bluuebunny/crossref_metadata_2025 huggingface dataset:
Diastolic dysfunction and cognitive impairment
Authors: Parker Alicia S. , Himali Jayandra J , Beiser Alexa S. , Short Meghan I. , Kautz Tiffany , Vasan Ramachandran S. , Seshadri Sudha ,   Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases, UT Health San Antonio
Published: December 2020

Background

The relationship between diastolic dysfunction and cognition is undefined. Diastolic dysfunction is common, disproportionately affects females, and is increasing in the community. While earlier studies suggested that management of diastolic dysfunction did not improve cardiovascular mortality, there is increasing evidence that diastolic dysfunction affects patient outcomes. Our clinical observation is that patients with diastolic dysfunction tend to have increased white matter hyperintensities on imaging. If diastolic dysfunction is found to be associated with cognitive impairment, that would suggest diastolic dysfunction is a novel modifiable risk factor for the development of dementia.

Method

Echocardiographic, MRI and neuropsychological data collected by the Framingham Heart Study, Offspring Cohort, at Exam 8 was reviewed. Diastolic measures were related to MRI measures of total cranial brain volume, hippocampal volume and white matter hyperintensities, and to neuropsychological evaluations.

Result

Data from 1438 participants (Figure 1) showed that increasing E/E’ ratio, indicating increasing diastolic dysfunction, was associated with increased executive function impairment in the Similarities (β±SE:‐0.29±0.09,p<0.002) and FAS Phonemic Fluency (‐1.27±0.33,p<0.001) tasks. Participants with moderate to severe diastolic dysfunction performed more poorly on Logical Memories (‐0.70±0.34,p<0.036) and FAS Phonemic Fluency (‐2.75±1.11,p<0.014), and trended towards increased impairment on Similarities (‐0.59±0.30,p<0.052) (Table 1). Data from 1217 participants (Figure 2) showed that those with mild diastolic dysfunction trended towards increased white matter hyperintensities (0.11±0.07, p<0.105); participants with moderate‐to‐severe diastolic dysfunction had increased white matter hyperintensities (0.30±0.09,p<0.001) (Table 2). Data from 1415 participants showed that increasing E/E’ ratio was associated with increased incident mild cognitive impairment (HR 1.29 [95%CI: 1.01, 1.66], p<0.043; Table 3).

Conclusion

Diastolic dysfunction was associated increased incident mild cognitive impairment. Increased diastolic dysfunction was associated with impaired executive function and verbal memory on neuropsychological testing, along with increased cerebral small vessel disease as demonstrated by white matter hyperintensities on MR imaging. As cerebral small vessel disease clinically presents with executive function impairment, these results align well. An amnestic impairment was also seen, such as can occur in Alzheimer’s disease. This study suggests that diastolic dysfunction is a novel modifiable risk factor for the development of dementia. Further research examining management of diastolic dysfunction on cognitive outcomes would be of benefit.
Scientific appraisal of the health app review tool: A validation and usability testing protocol
Authors: Faieta Julie , Erickson Kirk I , Digiovine Carmen , Best Krista
Published: December 2020

Background

There is a critical need to develop and evaluate effective tools to support the quality of life for those with Alzheimer’s disease (AD). Apps focused on health and function have great potential to fulfill this need through education, health and behavior tracking, and interactive capabilities. However, current app evaluation tools lack specificity to the AD and caregiver population and fail to assess factors specific to the unique needs of AD. The Health App Review Tool (HART) was designed to characterize the features of apps and then match these features to the needs and abilities of those affected by AD. The purpose of this study is to evaluate the reliability and validity of the HART and to refine the structure and content of the HART according to findings.

Method

This study will be carried out across Quebec, Columbus, and Pittsburg. A sample of ≥300 health care professionals working with the AD population will be recruited to complete the HART at two time points based on one of four apps and case studies. Inter and intra‐rater reliability will be assessed according to app/case study allocation and between time points. Confirmatory factor analysis and Rasch analysis of time 1 scores will be used to assess psychometric soundness. A sample of ≥12 researchers and clinicians will participate in focus groups according to the think‐aloud qualitative approach to systematically assess each item in the HART. Feedback from both psychometric and qualitative assessments will be used to refine the HART.

Result

We anticipate that the current version of the HART will be have redundant items as indicated by residual correlation and that the current factor loading will indicate the need for item relocation. In addition, we anticipate qualitative feedback will indicate that branching structure and more limited item list would be preferable.

Conclusion

Initial investigations into the HART indicate promise as a clinically valuable instrument, however, additional development of the HART content and structure are needed prior to its widespread use. The HART is anticipated to impact the uptake and use of health and function supporting apps within the AD and caregiver population.
Relationship between the number of subjective cognitive decline domains involved and the neuroimaging biomarkers of Alzheimer’s disease: The SILCODE Study
Authors: Wang Xiaoqi , Sun Yu , Bi Qiuhui , Shu Ni , Han Ying
Published: December 2020

Background

Subjective cognitive decline (SCD), one of the earliest manifestations in preclinical Alzheimer’s disease (AD), may involve one or more cognitive domains including memory, language, executive and others. Converging evidence has revealed the association between SCD and AD biomarkers such as amyloid deposition and neurodegeneration alterations. However, most of the studies about SCD limited to memory domain and whether the increasing number of SCD domains involved is related to the neuroimaging biomarkers of AD remains largely unknown.

