bluuebunny/crossref_metadata_2025 huggingface dataset:
Cognitive and psychosocial predictors of everyday function
Authors: Farias Sarah Tomaszewski , Eng Chloe W. , Chan Michelle L. , Gilsanz Paola , Whitmer Rachel A.
Published: December 2020

Background

Subtle declines in functional abilities, including difficulties completing instrumental activities of daily living (IADLs; e.g., managing finances), can be very early indicators of Alzheimer’s Disease and related disorders (ADRD). Cognitive difficulties are major determinants of IADL difficulties, but account for less than half the variance in performance. Psychosocial variables, such as depression, loneliness, and perceived emotional support may also influence a person’s functional status independent of their cognition. The present study examined cognitive and psychosocial predictors of IADL functioning across an ethnoracial diverse cohort.

Method

The Kaiser Healthy Aging and Diverse Life Experience (KHANDLE) cohort is comprised of Kaiser Permanente Northern California members (approximately even proportions of Caucasians, African Americans (AA), Asians, and Latinos) who are age ≥65, without a diagnosis of cognitive impairment or dementia, and who participated in Multiphasic Health Checkups between 1964‐1977. At enrollment, participants completed a self‐report measure of IADL, neuropsychological testing measuring memory and executive functioning, and psychosocial questionnaires measuring depression, loneliness, and emotional support. Analyses include 1, 485 participants (448 Caucasian (30.2%), 386 AA (26.0 %), 362 Asian (24.4%), and 289 Latino (19.5%). Cox proportional hazards models estimated the associations between psychosocial factors and cognitive domains overall and within ethnoracial groups.

Result

Average baseline age was 75.6 and 59.6% were female. AA were less likely to report excellent/very‐good heath (30.1%) verses Caucasians (50.4%), Asians (45.0%), and Latinos (45.3%). After controlling for age, education, gender, and self‐rated health, loneliness predicted IADL performance independent of both memory (p<0.0001) and executive functioning (p<.0001). Emotional support predicted IADLs, independent of memory (p=0.0048) and executive functioning (p=0.0098). Depression was not independently associated with IADLs. Relationships were similar across the four ethnoracial groups.

Conclusion

Few studies have simultaneously examined cognitive and psychosocial predictors of IADLs across such a diverse group of older adults. Our study indicates that greater loneliness and lower perceived emotional support are associated with worse IADL function, independent of cognitive performance across ethnoracial groups. While the directionality of these relationships need further study, interventions aimed at decreasing social isolation may ultimately help to keep individuals functioning more independently in their daily lives.
APOE4, lifestyle factors, and cognitive decline: A population‐based cohort study
Authors: Dhana Klodian , Aggarwal Neelum T , Rajan Kumar B , Barnes Lisa L , Evans Denis A , Morris Martha Clare
Published: December 2020

Background

While prevention trials are recruiting individuals at high risk of dementia, including those who are genetically predisposed, it has become uncertain whether these interventions, in particular, lifestyle factors can lessen the increased genetic risk. We investigated whether the association between lifestyle factors and cognitive decline differed as a function of APOE4 status in an elderly population.

Method

Using data from the Chicago Health and Aging Project, a population‐based cohort study, we defined a healthy lifestyle score based on non‐smoking, >=150 min/week moderate/vigorous physical activity, light‐to‐moderate alcohol consumption, high‐quality MIND diet, and engagement in late‐life cognitive activities, yielding an overall composite score that ranged from 0 to 5. Global cognitive function was assessed using brief tests of episodic memory, executive function, and the MMSE in approximately 3‐year cycles for over 18‐years. We examined the association of adherence to lifestyle factors with cognitive decline separately in those with and without APOE4 using a linear mixed effect model adjusted for age, sex, education, race, cardiovascular disease, time, and their interactions with time.

Result

Of 3,886 older adults included in the study, 1,269 (33%) were APOE4 carriers. Compared to non‐carriers, APOE4 carriers were younger (71y vs. 72y; p<0.001), mostly African American (68% vs. 57%; p<0.001), and had a lower global cognitive score at baseline (0.37 vs. 0.43; p=0.01). In the multivariable‐adjusted model, a higher healthy lifestyle (4‐5 healthy lifestyle factors versus 0‐1 factor) was associated with a slower rate of cognitive decline in both carriers (beta=0.029; p<0.001) and non‐carriers (beta=0.011; p=0.013). However, when we created a propensity score‐matching sample where groups with and without APOE4 were not different concerning age, gender, race, education, baseline global cognitive score, and sample size, these associations differed by APOE4 status. In the matched sample, adherence to a healthy lifestyle was not associated with a cognitive decline in non‐APOE4 carriers (beta=0.002; p=0.763) but remained significant in APOE4 carriers (beta=0.046; p<0.001).

Conclusion

A healthy lifestyle should be promoted to everyone, especially to individuals with a genetic predisposition for Alzheimer’s dementia.
The aetiology of frontal white matter lesions in Alzheimer’s disease are associated with both neurodegenerative and ischemic mechanisms
Authors: McAleese Kirsty E. , Miah Mohi , Graham Sophie , Baker Georgie , Walker Lauren , DeCarli Charles , Koss David , Attems Johannes
Published: December 2020

Background

We have previously shown that the pathogenesis of parietal white matter lesions (WML) seen in Alzheimer’s disease (AD) can be associated with degenerative loss as a result of Wallerian degeneration activated by hyperphosphorylated tau (HPτ) [1]. In a subset of these cases, we investigated the the pathological composition and aetiology of WML from the frontal region.

