bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacokinetic, pharmacodynamic and transcriptomic analyses of verubecestat treatment in 5XFAD mice
Authors: Territo Paul R. , Quinney Sara K. , Biesdorf Carla , Masters Andrea R. , Onos Kristen , Haynes Leslie , Keezer Kelly , Cope Zackery A. , Meyer Jill A. , Peters Jonathan , Persohn Scott C. , Figueiredo Lucas , Bedwell Amanda A. , Eldridge Kierra , Speedy Rachael , Sasner Michael , Howell Gareth , Carter Gregory W. , Oblak Adrian L. , Lamb Bruce T. , Rizzo Stacey J. Sukoff
Published: December 2020

Background

The Preclinical Testing Core (PTC) of the Model Organism Development for Late Onset Alzheimer’s Disease (MODEL‐AD) consortium established a preclinical strategy with go/no‐go decision points that permits unbiased assessments of potential therapeutic agents. In models at disease‐relevant ages, this strategy includes: 1) drug formulation, stability, and in vivo pharmacokinetics (PK); and 2) pharmacodynamics (PD) readouts of target engagement and disease modifying activity via non‐invasive PET/MRI, behavior, and transcriptomics. As part of the pipeline validation, verubecestat (VER), a BACE1 inhibitor, was selected for testing in 5XFAD mice.

Methods

PK analysis was performed in 6 month aged 5XFAD mice of both sexes, for both oral gavage (PO) and drug milled into diet (10‐100 mg/kg) with blood and brain concentrations analyzed via LC/MS. PK/PD modeling determined dosing regimen for chronic treatments started at 3 months. All PD endpoints (n = 10‐15/sex/genotype/treatment) were measured at 6‐7 months of age, and included: 18‐FDG PET/MR, 18F‐AV45 PET/MR, autoradiography, immunohistochemistry, and behavioral assessments. Post treatment gene expression profiling was conducted using the nanoString and aligned to AMP‐AD consensus clusters.

Results

Initial PK analysis revealed rapid clearance of VER following PO dosing, thus all PD experiments were performed via chronic exposure to drug formulated in diet (10, 30, and 100 mg/kg/day). Prophylactic treatment with VER produced robust coat color changes consistent with hair color changes reported in the clinic. Moreover, VER resulted in dose‐dependent reductions in amyloid deposition via 18F‐AV45 PET, but did not alter glucose uptake via 18F‐FDG PET. VER failed to improve cognition in 5XFAD mice. Transcriptomics revealed dose depended genes expression that mapped to AMP‐AD consensus clusters for immune response, DNA repair, and RNA metabolism.

Conclusions

The effects of VER dosing on PD endpoints revealed the expected results consistent with clinical findings. Moreover, VER failed to improve cognitive behavior in 5XFAD mice, in line with the lack of cognitive improvement in patients. Together these data positive support for pipeline validation of the MODEL‐AD PTC, and highlight the importance for post‐treatment transcriptomics to align model systems with drug mechanism of actions.
Reliability of fractional anisotropy in diffusion tensor imaging of healthy subjects in the ADNI database
Authors: Chen Qianyun , Abrigo Jill , Chu Winnie C.W.
Published: December 2020

Background

Diffusion tensor imaging (DTI) detects white matter microstructural changes in early Alzheimer’s Disease (AD), and can potentially serve as a sensitive biomarker in longitudinal scans. In this study we determined the reliability of DTI‐derived fractional anisotropy (FA) in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset, which to our knowledge has not been reported.

Method

We selected 21 healthy subjects (12 women and 9 men; age range, 60‐89 years) from the ADNI2 with two sets of DTI performed within 3 months serving as surrogate test‐retest datasets. The subjects’ cognitive status remained stable within one year. The MRI was performed on the same 3.0 T GE scanner following ADNI standard protocol for DTI acquisition (2.7×2.7×2.7 mm3, b=1000 s/mm2, 5 b0 and 41 diffusion weighted volumes). FMRIB Software Library (FSL) was used to process the DTI data to derive the FA scalar map. The two FA maps of the same subject were first co‐registered and then aligned to the JHU DTI atlas by using both linear and non‐linear registration method. A pre‐defined white matter region‐of‐interest (ROI) on the atlas was applied to the registered FA map to derive the value. The ROI related to AD were selected for analysis and included the corpus callosum (body, genu, splenium), corticospinal tract, superior longitudinal fasciculus, fronto‐occipital fasciculus and cingulum (cingulate gyrus, hippocampus). Reliability was assessed using intraclass correlation coefficient (ICC) and coefficient of variation (CoV) of the mean value within the ROI.