Method

Multimodal imaging techniques, including 18F‐florbetapir PET (AV45‐PET), 18F‐fluorodeoxyglucose PET (FDG‐PET), structural and resting‐state functional MRI, were performed in 63 SCD subjects and the regional imaging measures of 12 selected regions of interests (ROIs) were calculated, namely standard uptake value ratio (SUVr) of AV45‐PET and FDG‐PET, cortical thickness and fractional amplitude of low‐frequency fluctuation (fALFF) values. The total number of cognitive domains with reported complaints and the severity of memory complaints were assessed for each SCD subject. Partial correlation analyses were conducted to test the relationship between these SCD features and the neuroimaging markers of AD.

Result

SCD who reported multidomain complaints (multidomain SCD, md‐SCD, n=34) had greater amyloid burden, elevated fALFF values and thickened cortical thickness in the posterior cingulate gyrus and middle temporal gyrus than SCD who reported merely memory complaints (single domain SCD, sd‐SCD, n=29) (Figure 1). Even when regarded as continuous variable, the number of SCD domains involved was positively correlated with the degree of amyloid load in posterior cingulate, fALFF values in middle temporal, posterior and anterior cingulate and cortical thickness in precuneus (Figure 2). Additionally, the severity of memory complaints measured by the SCD questionnaire (SCD‐Q9) was only related to cortical thickness, but no significant association with other imaging markers was found (Figure 3).

Conclusion

An increased number of SCD domains involved was correlated with amyloid accumulation and may also be indicative of an underlying compensatory mechanism medicated by brain structures and functions alterations. Therefore, the reported number of SCD domains may be a potential valuable feature of SCD‐plus for AD risk and is promising for predicting AD pathologies.
Connecting with minority group Indonesians in the Netherlands
Authors: Utomo Amalia Fonk
Published: December 2020

Background

There are 16.151 registered Indonesian living in The Netherlands (source: Indonesian Embassy in The Netherlands). Around 800.000 Dutch people in 4 generations have Indo‐European roots. Besides Indo‐Europeans, around 40.000 people from Moluccan descent live in the Netherlands.(source: latitudes.nu) and 1.500 Indonesian are studying in The Netherlands, Alzheimer Indonesia Nederland & Alzheimer Nederland have a collaboration under the Twinning Program of Alzheimer's Disease International. This is a three‐year program for 2017‐2019 and a renewal of the previous program and funded by the Dutch government. Part of the funding is directed to activities for Indonesians in The Netherlands.

Method

In 2017 a foundation, Stichting Alzheimer Indonesia Nederland was created in the Netherlands to support and raise awareness within the Indonesian community living in the Netherlands about dementia and efforts in Indonesia. Accessing Indonesian Communities: religious, art and culture, professionals and government sharing information about the foundation and developments in Indonesia by connecting to more than 20 Alzheimer Indonesia’s chapters. By mid 2019 more than 2000 Dementia Friends and 50 volunteers are arranged in 8 cities: Groningen, Den Haag, Eindhoven, Amsterdam, Arnhem, Rijswijk, Zoetermeer, Rotterdam – The Netherlands and 2 cities in Indonesia: Jakarta and Malang. The foundation also connected to home care and nursing homes, an Alzheimer centre at the University and Alzheimer Café and two migrant organisations. We found that it is useful to explain Indonesian culture and behavior with the aim to help them to make their care accessible to Indonesian people. This is useful for both home care and nursing home care.

Result

4000 Dementia Friends, 60 volunteers, 83 Activities, 16 Cities in The Netherlands and 4 Cities in Indonesia.

Conclusion

Instead of generalisation, customized social, culture and religion approach and treatment are needed and helpful for minority migrant.
Memory and music: The role of musical training in verbal and visual working memory in musician and non‐musician adult subjects: Preliminary results
Authors: Garcia Lydia Moya , Feldberg Carolina , Tartaglini María Florencia , Hermida Paula Daniela , Irrazabal Natalia , Somale Verónica , Stefani Dorina
Published: December 2020

Background

Memory has been studied broadly in recent decades. Within the different systems that constitute this multidimensional construct, working memory is one of the components that generated the most unknowns, given the various processes put into play for its operation. The Cognitive Reserve Theory’s framework postulated that musical training is an activity that can help to protect and enhance such mnemic processes and those related to it. The main objective of this study is to explore the possible differences in working memory between musicians and non‐musicians normal adults.

Method

The steps for a cross‐sectional study were used. A total of 77 subjects between 18 and 55 years (32 musicians and 45 non‐musicians) were interviewed. The main materials used were Musical Training Questionnaire‐Argentine (Gooding, Abner, Jicha, Kryscio and Schmitt, 2014; Feldberg et al., 2019) to quantify the musical training in each subject (musicians also should have at least 5 years of musical training), and BIMeT‐Verbal and Visuospatial versions (Injoque‐Ricle, Barreyro, Formoso and Burin, 2018; Barreyro, Injoque‐Ricle, Formoso and Burin, 2019) to asses various aspects of verbal and visuospatial working memory. Measures of central tendency and dispersion were obtained to describe the socio‐demographic and musical training variables. Consequently, a normality test was performed and the Mann‐Whitney U test was used to contrast performance between groups. An error probability minor or equal to 0.05 was established, and data were analyzed by SPSS statistical software version 22.0.

Result

The results indicated a better performance by the group of musicians in a great extent of tests that set up the BIMeT‐V (direct letters score, p=0.049; direct letters span, p= 0.013; digit‐letter score, p=0.007; digit‐letter span, p=0.016) and BIMeT‐Ve (simple star score, p=0.001; simple star span, p=0.001; interferic star score, p=0.000; interferic star span, p=0.001; interferic blocs score, p=0.000; interferic blocs span, p=0.000).