Method

Frontal WML from 40 post‐mortem brains (AD, n=19; controls, n=21) were quantitative assessed for WML severity, axonal loss and demyelination, as well cortical measures of HPτ, amyloid‐beta (Aβ) and WM‐small vessel disease (SVD) score. Biochemical assessment included the Wallerian degeneration‐associated protease calpain and the ratio of myelin‐associated glycoprotein (MAG) and proteolipid protein (PLP) as a measure of hypoperfusion.

Result

No significant difference was revealed in WML severity between controls and AD. WML severity was associated with axonal and myelin loss in AD (both P<0.02), but only myelin loss in controls (P<0.0001). WML severity correlated with WM‐SVD score in both controls (P<0.0001) and AD (P <0.05); no association between WML severity and HPτ was revealed in the AD group. Calpain was increased in AD but this was not significant, and calpain correlated with Aβ (P<0.05). No significant difference was seen in MAG:PLP between AD and controls.

Conclusion

Frontal WML in AD are likely influenced by both ischemic and degenerative mechanisms in contrast to the posterior WM that has a prominent degenerative influence. This study highlights important regional differences in the pathogenesis of WML that may be diagnostically relevant. (1) McAleese et al (2017) DOI 10.1007/s00401‐017‐1738‐2
Longitudinal factors associated with living well outcomes in people with mild‐to‐moderate dementia: Initial findings from the IDEAL cohort
Authors: Matthews Fiona E , Gamble Laura , Clare Linda ,   the IDEAL Study Research Group
Published: December 2020

Background

Understanding the factors associated with quality of life (QoL), satisfaction with life (SwL) and wellbeing can help us become more effective in optimizing the potential for people with mild‐to‐moderate dementia to ‘live well’ with the condition. Identifying individuals at risk of declining well‐being could help to target support more appropriately, but there is little evidence available about factors that may influence ability to ‘live well’ longitudinally.

Methods

We used longitudinal data from 1547 individuals with mild‐to‐moderate dementia participating in the IDEAL cohort, who have been assessed on entry and followed up 12 months and 24 months later. We examined how factors found to be important at baseline were associated with change over time using growth curve modelling. Factors were grouped into four domains: psychological characteristics and health; physical health; social capitals, assets and resources; and functional ability.

Results

Psychologically, individuals who were less depressed and lonely, and had positive attitudes to ageing, had better QoL, SwL and wellbeing over three waves. Decreasing loneliness was associated with increasing QoL and Wellbeing, increasing depression with decreasing SwL, and a decrease in their attitude to ageing less wellbeing over time. Physically, better self‐rated health, sleep quality, eyesight, hearing, appetite and olfaction predict better QoL and wellbeing, and all but olfaction predict better SwL, over the 3 waves. Socially, less isolation, greater cultural capital and greater reciprocity and trust in the local neighbourhood predict better QoL, SwL and wellbeing over the 3 waves. Good functional ability was associated with better QoL, SwL and wellbeing over the 3 waves.

Conclusions

Using longitudinal data showed remarkable consistency with different methods of measuring how people with dementia “live well”. Understanding these longitudinal changes is vital to identify potential factors for intervention.
A loss of neuronal inhibition best explains EEG abnormalities in preclinical Alzheimer’s disease: A multiscale computational modeling study
Authors: van Nifterick Anne M. , Gouw Alida A. , Scheltens Philip , Stam Cornelis J. , de Haan Willem
Published: December 2020

Background

A better understanding of the earliest functional brain changes in human preclinical Alzheimer’s Disease (AD) may improve diagnosis and intervention. Evidence accumulating from experimental neurophysiological research illustrates that neuronal excitation/inhibition imbalance is an early sign of AD (Palop and Mucke, 2016). However, how this microscale phenomenon relates to the typical changes in oscillatory activity during preclinical AD stages at the macroscale as assessed by electroencephalography/magnetoencephalography (EEG/MEG), remains unclear. This computational modeling study of a network of coupled neural masses aims to find the most probable pathophysiologic mechanism by linking the microscopic level of neurons with the macroscopic level of observable human brain dynamics.

Method

The brain dynamics simulation model consists of 78 neural mass models (describing regional brain activity), coupled according to human DTI‐based structural network topology (Ponten et al., 2010). The model produces EEG‐like data that can be analyzed the same way as patient recordings. We first examined the effect of gradually increasing or decreasing global excitability of either inhibitory or excitatory neurons on overall oscillatory behavior (average total and relative power, peak frequency and spike density), by changing the average membrane threshold potential. Consequently, these four different scenarios were compared with (CSF) amyloid‐positive mild cognitively impaired (MCI) patient data (Gouw et al., 2017) to identify the most compatible underlying mechanism.

Result

The results confirm previous literature (Isaacson and Scanziani 2011), showing an overall stronger effect of changes to inhibitory neurons on oscillatory activity compared to excitatory neurons. Simulating a decrease in inhibition of the network is associated to a reduction in peak frequency, lower relative alpha power and higher relative theta power, which best matches to preclinical AD data (Gouw et al., 2017). The decreased inhibition scenario resulted furthermore in a strong increase in total power and the highest spike density levels.

