bluuebunny/crossref_metadata_2025 huggingface dataset:
The clinical risk factors of cerebral microbleeds and its relationship with cognitive dysfunction
Authors: Yuan Junliang , Li Xuanting , Hu Wenli
Published: December 2020

Background

To explore the risk factors of cerebral microbleeds (CMBs) and the relationship between CMBs and cognitive impairment, and to provide more theoretical basis for the prevention and treatment of CMBs and vascular cognitive impairment.

Method

The CMBs group was classified according to the number and location. The basic clinical data were collected and the subjects all received the cognitive tests using Mini‐Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA) and the Neuropsychological Assessment Scales.

Result

A total of 138 subjects [71 participants in CMBs group and 67 as control] were enrolled, with an average age of 64.36±10.14 years. Ordered logistic regression analysis showed diastolic blood pressure (OR=1.05, 95% CI: 1.01‐1.09), history of ischemic stroke and transient ischemic attack (TIA) (OR=7.74, 95% CI: 2.74) ‐21.88), white matter hyperintensities (OR = 2.01, 95% CI: 1.46‐2.78) are independently associated with CMBs (P<0.05). Spearman correlation analysis showed that MMSE, MoCA, memory and executive function were correlated with CMBs (MMSE r=‐0.24, P=0.005; MoCA r=‐0.32, P<0.001; memory r=‐0.28, P=0.001; execution function r = ‐0.33, P<0.001). Multivariate linear regression analysis showed that MoCA score, memory and executive function were negatively correlated with CMBs number after adjusting for gender, age, years of education, other imaging biomarkers of cerebral small vessel disease and vascular risk factors (MoCA β=‐0.88, P=0.012; memory β = ‐0.22, P = 0.002; executive function β = ‐0.13, P = 0.001). As for the location, the results showed that the executive function of patients with strict lobe CMBs was lower than that of control group (P=0.046). In terms of speed and motion control, the differences between deep group and control group (P=0.037), deep group and infratentorial group (P=0.005) were statistically significant.

Conclusion

Diastolic blood pressure, history of ischemic stroke / TIA, white matter hyperintensities were independent risk factors for CMBs. CMBs are associated with cognitive dysfunction. CMBs in the strict lobe area are associated with the decline of executive function, and CMBs in the deep area are associated with the decline of speed and motor control ability.
A study on the lifestyle types of Koreans through time use
Authors: Yang Min Ah , Won Kyung‐A , Lim Seung‐Ju , Park Kang‐Hyun , Park Ji‐Hyuk
Published: December 2020

Background

In this study, the purpose of the research is to utilize data obtained through the survey of national life hours conducted on a national basis in 2014 as basic data in the study of future life style types for the purpose of the study to identify lifestyle types based on age and region of Koreans.

Method

The life balance triangle model is an approach to find out how the use of time is balanced between each area, after dividing living time largely into essential, compulsory, and free time. In this study, we looked at living hours in three main categories: Required maintenance time, mandatory time, and free time.

Result

People in their teens, 20s and 50s took up the rational life seeking type, those in their 30s and 40s took the achievement seeking type, and those in their 60s, 70s and 80s took the passive reality seeking type. Required maintenance time took up the most time in Jeollabuk‐do, mandatory time took up the most time in Ulsan, and free time took the most time in Gangwon Province. It was found that the higher the age group, the lower the satisfaction level of life. Daejeon had the highest level of satisfaction with life in each region, and Ulsan ranked the lowest in terms of satisfaction with life. Satisfaction with life was high in the order of rational life seeking type, achievement seeking type and passive reality seeking type.

Conclusion

Because the role of old age in life cycle is not established compared to other age groups, the transition to old age is difficult, so identifying their time‐use patterns is the basis for understanding the role of old people. Because time is based on how people structure their daily lives, the use of time is linked to work. Time‐use patterns provide the nature and level of participation and are useful for assessing health and well‐being. Therefore, it is necessary to provide systematic education and information to participate in balanced daily life through proper time management.
Capacity of the health facilities to manage Alzheimer’s and related dementia diseases in Mukono district: Challenges and recommendations
Authors: Joloba Stephen Samuel
Published: December 2020

Background

With the projected increase in number of older persons in both low and middle income countries, the burden of Alzheimer’s and related dementia diseases (AD/ARDs) is projected to increase as well. However, the health systems inadequately prepared to offer optimal care for patients with AD/ARDs, despite the growing disease burden. Hence, the aim of this study was to assess the capacity of the health facilities to optimally manage Alzheimer’s and related dementia diseases in Mukono district.

Methods

We conducted a cross‐sectional between August and December 2018. A survey of 32 facilities (3 hospitals, 2 health center IV (HCIV), 15 health center III (HCIII) and 6 health center II (HCII) and 6 Private health facilities) in Mukono district. We conducted a thorough assessment of medical records, interviewed heads of the facilities and questionnaire was administered to 46 health workers. The study assessed the service provision for AD/ARDs, Knowledge of AD/ARDs management, challenges and opportunities.

Results

Out of 32 health facilities assessed, 4 in 10 (42%)facilities reported managing (diagnosing/treating) clients with AD/ARDs, and majority (90.2%) were run by Non‐Physician Health Workers (NPHW). Only 2 in 10 of had guidelines for managing AD/ARDs. About less than half (46.4%) had AD/ARDs medicines in stocks (mainly Haloperidol) and all of the private facilities lacked essential medicine to treat AD/ARDs. All health center Iis lacked drugs for AD/ARDs. A significant knowledge gap in assessing and diagnosing AD/ARDs was observed among all the health workers. All health workers highlighted the need for addition training in AD/ARDs. Multitude of client and health provider challenges were observed in this study.