Conclusion

The results of this work are consistent with those that have been previously researched, providing evidence regarding the role of music training in enhancing mnesic processes, especially in verbal and visuospatial aspects of working memory.
A comparison of neurocognitive decline in older adults in same‐sex and opposite‐sex relationships
Authors: Manca Riccardo , Venneri Annalena
Published: December 2020

Background

Individuals from sexual minorities experience health inequalities that have a detrimental impact on both physical and mental health. This disadvantage may particularly affect ageing people by exacerbating symptoms of chronic conditions, such as Alzheimer’s disease (AD) and generating more complex care needs. However, neurocognitive functioning and impairments due to neurodegenerative diseases in the lesbian, gay and bisexual (LGB) ageing population remain under‐investigated. Race and mood problems may confer higher risk for subjective cognitive complaints, while being in a relationship may mitigate the risk of cognitive impairment in LGB older adults.

Method

Clinical data for this study were selected from the National Alzheimer’s Coordinating Center’s Uniform Data Set and structural MRI data included were collected in 14 Alzheimer’s Disease Research Centres. Twenty patients with AD and 20 healthy controls (HC) in same‐sex relationships were identified and matched to groups of participants (20 AD and 20 HC) in opposite‐sex relationship by sex, age, education, cognitive status, diagnosis and APOE status. Interactions between diagnosis and relationship on all measures were investigated. Additional post hoc analyses were carried out in the same‐sex and opposite‐sex groups separately.

Result

No diagnosis‐by‐relationship interactions were found on any variable, although patients in the same‐sex group were more likely to present with at least one neuropsychiatric symptom. The opposite‐sex group had grey matter atrophy mainly in medio‐temporal and insular areas, while in the same‐sex group it extended also in medial frontal and posterior cingulate areas.

Conclusion

Our preliminary findings suggest that neurocognitive decline due to AD may express similarly across individuals, independently of relationship type, thus further suggesting a possible role of relational status as a protective factor. However, the same‐sex group of patients, compared to HC, appeared to be more likely to experience at least one neuropsychiatric symptom and to have atrophy in fronto‐limbic and insular areas, in line with previous studies. Future investigations should clarify whether AD‐related symptoms may manifest differently in people from sexual minorities, along risk and protective factors, in order to inform prevention programs and treatment planning.
Reasons for study exclusion by sex in lanabecestat studies AMARANTH and DAYBREAK‐ALZ
Authors: Zimmer Jennifer A. , Andersen Scott W. , Wessels Alette M. , Shering Craig , Sims John R.
Published: December 2020

Background

Sex‐based differences in pathophysiology and clinical presentation of Alzheimer’s Disease (AD) have been reported. These differences could impact trial eligibility. This analysis of screening data assesses the most common reasons for exclusion within sex.

Method

Phase 2/3 AMARANTH (NCT02245737) enrolled early AD (MCI due to AD, mild AD dementia) with MMSE 20‐30 and RBANS DMI ≤85. Phase 3 DAYBREAK‐ALZ (NCT02783573) enrolled mild AD with MMSE 20‐26. For MCI, NIA‐AA criteria were met, with CDR of 0.5 and memory box score ≥0.5. For mild AD, NIA‐AA criteria were met, with CDR of 0.5 or 1 and memory box score ≥0.5. Both studies enrolled participants 55‐85 years‐of‐age with proof of amyloid (PET scan or cerebrospinal fluid). Excluded participants meeting prespecified criteria were permitted ≤2 rescreens. Reasons for exclusion and patients randomized are presented by sex. The top three reasons for exclusion are compared by female and male subsets. In AMARANTH, participants could fail >1 criterion. For DAYBREAK‐ALZ, MMSE exclusion is further divided into MMSE score subsets (<20 or >26, when available). Statistical comparisons are made using Pearson’s Chi‐Square and not adjusted for multiplicity.

Result

For both studies, proportions of females represented in reasons for exclusion and randomization are similar (AMARANTH: 52% vs. 53%; DAYBREAK‐ALZ: 57% vs. 59%). In AMARANTH, MMSE score not within range was more commonly reported and lack of presence of amyloid was less commonly reported in the female subset than the male subset (17.8% vs 13.5% (p<0.001) and 22.4% vs 24.5% (p<0.05) of reasons, respectively). In DAYBREAK‐ALZ, proportions of reasons for exclusion in sex subsets were similar. However, MMSE score <20 was more common and MMSE score >26 less common as a reason for exclusion in the female subset compared to the male subset (females vs. males: score <20: 24.6% vs 18.3%, score >26: 12.8% vs 19.7%; p<0.001 for each).

Conclusion

These results suggest females presenting for screening may have more advanced disease. Possible reasons include late referral of females due to advanced verbal memory skills delaying recognition of disease, social circumstances, faster disease progression of females identified from clinical trial site databases, or differences in educational attainment.
Amyloid imaging for cognitive studies in cohorts with racial and ethnic diversity
Authors: Sano Mary , Zhu Carolyn W , Aloysi Amy , Grossman Hillel , Loizos Maria , Hedden Trey , Kinsella Michael T , Neugroschl Judith
Published: December 2020

Background

To compare rates of amyloid positivity in non‐Hispanic whites with diverse cohorts including Hispanic, Black, Asian, and other research participants.