Conclusion

This study provides theoretical support for the hypothesis that inhibitory (inter)neuron dysfunction is one possible mechanism underlying cortical oscillatory activity changes and a hyperactive network in early AD, in line with recent insights from experimental animal studies.
Revisions and updates to the Everyday Cognition (ECog) scales
Authors: Farias Sarah Tomaszewski , Huss Olivia , Chan Michelle L. , Ruiz Rene
Published: December 2020

Background

Accurate and reliable assessment of everyday functional abilities among older adults is important in clinical and research settings. The Everyday Cognition scale (ECog) was designed over a decade ago to measure early everyday functional limitations across multiple domains: Everyday Memory, Language, Visuospatial Abilities, Planning, Organization, and Divided Attention. The ECog has been shown to be sensitive to early detection of neurodegenerative disease such as Alzheimer’s, and in tracking disease progression. The goal of the current study was to update the content of the ECog and ensure its culturally applicable to diverse older adult populations.

Method

42 individuals were included in the study. Participants included older adults with and without Mild Cognitive Impairment (MCI) and their informants/study partners. 66% of the sample was of an ethnic minority. We utilized iterative cognitive interviewing methods to examine the understandability and cultural relevance/applicability of ECog items. This information was then used to modify existing items, delete poor items, and develop new items as needed. Two rounds of interviews were completed with older adults and informants. The purpose of Round 1 was to inform the revision of existing items and elicit new items. The purpose of Round 2 was to confirm the understandability of items revised or produced from Round 1. All interviews were transcribed verbatim and analyzed using standard qualitative methods.

Result

Based on analysis of interview feedback, instructions to the ECog were modified slightly to emphasize current performance is being compared to an individual’s own baseline level of function. Response options remained primarily unchanged from the original version. When evaluating each of the individual items, participant feedback lead to 15 of the 39 original items being revised to improve item clarity and understandability. A total of 4 items were deleted;3 due to outdated content (e.g., using a map, balancing a checkbook) and 1 because it was vague. A total of 6 entirely new items were developed, primarily to cover more contemporary activities (e.g., use of technology).

Conclusion

The final revised ECog includes 41 items. Future work will validate the revised ECog by measuring it in association with neuropsychological performance, external measures of disease, and other functional measures.
Accountable care organizations and racial and ethnic disparities among patients with Alzheimer’s and related dementia diseases
Authors: Chen Jie
Published: December 2020

Background

The accountable care organization (ACO) is a new care coordination model and reimbursement mechanism that incentivizes providers to deliver high‐quality and well‐coordinated care. This study is the first to provide evidence on the ACOs enrollment and quality of enrolled ACOs among patients with ADRD, and evidence associated with racial disparities in quality of care for persons with ADRD.

Method

Our study used 2017 Centers for Medicare and Medicaid Services Medicare inpatient claims data and Medicare Beneficiary Summary File. Our study focused on patients who had a diagnosis of ADRD. We further linked the CMS claims data with the 2017 MSSP ACO data to capture the patient’s participation of the ACO. The CMS ACO quality measures were used to examine the quality of the ACOs among those who enrolled in the ACOs. In this study, we examined four 4 ACO quality measures related to hospital care quality: risk standardized, all condition readmission (ACO 8), all‐cause unplanned admissions for patients with diabetes (ACO 36), heart failure (ACO 37), and multiple chronic conditions (ACO 38). Finally, we merged our data with the 2017 American Community Survey, Area Health Resource File, and the American Hospital Annual survey to capture the geographic and hospital characteristics.

Results

In 2017, 37% of Medicare beneficiaries with ADRD were enrolled in the ACO. Substantial variation of the ACO participation by patients’ races and ethnicities was observed, ranging from 38% among the white to 14% among the Native ADRD patients. Regression results showed that compared to white, African American, Hispanic, Asian, and Native Medicare beneficiaries with ADRD were significantly less likely to enroll in the ACOs. Among those enrolled in the ACOs, we further observed ACO 8, ACO 36, ACO 37, ACO 38 were significantly higher, i.e. worse quality, among African American, Hispanic, and Native ADRD patients.

Conclusions

Results suggested that policymakers should create incentives for minority‐serving providers to participate in ACOs and provide minority‐serving ACOs with structural assistance to ensure that they can successfully attain their performance goals.
Investigating Aβ plaque development using FTIR micro‐spectroscopy on native postmortem human brain tissue
Authors: Röhr Dominik , Boon Baayla D.C. , Großerüschkamp Frederik , Bouwman Femke , Hoozemans Jeroen J.M. , Rozemuller Annemieke J.M. , Gerwert Klaus Bernhard
Published: December 2020

Background

Fourier‐transform infrared microspectroscopy (FTIR) enables the resolution of various chemical compounds and the secondary structure of proteins in tissue sections1. We used FTIR to investigate Aβ plaques with regard to their supposed development process from diffuse to cored plaques. A central process in plaque formation is the misfolding of Aβ and its subsequent assembly into β‐pleated fibrils, which accumulate in amyloid deposits. Misfolded Aβ is believed be neurotoxic and to exhibit oxidative properties2. We aim to contribute to the understanding of mechanisms that lead to the emergence of Aβ plaques and processes that are associated with the characteristic plaque morphologies.

