bluuebunny/crossref_metadata_2025 huggingface dataset:
Polygenic risk score for Alzheimer’s disease is related to amyloid positivity in subjective cognitive decline: The SCIENCe project
Authors: van der Lee Sven J. , Ebenau Jarith L. , Jansen Iris E. , Verberk Inge M.W. , Scheltens Philip , Teunissen Charlotte E. , Barkhof Frederik , Reinders Marcel J.T. , Van Berckel Bart N.M. , Holstege Henne , van Der Flier Wiesje
Published: December 2020

Background

The majority of individuals with subjective cognitive decline (SCD) is worried well, but in some the subjective experience of cognitive decline herald’s incipient neurodegenerative disease. Understanding the determinants of disease in SCD is important to separate wheat from chaff. Here we studied APOE and a polygenic risk score for Alzheimer’s disease (AD) in a cohort of SCD that was classified according to the ATN‐framework.

Method

We classified 542 participants with SCD (59.2±8.7 years, 38.9%Female, MMSE 28.3±1.5) from the Amsterdam Dementia Cohort and SCIENCe project according to the ATN‐framework, as determined by amyloid PET or CSF Abeta(A), CSF p‐tau(T) and MRI‐based medial temporal lobe atrophy(N). We reduced the number of categories to three: controls (A‐T‐N‐ or normal AD biomarkers, N=310(57%)), non‐AD pathologic change (A‐T‐N+, A‐T+N‐, A‐T+N+, N=142 (26%)) and the Alzheimer’s continuum (A+T‐N‐, A+T‐N+, A+T+N‐, A+T+N+, N=90(17%)). We determined APOE ɛ4 and 39 other genetic variants that were associated in previous studies with AD using array genotyping or imputation. A weighted AD polygenic risk score (AD‐PRS) was calculated based on 39 variants (excluding APOEɛ4). Logistic regression models were fitted for the associations between AD‐PRS and APOEɛ4 with Alzheimer’s continuum and non‐AD pathological changes. For 324 participants follow‐up for dementia was available (3.1±2.5 year) and progression could be studied. Cox proportional hazard models were used to analyse progression to all‐cause dementia (N=36, 6.6%) and AD‐dementia (N=22, 3.6%). Associations were corrected for 5 ancestry principal components.

Result

The APOE ɛ4 genotype was associated with Alzheimer’s continuum (OR=3.6, 95%CI 2.4‐5.3, P=3.0×10‐10) as well as non‐AD pathologic changes (OR=1.5, 95%CI 1.1‐2.2, P=1.6×10‐2). The AD‐PRS was associated with Alzheimer’s continuum (ORper 1‐SD=1.4, 95%CI 1.1‐1.8, P=3.5×10‐3), but not with non‐AD pathologic changes (OR=1.1, 95%CI 0.9‐1.3, P=0.64). In the progression analysis: APOEɛ4 was associated with all‐cause dementia (HR=1.7, 95%CI 1.1‐2.7, P=2.3×10‐2) as well as AD‐dementia (HR=2.3, 95%CI 1.3‐4.2, P=4.5×10‐3). The AD‐PRS was not associated with progression to all‐cause dementia (HR=0.9, P=0.4) or AD‐dementia (HR=1.4, P=0.13).

Conclusion

In individuals with SCD APOE ɛ4 and an AD‐PRS are associated with the presence of amyloid biomarkers (Alzheimer’s continuum), showing that genetic factors can identify individuals at risk in individuals that are cognitively normal.
CSF and FDG‐PET study of the AD continuum: Biochemical and imaging features of two different mechanisms of neurodegeneration
Authors: De Lucia Vincenzo , Bonomi Chiara Giuseppina , Motta Caterina , Assogna Martina , Scaricamazza Eugenia , Martorana Alessandro , Koch Giacomo
Published: December 2020

Background

Alzheimer's Disease (AD) is a biological and clinical continuum which diagnosis necessarily passes through the analysis of CSF and/or imaging biomarkers. Presence of amyloidosis introduces the concept of AD continuum while the presence of either CSF tau pathology or 18FDG‐PET imaging introduce to the concept of neurodegeneration. However isolated amyloidosis, which is part of the AD continuum often presents with positive 18FDG‐PET although CSF tau levels remain within the range. Here we aimed to investigate the neuropsychological, CSF and 18FDG PET biomarkers of the AD continuum in order to better understand the usefulness of the NIA‐A criteria in terms of diagnosis and prognosis of the disease.

Method

We evaluated 101 patients suffering from amnestic and mild cognitive impairment from March 2018 to January 2019 in our Memory Clinic at the Policlinico Tor Vergata, Rome. Patients underwent neuropsychological assessment, ApoE genotyping, 18FDG PET and lumbar puncture to evaluate CSF biomarkers (Aβ‐42, t‐Tau, p‐Tau) for diagnostic purposes. We classified all patients following the NIA‐A criteria.

Result

Individuals with AD continuum despite the absence of tau pathology in CSF show images of neurodegeneration. Their pattern remain however different from those suffering from AD, having reduced or even absent involvement of the frontal lobes in 18FDG PET studies. Similar results were not obtained in neuropsychological assessment . Frontal lobe hypometabolism and executive function impairment in A+T+ subjects were associated with CSF t‐Tau and p‐Tau increase. 18FDG PET neurodegeneration and Tau degeneration refers to different mechanisms of cell damage, whereas CSF lactate doesn’t correlate with 18FDG PET hypometabolism.