Methods

Participants were enrolled in the ADRC, completed the Unified Data Set (UDS) and underwent amyloid imaging (2011‐2019). Racial and ethnic origin was self‐reported. Referral source and study enrollment were recorded. Amyloid images received a clinical read by a neuro‐radiologist who was blinded to patient characteristics used to determine amyloid status, regardless of study‐specific amyloid determination.

Results

191 cases who had received amyloid imaging were identified. 113 were non‐Hispanic white and 78 were minorities (36 non‐Hispanic Black, 28 Hispanic, 6 Asian, 8 other). Aside from the most common referral source from physicians (42%) for participants in both white and minority groups (42%), referral sources differed between white and minority participants. Amyloid imaging was performed using Amyvid (florbetapir F18 injection, n=94) and Neuraceq (florbetaben F18, n=97, 50.8%) tracers but usage differed between white and minority groups. Participant characteristics were: mean age 68.1 (SD=10.8) at time of scan, 52.9% male, mean CDR Sum of Boxes 0.8 (SD=1.3), 57.9% had no Apolipoprotein e4 alleles. Differences in these measures were not statistically significant between white and minority groups. Education (16.7±2.5 vs. 15.0±3.3) and cognitive composite scores (5.0±1.8 vs. 4.5±1.4) were higher in white compared to minority group (both p<0.01). Amyloid positivity was 27.4% (31/113) in whites, significantly higher than 9.0% (7/78) among minorities (p=0.002). Both groups demonstrated increasing amyloid positivity with age with whites ranging from 11.8% in those younger than 70, 34.0% in those age 70‐79, to 66.7 % in those 80 or older, and ranging from 4.7%, 14.3%, 14.3% in minorities in the same age groups, respectively. Results from analysis restricted to those with a UDS determined diagnosis of normal cognition, aMCI or AD remained the same.

Conclusions

In this relatively small convenience sample from diverse sources of recruitment and differential use of tracers for imaging studies we confirm previous impressions of lower rates of amyloid positivity in aging minority cohorts despite poorer cognitive performance. Both white and minority cohorts demonstrated age related increase in the presence of brain amyloid positivity.
Novel insights into risk of dementia after traumatic brain injury: A systematic review, meta‐analysis, and heterogeneity analysis
Authors: Gardner Raquel C. , Bahorik Amber L , Mangal Paul , Allen Isabel Elaine , Yaffe Kristine
Published: December 2020

Background

Traumatic brain injury (TBI) is an established risk factor for dementia. Risk estimates have varied substantially across studies with recent studies reporting higher risk in veterans, men, or at the extremes of age. We performed the largest and most comprehensive systematic review of risk of post‐TBI dementia with the aim of specifically investigating contributors to heterogeneity including age, sex, and veteran status.

Method

We performed a systematic review and meta‐analysis of all‐cause dementia after all‐severity TBI (search window 1/1990‐1/2019). We identified observational studies reporting age‐adjusted risk for all‐cause dementia after TBI among individuals with average age ≥40 years. Data were pooled using random‐effects models. Between study variability was assessed using the I2 index. We further evaluated sources of heterogeneity according to covariates including mean age, sex distribution (majority male vs. majority female), veteran status, design (case‐control vs. cohort), outcome/exposure ascertainment (ICD‐9 vs. other) and publication year using sub‐groups and meta‐regression analysis. Funnel plot inspection and Egger and Begg statistics were used to evaluate publication bias.

Result

Data from 41 studies representing N=7,736,173 individuals were included in the analysis. Overall pooled risk ratio (RR) for dementia after TBI was 1.71 (95% confidence interval [CI] 1.47,1.98) with no evidence of publication bias. There was substantial heterogeneity (I2= 98.6%; Q test p<0.001). Removal of each study in turn did not reduce heterogeneity. No significant differences were observed in risk estimates for dementia after TBI according to veteran status, study design, outcome/exposure ascertainment, or publication year (all p’s >0.09). However, risk estimates were significantly higher in studies with lower mean age (mean age <50y RR 2.52 [1.80,3.53]; 50‐70y RR 1.73 [1.34,2.24]; >70y RR 1.41 [1.17,1.71]; p=0.01; see Figure) and in studies that were majority male (majority male RR 2.16 [1.74‐2.69]; majority female RR 1.44 [1.22,1.70]; p=0.01). Mean age and sex distribution accounted for 27.5% and 27.9%, respectively, of the observed heterogeneity.

Conclusion

TBI is associated with a 71% increased risk for dementia. While risk was not modified by veteran status, risk was significantly higher in studies with younger mean age and majority male populations. These findings may inform targeted TBI prevention efforts.
Differential transcript usage unravels transcriptional alterations in Alzheimer's disease human brains
Authors: Marques‐Coelho Diego , Iohan Lukas , Lambert Jean‐Charles , Costa Marcos Romualdo
Published: December 2020

Background

Alzheimer’s disease (AD) is the leading cause of dementia in aging individuals. Several studies have shown that 60‐80% of late‐onset AD attributable risk has an important genetic component. However, a comprehensive overview of gene expression alterations in the diseased brain remains elusive.

Method

In this work, we compared the differential expression of genes in different regions (temporal and frontal lobes) of the brain of healthy and AD adult subjects from three large datasets: MAYO Clinic; Mount Sinai Brain Bank (MSBB) and ROSMAP. We also used isoform switch analysis to identify genes with altered transcript usage. Finally, we assigned altered genes to specific cell types of the adult brain and evaluate the expression of AD risk genes previously identified in pan‐genomic association studies.