Conclusion

Health facilities in Mukono district are inadequately prepared to offer optimal services for management of AD/ARDs. AD/ARDs drugs, knowledge gap and human resource for health presented a great challenge. In order to address the inadequately capacity to manage AD/ARDs, emphasis should be dwelt on strengthening the health facilities; including specialized training in assessment and diagnosis of AD/ARDS and improving the drugs and commodities supply chain in Uganda.
White matter hyperintensity increases are a feature of familial AD and are associated with increased brain atrophy
Authors: Walsh Phoebe , Sudre Carole H. , Manning Emily N. , Fiford Cassidy M. , Veale Thomas , Cash David M. , Ryan Natalie S. , Lashley Tammaryn , Frost Chris , Fox Nick C. , Barnes Jo ,   the DIAN Study Group
Published: December 2020

Background

Relatively little is known about how white matter hyperintensity (WMH) changes relate to well‐characterised markers of disease progression such as brain atrophy rates in autosomal dominant familial AD (ADAD). Such analyses may improve models of disease progression and indicate whether WMH accrual and brain atrophy are associated features over the disease course.

Methods

We investigated WMH accrual in the Dominantly Inherited Alzheimer Network (DIAN) cohort. Participants included 72 controls, 95 PSEN1, 7 PSEN2 and 27 APP mutation carriers, with longitudinal multi‐modal imaging. WMH were segmented using a semi‐automated protocol. Brain atrophy rate was calculated using the boundary shift integral (BSI). Three statistical models were used: Model 1 used mixed‐effect linear regression to assess WMH accrual by mutation presence or type, adjusting for evidence of cognitive impairment (symptomatic status as defined using CDR). Model 2 assessed the effect of estimated years to onset (EYO) on WMH accrual. Model 3 estimated correlations between residual rates of change after allowing mean rates of change in WMH and brain volume to depend on proximity to expected onset. All models (1‐3) were allowed to depend upon total intracranial volume.

Results

The table shows summary statistics and rates of change including annualised rates of WMH accrual and brain atrophy. Results from Model 1 showed differences in WMH accrual between mutation groups after adjustment for symptom status (p<0.001), with APP having higher rates of accrual than all other groups. Model 2 demonstrated WMH increases were associated with EYO in PSEN1 and APP groups (p≤0.001, both tests), with an accelerating rate of accrual observed approaching and passing estimated onset in the PSEN1 and PSEN2 groups (p≤0.005, both tests). Model 3 demonstrated associations between residual rates of change in WMH and brain volume in the PSEN1 (r 0.76, p<0.001) and APP (r 0.55, p=0.03) groups (the figure shows crude rates).

Conclusion

Mutation type has an impact on WMH accrual, with APP mutation carriers in this cohort gaining more WMH over time. WMH changes are an important biomarker in ADAD with burden increasing with EYO. WMH and brain atrophy changes track together across the AD disease course.
Dissecting frontotemporal dementia: Correlations between neuropsychiatric symptoms and neuropathology
Authors: Scarioni Marta , Gami‐Patel Priya , Timar Yannick , Seelaar Harro , van Swieten John C. , Rozemuller Annemieke J.M. , Dols Annemiek , Scarpini Elio , Galimberti Daniela , Bank Netherlands Brain , Hoozemans Jeroen J.M. , Pijnenburg Yolande A.L. , Dijkstra Anke A.
Published: December 2020

Background

Frontotemporal dementia (FTD) is a group of young‐onset neurodegenerative syndromes characterized by changes in social cognition, behaviour, language, and psychiatric symptoms, the latter being increasingly recognized to be part of the early clinical presentation. The pathology of FTD, termed frontotemporal lobar degeneration (FTLD), is characterized by distinct molecular classes of aggregated proteins, the most common being TAR‐DNA binding protein 43 (TDP‐43), tau, and fused in sarcoma (FUS). With a few exceptions, it is currently not possible to predict the underlying pathology based on the clinical syndrome.

Method

In this study, we set out to investigate the relationship between pathological and clinical presentation at single symptom level in a cohort of 150 brain donors. The presence or absence of symptoms from the current clinical guidelines, together with neuropsychiatric features such as hallucinations and delusions, were scored and compared across pathological groups.

Result

Our cohort consisted of 68.6% FTLD donors (35.3% TDP‐43, 28% tau, and 5.3% FUS) and 31.4% non‐FTLD donors with a clinical diagnosis of FTD and a different pathological substrate such as Alzheimer’s disease (23%). The presence of hyperorality pointed to FTLD rather than non‐FTLD pathology (P < 0.001). Within the FTLD group, hallucinations in the initial years of the disease were related to TDP‐43 pathology (P = 0.02), including but not limited to C9orf72 repeat expansion carriers. The presence of perseverative or compulsive behaviour was more common in the TDP‐B and TDP‐C subtypes (P = 0.002).

Conclusion

Our findings indicate that neuropsychiatric features are common in FTLD and can form an important indicator of underlying pathology. In order to further improve diagnostic accuracy and to allow better inclusion of patients in targeted molecular trials, the routine evaluation of patients with frontotemporal dementia should include the presence and nature of neuropsychiatric symptoms.
Using graph theory to detect ageing and Alzheimer’s disease‐ related changes in the structure of cognitive networks
Authors: Wright Laura , De Marco Matteo , Venneri Annalena
Published: December 2020

Background

In accordance with the physiological networks which underlie it, human cognition is characterised by both segregation and interdependence of a number of cognitive domains. Cognition itself, therefore, constitutes a network, the organisation of which may be quantifiable using methods of graph theory. The present study aimed to exploit graph theory methods to assess changes in cognitive profiles throughout healthy ageing and further interrogate how such profiles may differ in the presence of pathology.