Conclusion

AD continuum is characterized by different pattern of CSF and imaging biomarkers. Neurodegenerative mechanisms related to amyloidosis differ qualitatively and quantitatively from those associated to tau pathology and the presence or the absence of ε4 polymorphism. These features represent an important step forward in our understanding of AD pathophysiology.
Audiovisual integration improves task performance in AD and bvFTD
Authors: McLoughlin Bethany , Benhamou Elia , Sivasathiaseelan Harri , Hardy Chris J.D. , Bond Rebecca L. , Russell Lucy L. , Rohrer Jonathan D. , Warren Jason D. , Agustus Jennifer L.
Published: December 2020

Background

Complex analysis of sensory inputs, such as auditory scene analysis and spatial localisation, is impaired in Alzheimer’s disease (AD) and behavioural variant frontotemporal dementia (bvFTD). Multisensory integration research demonstrates that synchronous stimulation in one sense (e.g. vision) can modify processing of suboptimal sensory inputs from another sense (e.g. hearing) in the healthy brain. However, the potential benefit of multisensory stimulation to reduce common symptoms in dementia has not been fully examined.

Method

Patients living with AD (n = 20) or bvFTD (n = 12), and healthy age‐matched controls (n = 18) were recruited to perform three brief cognitive tasks: 1. Cocktail party effect, identify a name spoken in a noisy environment; 2. Spatial ventriloquism, discriminate the location of an auditory stimulus (left/right of centre); and 3. Detect a suboptimal visual stimulus. Task performance was compared between unisensory, audiovisual congruent, and audiovisual incongruent conditions, and between groups.

Result

1. Identification of spoken names in a noisy auditory environment was significantly worse for both patient groups than controls. All groups performed significantly better when viewing an accompanying video of congruent lip movements. The AD group showed some improvement for incongruent videos that cued the onset of the spoken name. 2. Auditory spatial discrimination was significantly worse in the AD group than controls, but both groups were significantly biased by the locations of the accompanying visual stimulus. The bvFTD group was only influenced by spatially incongruent visual stimulation. 3. Detection of a near‐threshold peripheral visual stimulus was improved by a synchronous auditory stimulus, irrespective of spatial congruency, in the bvFTD and control groups. In the AD group, only spatially congruent or neutral auditory stimuli benefitted visual stimulus detection.

Conclusion

Congruent audiovisual stimulation improves the ability of people living with AD or bvFTD to understand voices in a noisy environment, locate auditory sounds, and detect unreliable visual events. Congruency of audiovisual stimulation in different domains (e.g. semantic, spatial) provides evidence for disease‐specific stratification of multisensory integration profiles. As such, multisensory integration provides a mechanism to improve reliability of sensory inputs and the potential to alleviate symptoms in daily life if tailored according to disease.
Spanish translation and cultural adaptation of the memory support system: A pilot study
Authors: Santos Octavio A , Espinoza Dairlin , Pedraza Otto , Chandler Melanie
Published: December 2020

Background

Subjective cognitive decline (SCD) affects 1 in 9 Hispanics aged ≥45 in the U.S., including 1 in 3 who report that SCD interferes with instrumental activities of daily living (IADLs) and 1 in 2 who give up IADLs or need help performing household tasks. A curriculum and calendar/note‐taking system [Memory Support System (MSS)] has proven effective to sustain independence in IADLs in patients with mild cognitive impairment, and protect mood among program partners compared to controls. Until recently, the MSS had only been utilized among English‐speaking, predominately Caucasian, samples.

Method

This study investigated the use of a translated and culturally‐adapted MSS in 20 Spanish‐speaking participants with SCD [80% female, age M = 66.8 (SD = 10.3), education M = 14.8 (SD = 3.6)] and their program partners. A within‐subject multiple baseline design in a 10‐session, 2 to 6‐week MSS training schedule was utilized. Outcome measures included treatment adherence and self‐ and informant‐report questionnaires of IADLs, anxiety, depression, self‐efficacy, caregiver burden, and quality of life.

Result

MSS training significantly improved adherence to the MSS calendar by treatment completion (d = ‐3.75). Participants with SCD also showed significant improvement in overall functional status (d = 0.72), and in daily activities requiring organizational skills (d = 0.66). Symptoms of depression (d = 0.99) and anxiety (d = 0.84) also improved by treatment end, and program partners reported significant improvement in their own anxiety (d = 0.84). There was a significant association between MSS adherence and anxiety in participants with SCD (r = ‐.51).

Conclusion

Overall, preliminary findings suggest that with appropriate training, Spanish‐speaking participants with SCD can and will use a memory notebook system to help compensate in daily life for their SCD and decrease emotional distress. Future research should investigate the Spanish MSS efficacy over time in a randomized controlled trial.
Differences in lifestyle factors based on latent class analysis cognitive profiles in non‐demented older adults
Authors: Boots Elizabeth A , Drabick Deborah AG , Delano‐Wood Lisa , Bondi Mark W , Libon David J , Lamar Melissa
Published: December 2020

Background

Modifiable lifestyle factors such as diet and physical activity are associated with cognitive function in aging adults. However, less is known regarding the intersection between lifestyle factors and cognitive heterogeneity in this same population. Understanding the types of dietary and physical activity patterns that are associated with differing cognitive profiles in normal aging could provide clinically meaningful data to promote cognitive health. Therefore, we characterized cognitive subgroups within a community‐dwelling sample of non‐demented, non‐depressed older adults and examined whether resulting cognitive subgroups differed on dietary and physical activity measures.