Result

We show that gene expression is dramatically altered in the temporal lobe (TL), but not in the frontal lobe (FL), suggesting regional specificities in transcriptional alterations. Moreover, we show that a large set of genes without alteration in the classical differential expression (DEG) analysis do have alterations in the transcript usage ratio in AD. Ontology analysis for genes with differential transcript usage (gDTUs) show enrichment for key biological processes associated with AD pathology, which are not observed for DEGs only. Using single‐cell RNAseq data, we are able to assign DEGs and gDTUs to individual cell types of the adult brain and show that genes associated with synaptic transmission are mostly affected in GABAergic neurons. Lastly, we show that 52 out of 116 putative AD risk factors expressed in neural cells, microglia or endothelial cells of the adult human brain are differentially expressed in the TL, whereas only 13 are altered in the FL of AD patients. Among those altered genes, we detect an increased expression of APP isoforms containing the Kunitz protease inhibitor (KPI) domain, which is associated with plaque deposition.

Conclusion

Altogether, our work proposes a novel integrative strategy to analyse transcriptional data in AD based on both gene/transcript expression and cell‐type specificities and reveal an alteration of APP expression that could contribute to explain the increased production of Abeta 1‐42 in the AD brain.
Assessment of beta‐amyloid deposition using gray matter delineation by early‐phase F‐18 florbetaben PET in patients with brain atrophy
Authors: Jeong Shin Young , Yoon Uicheul , Kang Kyunghun , Lee Sang‐Woo
Published: December 2020

Background

In patients with brain atrophy, it can be difficult to distinguish between pathologic amyloid accumulation of gray matter and nonspecific uptake of white matter in F‐18 florbetaben (FBB) PET. We evaluated gray matter edges delineation method derived from the perfusion phase of FBB PET (GM_eFBB) and investigated whether standard visual diagnosis (STD) can be improved the confidence level and concordance rate when we used STD combined GM_eFBB in patients with idiopathic normal pressure hydrocephalus (iNPH).

Method

Two‐phase FBB PET and brain MRI were performed in 42 iNPH patients with subjective cognitive impairment. Gray matter delineation using each individual’s brain MRI (GM_MR) was performed and a cut‐off value of SUVR was evaluated to find the GM_eFBB closest to GM_MR. Two nuclear medicine physicians blindly and independently evaluated all late‐phase FBB images, initially employing the STD method and later the STD combined GM_eFBB method. Binary classification (positive/negative) and subjective confidence (three‐point scale) of diagnosis were evaluated. A Pearson correlation coefficient (PCC) between GM_eFBB and GM_MR was determined, and the Wilcoxon signed‐rank test was used to evaluate differences in subjective confidence between two methods. Intraclass correlation coefficient (ICC) and concordance correlation coefficient (CCC) were determined for two methods.

Result

The GM_eFBB obtained by cut‐off value that determined as 50% of the peak SUVR was closest to the GM_MR. PCC was greater than 0.97 for all lobes (p<0.0001). The STD combined GM_eFBB method resulted in significantly greater subjective confidence in the readings (p = 0.027). The CCC for the STD method was 0.65, and for the STD combined GM_eFBB method was 0.73. The ICC was higher for the STD combined GM_eFBB method (0.73, 95%CI 0.56–0.85) than for the STD method (0.65, 95% CI 0.44–0.79). The binary classification was concordant in 83.3% of the scans using the STD method and in 88.1% of the scans using the STD combined GM_eFBB method.

Conclusion

The STD combined GM_eFBB method can facilitate assessment of beta‐amyloid deposition in gray matter in patients with iNPH. The method may be applicable to patient with brain atrophy who may be difficult to judge of beta‐amyloid presence in gray matter.
Does the impact of a multidomain intensive lifestyle intervention on cognitive function depend on baseline frailty?
Authors: Simpson Felicia R , Carmichael Owen T , Hayden Kathleen M , Hugenschmidt Christina , McCaffery Jeanne , Ojeranti Daniel , Pajewski Nicholas M , Roman‐Ashby Glorian , Yasar Sevil , Espeland Mark A
Published: December 2020

Background

Type 2 diabetes and obesity, separately and in combination, are known to accelerate cognitive decline, increasing one’s risk of dementia. While lifestyle interventions may be expected to mitigate cognitive decline and dementia risk through multiple pathways, the Action for Health in Diabetes (Look AHEAD) randomized controlled clinical trial found no overall benefit from 10 years of multidomain intensive lifestyle intervention (ILI) compared to diabetes support and education (DSE). However, there was some evidence that the impact of the intervention on cognitive outcomes was heterogeneous, ranging from benefit for individuals with lower body mass index and no history of cardiovascular disease to harm for the heaviest individuals with a history of cardiovascular disease history. We hypothesized that the impact of the intervention on cognitive function may vary among individuals grouped according to a geroscience construct for biological aging, the Rockwood deficit accumulation frailty index (FI).

Method

A standardized battery of cognitive function tests was administered to 3,708 Look AHEAD participants, 10‐13 years after they had been randomized to 10 years of ILI or the DSE control condition. Participants, who were aged 45‐76 at baseline, were grouped according to tertiles of a 38‐item FI calculated from baseline characteristics. Analyses of covariance with interaction terms were used to assess the consistency of any intervention effects among FI tertiles.