Method

FTIR was performed on native human brain sections from AD cases (n = 7, plus 3 control cases). Subsequent immunohistochemical staining against Aβ was performed on the same tissue section. In cooperation with neuropathology experts we conducted a spectral analysis of specific plaque types (N = 167 plaques total), with annotations based on well‐described morphologies (diffuse, compact, classic cored).

Result

We observed increased contents of β‐sheet protein in different plaque types and interpret these findings with regards to proposed maturation sequences3. A red‐shift of the Amid 1 absorbance band suggests the formation of fibrils in plaques. Additionally, we investigated the lipid composition in different plaque types and compared these findings to previously described lipid alterations in AD brain4.

Conclusion

By clarifying the relationship between Aβ fibrillation and different plaque types, we give evidence to hypotheses regarding plaque maturation. Our investigation of lipid alterations in plaques illuminate the neurotoxicity of Aβ and its relevance in AD pathology from a different angle. The capability to examine proteins and lipids simultaneously, marker‐free and under native conditions emphasize the research potential of vibrational spectroscopy in neurodegeneration5. References: (1) Kallenbach‐Thieltges, A. and Großerüschkamp, F.; et al., (2013) J. Biophotonics, 6, pp. 88‐100. (2) Butterfield, D. A.; Swomley, A. M. and Sultana, R., (2013) Redox Signal, 19, pp. 823‐835. (3) Thal, D.; et al. (2006) SAGE KE, 6, pp. 1‐9. (4) Prasad, M.; et al., (1998) Neurochem. Res., 23, pp. 81‐88. (5) Shahmoradian, S.H.; et al., (2019) Nat. Neurosci., 22, 1099‐1109.
In support of a national dementia plan: A follow‐up study for dementia incidence and risk profiling in Filipino homes
Authors: Dominguez Jacqueline C , Fowler Krizelle Cleo , De Guzman Ma Fe Payno
Published: December 2020

Background

Dementia is a growing public health priority. Alzheimer’s disease, the most common dementia subtype, is expected to hit 12 million seniors in Southeast Asia by 2050. In the Philippines, a baseline community study found a 10.6% prevalence. (Dominguez et al, 2018) Despite the results, a national dementia plan is yet to be developed. To support the initiative, the study quantifies the dementia incidence of community‐based seniors and determines its risk factors.

Method

This study employed a prospective cohort design, a continuation of the baseline (2009) Marikina Memory and Aging Project (MMAP) in Metro Manila. A total of 1,222 participants were seen to be eligible for follow‐up based on baseline cognition (normal or Cognitively‐Impaired‐Not‐Demented (CIND) status). For dementia incidence, person‐years were calculated. To determine the risk factors, Cox regression was used. Characteristics evaluated were demographics, medical history, and other factors (e.g. living arrangements and MCI status). All analyses were at 95% confidence level.

Result

A total of 831 (60.8%) participants were reassessed and the most common reasons for exclusion were migration and unavailability of respondent. The mean follow‐up time for this study was 3.2 years. Incidence rate was at 16 (CI: 13 to 20) cases per 1,000 person‐years (pyr) with 17 (CI: 12 to 21) per 1,000 pyr for females while 14 (CI: 9 to 21) per 1,000 pyr for males. About 4 in every 5 incident cases were Alzheimer’s disease. Note that male seniors had longer years in education, more comorbidities, and more self‐reported alcohol abuse. On the other hand, female seniors experienced more depressive episodes and more of them reported living alone compared to males. Dementia incidence was significantly associated with MCI status and requiring living assistance (controlling for age, sex, and education). Specifically, having such characteristics doubled the risk of having the disease.

Conclusion

The Philippines is projected to be one of the countries that would experience the consequences of the rise in dementia cases if left unprepared. The National Dementia Plan must then consider the current state of dementia in the country and the risk factors associated to it for better planning and disease management.
Social support moderates the influence of Alzheimer’s disease–related neurodegeneration on cognitive decline
Authors: Sung Kiyoung , Byun Min Soo , Yi Dahyun , Lee Jun Ho , Ko Kang , Sohn Bo Kyung , Kang Koung Mi , Sohn Chul‐Ho , Lee Dong Young
Published: December 2020

Background

Social support (SS) have been associated with decreased rate of cognitive decline in Alzheimer’s disease (AD). However, it is still unclear whether SS can moderate the influence of AD‐related neurodegeneration on cognitive decline. We aimed to test the hypothetical moderation effect of SS on the relationship between AD‐related brain atrophy and cognitive decline.

Method

Total 200 participants from the Korean Brain Aging Study for Early Diagnosis & Prediction of Alzheimer’s disease (KBASE), an ongoing prospective cohort study, were included for this analysis. Of the 200 participants, 130 were MCI and 70 were early AD. All participants underwent comprehensive clinical and neuropsychological assessment, multi‐modal neuroimaging including magnetic resonance imaging, and apolipoprotein E genotyping. AD‐signature cortical thickness (AD‐CT) was defined as a mean cortical thickness of several brain regions known to be sensitive to AD‐specific neurodegeneration. The Medical Outcome Study – Social Support Survey (MOS‐SSS), a 19‐iem brief, multi‐dimensional, self‐report social support survey, were administered to all participants to assess overall SS indices. Global cognitive performance was measured by the total score of the Consortium to Establish a Registry for Alzheimer’s Disease neuropsychological test battery (CERAD‐TS).