Method

121 non‐demented, non‐depressed participants (M age=67.69; 49.6% female; 60% minority; MMSE=28.62) completed a neuropsychological evaluation. Latent Class Analysis (LCA) utilizing six cognitive scores (CVLT Delayed Free Recall & Recognition Discriminability, ‘Animal’ and Letter Fluency, Letter‐Number Sequencing, & Boston Naming) revealed 4 cognitive subgroups with 1) high‐normal cognition (50.4%); 2) normal cognition (25.6%); 3) poor memory (15.7%); and 4) poor executive functioning (8.3%). A subset of participants completed the Sedentary Behavior Questionnaire and CHAMPS Physical Activity Questionnaire for Older Adults (n=96), and the Food Frequency Questionnaire (n=89). Weekly sedentary behavior and weekly moderate‐to‐vigorous physical activity (MVPA) total scores and a FFQ‐derived Mediterranean Diet (MedDiet) score were calculated according to published criteria. Differences between the four cognitive subgroups and these lifestyle variables were examined using ANCOVA adjusting for age, sex, race, word reading, depressive symptoms, and body mass index.

Result

There was a significant difference between cognitive subgroups (p=.016) for MedDiet consumption. Post‐hoc analyses revealed participants with high‐normal cognition had higher MedDiet scores than those with normal cognition (p=.001). There were no significant differences between cognitive subgroups for sedentary behavior (p=.695) or MVPA (p=.731) scores.

Conclusion

LCA‐defined cognitive subgroups within non‐demented, non‐depressed older adults showed group differences in MedDiet consumption (participants with high‐normal cognition greater than those with normal cognition). No group differences were seen with sedentary behavior or physical activity. When choosing ‘one thing’ to advise non‐demented, non‐depressed older adults about maintaining cognitive health, adherence to a MedDiet may mean the difference between good, better, and best cognitive aging.
Diagnostic accuracy of the 10/66 dementia assessment tool in Māori, Fijian‐Indian, Samoan and Tongan elders with memory problems living in South Auckland, New Zealand
Authors: Martinez‐Ruiz Adrian , Yates Susan , Cheung Gary , Dudley Makarena Diana , Krishnamurthi Rita , Fa'alau Fuafiva , Roberts Mary , Taufa Seini , Fa'alili Jacinta , Kerse Ngaire , Cullum Sarah
Published: December 2020

Background

New Zealand is a multicultural multilingual country which brings challenges if we aim to conduct a dementia prevalence study that is representative of the whole of NZ population. The 10/66 dementia assessment tool was developed for use in non‐English speaking communities in order to accurately measure the prevalence of dementia. It is a language‐fair, culture‐fair questionnaire used in epidemiological studies of dementia. It has been translated and adapted into a culturally fair instrument for use with Māori, Fijian‐Indian, Samoan and Tongan elders living in New Zealand (NZ).

Method

The translated and adapted 10/66 instrument versions were administered in the selected ethnicities. The results of the 10/66 dementia assessment it´s been tested in older people with and without dementia who have received a “gold standard” assessment in a local memory service in South Auckland. Each ethnic group included 15 subjects with dementia and 15 subjects without dementia.

Result

Data is still being collected and analysed. The results will be presented at the conference, however the preliminary results for both Māori and Fijian‐Indian communities showed that the 10/66 dementia assessment has a sensitivity and specificity above 85%.

Conclusion

We will test a culturally appropriate and scientifically rigorous method to calculate the prevalence of dementia in an inter‐ethnic community that includes Māori, Fijian‐Indian, Samoan and Tongan elders living in NZ. The information from this study can be used by the Ministry of Health to direct relevant resources towards raising awareness, reducing stigma, improving treatment and developing culturally appropriate dementia care services.
Effect of intensive versus standard blood pressure control on cerebral blood flow in SPRINT
Authors: Dolui Sudipto , Detre John A. , Cho Monique E. , Haley William E. , Launer Lenore J. , Punzi Henry A. , Rastogi Anjay , Still Carolyn H. , Weiner Daniel E. , Wright Jackson , Williamson Jeff D. , Wright Clinton B. , Nasrallah Ilya M.
Published: December 2020

Background

Hypertension is a major risk factor for cardiovascular and cerebrovascular disease including stroke, small vessel disease, and dementia. The Systolic blood PRessure INTervention (SPRINT) randomized trial prospectively evaluated the effects of intensive systolic blood pressure (SBP) control (target SBP<120mmHg) versus standard control (SBP<140mmHg) on cardiovascular outcomes in individuals without baseline diabetes or stroke, and included cerebral blood flow (CBF) measurements. Previous studies with much smaller sample sizes and shorter duration suggested stable CBF in response to intensive treatment (SBP<125mmHg) [1], but long term effects are unknown. We evaluated the long‐term effects of intensive blood pressure treatment on CBF.

Method

Whole brain CBF was measured at 3T using pseudocontinuous arterial spin labeled (ASL) perfusion MRI at baseline and after 3.9±0.3 years. Total white matter lesion (WML) load was measured from Fluid Attenuated Inversion Recovery T2 MRI. Data from 324 subjects with adequate ASL scan quality acquired from 6 sites were included.