Result

The median FI score was 0.20 at baseline, with 12% classified as frail (FI>0.21). Greater baseline FI was associated with poorer cognitive function in domains related to attention, processing speed, and executive function (all p<0.01), but not memory. Assignment to ILI was not associated with better cognitive functioning in any domain, and this finding was consistent across FI tertiles and inverse probability weighted analyses.

Conclusion

A 10‐year multidomain intensive lifestyle intervention that produced marked and sustained improvements in weight and physical activity did not provide cognitive benefits regardless of frailty at study entry. Although intervention effects on cognitive function were heterogeneous across the range of obesity and cardiovascular disease history, this heterogeneity was not evident across the range of deficit accumulation seen in the cohort.
Sex‐related differences in cognitive trajectories in older individuals with type 2 diabetes and overweight or obesity and the role of APOE4: Findings from the Look AHEAD and Look AHEAD‐MIND studies
Authors: Espeland Mark A , Bennett Wendy , Carmichael Owen T , Chao Ariana , Dutton Gareth , Hayden Kathleen M , Hugenschmidt Christina E , Kahn Steven , Luchsinger Jose , Neiberg Rebecca H , Roman‐Ashby Glorian , Olson Kayloni , Yassine Hussein N
Published: December 2020

Background

Women’s cognitive performance, particularly in the domains of verbal learning and memory, generally exceeds that of men. Among older individuals with diabetes and overweight/obesity, two conditions known to accelerate cognitive aging, it is unknown how these sex‐related differences in cognitive functioning unfold over time, i.e. whether any advantages seen in women result from less steep trajectories of cognitive decline than men, and whether any differences in rates of decline are moderated by the APOE4 genotype.

Method

A standardized battery of cognitive function tests was administered 2 to 4 times over the course of up to 10 years (mean 5.3 years) among 2583 adults (62% women) who averaged 68 years of age at their first assessment. Mixed effects models were used to compare cognitive function scores (verbal learning, executive function, and processing speed) at the first assessment and rates of cognitive decline over time between women and men, with covariate adjustment for potentially confounding risk factors for cognitive decline.

Result

At their first assessment, women significantly outperformed men on tasks of verbal memory and processing speed (both p<0.001), but not executive function (p=0.38). These differences were evident for those both with and without the APOE4 genotype. Over follow‐up, women and men had similar rates of cognitive decline in these domains, overall and among those without the APOE4 genotype (all p>0.05). However, the APOE4 genotype was associated with significantly greater rates of decline among women than men for verbal learning (37% vs 8% increase, p=0.04) and processing speed (28% increase vs 5% decrease, p=0.004), but similar increased rates of decline in executive function (p=0.67).

Conclusion

Female sex is associated with better cognitive functioning than male sex in key domains among older individuals with diabetes and overweight/obesity. Overall, this relative advantage is maintained over time among women without the APOE4 genotype. However, among those with the APOE4 genotype, rates of decline in verbal learning and processing speed are greater among women compared with men.
Assessment of brain iron accumulation in Alzheimer's disease with quantitative susceptibility mapping
Authors: Fan Xiang , Liu Xueru , Yan Lirong , Mok Vincent C. T. , Li Kuncheng
Published: December 2020

Background

Emerging evidence suggests that regional iron accumulation is involved in the early pathology of Alzheimer’s Disease (AD), which can be evaluated using quantitative susceptibility mapping (QSM). Therefore, the purpose of this study was to evaluate QSM as an early imaging biomarker in AD by comparing regional iron accumulation using QSM in patients with AD, mild cognitive impairment (MCI) and cognitively unimpaired (CU) subjects.

Method

Thirty‐seven patients with AD, twenty patients with MCI, and forty‐three CU subjects were recruited. All subjects received MRI QSM scans. All QSM images were reconstructed using NMEDI method. Using one‐way analysis of variance (ANOVA) test, the difference in regional iron accumulation between the three groups was studied in the regions of interest (ROI) including bilateral caudate nucleus and putamen. Pairwise multiple comparison was implemented using the least significant difference (LSD) method. For whole brain analysis, we applied a voxel‐based analysis using ANOVA followed by a post hoc analysis. A significant level of family‐wise error (FWE) corrected p < 0.05 with a cluster size of 30 voxels was applied to locate brain regions with significant differences among three groups. We used paired sample t test within 6‐month follow‐up data to see if there is any difference.

Result

Based on ROI analysis, average susceptibility of the bilateral caudate and left putamen was significantly different among groups (p<0.001, respectively). Maximal susceptibility of the left caudate was significantly different among groups (p<0.001). For the whole brain analysis, significant difference in iron accumulation among AD, MCI and CU was found in parahippocampus, caudate, putamen, insula, cingulate gyrus, cuneus, precuneus, angular gyrus, thalamus, fusiform, lingual gyrus, corpus callosum, cortex and subcortical white matter, some cerebellum structures and so on. No significant difference was detected with the follow‐up data in each group.