Result

There was a significant interaction between AD‐CT and SS on CERAD‐TS. Subgroup analyses demonstrated that the association between AD‐CT and CERAD‐TS was weaker in high SS group than in low SS group.

Conclusion

Our results suggest that SS may delay the progression of cognitive decline by moderating the influence of AD‐related neurodegeneration.
Effects of candesartan vs. lisinopril on neurocognitive functioning in executive mild cognitive impairment: The CALIBREX trial
Authors: Hajjar Ihab , Okafor Maureen O. , McDaniel Darius , Obideen Malik , Dee Elizabeth , Shokouhi Mahsa , Quyyumi Arshed , Levey Allan I. , Goldstein Felicia C.
Published: December 2020

Background

Observational studies suggest that angiotensin receptor blockers are associated with lower cognitive impairment. The CALIBREX (CAndesartan vs. LIsinopril effects on the BRain and Endothelial function in eXecutive MCI) trial aims to determine if this neurocognitive outcome in older adults with executive mild cognitive impairment (MCI) is due to blood pressure lowering effects or angiotensin receptors type 1 blockade.

Method

A randomized, double‐blind, clinical trial on a sample of 176 participants 55 years or older with mild cognitive impairment (MCI) and hypertension. Individuals were withdrawn from prior antihypertensive therapy and randomized to escalating doses of oral candesartan (up to 32 mg once daily) or lisinopril (up to 40 mg once daily). Open‐label antihypertensive drug treatments were added as needed to achieve blood pressure <140/90 mmHg. Participants underwent neuropsychological assessments at baseline, 6 and 12 months. The primary outcome was executive function (Trail Making Test Parts A and B, TMT) and secondary outcomes were episodic memory (Hopkins Verbal Learning Test‐Revised, HVLT‐R) and neuroimaging evidence of microvascular brain injury reflected by white matter lesions (WML). Outcome analyses followed an intention‐to‐treat approach with linear mixed models adjusted for trial group assignment and the interaction between time (visits) and trial group assignment.

Result

Of 176 randomized participants, 141 completed the trial (mean age=65 years; 55% women, 62% African Americans). Blood pressure control was equivalent for both groups but more participants withdrew from the lisinopril arm. At 12 months, the candesartan group had improved cognitive performance on TMT, B‐A (‐16.8 sec, 95% CI [‐30.3, ‐3.3]) while the lisinopril group had worse performance (11.5 sec [‐3.0, 26.0]; P‐value group*time=0.008). HVLT‐R delayed recall improved with candesartan by 1.0 (95% CI [0.3, 1.5]) whereas lisinopril improved by 0.3 (95% CI [‐0.3, 1.0]); P‐value group*time =0.026. There was no significant change in WML volume with candesartan (0.2 mm3, 95% CI [‐0.2, 0.7]) while the lisinopril group had a significant increase (0.9 mm3, 95% CI [0.4, 1.4]; P‐value group*time=0.06.

Conclusion

Candesartan demonstrates superior cognitive outcomes compared to lisinopril and may offer unique neurocognitive protection in older adults with executive MCI and hypertension.
Association of cognitive performance and psychological traits with diffusion‐weighted tract metrics in older adults with subjective cognitive decline and mild cognitive impairment
Authors: Wurdack Katharina , Schwarz Claudia , Benson Gloria , Horn Nora , Hayek Dayana , Köbe Theresa , Antonenko Daria , Wirth Miranka , Flöel Agnes
Published: December 2020

Background

Subjective Cognitive Decline (SCD) may represent the earliest clinical manifestation of Alzheimer’s disease (AD) (Jessen et al. 2014). In individuals with SCD and mild cognitive impairment (MCI), changes in white matter (WM) microstructure have been shown using diffusion weighted (DW) imaging (Brueggen et al. 2019). However, it is unknown to which extent these alterations are associated with cognitive and psychological deficits. Thus, this study aims to investigate the relationship between WM tract metrics and cognitive performance as well as psychological traits in pre‐dementia stages of AD.

Method

In total, 88 patients with MCI, 90 individuals with SCD, and 47 healthy controls (mean age 69±7 years) underwent neuropsychological testing and DW magnetic resonance imaging. Selected questionnaires on stress coping, worry, and rumination were included to evaluate the psychological profile of SCD. Fractional Anisotropy (FA) and Mean Diffusivity (MD) from the DW images were obtained for selected WM tracts of interest using the TRACULA pipeline (Yendiki et al. 2011). Composite scores for memory and executive function were calculated. General linear models adjusted for age, sex, education, cardiovascular risk, and group membership were conducted. Due to the exploratory nature of this study, we did not correct for multiple testing.

Result

Across the entire study sample, higher memory performance was associated with DW parameters of the angular bundle of the cingulum (higher FA, p=0.004; lower MD, p=0.019). Higher FA of the anterior thalamic radiation (ATR) was related to a lower memory score (p=0.049). Higher executive function was related to DW metrics of the uncinate fasciculus (UNC) (higher FA, p=0.038; lower MD, p=0.034) and of the ATR (lower MD, p<0.001). Within SCD subjects, MD of the UNC was positively associated with positive stress coping strategies (p=0.005).