Result

Demographics and scanner specific CBF values are provided in Table 1. The intensive treatment group was older (p=0.01), but was otherwise similar to the standard group at baseline. There was a significant effect on the longitudinal CBF change (p=0.006) of the intensive treatment (5.7% increase) compared to the standard treatment (4.0% decrease, Fig 1). Secondary analysis showed a significant increase in age‐adjusted fractional CBF for the intensive treatment group (p<0.001) with no change (p=0.24) in the standard treatment group. Change in CBF was not associated with change in WML.

Conclusion

Sustained intensive antihypertensive treatment does not reduce whole brain CBF, in fact it showed an increase in whole brain CBF relative to standard therapy. While improved CBF might contribute to the reduced WML progression observed in the intensive‐therapy group versus standard therapy in SPRINT[2], we did not observe a direct correlation between CBF changes and WML changes. References: (1) Croall et al. JAMA‐Neurol,2018; (2) Nasrallah et al., JAMA‐Neurol, 2019.
Neural‐cognitive changes across the lifespan: Evidence from reference ability neural network (RANN)
Authors: Argiris Georgette , Stern Yaakov , Habeck Christian
Published: December 2020

Background

Cognitive functions and their underlying neural substrates change across the lifespan (for a review, see Grady et al., 2012). In an attempt to capture these changes, most prior work utilizing a cross‐sectional approach have investigated age‐group differences in behavioral performance or neural activations related to particular functions. In the present study, we aimed to quantify neural changes in the brain associated with four principal cognitive domains by considering age as a continuous factor and linking regions displaying the greatest change in each domain with behavioral performance.

Method

We collected behavioral and fMRI data from 240 cognitively‐healthy community‐dwelling adults between the ages of 21 and 80 on a battery of tests relating to the four domains or “reference abilities” (i.e., Episodic Memory, Fluid Reasoning, Processing Speed, Vocabulary; see Stern et al., 2014). We applied a Gaussian kernel, centered on each year of life in our sample, in order to generate weights that would allow us to construct a brain map for each target age, derived from the weighted activations across all participants (Ericsson et al., 2008). Subsequent subtraction of these maps allowed us to quantify the age‐related differences, ∆=T(age) ‐ T(age+1), in each domain.

Result

Results indicated significant differences between successive ages around 40 years of age in two of the four domains: Fluid Reasoning and Processing Speed. Furthermore, for each domain, we selected those voxels for which change was the greatest and performed correlations between voxel activations and behavioral performance. For Episodic Memory, we observed significant positive correlations between behavior and activation namely in the bilateral rolandic operculum, thalamus, right postcentral gyrus, and left supramarginal gyrus, whereas for Processing Speed, we observed significant negative correlations largely in the supplementary motor area, left postcentral gyrus, right precentral gyrus, and cerebellum crus VI.

Conclusion

These findings emphasize the utility of analyzing lifespan changes along a continuum and reveal significant differences, suggesting a significant peak change, that is similar across domains.
Abnormal thickening and thinning of the cerebral cortex in idiopathic normal‐pressure hydrocephalus
Authors: Kang Kyunghun , Han Jaehwan , Yoon Uicheul , Lee Ho‐Won , Lee Sang‐Woo , Jeong Shin Young
Published: December 2020

Background

We investigated differences in cortical thickness utilizing automated surface‐based cortical thickness analysis in 2 groups: idiopathic normal‐pressure hydrocephalus (INPH) patients who had a positive response to the cerebrospinal fluid tap test and healthy controls. We also explored whether a relationship exists between cortical thinning and gait disturbance in INPH patients. We hypothesized that INPH patients might show a characteristic pattern of cortical thickness change and that there may be unique relationships between cortical thinning and gait disturbance in INPH patients.

Method

Forty‐nine INPH patients and 26 healthy controls were imaged with MRI, including 3‐dimensional volumetric images, for automated surface‐based cortical thickness analysis across the entire brain. Gait disturbance features related to INPH were determined using the Gait Status Scale (GSS).

Result

Compared with age‐ and gender‐matched healthy controls, unexpectedly, INPH patients showed statistically significant cortical thickening mainly in areas located in the high convexity of the frontal, parietal, and occipital regions. Additionally, cortical thinning mainly in temporal and orbitofrontal regions was observed in the INPH group relative to the control group. The GSS scores were negatively correlated with cortical thickness in the medial orbital part of the superior frontal gyrus, gyrus rectus, superior temporal gyrus, temporal pole, and insula.

Conclusion

A distinctive pattern of cortical thickness changes was found in INPH patients. We cautiously suggest that cortical thickening in INPH can result from reactive gliosis. Further, our results support the hypothesis that cortical thinning in INPH can result from neuronal degeneration. In addition, cortical thinning can play an important role in gait disturbances in INPH patients.
Clinical and biomarker trajectories in sporadic Alzheimer's disease: A longitudinal study
Authors: Yu Jin‐Tai , Wang Hui‐Fu , Shen Xue‐Ning , Li Jie‐Qiong , Suckling John , Tan Chen‐Chen , Wang Yanjiang , Feng Lei , Zhang Can , Tan Lan , Dong Qiang , Touchon Jacques , Gauthier Serge ,   Alzheimer’s Disease Neuroimaging Initiative
Published: December 2020

Background

It has been documented that β‐amyloid (Aβ) deposition, tau pathology and neuronal degeneration precedes clinical symptoms in autosomal dominant Alzheimer's disease (AD). Since the divergence on pathogenesis between sporadic and familial AD limits the extension of these findings to sporadic AD, where and magnitude of pathologic processes in sporadic AD are of significant importance to clinical management.