Method

A comprehensive neuropsychological test battery was performed in 6 participant groups; 3 groups of healthy adults split into the age ranges 18‐39 (N 75), 40‐64 (N 75) and 65 and over (N 70) and 3 patient groups including adults with amnestic mild cognitive impairment (MCI, N 75), non‐amnestic MCI (N 31) and Alzheimer’s type dementia (N 60). Partial correlations were performed on standardised scores between 16 cognitive tests. A binarised adjacency matrix was then created for each group in which significant correlations (p <.05) were retained as the connections or edges and each cognitive test represented a node. Network analysis measures were then applied to each matrix using the Brain Connectivity Toolbox.

Result

Network wide clustering and local efficiency of nodes showed an increase between the stages of normal ageing and this was considerably exacerbated by the presence of disease. Conversely, average betweenness centrality first showed an increase between the young and middle‐aged groups but was reduced compared to middle‐aged in the healthy older group. This reduction appeared to be again exacerbated within patients. These findings were particularly apparent between patients and healthy adults in tests of memory function.

Conclusion

While whole network approaches have become a staple of functional neuroimaging, such techniques have rarely been applied to the structure of cognition itself. Here, it has been demonstrated that the organisation of our cognitive networks is influenced not only by the ageing process but is further significantly altered by the presence of disease. Further investigation in this area may provide a novel approach for quantifying the effects of disease on cognitive function and could contribute to the development of sophisticated diagnostic tools in the future.
CSF proteomic changes in pre‐preclinical Alzheimer’s disease: A monozygotic twin study
Authors: Visser Pieter Jelle , Tomassen Jori , den Braber Anouk , Boomsma Dorret I , Campo Marta Del , Yaqub Maqsood , Van Berckel Bart NM , Scheltens Philip , Teunissen Charlotte E. , Tijms Betty M
Published: December 2020

Background

Drivers of amyloid beta (abeta) aggregation in early Alzheimer’s disease (AD) are poorly understood. Studies in autosomal dominant AD suggested that increased abeta production is an early feature. We aimed to identify early AD changes in the CSF proteome using a monozygotic discordant twin‐pair model. This model provides a proxy for disease progression as twins from pairs discordant for abeta aggregation who have normal abeta (a‐) can be considered to in an earlier stage of AD than discordant twins who have abnormal abeta (a+). We investigated whether CSF proteins associated with abeta aggregation in discordant a‐ twins correlated with markers of amyloid production using cross‐twin cross‐trait (CTCT) analysis.

Method

We included 48 cognitively normal monozygotic twin pairs from the EMIF PreclinAD study. We performed CSF proteomics by OLINK multiplex panels (673 proteins), and ELISA’s for tau, abeta40, and BACE1. We defined abeta aggregation by visual read on dynamic [18F]flutemetamol PET images. We compared CSF protein levels of twins that had both normal abeta (concordant a‐) with those of discordant twins with normal abeta (discordant a‐) and those of discordant twins with abnormal abeta (discordant a+). Enrichment analysis of proteins that differed between groups was performed using Gene Ontology. In CTCT analysis in the total cohort, we correlated protein levels of one twin with the concentration of abeta40 and BACE1, markers of abeta production, in the co‐twin. A significant CTCT correlation suggests that proteins have a common genetic background. Analysis were corrected for age and sex.

Result

Average age was 68 years (range 61‐86). Forty‐one pairs were concordant abeta‐, and 7 twin pairs were discordant for abeta aggregation. Relative to concordant a‐ twins, discordant a‐ twins showed a decrease in 1 protein and an increase in 74 proteins. Of the increased proteins, 61 were also increased in discordant a+ twins (figure). These proteins were enriched for nervous system development, immune activation and related processes. They correlated with abeta40 and BACE1 in CTCT analysis.

Conclusion

Around the onset of amyloid aggregation there is an increase in proteins involved in nervous system development and immune activation, which is related to increased amyloid production.
Sensor‐based activity and state recognition in dementia patients in stationary care as basis for situation‐aware assistive devices
Authors: Goerss Doreen , Köhler Stefanie , Haufschild Martin , Bader Sebastian , Kirste Thomas , Teipel Stefan J.
Published: December 2020

Background

Wearable sensors to monitor activity are easily available nowadays. Intelligent assistive technologies bear potential to offer innovative solutions that increase safety and facilitate independent activities in persons with dementia (PwD). It is important to incorporate knowledge about user‘s current state (e.g. cognitive and physical abilities) and situation to generate suitable interventions and provide meaningful assistance for PwD.

Method

Within the “SAMi”‐project, we set up an (ongoing) field study with PwD living in a nursing home. Participants wear smartwatches to measure activity (accelerometry) and enable indoor positioning via Bluetooth. In parallel, subjects' behavior is annotated in real time by trained observers using an elaborated scheme that contains activity, posture and place of the person, as well as disorientation, falls or request for help. The annotation scheme and possible intervention domains were derived from interviews with different groups of stakeholders. With the field study, we aim to identify in real time if a patient is at need of support and to select the most promising intervention in a given situation. Therefore, we plan to train algorithms on the synchronized sensor‐data and examine the accuracy of situation‐classification.

