably has a biphasic effect on brain cells. This study evaluated the dose‐ response relationship of ethanol on astrocytes in vitro, considering the importance of astrocytes in the support, maintenance and repair of neurons and the blood brain barrier (3). Cellular proteomics was performed to examine likely mechanisms underlying the effect.

Methods

An astrocyte cell line (U‐251) was used, incubating cells with increasing concentrations of ethanol. Cell viability and toxicity were evaluated by MTT (3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide) and LDH (Lactate Dehydrogenase) Assay assays respectively. Proteomic profiling was performed (LC‐MS/MS) to assess differential protein expression in response to ethanol in the hormetic range, and at different timepoints after exposure (12 and 24hrs).

Results

At low concentrations (0.1% to 1%) ethanol was stimulatory to U‐251 cell growth, and at high doses (5% to 20%) toxic effects were observed, demonstrating a biphasic curve in response to ethanol (Figure 1 & 2). Proteomic evaluation using cells exposed to hormetic doses of ethanol showed significant upregulation of proteins involved in DNA repair and cellular response to stress and DNA damage functions at 12 hours (Figure 3), while at 24 hours protein expression changes mostly related to apoptosis and regulation of reactive oxygen species (Figure 4).

Conclusion

These results show that at low doses ethanol has a hormetic effect on the U‐251 astrocyte cell line, and a biphasic dose response curve is observed across the full ethanol concentration range. Proteomics profiling suggests that mechanisms of cellular protection within the hormetic range include upregulation of stress response proteins, DNA protection and factors which promote cell growth.
Cortical cerebral microinfarcts and risk of stroke, dementia and mortality: The Rotterdam study
Authors: Rojas‐Saunero Liliana Paloma , Doolabi Arwin , Vrooman Henri A , Ikram M Kamran , Ikram M Arfan , Vernooij Meike W , Hilal Saima
Published: December 2020

Background

Cortical cerebral microinfarcts (CMIs) –a novel MRI marker of cerebral vascular pathology have been linked with dementia and impaired cognition in cross‐sectional studies. However, it is unknown if cortical CMIs are an indicator of further cognitive decline and incident clinical outcomes. We examine the risk factors of CMIs on 1.5T MRI and their association with cognitive decline and risk of stroke, dementia and mortality.

Method

2156 participants (median age: 74.6 (range: 70.7‐79.3 years, women 55.6%) with baseline MRI (acquired between January 2009‐December 2013) and no prevalent dementia were included. Data on incident clinical outcomes were available (until January 2016) were included. CMIs on 1.5T were graded based on a previously validated criterion on 3T and were defined as the hypointense lesions on T1‐weighted images, <5mm in diameter, restricted to cortex and perpendicular to the cortical surface Markers of cerebrovascular disease (cortical infarcts, white matter hyperintensities, lacunes, cerebral microbleeds) and neurodegeneration (volumes of total brain and hippocampus) were collected. Cognition was assessed using a detailed neuropsychological test at baseline and at follow‐up after five years.

Result

227 individuals (10.5%) had one or more cortical CMIs. The main risk factors of cortical CMIs were male sex (OR: 1.86, 95%CI: 1.23‐2.82), heart disease (OR: 1.81, 95%CI:1.24‐2.63), cortical infarcts (OR: 6.03, 95%CI:3.79‐9.58) and lacunes (OR: 1.12, 95%CI: 1.03‐2.29). Persons with cortical CMIs showed cognitive decline albeit non‐significant. During a mean follow‐up of 5.2 years, 14 (6.5%) individuals with cortical CMIs developed incident stroke, 10 (4.6%) incident dementia and 76 (3.5%) died. People with cortical CMIs at baseline had an increased risk of strokes (Risk Ratio (RR): 1.66, 95%CI:0.8‐3.11), mortality (RR: 1.18, 95%CI:0.97‐1.43) compared to individuals with no CMIs, unlike the risk of dementia (RR: 0.72, 95%CI: 0.27‐1.30) albeit non‐significant.

Conclusion

Cortical CMIs are highly prevalent in a population‐based setting and are associated with cardiovascular risk factors and increased risk of stroke and mortality albeit non‐significant. These findings provide new insights into the etiologic and prognostic significance of cortical CMIs. Future investigations will have to show whether screening and treating persons with cortical CMIs can effectively reduce the burden of stroke.
Effects of the 4‐week high intensity interval physical exercise intervention on physical fitness, cognitive function and electroencephalogram patterns in 6 Korean elderly
Authors: Lee Sun Min , Choi Muncheong , Chun Byoung‐O , Kang Dong Won , Kang Seung Wan , Sun Kyunghwa , Song Hong‐sun , Moon So Young
Published: December 2020

Background

This is a preliminary study to research the efficacy of a multicomponent and structured high intensity interval physical exercise intervention (PEI) on cognitive function in the not‐demented Korean elderly.

Method

We enrolled 6 not‐demented participants over the age of 70 from a community health center (77.0±4.7 years, 33.3% female). The PEI was conducted at the community health center for 4 weeks, 3 times a week, and 1 hour a day. It was a multicomponent structured physical exercise program consisting of muscle strength, flexibility, balance and aerobic exercises using elastic bands and ladder‐shaped floor plate, which was also a high intensity interval exercise program that allowed participants to maintain a 75 percent increase in their heart rate during exercise rather than the heart rate measured at rest. The outcome of this study was the effect of our PEI and was intended to be verified by conducting the physical fitness, cognitive function evaluation and electroencephalography, which were analyzed by paired t‐tests.

Result

After the PEI, some items of participants' physical fitness and cognitive function evaluation were improved: 30‐seconds sit‐stand test (16.2±7.0 vs 24.8±5.5, p<0.05), 2‐minutes stationary march (98.3±27.2 vs 143.7±36.9, p<0.05), literacy independent cognitive assessment (LICA) memory domain score (89.6±21.6 vs 111.0±19.1, p<0.05), LICA executive domain score (33.3±5.3 vs 37.0±5.1, p<0.05) and LICA total score (214.6±30.6 vs 241.6±22.8, p<0.05). In addition, the relative theta and delta power on temporal brain region were decreased and the relative beta power on frontal brain region was increased (p<0.05) after the PEI.

Conclusion

This study suggests that our high intensity interval PEI program could be helpful for the elderly with cognitive brain function as well as physical fitness, lower extremity muscular and cardiopulmonary endurance.