Method

In this longitudinal study, we analyzed data from 982 ADNI participants with abnormal amyloid accumulations who underwent cerebrospinal fluid (CSF) test, brain imaging and cognitive assessments. We compared the levels of clinical outcomes and biomarkers at baseline and the rates of change in follow‐up between different stages of AD. The slope of the regression model over years was applied to estimate rates of change for Aβ deposition, tau alteration, hypometabolism, brain atrophy, and cognitive decline.

Result

In total 167 healthy controls, 133 patients with preclinical AD, 451 patients with MCI due to AD, and 231 patients with dementia due to AD were studied. The levels of clinical and biomarkers at baseline and their change rates at follow‐up significantly differed among the four groups. In terms of average years, Aβ deposition was observed over a range of 45·6 years for CSF Aβ, and 31·1 years with amyloid imaging, although Aβ markers began to be abnormal at 27·8 years for CSF Aβ and 26·3 years for neuroimaging. When Aβ markers exceeded the threshold, CSF tau and other non‐ Aβ markers started to change, and patients were estimated to take 29·1 years (CSF tau),12·7 years (memory), 12·2 years (hippocampus atrophy), 10·1years (hypometabolism) to transition from clinically normal to dementia. Finally, CSF p‐tau significantly increased as dementia onset approached.

Conclusion

Our results reveal the trajectory of biomarkers in sporadic Alzheimer's disease is led by Aβ accumulation, followed by CSF tau change, memory deficits, brain atrophy, hypometabolism, cognitive decline, and lastly CSF p‐tau increase.
Cultural adaptation of the Tailored Activity Program (TAP) in Chile: Implementation challenges and pilot testing
Authors: Gajardo Jean , Aravena Jose , Navarrete Ignacia , Slachevsky Andrea , Gitlin Laura N
Published: December 2020

Background

The Tailored Activity Program (TAP) provides people with dementia with activities tailored to their capabilities and trains caregivers in their use. The TAP has been previously cross‐culturally adapted in different settings and countries. This study was aimed to develop a cultural adaptation of the TAP in Santiago, Chile.

Method

Complementary mixed‐method study following the 4‐phase Dynamic Adaptation Process (DAP) model (Aarons et al, 2012). Qualitative data was collected by conducting 1) interviews and ethnographic observation with caregivers, 2) weekly follow‐up meetings to provide ongoing feedback, and 3) a focus group with provider occupational therapists after the Implementation phase based on the DAP. Grounded theory (Strauss & Corbin, 1998) was used to guide qualitative analysis, to access the experiences of caregivers and providers, and to identify and describe adaptations and implementation outcomes based on the Framework and Coding System for Modifications and Adaptations of Evidence‐based Interventions (Stirman et al, 2013). Quantitative data for pilot testing was obtained through assessments at baseline and after intervention. Wilcoxon‐test and T‐test at p<0.05 were used to estimate the effect of the intervention on outcomes. Ethical approval was granted by the Ethics Scientific Committee "Servicio de Salud Metropolitano Oriente" in June 2017.

Result

Ten dyads (family caregivers and people with dementia) were recruited in this study after being referred from a neurologist specialized in dementia and they completed a regular 8‐session home‐based intervention of the TAP during 2017‐2018. Content, context, target level, and training adaptations were identified. After intervention, there was a statistically significant reduction on the number and severity of neuropsychiatric symptoms among individuals with dementia. Caregivers reported reduced depressive symptoms, improved perceived well‐being, and improved self‐confidence.

Conclusion

Sociocultural adaptations were identified in the adaptation of the TAP to the local context in Chile. The TAP was highly accepted by participants, especially caregivers, who acknowledged its personalized problem‐solving approach and positive effects. Positive outcomes were shown in both people with dementia and caregivers, in consistence with previous studies.
Evaluation of extracellular vesicles isolated from the cerebrospinal fluid and plasma from former National Football League players at risk for chronic traumatic encephalopathy
Authors: Muraoka Satoshi , Jedrychowski Mark P. , Yang Zijian , Tatebe Harutsugu , DeLeo Annina M. , Yukawa Kayo , Ko Jina , Wang Katherine , Ikezu Seiko , Gygi Steven , Issadore David , Tokuda Takahiko , Stern Robert A , Ikezu Tsuneya
Published: December 2020

Background

Chronic Traumatic Encephalopathy (CTE) is a tauopathy that affects individuals with a history of mild repetitive brain injury frequently seen in contact sports. Initial neuropathologic change of CTE consists of perivascular deposition of phosphorylated tau (p‐tau) in cortical neurons. Tau pathology progresses to form neurofibrillary tangles in neurons throughout the brain in later stages when patients show more clinical symptoms. Extracellular vesicles (EV) are known to carry neuropathogenic molecules in neurodegenerative disease and able to cross the blood brain barrier. We therefore examined the protein composition of EV separated from cerebrospinal fluid (CSF) and plasma in former NFL players with cognitive dysfunction, and an age‐matched controls.

Method

EVs were separated from CSF and plasma from former NFL players (n=4, 14) and controls (n=5, 12) by affinity separation or size exclusion chromatography, respectively. The EV protein profiling was characterized by SIMOA for tau and p‐tau and mass spectrometry. The protein data was analyzed for EV enrichment, differentially expressed proteins, pathway analysis and correlation with cognitive function, head impact and tau/p‐tau levels by biostatistics and bioinformatics.