Result

Mean ICC of the paired FA values for all ROIs were 0.97(range: 0.93‐0.99). The CoVs for selected ROIs were all within 8% and the median was all below 2%. The greatest variation was found in the right cingulum hippocampus with CoV of 2.03%, while smallest variation 0.89% was present in the left superior longitudinal fasciculus. No significant correlation was found between ICC and CoV.

Conclusion

Using short interval longitudinal scans of healthy subjects in the ADNI dataset as surrogate test‐retest datasets, we found FA values of DTI exhibited good reliability. Our results lay the foundation for our future analysis of longitudinal DTI datasets in the ADNI database.
Cognitive impairment and lower education predict physical frailty in an eight‐year longitudinal study in Brazil
Authors: Yassuda Monica Sanches , Borim Flavia Arbex , Cipolli Gabriela Cabett , Aprahamian Ivan , Neri Anita Liberalesso
Published: December 2020

Background

The cross‐talk between cognitive and physical systems is little understood. The present study aimed to verify whether physical frailty and cognitive impairment were related, in an eight‐year longitudinal analysis.

Method

The sample comprised 494 older adults who completed the Cardiovascular Health Study measures for the frailty phenotype and the Mini Mental State Examination at baseline and follow‐up. Participants included in the analyses were robust or pre‐frail at baseline. Logistic regression analyses were used to identify baseline characteristics associated with becoming frail 8 years later. The independent variables included in the model were sex, age, schooling and cognitive status at baseline.

Result

At follow‐up, 22.9% participants were classified as frail. Frail participants were significantly older (73.00±5.36 frail vs. 71.87±5.11 non‐frail) and among them there was a higher percentage of participants with cognitive deficits (35.5% versus 20.6%) at baseline. Results indicated that lower education (OR=0.94, z=‐2.06, p=0.040, CI 0.88 – 0.99) and cognitive impairment (OR=2.08, z=2.68, p=0.007, CI= 1.22 – 3.55) at baseline were predictive of frail status at follow up.

Conclusion

Older adults with cognitive impairment need to be seen as ideal target participants for interventions to delay frailty.
Cognitive leisure activities in later older adulthood may protect against accelerated rates of memory decline
Authors: Hyun Jinshil , Katz Mindy J. , Hall Charles B , Sliwinski Martin J. , Lipton Richard B.
Published: December 2020

Background

The effects of mental activities in early and midlife (e.g., educational attainment, occupational complexity) may be associated with delayed onset and faster rates of cognitive decline afterwards, as predicted by the cognitive reserve hypothesis (Stern, 2002, 2009). Importantly, continued mental activities in later life may help protect cognitive abilities from further decline (Use it or lose it hypothesis). The aim of the current study is to examine the effects of late‐life cognitive leisure activity on rates of cognitive decline over and above the effects of education and occupational complexity.

Method

The sample consisted of 687 individuals (mean age=78.5, mean follow‐up=2.9 years; 66.3% female; 59.2% Whites, 31.5% African Americans) enrolled in the Einstein Aging Study. Information on years of education, midlife occupation information, and participation in late life cognitive leisure activities (in the previous month prior to the clinic visit) were collected at baseline. Using mixed models, we assessed the influence of education, occupation, and late‐life leisure activities on levels and rates of decline in three cognitive domains: memory, executive function, and processing speed.

Result

More years of education, higher occupational complexity, and more frequent participation in late‐life cognitive leisure were associated with higher levels of cognition in most cognitive domains (Table 1). Education was associated with faster rates of cognitive decline in all three domains of cognition (ps<.05). Late‐life cognitive leisure activity was associated with slower cognitive decline in memory domain (p<.001). To rule out the possibility of reverse causation (i.e., cognitive impairment results in less frequent participation in cognitive leisure activity), we removed individuals who developed mild cognitive impairment within the first two consecutive annual clinic visits, and the findings did not change.