Conclusion

Our findings suggest that higher memory performance and executive functions are associated with favourable tract‐specific DW parameters in pre‐dementia stages of AD. The relationship of higher positive stress coping with WM microstructural alterations in SCD (i.e., increased MD of the UNC) might be explained by psychological compensatory mechanisms in the presence of early WM pathology. Further investigation is needed to elucidate possible clinical implications of these findings.
Alzheimer’s disease–related atrophy patterns in different definitons of subjective cognitive decline
Authors: Karakaşlı Ahmet Alp , Özkan Esra , Zorlu Nabi , Dogan Melike Karacam , Çap Duygu , Karaosmanoğlu Ayça , Karahan Sevilay , Saka Esen , Ayhan Yavuz
Published: December 2020

Background

Different criteria sets were suggested for better operationalization of subjective cognitive decline. In this study, we aimed to assess structural neuroimaging biomarkers of AD in different definitions of SCD.

Method

The study was conducted at Hacettepe University, Turkey. 101 participants over 55 years of age, with memory complaints and no identifiable impairment in a valid cognitive screening test (Z scores>‐1.5 in the Modified Mini Mental Test 3MS) were included. We evaluated whether (i) using a scale (Subjective Memory Complaints Questionnaire‐SMCQ) rather than a single question assessing the subjective complaint; (ii) utilizing neuropsychological test data in addition to a screening test; (iii) evaluating SCD + criteria (additional qualitative features of the complaint) and (iv) the exclusion of comorbidities that may be associated with memory complaints; would be associated with increased atrophy in AD‐related areas. Three different cortical thickness and two cortical volume patterns based on previous research were determined as the dependent variables. MR images were obtained with a 1.5 Tesla MRI scanner. Cortical thickness and gray matter volumes were estimated using the FreeSurfer Software package version 6.0 on 3D T1‐weighted MRI scans (MP RAGE), in accordance with ADNI‐1 MRI acquisition protocol. The multivariate regression models were performed for evaluating the relationship of each independent variable.

Result

Results suggested that age, sex, age of onset of memory complaints, depression or anxiety symptoms and vitamin B12 and vitamin D levels were associated with alterations in the structural markers of AD. Regarding different definitions of SCD; assessment of SCD + criteria, utilizing SMCQ, addition of neuropsychological test data and excluding individuals with comorbidities did not contribute to the validity of SCD in terms of the AD morphology.

Conclusion

Our findings indicate the importance of psychiatric evaluation in individuals with subjective memory complaints. The presence of depression and anxiety symptoms in a person with SCD may increase the likelihood of AD‐related brain morphological changes. Longitudinal studies, better assessment of the phenotype, inclusion of different diagnostic groups may help to refine the definition of SCD and the addition of criterion which may point to early morphological changes. This study has been funded by TUBITAK 214S048, Hacettepe THD‐2018‐17363.
Peripheral inflammation influences α‐synuclein toxicity and neuropathology in Parkinson’s disease models
Authors: Vitola Pietro , Balducci Claudia , Baroni Michela , Santamaria Giulia , Artioli Luisa , Castiglioni Marta , Caldinelli Laura , Pollegioni Loredano , Forloni Gianluigi
Published: December 2020

Background

Parkinson’s disease (PD) and its related disorders, including Lewy body dementia, are devastating progressive neurodegenerative pathologies arising from the interaction between environmental factors and genetic susceptibility. Since the discovery of α‐synuclein as the main constituent of Lewy bodies and neurites, and the identification of mutations in the gene encoding for the protein in familial form of PD, numerous efforts have been made to clarify the pathogenic role played by α‐synuclein. Oligomeric assemblies of α‐synuclein, originating from its aberrant aggregation, represent the most harmful species. Besides direct action on neurons, α‐synuclein oligomers may act through non‐cell‐autonomous pathways involving chronic and/or dysregulated activation of glial cells. Initially considered as a mere secondary phenomenon, inflammation is now viewed as the bridge between genetic susceptibility and environmental factors co‐fostering PD.

Method

To get direct insight on the role of neuroinflammation in influencing PD pathogenesis, we have developed a “double‐hit” in vivo approach, based on the peripheral administration of lipopolysaccharides (LPS) to C57 naïve mice, followed, one month later, by the intracerebroventricular injection of low dose of α‐synuclein oligomers characterized by atomic force microscopy. LPS was also injected to a‐synuclein A53T transgenic mice, motor and cognitive behavior was analyzed together with histopathological examinations in both models.

Result

LPS induced a long‐lasting inflammatory response in the CNS, facilitating the detrimental activities of α‐synuclein oligomers: memory deficits and histopathological alterations. LPS‐activated microglia and astrocytes respond differently to the oligomers, with microglia further activated and acquiring a proinflammatory M1 phenotype, and astrocytes appearing atrophic. In addition, the peripheral administration of LPS in the A53T transgenic PD mouse model aggravated cognitive deficits, together with an increased microgliosis. Again, astrocytes responded differently from microglial cells to the double challenge presented by A53T genetic background and the treatment with LPS.