Result

The level of t‐tau and p‐tau in plasma EVs from former NFL players was significantly elevated although there was no significant change in CSF EV compared to the control. The 95 proteins were commonly identified between the paired plasma‐CSF from the same patients, but there was no significant correlation with the disease status. Collagen alpha‐3(VI) chain (COL6A3), ‐1(VI) chain (COL6A1) and Reelin (RELN) were differentially expressed in former NFL players’ plasma EVs. A combination of these 3 proteins in plasma EV was able to distinguish former NFL players from controls with 85% accuracy by machine learning.

Conclusion

These data suggest that COL6A3, RELN and COL6A1 in plasma EV can be potential biomarker for monitoring the CTE development. We need further evaluation of CSF EV by increasing the sample number size in future studies.
Estimating the global mortality from Alzheimer’s disease and other dementias: A new method and results from the Global Burden of Disease study 2019
Authors: Nichols Emma , Vos Theo
Published: December 2020

Background

Alzheimer’s disease and other dementias (dementia) is currently a leading cause of mortality and morbidity globally, and the total number of individuals effected by dementia will likely increase in the future with corresponding increases in population growth and aging. However, inconsistencies in coding practices in vital registration systems both over time and between countries complicate the estimation of dementia mortality. This study updated and improved on previous methods developed for the Global Burden of Disease (GBD) study for the estimation of global dementia mortality.

Method

We conducted a systematic review on the excess risk of death in those with dementia, and analyzed these data using a Bayesian meta‐regression model. We calculated total excess deaths as the product of absolute risk and country‐by‐country prevalence estimates from the GBD study. We then multiplied the estimates of total excess deaths by the proportion of dementia deaths that occur in those with severe, end‐stage disease to calculate the total number of deaths that could be legitimately assigned to dementia as the underlying cause of death.

Result

Attributable risk of dementia increased with age, reaching 0.17 (95% uncertainty interval, 0.05 to 0.58) in the 95+ age group. We estimated there were 1.55 (0.35 to 4.54) million deaths globally due to dementia in 2019. Far more deaths occurred in women (1.02 million; 0.23 to 2.96) than men (0.54 million: 0.12 to 1.58), giving a female to male ratio of 1.90 (1.82 to 1.99). Due to population aging, the all‐age mortality rates increased by 38.0%; 33.1 to 43.7 between 1990 and 2019.

Conclusion

The increase in the number of dementia deaths will continue due to population aging. Given the rising volume of dementia mortality, the development of valid methods of mortality estimation for dementia is critical. This updated estimation method eliminated all dependency on estimates from vital registration systems, which are known to be biased. However, future efforts should aim to further strengthen this analysis in order to provide more accurate information on dementia mortality for use by both researchers and policy‐makers.
Generation of nonhuman primate models of Alzheimer’s disease
Authors: Sasaguri Hiroki , Sato Kenya , Kumita Wakako , Nagata Kenichi , Sakuma Tetsushi , Yamamoto Takashi , Saido Takaomi C. , Sasaki Erika
Published: December 2020

Background

Alzheimer’s disease (AD) is the leading cause of dementia worldwide. Despite the considerable research efforts, exact pathomechanisms still remain unknown, and no effective treatment is available. AD research field have mainly utilized mouse models for decades, but species differences between rodents and primates may constrain us from understanding the precise disease mechanisms.

Method

We utilized Transcription Activator‐Like Effector Nuclease (TALEN) to delete the 3’ splicing site (SS) of exon 9 of the presenilin 1‐encoding gene (PSEN1) in the common marmoset (Callithrix jacchus), a small new world primate.

Result

We successfully deleted the 3’ SS of the PSEN1 gene (PSEN1‐ΔE9) in the marmoset embryos by microinjection of TALEN, and obtained mutant PSEN1 neonates. Sequence analysis of mRNA in these embryos and neonates confirmed skipping of exon 9 as expected, which has been reported as a pathogenic mutation causing familial AD. Quantitative analysis of amyloid‐β (Aβ) in the cultured medium of primary fibroblasts revealed elevation of Aβ42/Aβ40 ratio in PSEN1‐ΔE9 fibroblasts. WB analysis detected un‐cleaved full‐length PS1 protein as well as N‐ and C‐terminal fragments of PS1 protein in the PSEN1‐ΔE9 fibroblasts.

Conclusion

To our knowledge, we have successfully generated the word’s first AD model of non‐human primates. These animals are expected to show early amyloid pathology in the brain and to contribute to cutting‐edge research to elucidate primate‐specific mechanism in AD. In addition, we will make the mutant animals available to researchers worldwide in the fight against AD in the future.
Big data analysis of Korea health insurance review and assessment service for prescription quantity and cost of drugs on types of dementia from 2017 to 2019
Authors: Eun Hun Jeong , Choi Mal Rye , Kim Hyun Gi
Published: December 2020

Background

Recently, the Republic of Korea has entered the aging society, and the diagnosis rate for dementia is increasing, and the number of prescription drugs is increasing accordingly. Therefore, this study intends to study the number of prescriptions and the cost of prescription according to the detailed type of dementia by using big data of Korea Insurance Review & Assessment Service.