Conclusion

The results suggest that mental activities may protect against late‐life cognitive impairment in varying ways. Although the effects of distal mental activity (e.g., education) may be accumulated decades ago and delay the onset of cognitive impairment in late life, the effects of proximal mental activity (e.g., late‐life cognitive leisure) may have continuing benefits in buffering rapid memory decline.
Cross‐cultural acceptability of interventions at the end of life in dementia: Video vignette study design and pilot evaluation (ERC CONT‐END WP1)
Authors: van der Steen Jenny T , Azizi Bahar , Nakanishi Miharu , Shinan‐Altman Shiri , Mehr David R , Radbruch Lukas , Gaertner Jan , Werner Perla , Achterberg Wilco P , Tilburgs Bram , Smaling Hanneke JA
Published: December 2020

Background

In dementia, gradual cognitive and physical decline imply that control over life is typically lost. Interventions such as advance care planning (ACP), technology, or‐more extreme‐euthanasia can increase control over the end of life. So far, little is known about acceptability of these interventions from the perspective of persons with dementia and others involved. This study examines the cross‐cultural acceptability of four end‐of‐life interventions in dementia which contain an element of striving for control. We describe the development and pilot‐testing of video vignettes that explain interventions in a standardized manner.

Method

The CONT‐END study Work Package 1 (NTR 7985) employs a cross‐sectional mixed‐methods design to assess acceptability of two types of ACP, technology use at the end of life and euthanasia, in three groups (persons with dementia, their family caregivers and physicians) in six countries (Netherlands, Japan, Israel, USA, Germany, Switzerland). Participants (150 per country) are interviewed about acceptability of the interventions. We will examine different acceptability by group and country and explore potentially associated factors such as coping style. We are pilot testing the acceptability, feasibility and burden of four video vignettes in persons with dementia and their family caregivers in the Netherlands.

Result

We will demonstrate the video vignettes to explain the interventions. The first interviews indicate that persons with dementia and their family caregivers find the scripts of the video vignettes understandable, acceptable, feasible and not burdensome. They additionally commented on the subject matter in that they felt a current need for ACP on, for example, hospitalization, but would prefer to discuss need for technology and euthanasia later. We will present the pilot results and discuss hypotheses about acceptability of the four interventions in the three groups and six countries.

Conclusion

The CONT‐END study will provide insight into cross‐cultural acceptability of interventions in dementia care from the perspective of persons with dementia, their family caregivers and physicians. This can help to better align interventions with preferences. The study will also result in a more fundamental understanding as to how and when having control at the end of life in dementia is perceived as beneficial or perhaps harmful.
Dependence clusters in Alzheimer’s disease and Medicare expenditures: A longitudinal analysis from the Predictors Study
Authors: Zhu Carolyn W , Lee Seonjoo , Ornstein Katherine , Cosentino Stephanie , Gu Yian , Andrews Howard , Stern Yaakov
Published: December 2020

Background

Dependence has been proposed as a holistic, transparent, and meaningful representation of dementia disease severity to quantify and stage disease progression. Modeling clusters in dependence trajectories can help understand changes over time in the course of dementia and related cost of care.

Method

199 initially community‐living patients with probable AD in early stages of the disease were recruited to the Predictors 2 Study from three academic medical centers in the US. Patients were followed for up to 10 years and had at least two Dependence Scale (DS) recorded. Non‐parametric K‐means cluster analysis for longitudinal data (KmL) was used to identify dependence clusters. Medicare expenditures (1999‐2010) were compared between clusters at 6‐month intervals and cumulatively over 5 years.

Result

KmL identified two distinct DS clusters: (A) high initial dependence, faster decline, and (B) low initial dependence, slower decline. At baseline, DS score in cluster A was on average 2.25 points higher than in cluster B (p<0.0001). DS scores in both clusters steadily worsened (cluster A by 0.74±0.038 points, cluster B by 0.42±0.038 points every 6 month, both p<0.001), with significant between‐cluster differential rate of change over time (p<0.0001). At baseline, patients in cluster A were older, more likely to be female, have worse functioning and cognition, and more likely to have psychiatric symptoms than those in cluster B. Average per person Medicare expenditures in a 6‐month interval was higher in cluster A than B ($5,456 vs. $2,715). Adjusting for patient characteristics, cluster A was associated with an average of $1,554 higher Medicare expenditures every 6 months cluster B. By year 5, differences in expenditures between clusters accumulated to $54,557 per person in cluster A, twice as high as $27,153 for cluster B.

Conclusion

Distinct DS clusters with subtle differences at baseline and rates of decline over time were associated with widening difference in expenditures over time. Dependence is a useful measure to capture long‐term costs associated with dementia. Better characterization of dependence clusters has significant implications for understanding disease progression, trial design and care planning.
Palmar creases in Alzheimer’s disease: An observational study
Authors: Ramdane Said
Published: December 2020

Background

The pattern of palmar creases is determined by the interactions of environmental and genetic factors. Numerous studies have indicated associations of aberrant patterns of palmar creases with different disease conditions. Deviations in the configurations of palmar creases in Alzheimer’s disease (AD) could be indicative of insults during early intrauterine development. The aim of the present study was to analyze the pattern of palmar flexion creases in Alzheimer’s disease patients compared to healthy non‐demented elderly subjects.