Result

To date, we included nine PwD in the age of 76‐96 years in moderate to severe stages of dementia (MMSE 5‐18). We gained >183 hours of observational data, accompanied by sensor data. We observed 134 events of disorientation, 95 events of caregiver support but only 3 requests for help. Ca. 79% of the annotated time patients wore the smartwatch. The majority of patients accepted the device (despite advanced cognitive decline). Setting up the technical infrastructure for the indoor positioning was challenging, for example due to restricted access to power points.

Conclusion

Analysis of data from wearable and ambient sensors bears potential to build a situation‐aware assistive device and is feasible to acquire in the setting of dementia patients living in nursing homes. A large number of situations where need for help became obvious was matched only by very few instances of active help seeking by the patients. This emphasizes the necessity for automated sensor‐based recognition of such situations.
Experiences of caregivers of people with dementia participating in a community‐based dementia caregiver program
Authors: Seo Hyun‐Ju , Kim Seong Min , Park Jeong Min , Choo Il Han
Published: December 2020

Background

Caregivers often experience multiple challenges in their caregiving roles and responsibilities. In South Korea, a community based‐dementia caregiver program was introduced as one of public health policies. Understanding of caregivers' perspective and experience participated in a community based‐dementia caregiver program might be important to improve the quality of care of caregivers of people with dementia and refine the public policy program. The objectives of this study were to describe (1) how a community based‐dementia caregiver program helped caregivers of older adults with Alzheimer disease and related dementia, and (2) suggestions of the program to increase participation of caregivers.

Method

A descriptive phenomenological study using thematic analysis with SUMARI software was used. A total of 12 Korean caregivers were interviewed at post‐intervention of 8 week‐Korean dementia caregivers' program provided by government funded dementia management center, called as CHIMAE ANSIM CENTER. Interview guide for qualitative interviews with caregivers were as follows.

1) How does a community based‐dementia caregiver program help caregivers of older adults with Alzheimer disease and related dementia? 2) Did it help you deal with significant changes you experienced as a caregiver? Why or why not? 3) Which features of the program do caregivers find most and least helpful? 4) Do you have any other suggestions or anything else to improve?

Result

Several key themes with related subthemes will be emerged. The present study will show that participation in this program help caregivers have their care strategies positively leading to emotional and health benefits on the care dyads, and suggest the improvements to increase acceptability of this program. The specific study findings will be demonstrated in poster presentation of the conference.

Conclusion

The present study will be the first study that demonstrated caregivers' experiences participated in a community based‐dementia caregiver program introduced as a public policy to challenge and cope the dementia of South Korea.
Biomarker counseling, disclosure of diagnosis, and follow‐up in patients with mild cognitive impairment: A European survey of EADC centers
Authors: Frederiksen Kristian Steen , Nielsen Rune , Robinson David , Hausner Lucrezia , Hanseeuw Bernard J , Nobili Flavio Mariano , Rikkert Marcel GM Olde , Hugon Jacques , Andersen Birgitte Bo , Mendonca Alexandre , Traykov Latchezar , Yener Görsev , Scarmeas Nikolaos , Sloan Stephanie , Gabryelewicz Tomasz , Ousset Pierre Jean , Hort Jakub , Rouaud Olivier , Gabelle Audrey , Sheardova Katerina , Engelborghs Sebastiaan , Dubois Bruno , Grimmer Timo , Apollonio Ildebrando , Perneczky Robert , Spiru Luiza , Koivisto Anne M , Santana Isabel , Ceccaldi Mathieu , Waldemar Gunhild
Published: December 2020

Background

The concept of mild cognitive impairment (MCI) was developed as a research to capture a group of patients with objectively measurable cognitive impairment not fulfilling the criteria for dementia but has since diffused into clinical practice in many centers. The objective of the present survey was to assess practices with regards to diagnostic procedure and disclosure including biomarker counselling and management in patients with MCI.

Methods

The present study was designed as an online survey of medical doctors working in European Alzheimer Disease Centers (EADC).

Results

A total of 34 center coordinating doctors out of 41 (80.9 %) and 110 out of 213 (50.6 %) individual doctors responded to the survey. Almost all respondents had access to MRI (98.2%; n=108) and CSF sampling (91.8%; n=101), whereas fewer had access to 18F‐FDG‐PET (74.5%; n=82) and amyloid PET (50.9%; n=56). Most, but not all respondents, always or usually discussed the decision to order biomarkers with patients with MCI (85.7%; n=90) and dementia (81.1 %; n=86). Nearly half (49.5 % n=54) of respondents found that the diagnosis of MCI was meaningful to a great extent, whereas this was 75.5 % (n=84) for dementia (z=3.77; p=0.0002). Almost all respondents reported always or usually following up MCI (95.2%; n=100) and dementia patients (90.48%; n=95). Half (50.5%; n=53) of respondents reported following MCI patients for 5 or more years and for dementia 45.3% (n=48).

Conclusion

We found that biomarkers are widely used in patients with MCI, but that not all patients receive adequate pre and post biomarker counselling. For a considerable proportion of practices, we found considerable variability across centers. This may indicate that clinicians lack guidance on issues related to diagnostic disclosure including biomarker sampling.
Refining omega‐3 supplementation trials in APOE4 carriers for dementia prevention
Authors: Yassine Hussein N. , Cordova Isabella , He Xulei , Solomon Victoria , Mack Wendy J. , Harrington Michael G. , Braskie Meredith N. , Schneider Lon
Published: December 2020

Background

Despite the observed association of the omega‐3s docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) intake or blood levels with Alzheimer’ disease (AD) incidence and cognitive outcomes, omega‐3 clinical trials have largely been negative. Carrying the APOE4 allele is the strongest genetic risk factor for AD. Therefore, identifying how APOE4 affects the response to omega‐3 supplementation can help refine newer and more personalized trials. DHA supplementation increases EPA levels and EPA has strong anti‐inflammatory effects. The ratio of EPA to arachidonic acid (EPA/AA) is a marker of tissue inflammation.