Method

Authors visited the Big Data Hub at Korea Health Insurance Review & Assessment Service homepage. After extracting data on the prescription quantity and cost of drugs for 3 years from 2017 to 2019 for dementia subtypes(F00, F01, F02, F03) in Big Data Homepage, the data were analyzed and statistically verified using Microsoft Excel and IBM SPSS version 23.0. Jonckheere‐Terpstra test for hypothesis evaluation applicated. The currency exchange rate was 1170.24 Korean won per 1 US dollar as of January 25, 2020 ICD‐100(WHO 2007 version) Diagnostic criteria including F00 Dementia in Alzheimer`s disease(G30), F01 Vascular dementia, F02 Dementia in other diseases classified elsewhere, F03 Unspecified dementia were applicated.

Result

Prescription Quantity from 2017 to 2019: 2017 F00 3,498,000,000 F01 302,024,085 F02 16,392,196 F03 109,765,584 2018 F00 40,602,837 F01 4,206,130 F02 3,009,702 F03 1,795,276 2019 F00 51,654,756 F01 3,229,505 F02 281,612 F03 1750040. Cost of Drugs from 2017 to 2019: 2017 F00 19,810,000,000won F01 1,985,000,000won F02 102,331,031won F03 713,251,799won 2018 F00 23,000,000,000won F01 2,340,000,000won F02 116,000,000won F03 771,000,000won 2019 F00 27,868,782,161won F01 1,709,269,727won F02 113,159,188won. Average Prescription Quantity Number for 3 years(p=0.602): F00 : 1,196,752,531 F01 : 103,153,240 F02 : 6,561,170 F03 : 37,770,300. Average Cost of Drugs for 3 years(p=0.602) : F00 : 23,559,594,054 Korean won(20,132,275.48 US dollar), F01 : 2,011,423,242 Korean won(1,718,812.59 US dollar), F02 : 110,496,740 Korean won(94,422.29 US dollar), F03 : 740,454,665 Korean won(632,737.44 US dollar).

Conclusion

From 2017 to 2019, drug prescriptions and medication costs are on the rise. Prescription and cost of dementia by type of dementia were highest in F00 Dementia in Alzheimer's disease (G30), followed by F01 Vascular dementia, F03 Unspecified dementia, and F02 Dementia in other diseases classified elsewhere.
Environmental toxicity exposure and ability to perform instrumental activities of daily living in several U.S. geographic locations
Authors: Feger Danielle M , Corrigan Anne E , Crane Breanna M , Carlson Michelle C
Published: December 2020

Background

Instrumental activities of daily living (IADLs) are complex tasks important for independent living, such as cooking, shopping, and managing finances. Older adults may report difficulty performing IADLs in preclinical dementia or mild cognitive impairment (MCI). Cognitive function has been shown to be lower in individuals with increased environmental toxicity exposure. However, little is known about an individual’s environmental toxicity exposure in relation to their ability to perform IADLs. We hypothesize that older adults with greater environmental toxicity exposure will be more likely to report difficulty performing IADLs.

Method

Participant data (N=3578) were from the baseline year (1990) of the Cardiovascular Health Study (CHS). Average environmental toxicity exposure was estimated for each participant using 1990 data from the US Environmental Protection Agency Risk‐Screening Environmental Indicators (RSEI) model. Six IADLs were measured; IADL performance was discretized as 1 = proficient (no self‐reported difficulty performing any IADLs), and 0 = not proficient (any self‐reported difficulty). Average toxicity exposure was base‐10 log transformed to aid in model fitting. Univariate and multivariate logistic regression models estimated the relationship between environmental exposure and IADL proficiency; multivariate models were adjusted for participant age, sex, race, education, income, baseline Modified Mini‐Mental State score, and cohort recruitment site.

Result

In the univariate model, higher toxicity concentration was associated with decreased odds of IADL proficiency (OR=0.79, p<0.001). After adjustment, no significant relationship between toxicity exposure and IADL difficulty was observed (OR=0.929, p=0.553); however, individuals in North Carolina were less likely to report being proficient in all IADLs relative to those in California (OR=0.657, p=0.013), and individuals in Maryland were marginally less likely to report full IADL proficiency relative to those in California (OR=0.736, p=0.098).

Conclusion

Individuals in North Carolina and Maryland were less likely to successfully perform all IADLs, even after adjustment for possible confounders. Ability to perform IADLs is critical for maintaining older adults’ independence, yet geographic location is rarely considered as a potential risk factor for IADL difficulty. It is unclear what factors beyond socioeconomic status contributed to observed regional disparities.
Evaluating everyday preferences assessment over time between people with cognitive impairment and their care partners
Authors: Wilkins James M , Okereke Olivia I
Published: December 2020

Background

As cognitive impairment progresses, people with cognitive impairment and dementia increasingly rely on surrogate decision‐makers for everyday activities. Yet, little is known about concordance over time on assessment of everyday preferences between persons with cognitive impairment and their care partners, acting as proxies.

Method

The sample included 44 dyads of persons with cognitive impairment (Clinical Dementia Rating Scale ≥ 0.5) and their care partners. We used the Preferences for Everyday Living Inventory (PELI) to assess preferences for activities and lifestyle choices among persons with cognitive impairment. The PELI was concurrently but separately administered to care partners, who answered as proxies. Assessments were completed at baseline and again approximately one year later. Paired sample t‐tests were used to assess for changes in repeat measures as well as to estimate differences in preference assessment between self‐ratings of persons with cognitive impairment and proxy‐ratings of care partners at baseline and one‐year follow‐up.