Conclusion

This study described brain iron accumulation patterns using QSM during AD progression. This may reveal secondary neuronal changes due to pathologic processes (e.g. oxidative stress) in AD. In addition, this study is the first to observe QSM changes in certain cerebellar regions. Further study is needed to confirm this finding.
Principal component analysis of brain metabolism in symptomatic Alzheimer's disease patients: A positron emission tomography with 18F‐fluorodeoxyglucose (PET‐FDG) study
Authors: Demey Ignacio , Mendez Patricio Alexis Chrem , Bérgamo Yanina , Urrutia Leandro , Campos Jorge , Falasco German , Sevlever Gustavo , Allegri Ricardo F , Vazquez Silvia
Published: December 2020

Background

Patients with symptomatic Alzheimer's Disease (AD) usually present alterations in their cerebral metabolism measured by Positron Emission Tomography with 18F‐fluorodeoxyglucose (PET‐FDG). In the amnestic AD phenotype, the regional differences reported between patients with Mild Cognitive Impairment due to Alzheimer's Disease (MCI‐AD) and AD Dementia (ADD) have not been consistent. Within the ATN scheme, this study detects Neurodegeneration (N). There are no published studies that correlated the metabolic value of each cortical region and the quantification of cognitive performance. Objective: To analyze brain metabolism by regions measured by Positron Emission Tomography with PET‐FDG in patients with MCI‐AD and ADD, and correlate the regional metabolic values with the severity of neuropsychological clinical variables.

Method

In this cross‐sectional study, 24 patients with MCI‐AD and 22 with ADD were included , all right‐handed and PET–PIB positive, matched by sex, age, and education, with differences in different cognitive variables (p<0.01). All were studied with PET‐FDG with automated parcellation using the Klein and Tourville atlas. Differences between groups (Anova) were analyzed, and a Principal Component (PC) analysis was performed to summarize the vectors of higher variability. Vectors were compared through diagnoses and correlated with neuropsychological evaluation and other clinical aspects.

Result

Patients with ADD showed lower metabolism than patients with MCI‐AD (p<0.05) in different regions of interest. Four PCs were identified that summarized 84.77% of the metabolism variability of the cortices analyzed. No significant differences were found in the magnitude of the CP between MCI‐AD and ADD patients (p>0.05). The first CP represented the magnitude of the overall metabolism and correlated with the age of the patients (p:0.04), the second CP weighted negatively frontal and positively occipital metabolism, and correlated negatively with semantic fluency (p:0.02), phonological fluency (p:0.04) and TMT‐A (p:0.003). The third CP considered parahippocampal regions and correlated with recognition in verbal episodic memory (p:0.01).

Conclusion

Dimension reduction analysis represents a novel approach to summarize neuroimaging data. In this sample of patients with PET‐PIB positive and symptomatic AD, CP extraction demonstrates a close correlation between regional metabolism and performance in neuropsychological tests associated with those regions.
Actigraphy as a proxy biomarker for motoric agitation in Alzheimer disease
Authors: Burhan Amer M. , Knuff Amber , Seitz Dallas
Published: December 2020

Background

Agitation is an important symptom of dementia and is commonly assessed using clinician and/or caregiver rated scales. These scales are useful but they rely on a mixture of direct and indirect observations and therefore are subject to limited reliability and validity depending of factors such as staffing. Actigraphy is a tool to assess motoric activity, a core feature of agitation. There is a growing interest in using Actigraphy as a tool to diagnose and monitor agitation of dementia. We previously published a report demonstrating feasibility and a correlation between Actigraphy and informant‐based rating of physical agitation in a sample of hospital and nursing home patients with Alzheimer in moderate level of cognitive impairment from Kingston Ontario, Canada.

Method

This is an extension to our previous observational, cohort study now involving a sample of older adults with Alzheimer disease and agitation from London Ontario, Canada in hospital and nursing home with severe level of cognitive impairment. Measurements: Baseline characteristics included demographics, severity of cognitive impairment, medical comorbidity, and agitation symptoms assessed using CMAI and NPI. Actigraphy was measured over several continuous days.

Results

Twenty participants were enrolled (mean age=81.3/years, SD=7.97; Male=12; mean MMSE=6.3, SD=5.7; mean CMAI score=66.83, SD=10.79). Pearson correlation coefficient was explored between agitation and Actigraphy measures. We found that total CMAI scores correlated with 24‐hours Actigraphy data (r(18)= 51, p= .02), further analysis showed that only physical non‐aggressive agitation correlated with 24‐hours actigraphy measures (r(18)= 0.49, p=.03), this was mainly related to day‐time and evening‐time Actigraphy but not overnight.

Conclusions

Actigraphy was correlated significantly and moderately with informant‐based methods for measuring physical agitation in individuals with dementia and showed a temporal pattern of activity. Further studies are required to understand the application of Actigraphy as a biomarker for motoric agitation in this population.
Activation of distinct synaptic populations regulates extracellular release of ILEI⁄FAM3C and Aβ
Authors: Nakano Masaki , Mitsuishi Yachiyo , Watanabe Naoki , Hibino Emi , Saito Takashi , Saido Takaomi C. , Suzuki Toshiharu , Nishimura Masaki
Published: December 2020

Background

Previously, we reported a novel role of the secretory protein ILEI (also referred to as FAM3C) in modulation of APP metabolism. ILEI binds to the γ‐secretase complex and destabilizes APP C–terminal fragments (CTFs) to suppress Aβ production without inhibiting γ‐secretase activity. ILEI is localized in the trans–Golgi network and the endocytic vesicles where Aβ is produced from PS1:APP–CTFβ complexes. Synaptosome fractionation analysis further indicated that ILEI is colocalized with APP and the γ‐secretase complex at the synaptic vesicle. In this study, we investigated how activation or suppression of a specific synapse population affects extracellular release of ILEI and Aβ.