Method

We examined the effect of APOE4 on the change in plasma and cerebrospinal fluid (CSF) EPA/AA in two different clinical trials: the ADCS‐sponsored DHA trial in patients with mild AD (n=402), and the Brain DHA Delivery Pilot trial in cognitively normal participants (n=33). In both trials, participants were randomized to high doses of algal DHA (2 grams per day). A subset of the ADCS‐sponsored study underwent MRIs for measurement of hippocampal volumes (n=86).

Result

Plasma EPA/AA was significantly lower in APOE4 carriers compared to non‐carriers after high dose DHA supplementation in both trials. CSF EPA/AA differed by APOE4 genotype in the Brain DHA Delivery Pilot, with APOE4 non‐carriers having two times greater increase in CSF EPA/AA than APOE4 carriers (30 vs. 14% increase, p=0.001) after supplementation. Greater increase in plasma EPA/AA was positively correlated with less decline in the right hippocampal volume (r=0.31, p=0.03) with APOE4 modifying this association (interaction p value, p=0.01, Figure 1).

Conclusion

APOE4 appears to limit the conversion of DHA to EPA after DHA supplementation by promoting EPA’s mitochondrial oxidation. These changes start before the onset of dementia. We propose that the plasma EPA/AA can serve as a biomarker for DHA supplementation efficacy. Prospective validation of this biomarker can guide the development of more personalized omega‐3 interventions designed to reduce the increased AD risk with APOE4.
Legacy of a 10‐year multidomain lifestyle intervention on the cognitive trajectories of overweight and obese individuals with type 2 diabetes mellitus
Authors: Hayden Kathleen M. , Luchsinger Jose , Carmichael Owen T. , Dutton Gareth , Johnson Karen C , Kahn Steven , Rapp Stephen R. , Yasar Sevil , Neiberg Rebecca H. , Espeland Mark A.
Published: December 2020

Background

Look AHEAD MIND was designed to examine whether a randomized clinical trial designed to induce and sustain long‐term weight losses led to cognitive benefit and to determine the role that baseline weight or history of cardiovascular disease (CVD) played in modifying this association.

Method

Participants (N=3,826; 45‐76 years) were randomized to an intensive lifestyle intervention (ILI) or to diabetes support and education (DSE). We derived a cognitive composite score based on standardized scores on the Look AHEAD battery of tests, including: Digit Symbol Substitution Test (DSST), Rey Auditory Verbal Learning Test, Modified Mini‐Mental State Exam, Trail Making Test (TMT) Parts A&B, and Stroop Color‐Word Test. Mixed effects models were used to determine whether random assignment to ten years of ILI or DSE would leave a legacy of different trajectories of cognitive function over 6‐8 subsequent years. Subgroups identified in our prior work as having potentially different intervention effects including those with BMI >=30 at randomization, and those who had a history of CVD at baseline randomization were studied.

Result

There were no significant differences in cognitive composite scores over time by intervention arm. However, there was a significant difference in performance on the TMT‐A (p<0.05), with individuals randomized to ILI performing better than the DSE group at the first two cognitive assessments. These relationships did not differ by baseline BMI. Analyses to examine interactions between baseline CVD status and intervention arm suggested those with baseline history of CVD randomized to ILI performed worse than the DSE group on the DSST (p=0.023) and the Stroop Test (p=0.003) over time. This trend for worse performance among ILI participants with CVD history was seen across all tests but only significant for the DSST and Stroop.

Conclusion

There were no significant differences in long‐term cognitive performance by randomization arm with the exception of TMT‐A. Interactions by baseline CVD history on two tests of executive function were found, although all tests showed similar yet non‐significant results. Participants with a history of CVD at baseline do not appear to have received cognitive benefits from the ILI intervention.
Clonal Hematopoiesis of indeterminate potential and the risk of mild cognitive impairment or probable dementia in the Women’s Health Initiative Memory Study
Authors: Hayden Kathleen M. , Leng Xiaoyan Iris , Manson JoAnn E. , Desai Pinkal , Kitzman Jacob , Jaiswal Siddhartha , Whitsel Eric A. , Reiner Alexander P
Published: December 2020

Background

Clonal Hematopoiesis of Indeterminate Potential (CHIP) occurs when hematopoietic stem cells in bone marrow undergo somatic mutations and yield genetically distinct leukocyte subpopulations with increased expression of inflammatory genes in innate immune cells. Genes commonly mutated in CHIP are associated with DNA methylation, inflammation, generation of reactive oxygen species, and DNA damage response. Factors associated with CHIP, including inflammation, cardiovascular disease (CVD), metabolic disorders, and stroke are risks for Alzheimer’s disease and other dementias, however the association between CHIP and dementia is unknown. We examined the association between CHIP and the incidence of MCI or probable dementia over 22 years of follow‐up in the Women’s Health Initiative Memory Study (WHIMS). We also examined these associations by common driver mutations for CHIP.

Method

Women without a baseline (1993‐1998) history of stroke, who participated in WHIMS and had baseline blood sample, were followed with annual cognitive assessments, adjudication of MCI or probable dementia, and provided self‐report of dementia diagnoses for up to 22 years. CHIP was defined by whole genome sequencing through TOPMed. Proportional hazards models were used to examine survival to onset of cognitive impairment (mild cognitive impairment (MCI), probable dementia, or self‐reported dementia).