Result

Our previous factor analysis of the 55‐item PELI identified four factors: autonomous choice, social engagement, personal growth, and keeping a routine. Within each factor of the PELI, there appeared to be consistency in self‐ratings for persons with cognitive impairment and proxy‐ratings by care partners between baseline and annual follow‐up (paired t‐test, p‐value > 0.05; Pearson correlation, r > 0.7). Comparing self‐ratings from persons with cognitive impairment and proxy‐ratings by their care partners, however, there was significant discrepancy for preferences related to “social engagement” (e.g., regular contact with family, meeting new people, volunteering) at baseline and one‐year follow‐up (paired t‐test, p‐value < 0.05). There did not appear to be significant differences by paired t‐test (p‐value > 0.05) with respect to the raw change scores from baseline and one year‐follow within each PELI factor.

Conclusion

This study yields new insights regarding the stability of everyday preferences for persons with cognitive impairment over time as well as apparent stability in areas of significant discrepancy between self‐ratings of persons with cognitive impairment and the proxy‐ratings of care partners.
Gut microbiota interacts with intrinsic brain activity of patients with amnestic mild cognitive impairment
Authors: Peng Guoping
Published: December 2020

Background

To explore the potential relationships among gut microbiota (GM), local brain spontaneous activity and neuropsychological characteristics in amnestic mild cognitive impairment (aMCI) patients.

Method

Twenty aMCI and 22 healthy control (HC) subjects were recruited. The GM composition was determined by 16S ribosomal RNA gene sequencing. Resting‐state functional magnetic resonance imaging scans were performed, and fractional amplitude of low‐frequency fluctuations (fALFF) was calculated across different frequencies. Spearman or Pearson correlation analysis was used to analyze the relationship between spontaneous brain activity and cognitive function, GM composition.

Result

aMCI patients had altered GM state and local spontaneous brain activity as compared with HC subjects. Correlation analysis showed that aMCI and HC groups had different “GM–intrinsic brain activity interaction” patterns. In aMCI group, the relative abundance (RA) of Bacteroides from phylum to genus level was positively correlated with fALFF value in the right middle temporal gyrus in slow 4 and negatively with that of cerebellar vermis in typical band. The Clostridiaceae RA was positively correlated with the fALFF value of the right lingual gyrus in the typical band (0.01‐0.08 Hz). The Clostridiaceae and Blautia RA was positively correlated with the fALFF value of the left cerebellum in slow 4 (0.027–0.073 Hz). At slow 5 (0.01–0.027 Hz), the Firmicutes RA was negatively correlated with the fALFF value in the right inferior frontal gyrus. Correlation analysis showed that Clostridium members (Lachnospiraceae and Blautia) were positively while Veillonellaceae was negatively linked with cognition test. While Bacteroides was positively correlated with attention and computation, and negatively correlated with the three‐step command score.

Conclusion

aMCI patients have a specific GM‐intrinsic brain activity‐cognitive function interaction pattern.
Can plasma amyloid‐beta levels be considered as a potential biomarker to discriminate preclinical Alzheimer’s disease?
Authors: Wang Xiaoni , Jiang Jiehui , Han Ying
Published: December 2020

Background

We investigated plasma amyloid‐beta (Aβ) levels across Alzheimer’s spectrum from normal control (NC) to cognitive impairment (CI) vis preclinical AD (PreAD) as well as their association with central biomarkers to explore their potential as a pre‐screening tool for identifying early AD.

Method

One hundred and thirty‐nine participants (50 NC, 34 PreAD and 55 CI) from SILCODE project and memory clinic in Xuanwu Hospital were included. Preclinical AD patients were defined as cognitively normal subjects with positive amyloid‐PET. Cognitive impairment patients were defined as objective cognitive impairment due to AD. Plasma Aβ40 and Aβ42 were measured using Meso Scale Discovery technology. Analysis of covariance (ANCOVA) was used to examine the plasma Aβ levels across the three groups. A general linear model analysis was used to test for association between plasma Aβ levels and amyloid burden, gray matter volume (GM) and amplitude of low frequency fluctuation (ALFF). Further, mediating effect of amyloid burden on association between plasma Aβ levels and neurodegeneration biomarkers were tested.

Result

The levels of plasma Aβ42/Aβ40 and Aβ42 levels were different among three groups (for Aβ42 [pg/ml]: 12.27(4.35) in NC, 10.93(3.00) in PreAD, and 10.08(2.73) in CI [P=.045 adjusted for carrier of ApoE ε4 allele, age, sex, and education]; for Aβ42/Aβ40: 0.017(0.005) in NC, 0.014(0.003) in PreAD, and 0.013(0.004) in CI [P <. 001]) (Figure 1). Globally, Plasma Aβ42 and Aβ42/Aβ40 ratio negatively correlated with global SUVR (p=0.007 and p=0.001) and positively correlated with gray matter volume (p=0.011 and p<0.001). Plasma Aβ40 showed significantly positive correlation with ALFF (p=0.008) and Aβ42/Aβ40 ratio showed an opposite correlation with ALFF (p=0.019) (Figure 2). Global SUVR significantly mediates the relationship between plasma Aβ42/Aβ40 ratio and gray matter volume (average causal mediation effects 95%CI: 13.912‐86.439).

Conclusion

The present data show plasma Aβ42/Aβ40 ratio were lower in patients with cognitive impairment than preclinical AD than normal controls. Plasma Aβ were correlated with brain amyloid deposition, structural atrophy and functional alteration. These results suggest the potential for plasma Aβ serving as a more cost‐effective prescreening tool in clinical practice.