Method

In order to measure ILEI concentration, we first generated monoclonal antibodies against recombinant ILEI and setup sandwich ELISA. ILEI and Aβ concentrations in the interstitial fluid of cerebral cortex of freely moving mice were monitored by microdialysis. Using humanized mutant APP–knockin mice, we examined an effect of selective agonist or antagonist for a specific population of neurotransmitter receptors on ILEI and Aβ secretion.

Result

Microdialysis study using APP–knockin mice revealed that interstitial fluid concentration of ILEI was fluctuated and roughly parallel with a level of locomotor activity but not with that of Aβ. Reverse dialysis treatment with anesthetics, tetrodotoxin and tetanus toxin markedly decreased both of ILEI and Aβ in the interstitial fluid. On the other hands, treatment with agonist (diazepam) and antagonist (picrotoxin) for GABAA receptor decreased and increased both ILEI and Aβ, respectively.

Conclusion

Our results suggest that presynaptic ILEI and Aβ are similarly released into the extracellular space in a synaptic activity–dependent manner. Especially, ILEI secretion is largely dependent on GABAA receptor activity.
Ribosomal protein synthesis is decreased in tauopathy as revealed by noncanonical amino acid labelling
Authors: Evans Harrison Tudor , Benetatos Joseph , Bodea Liviu Gabriel , Götz Jürgen
Published: December 2020

Background

Tau is a scaffolding protein which serves multiple cellular functions that are perturbed in neurodegenerative diseases, including Alzheimer’s disease (AD) and frontotemporal dementia (FTD). Recently we demonstrated that amyloid‐b, the second hallmark of AD, induces de novo protein synthesis of tau, with this activation being found to be tau‐dependent. This raised the question of whether FTD‐tau by itself affects protein synthesis.

Method

In order to examine protein synthesis, we optimised non‐canonical amino acid (NCAA) labelling to label newly synthesised proteins in vivo in the K369I tau transgenic K3 mouse model of FTD. Combining this technique with either fluorescent non‐canonical amino acid tagging (FUNCAT) or bio‐orthogonal non‐canonical amino acid tagging (BONCAT), we were able to visualise and purify newly synthesised proteins from mouse brain tissue. We also used polysome profiling in primary neurons to further explore the effect of tau on ribosome biogenesis.

Result

Our analysis reveals massively decreased protein synthesis in neurons containing pathologically phosphorylated tau, a finding we confirmed in P301L mutant tau transgenic rTg4510 mice. Using quantitative SWATH‐MS proteomics, we identify alterations in the synthesis of 247 proteins in de novo proteome of K3 mice, including the decreased synthesis of the ribosomal subunit proteins RPL23, RPLP0, RPL19 and RPS16, a finding that was validated in both K3 and rTg4510 mice. We also demonstrate that there is a decrease in overall abundance of one of these proteins, RPL23, and that this decrease correlated with the levels of both total and AT8 phosphorylated tau. Lastly, we recapultate these findings in human tissue, with FTD‐brains showing significantly lower levels of RPL23 than healthy controls.

Conclusion

Together, our findings present a potential pathomechanism by which pathological tau interferes with cellular functions through the dysregulation of ribosomal protein synthesis.
Polygenic effect of cholesterol metabolism pathway‐accelerated pathological changes and disrupted default mode network trajectory across the Alzheimer’s disease spectrum
Authors: Zang Fei Fei , Zhu Yao , Liu Yi Xin , Fan Dan Dan , Wang Qing , Zhang Qian Qian , He Cancan , Zhang Zhijun , Xie Ming Chun
Published: December 2020

Background

The cumulative genetic effect of cholesterol metabolism (CM) pathway may be a candidate cause for disrupted brain network and impaired cognitive phenotypes, dependent on the pathological changes of Alzheimer’s disease (AD) spectrum. We aim first to explore the relation of polygenic scores (PGS) underlying CM pathway with cerebrospinal fluid (CSF) biomarkers and cognition of AD, and second to investigate the role of genetic protective scores (GPS), genetic risk scores (GRS) and relative risk scores (RRS) of CM pathway on the anterior and posterior default mode network (aDMN and pDMN) trajectories across the AD spectrum.

Method

We analyzed data of 113 participants of AD spectrum from the Alzheimer's disease Neuroimaging Initiative database, with demographic, global cognitive, genetic, CSF, and resting‐state functional MRI images at baseline available. Then PGS were calculated based on the odds ratio of minor allele. Linear and nonlinear regression were employed to explore the relationship between pairs of PGS, cholesterol metabolites in the blood, CSF biomarkers, and cognitive performance, and multivariate linear regression to investigate the main and interactive effect of PGS×disease on the DMN.

Result

PGS of CM pathway were significantly correlated with levels of CSF biomarkers but not cognition directly. Several cholesterol metabolites were associated with t‐Tau but not p‐Tau and Aβ levels of CSF biomarkers, and the latter of which could impact cognitive performance in a nonlinear manner. In addition, CM related blood biomarkers could influence cognitive function directly. Further, accumulative effects of GPS, GRS, and RRS on the aDMN and pDMN were in absolutely diverse trajectories across the AD spectrum. However, brain regions of PGSΧdisease effects were mainly concentrated in the cortical frontal‐parietal network and subcortical basal ganglia network. There was also a certain rule for the brain maps of cholesterol metabolites associated with DMN, where sensory‐motor network and posterior cingulate cortex occupied.

Conclusion

The cumulative genetic effect of CM pathway could affect DMN and cognition dependent on the pathological levels of AD and firstly demonstrated that protective genes, risky genes and relative risk within CM pathway had different trajectories effects on the subsystems of DMN across the AD spectrum.