Result

We classified 934 women into two groups, CHIP (11%) and no CHIP (89%). A total of 300 women developed cognitive impairment by Year 22. Survival analyses for time to cognitive impairment was adjusted for baseline age, education, 3MS score, hypertension, diabetes, and BMI. There was no difference in risk of cognitive impairment between the women with and without CHIP (p = 0.63). When CHIP was categorized by gene‐specific driver mutations, survival free of impairment among women with DNMT3A mutations was not different from those without CHIP. Risk for impairment was higher among women with TET2 (HR 1.75, p=0.19). Overall results were not statistically significant, however power was limited by low numbers of women with CHIP (see Figure).

Conclusion

CHIP was not associated with cognitive outcomes overall but when stratified by the primary CHIP mutations (DNMT3A or TET2), different trends emerged. Future work in WHIMS will explore the cognitive performance over time by different CHIP mutations.
Linking electronic dementia care records to national inpatient data in dementia with Lewy bodies: Frequency, duration and cost implications of hospitalization and recording of delirium episodes
Authors: Mueller Christoph , FitzGerald James M , Perera Gayan , Rajamani Anto Praveen Rajkumar , Bhattarai Manorama , Price Annabel , Ballard Clive , Stewart Robert , Aarsland Dag
Published: December 2020

Background

Increased hospitalization is a major component of dementia impact on individuals and cost but has rarely been studied in dementia with Lewy bodies (DLB). In particular episodes of delirium and related hospitalizations have been described as a prodrome of dementia with Lewy bodies. Our aims were to harness a novel linkage between dementia/mental health care records and national hospitalization data in England to (1) describe risk and duration of hospital admissions in patients with DLB and (2) to assess the incidence of delirium recording before and after a diagnosis of dementia is established in patients with DLB and compare findings to a matched cohort of patients with Alzheimer’s disease (AD).

Method

In a large database of mental health and dementia care in South London we identified 194 patients with DLB and 1:4 matched these with 776 patients diagnosed with AD on age, gender, and cognitive status.

Result

Rates of hospital admissions in the year after dementia diagnosis were significantly higher in patients with DLB compared to patients with AD or the catchment population. Patients with DLB had on average almost four additional hospital days per person‐year than patients with AD and incurred higher hospitalization‐related costs. Further, patients with DLB had significantly more episodes of delirium recorded in the year before dementia diagnosis than patients with AD. Whereas the incidence of recording of delirium episodes reduced substantially in patients with DLB after dementia diagnosis, it remained significantly higher than in patients with AD.

Conclusion

Patients with DLB are more frequently admitted to general hospital and utilize inpatient care to a substantially higher degree than patients with AD. Establishing a diagnosis of dementia reduces episodes classified as delirium in patients with DLB and might lead to fewer potentially harmful interventions as hospitalization or use of antipsychotic medication. These data highlight an opportunity to reduce hospital days and episodes classified (and treated) as delirium by identifying DLB earlier and providing more targeted care focused on the specific triggers for hospitalization and associations of prolonged stay.
ATN classifications in a mixed cohort of frontotemporal lobar degeneration (FTLD) and Alzheimer’s disease (AD) pathology using cerebrospinal fluid neurofilament light chain (NFL)
Authors: Cousins Katheryn Alexandra Quilico , Phillips Jeffrey S. , Irwin David J. , Lee Eddie B. , Wolk David A. , Shaw Leslie M. , Gibbons Garrett S. , McMillan Corey T. , Trojanowski John Q. , Grossman Murray
Published: December 2020

Background

The ATN framework combines cerebrospinal fluid (CSF) amyloidβ 1‐42 (Aβ1‐42), phosphorylated tau (p‐tau), and total tau (t‐tau) to diagnose individuals along the continuum of Alzheimer’s disease (AD). While ATN profiles indicative of AD are highly accurate, profiles indicating normal, non‐AD pathology, or concurrent AD and non‐AD pathology are inconsistent, due in part to the insensitivity of t‐tau to non‐AD pathologies, such as frontotemporal lobar degeneration (FTLD). We test a modified framework that replaces t‐tau with neurofilament light chain (NFL), a CSF marker of axonal degeneration.

Method

We compare ATN classifications using t‐tau (ATNt) and NFL (ATNf) in an pathology‐confirmed autopsy cohort of 72 AD (3 with concurrent FTLD) and 26 FTLD (14 with concurrent low‐high AD). In an independent living sample, receiver operating characteristic (ROC) analyses defined an optimal NFL cut‐point using 18 hereditary FTLD (10 C9ORF72, 3 MAPT, 2 progranulin, and 3 TARDBP) and 27 matched control subjects without cognitive impairment. Published cut‐points (Shaw et al., 2009) defined A (Aβ1‐42<192 pg/mL), T (p‐tau>23 pg/mL), and Nt (t‐tau>93 pg/mL) status, and the above ROC‐threshold (NFL>1003 pg/mL) defined Nf status to create a CSF‐based ATNt and ATNf profile for each patient.

Result

ATNt and ATNf were equally likely to identify Alzheimer’s continuum disease based on Aβ1‐42. Fisher’s test indicated no difference in Nf‐positivity (41 of 72) and Nt‐positivity (44 of 72) for AD pathology (p=0.73). ATNf correctly identified 25 of 26 FTLD cases as non‐AD pathology; 21 FTLD cases were classified as non‐AD (A‐T‐Nf+/A‐T+Nf+), 4 as non‐AD and concurrent AD (A+T‐Nf+), and 1 misclassified as normal (A‐T‐Nf‐). Fisher’s test showed that ATNf was significantly more likely to identify FTLD as non‐AD pathology than ATNt (OR = 152.9, CI = 16 – 7639, p < 0.001); under ATNt, only 3 FTLD cases were classified as non‐AD (A‐T‐Nt+/A‐T+Nt+), while 19 were misclassified as normal (A‐T‐Nt‐) and 4 as early AD pathologic change (A+T‐Nt‐).