Conclusion

The peripherally‐induced neuroinflammation potentiates the α‐synuclein oligomer actions and aggravates cognitive deficits in A53T mice. The management of both peripheral and central inflammation may offer a promising therapeutic approach to prevent or slow down some pathological aspects in α‐synucleinopathies.
Effect of APOE‐E4 gene dose on regional early neuroinflammation and beta‐amyloid deposition in cognitively normal elderly volunteers
Authors: Snellman Anniina , Ekblad Laura L. , Tuisku Jouni , Helin Semi , Bucci Marco , Karjalainen Tomi , Parkkola Riitta , Karrasch Mira , Rinne Juha O.
Published: December 2020

Background

Epsilon 4 allele (E4) of APOE gene is an important genetic risk factor for late onset Alzheimer’s disease (AD). We investigated differences in regional neuroinflammation and beta‐amyloid (Aβ) deposition in vivo in cognitively normal homozygotic (Group 1: E4/E4) or heterozygotic (Group 2: E4/E3) carriers of the APOE*E4 allele in comparison to non‐carriers (Group 3: E3/E3), using [11C]PK11195 and [11C]PIB positron emission tomography (PET).

Method

60‐75‐year‐old participants with known APOE genotype were recruited via Auria Biobank (Turku, Finland). For this interim analysis, altogether 22 subjects with MMSE scores ≥ 26 were included (E4/E4 n=10; E4/E3 n=5; E3/E3 n=7). All participants underwent [11C]PIB PET, [11C]PK11195 PET, brain 3T‐MRI and neuropsychological testing. Tracer uptake was evaluated as standardized uptake value ratios (SUVR60‐90; [11C]PIB) or distribution volume ratios (DVR; [11C]PK11195) in a composite volume‐of‐interest (VOI) for Aβ deposition (including prefrontal cortex, precuneus, parietal cortex, anterior cingulate, posterior cingulate and lateral temporal cortex) and in medial temporal cortex for tau deposition. Analysis was performed using non‐parametric Kruskall‐Wallis and Spearman’s correlation tests.

Result

Differences between groups did not reach statistical significance yet in this interim analysis. However, a progressive increase in [11C]PIB uptake from E3/E3 (SUVR60‐90 1.8 ± 0.7) to E4/E3 (SUVR60‐90 2.0 ± 0.6) and E4/E4 (SUVR60‐90 2.4 ± 0.6) was already seen in the composite VOI including brain regions typical for early Aβ accumulation1 (Figure 1). CERAD total score had a fair negative correlation with [11C]PIB composite SUVR60‐90(rs= ‐0.48, p=0.023) in the whole population. In addition, a trend towards higher [11C]PK11195 uptake in E4/E4 (DVR 1.26 ± 0.08) compared to E3/E3 (DVR 1.18 ± 0.03) in the composite VOI was detected (p=0.07), but no correlation between [11C]PK11195 composite DVR and CERAD total score (rs= ‐0.13, p=0.58), or [11C]PIB SUVR (rs= ‐0.005, p=0.98) was found.

Conclusion

The study is still ongoing; however, the interim data suggest that cognitively intact elderly APOE*E4 carriers have both higher Aβ deposition and higher level of activated glia in the brain regions typical for early AD pathology.
Evaluation of a retinal deep phenotyping platform to detect the likely cerebral amyloid PET status in humans
Authors: Soucy Jean‐Paul , Chevrefils Claudia , Osseiran Sam , Sylvestre Jean‐Philippe , Beaulieu Sylvain , Pascoal Tharick A , Arbour Jean Daniel , Rhéaume Marc‐André , Villeneuve Sylvia ,   Prevent‐AD Research Group, Nasreddine Ziad S , Rosa‐Neto Pedro , Gauthier Serge , Robillard Alain , Chayer Céline , Black Sandra E. , Kertes Peter J , Shahawy Hossam El , Chen John J , Knopman David S. , Lowe Val J , Lesage Frédéric
Published: December 2020

Background

Translating recent advances in the diagnosis of Alzheimer’s disease (AD) and other dementias to clinical practice using biomarker‐based approaches requires accessible, affordable biomarkers. This protocol tested the performance of a Retinal Deep Phenotyping platform for the detection of likely positron‐emission tomography (PET) amyloid status (negative or positive) in human subjects. This platform generates data rich retinal reflectance images captured non‐invasively with a Metabolic Hyperspectral Retinal Camera (MHRC) yielding specific spatial‐spectral features which are analyzed by a machine learning algorithm relatively to a recognized gold standard biomarker (in this case PET amyloid imaging).

Methods

134 subjects (50 years and older) from 3 clinical sites were included, 94 with normal, 40 with abnormal cognition, imaged with the MHRC and amyloid PET (unanimous visual reads from a panel of 3 expert reviewers; 42 amyloid positive, 92 negative). Over 600 spatial‐spectral features were extracted from hyperspectral retinal images obtained at 450‐900 nm. After a feature selection based on F‐score ranking, a classifier was trained on the datasets from 87 patients (2/3 of the cohort) using the most discriminating features. The classification performance was then evaluated with the datasets from the remaining 47 patients.

Results

Resubstituting the training set of 87 patients into the classifier yielded sensitivity and specificity values of 88% and 91%, respectively. The training misclassification rate was predicted using the k‐fold loss metric, with a predicted error rate of 19%. To verify this performance, the test set of 47 patients was classified by the model resulting in sensitivity and specificity values of 80% and 81%, respectively.