Conclusion

ATNf designations using NFL were more accurate than t‐tau when assessing a mixed AD‐FTLD pathology cohort. Future biomarker strategies to detect both AD and non‐AD neuropathologies, such as FTLD, should consider alternative markers for N.
Theory of Mind in mild cognitive impairment: Relationship with the default mode network (DMN)
Authors: Michaelian Johannes Carapiet , McKinnon Andrew C , Mowszowski Loren , Duffy Shantel L , Guastella Adam , Naismith Sharon L
Published: December 2020

Background

It has been well established that older adults presenting with amnestic Mild Cognitive Impairment (aMCI) are not only at a higher risk of developing dementia compared to individuals with non‐amnestic Mild Cognitive Impairment (naMCI) and older adult controls, but also demonstrate impairments in Theory of Mind (ToM) ability, which has been associated with smaller limbic structure volumes. In the present study, we sought to examine any alterations in resting‐state functional connectivity within the brain's default mode network (DMN) in a sample of adults with MCI previously reported to demonstrate poorer ToM abilities.

Methods

17 adults with aMCI, 26 adults with naMCI and 16 older adult controls completed the Reading the Mind in the Eyes Test, followed by resting‐state functional magnetic resonance imaging.

Results

After controlling for age and correcting for multiple comparisons, adults with aMCI demonstrating poorer ToM abilities revealed significantly decreased functional connectivity between the left lateral temporal cortex (LTC) and the right temporal pole (b = .07, t(23) = 3.73, p = .02), as well as between the left LTC and both the left (b = .06, t(23) = 3.32, p = .03) and right (b = .04, t(23) = 2.91, p = .049) temporoparietal junctions ,relative to adults with naMCI.

Conclusions

Our findings suggest that deficits in connectivity across a more widely distributed network of brain regions such as the DMN may be contributing to ToM deficits in aMCI, beyond the previously identified changes in limbic structure volumes. Moreover, in a broader clinical sense, these results contribute to a growing body of evidence highlighting that it is important to include measures of social cognitive function in the routine clinical workup of individuals with suspected MCI.
Identification of ADAMTS4 as an APP‐cleaving enzyme at 669 site in the APP669‐711 production pathway
Authors: Tomita Taisuke , Matsuzaki Masaya , Kaneko Naoki , Yokoyama Miyabishara , Yoshizawa Yota , Iwamoto Shinichi , Tanaka Koichi
Published: December 2020

Background

Amyloid‐β peptide (Aβ) is deposited in the brains of Alzheimer disease (AD) patients, and proteolytically derived from its precursor protein, APP. APP669‐711 (a.k.a. Aβ(‐3)‐40) is a novel APP‐derived peptide detected in the plasma using immunoprecipitation‐matrix‐assisted laser desorption ionization‐time‐of‐flight mass spectrometry (IP‐MS). We have reported that the composite plasma biomarker, which is combination of APP669‐711/Aβ1‐42 ratio and Aβ1‐40/ Aβ1‐42 ratio, surrogates the accumulation of Aβ in brain (Kaneko et al., Proc Jpn Acad Ser B Phys Biol Sci. 2014; Nakamura et al., Nature 2018). However, the mechanism of APP669‐711 production is largely unclear.

Method

We analyzed the effects of several inhibitors and genetic knockouts on the production of APP699‐711 in cultured cells.

Result

Endogenous APP669‐711 was detected in the conditioned medium of BE2‐(C), Neuro2a and A549 cells by IP‐MS. Pharmacological experiments revealed that APP669‐711 is generated by sequential cleavages by GM6001‐sensitive metalloprotease at 669 site and γ‐secretase. Based on the preferences of the substrate sequence, we focused on ADAMTS4, which is the secreted metalloprotease with thrombospondin motif. Overexpression of ADAMTS4 resulted in the overproduction of APP669‐711, which was diminished by the catalytically inactivating mutation (i.e., E362A). Furthermore, endogenous APP669‐711 production was decreased in ADAMTS4 knockout cells.

Conclusion

These results indicate that ADAMTS4 is involved in the production pathway of APP669‐711, a novel plasma biomarker for Aβ deposition in the brain.
Aquaporin4 facilitator decreases insoluble amyloid b of 5XFAD mouse brain
Authors: Kwee Ingrid L. , Igarashi Hironaka , Huber Vincent J. , Ueki Satoshi , Suzuki Yuji
Published: December 2020

Background

Most brain degenerative diseases are recognized as pathologic protein accumulating diseases. To date, there have been no established treatments that promote clearance of pathological proteins. Enhancing clearance, and thus preventive reduction of accumulation of pathological proteins is an obvious target for new treatment development for this category of brain diseases. Aquaporin4 (AQP4) is one of the water channel proteins abundant in brain astrocytes, and controls excretion of metabolites from inside the brain parenchyma to the cerebrospinal fluid. It has been reported that a functional decline of AQP4 is one of the causes of intracerebral pathological protein accumulation diseases, such as amyloid‐β in Alzheimer's disease, and tau accumulation in head trauma. Therefore, promotion of AQP4 function can be expected to prevent/ameliorate intracerebral pathological protein accumulation. We administered TGN‐073, a small sized molecule that facilitates AQP4 function developed by our laboratory, to Alzheimer model 5xFAD mice and assessed its effect on Ab accumulation.

Method

1. Waste clearance disturbance in 5xFAD mice was assessed using the JJVCPE MRI method in 7month old 5xFAD mice and their litter mates. 2. 5xFAD mice were divided into two groups. One group received 400mg/kg TGN‐073 daily through gavage between the ages of 4 to 7months. The second group received the same volume of water. Soluble and insoluble amyloid b 40/42 was subsequently assessed in the hippocampus and cortex of these two groups.

Result

TGN‐073 decreases insoluble amyloid b (Ab) 40 and Ab42 in Alzheimer transgenic mouse (5xFAD mice) brain parenchyma, whereas no significant difference was seen in the clearance of soluble Ab40 or Ab42.

Conclusion

Waste clearance from brain has been found to be reduced in AQP4 knockout mice and APP‐PS1 Alzheimer transgenic mice. The reduction in clearance is further found to be associated with a decrease in aquaporin 4(AQP4) function in an Alzheimer's disease model mouse. Part of Ab accumulation causation is evoked by reduced waste clearance in 5xFAD mouse. Our study shows that the AQP4 facilitator TGN‐073 prevented the insoluble Ab accumulation in 5xFAD mouse through facilitation of AQP4 activity.
Quality of life and disease burden in patients with MCI and dementia
Authors: Moon Woori
Published: December 2020

Background

Understanding of Health Related Quality of Life (HRQoL) and disease burden from Mild Cognitive Impairment (MCI) and dementia is critical to properly manage growing clinical and social burden of cognitive disorder. While each type of cognitive disorders requires different management strategy, studies separately evaluating HRQoL and disease burden of different types of dementia are sparse. Particularly, there is no study estimating disease burden from MCI. Therefore, we investigated 1) the loss of HRQoL from each of MCI, Alzheimer’s Dementia (AD), Vascular Dementia (VD), and dementia total, 2) the disease burden of each disorder in Disability Adjusted Life Year (DALY) with population representative cohort data.

Method

Euro‐QoL‐5D index scores and clinical data of 6,520 elderlies are derived from Korean Longitudinal Study on Cognitive Aging and Dementia (KLOSCAD) cohort. We built a multiple linear regression model to estimate the adjusted impact of cognitive disorder on HRQoL. For calculation of DALY, disease specific prevalence, mortality, remission rate are obtained from Korean Longitudinal Study on Health and Aging (KLOSHA) and KLOSCAD cohort. The current and future DALY from MCI, AD, VD and total dementia is calculated by standardized method according to the World Health Organization’s guideline.

Result

After adjustment of covariates, VD causes the most substantial HRQoL loss of ‐0.309, followed by AD (‐0.143) and MCI (‐0.017). Patients with CDR ≥2 experience significantly higher loss of HRQoL (‐0.498) than patient with CDR 1 (‐0.151) or CDR <1 (‐0.096). In 2015, DALY per 100,000 attributed to AD, VD and dementia total is 417, 237, and 931 respectively. The DALY from MCI (412 per 100,000) is almost same with that of AD. The projected DALY from MCI and dementia in 2065 (9,543 per 100,000) is more than seven times bigger than 2015 (1,343 per 100,000).

Conclusion

Cognitive disorders, especially VD, cause significant loss of HRQoL in elderlies. The disease burden from MCI as well as dementia is substantial at present and rapidly grows. From MCI stage, the early efforts should be made to prevent HRQoL loss and to manage increasing disease burden. (Supported by Korean Health Technology R&D Project, Ministry of Health and Welfare, grant number HI15C3206.)
Decreased plasma Aβ levels were not associated with post‐stroke cognitive impairment
Authors: Lu Wenhui , Zhao Yi , Shang Suhang , Chen Chen , Wang Jin , Qu Qiumin
Published: December 2020

Background

It has been reported that stroke promotes the deposition of Aβ in the brain, which may be associated with post‐stroke cognitive impairment. Considering plasma Aβ is closely related to Aβ deposition in the brain, in the present study, we investigated the relationship between plasma Aβ levels and cognitive dysfunction after stroke.

Method

A total of 138 patients of acute ischemic stroke (within 2 weeks of onset) who were hospitalized in the Neurology Department of the first affiliated hospital of Xi 'an Jiaotong University and 138 age‐matched controls were enrolled between Jan1, 2017, and Oct 30, 2018. The Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) was used to assess the pre‐existing cognitive status. A validated Chinese version of the Mini‐Mental State Examination was used to assess cognition. Fasting venous blood was taken in the morning and plasma Aβ42, Aβ40, sLRP1, and sRAGE levels were measured by ELISA. The relationship between plasma Aβ and cognitive impairment was analyzed using logistic regression analysis.

Result

Among acute ischemic stroke 138 patients, 37 patients met the criteria for cognitive impairment, the incidence of cognitive impairment was 26.81%. Plasma Aβ42, sLRP‐1 and Aβ42/Aβ40 ratio were decreased in the acute ischemic stroke group. While plasma Aβ40, Aβ42, sLRP‐1, sRAGE levels and Aβ42/Aβ40 ratio had no significant difference between cognitive impairment group and the normal cognitive group. The multivariate analysis showed that plasma Aβ40, Aβ42, sLRP‐1, sRAGE levels and Aβ42/Aβ40 ratio were not associated with post‐stroke cognitive impairment.

Conclusion

Plasma Aβ42, sLRP‐1 and Aβ42/Aβ40 ratio were decreased after acute ischemic stroke, however, the levels of plasma Aβ and transports were not associated with post‐stroke cognitive impairment.