Conclusions

The Retinal Deep Phenotyping platform shows promise for detecting the likely cerebral amyloid PET status in human subjects and could serve as a screening tool to identify subjects in the AD continuum, for instance in a clinical or drug development context. The platform could also be used for the detection of other biomarkers involved in cognitive decline.
Simvastatin maintains white matter integrity in healthy middle‐aged adults with increased risk for Alzheimer’s disease: A secondary analysis of a randomized controlled trial
Authors: Vogt Nicholas M , Hunt Jack FV , Ma Yue , Van Hulle Carol A , Adluru Nagesh , Lazar Karen K , Asthana Sanjay , Johnson Sterling C. , Bendlin Barbara B , Carlsson Cynthia M
Published: December 2020

Background

The brain is the most cholesterol‐rich organ and myelin contains 70% of total brain cholesterol. Statins are potent cholesterol‐lowing medications used by millions of adults for prevention of cerebrovascular disease, yet the effect of statins on cholesterol‐rich brain white matter (WM) is largely unknown. In this study, diffusion tensor imaging (DTI) data collected during an 18‐month randomized controlled trial in healthy middle‐aged adults with a parental family history of Alzheimer’s disease (ClinicalTrial.gov NCT00939822) was used to determine the effect of simvastatin (40mg/daily) on WM integrity.

Method

73 participants were randomly assigned to drug or placebo (placebo group: N=38, baseline age 55.7±8.0yrs, 76.3% female; simvastatin group: N=35, baseline age 56.7±6.3yrs, 68.6% female) and underwent MRI (T1‐weighted, T2FLAIR, and DTI at baseline, 6m, 12m, and 18m). DTI parameter maps were used for longitudinal WM microstructure and tract‐based spatial statistics analyses. Total gray matter (GM), WM, and WM hyperintensity (WMH) volumes were calculated from T1‐weighted and T2FLAIR imaging. ANCOVA models (covariates: age, sex, APOE4‐genotype) tested the effect of treatment group on percent change in neuroimaging measures at each study visit. Model‐based path analysis tested whether the effects of simvastatin on WM microstructure were mediated by change in serum total cholesterol (TC) levels.

Result

There were no differences in baseline neuroimaging measures between treatment groups. At 18 months, the simvastatin group showed significantly attenuated decline in fractional anisotropy (FA) and attenuated increase in radial diffusivity (RD) in total WM relative to the placebo group (Fig1). At 12 and 18 months, the simvastatin group showed preserved WM volume relative the placebo group, but no differences in GM or WMH volume (Fig2). Approximately 30% of the effect of simvastatin on change in WM microstructure was mediated by change in serum TC (Fig3).

Conclusion

18 months of simvastatin use in statin‐naïve middle‐aged adults resulted in preserved WM microstructure and volume compared to placebo, suggestive of a potential protective effect of simvastatin on WM. Changes in FA and RD (but not axial diffusivity) suggest simvastatin‐induced alterations in myelin content, and partial mediation by change in serum TC suggests pleotropic effects of simvastatin on WM.
Longitudinal inferior temporal FTP‐PET signal increase is associated with contemporaneous longitudinal temporal lobe cortical thinning in preclinical Alzheimer’s disease
Authors: Hampton Olivia L. , Buckley Rachel F. , Properzi Michael J. , Chhatwal Jasmeer P. , Johnson Keith A. , Sperling Reisa A. , Schultz Aaron P.
Published: December 2020

Background

Flortaucipir (FTP)‐PET enables visualization of in vivo paired helical filament tangles, a hallmark of Alzheimer’s disease (AD) pathological progression. Due to its recent implementation, most studies have only analyzed its cross‐sectional associations. This work leverages longitudinal measurements of inferior temporal (IT)‐FTP to better understand the temporal relationship of tau accumulation and neurodegeneration through analyzing the change in IT‐FTP signal on change in contemporaneous cortical thickness across the brain in clinically‐normal (CN) older adults.

Method

T1‐weighted MRI scans were processed using Freesurfer (FS) v6 longitudinal pipeline (Reuter et al., 2012) and we computed bi‐hemispheric thickness values in all 34 ROIs. 18F FTP‐PET images in 124 participants (2‐3 timepoints, range 1.21‐5.19 years; Table 1) were aligned within subject before being co‐registered to FS longitudinal base images. SUVR measures were calculated using cerebellar gray as the reference region, with IT signal used as a tau proxy for all analyses. Participants also underwent 11C Pittsburgh Compound‐B (PiB) imaging at baseline. We calculated slopes with respect to time for IT tau signal and cortical thickness in each ROI using linear regressions for each participant. For all analyses, we used IT‐FTP slope to predict thickness slope in each ROI using a linear regression covarying for sex and baseline age. We also divided our sample into PiB+ (N=41) and PiB‐ (N=83) groups based on a global 1.186 PiB DVR threshold to understand the impact of IT tau change on cortical thinning in a preclinical AD (PiB+) sample.

Result

Greater IT tau slopes were associated with accelerated contemporaneous cortical thinning in temporal regions (Fig. 1A). PiB+ individuals were found to drive the IT‐FTP slope effect on temporal atrophy (ps < 0.001, Fig. 1B, 2). Particularly, the entorhinal cortex showed the strongest effect (t(37); p<0.00005; Fig. 2). No ROI in the PiB‐ group yielded a significant IT tau slope‐associated rate of atrophy (Fig. 1C).

Conclusion

We found that in CNs with increasing IT‐FTP signal, temporal regions are susceptible to neurodegeneration. However, high PiB individuals drive this relationship. Our longitudinal results confirm previous research with cross‐sectional IT tau and provide evidence for contemporaneous cortical thinning in temporal regions in preclinical late onset AD.