Method

We have analyzed palmar creases patterns in an elderly population comprising a group of 120 consecutive patients with probable Alzheimer’s disease (Mean age: 73.7±7.8; range: 55‐85 years; 64 females) (DSM‐IV, NINCDS‐ADRDA criteria) and a group of 198 consecutive non demented healthy controls (Mean age: 73.2±8.3; range: 63‐89 years; 112 females). Study subjects were recruited from a community elderly in Skikda‐Algeria, (2018‐2019).

Result

The palmar creases of the healthy elderly subjects showed the normal palmar creases to be the most prevalent (85.35%), followed by Suwon crease (7.07%), Simian crease (5.05%) and Sidney crease (2.52%). In AD patients the normal crease was 67.50%, followed by Simian (15.83%), Suwon (12.50%) and Sydney (4.16%) creases. AD patients had significant higher frequency of aberrant palmar creases compared to controls: 32.50% vs. 14.64%, p= 0.0001. By gender, the difference between cases and controls was significant both in men: 33.92% vs. 15.11% respectively, p= 0.009; and in women: 31.25% vs. 14.28% respectively, p= 0.007. Simian crease was found to be significantly more frequent in the AD group than in control, both in males: 17.85% vs 5.81%, p= 0.022; and in females: 14.06 vs 4.46%, p= 0.023. Bilateral occurrence of Simian crease showed no significant difference between the two groups. No significant difference was found between the two groups in Suwon or Sydney creases frequencies.

Conclusion

These results show simian crease was found to be twice as common in Alzheimer’s disease patients compared to controls. In addition to revealing the status of palmar creases, present study indicates that palmar creases configurations may give clues for an early and noninvasive method of diagnosis. Further large sample population studies are warranted.
Duration of verbal fluency inter‐word intervals and risk of cognitive impairment
Authors: Ayers Matthew , Bushnell Justin , Gao Sujuan , Wadley Viriginia G , Unverzagt Fred W. , Clark David G.
Published: December 2020

Background

Verbal fluency tasks have widely recognized value for dementia diagnosis. Some studies suggest that detailed analysis of verbal fluency word lists may aid in prediction of future cognitive decline or dementia.

Method

We identified 701 stroke‐free participants in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, all of whom performed in the normal range on a cognitive screening test at baseline, but who suffered from acute or progressive incident cognitive impairment (ICI) during subsequent years. These cases were matched with 701 controls who did not suffer subsequent cognitive decline. Baseline letter F and animal fluency recordings were automatically transcribed using Amazon Web Services’
Transcribe
, then manually corrected using a Matlab‐based graphical transcription tool for precise capture of utterance latencies and durations. We performed two statistical analyses on the durations of inter‐word intervals (IWI). The first employed mixed‐effects linear models with IWI as the dependent variable and several lexical (e.g., frequency, edit distance from previous word, etc.) and demographic covariates. The second employed Cox proportional hazards (CPH) models, with time to ICI as the dependent variable and summary measures of IWI (sum of z‐scores) as key predictors of interest.

Result

Mixed‐effects models show that semantic similarity of consecutive words and overall within‐task latency of words are the strongest predictors of IWI, but that future progressive cognitive decline is associated with longer IWI on the animal fluency task. CPH models show significant independent contributions of animal fluency raw score and IWI summary score. Slowing of word retrieval reflected by the latter score was associated with greater risk for cognitive decline.

Conclusion

Detailed analysis of IWI measured during fluency tasks may enhance the prognostic value of verbal fluency tests. The effect appears to be strongest with animal fluency predicting progressive decline.
Cognitive decline prediction using an MRI‐based classifier of arteriolar sclerosis and small vessel atherosclerosis
Authors: Makkinejad Nazanin , Evia Arnold M , Tamhane Ashish A , Bennett David A. , Schneider Julie A. , Arfanakis Konstantinos
Published: December 2020

Background

Arteriolar sclerosis and small vessel atherosclerosis are two age‐related neuropathologies that are common in older adults and have been linked to cognitive decline and dementia. Definitive diagnosis of either pathology is only possible at autopsy. The purpose of this work was to develop a model that predicts the presence of arteriolar sclerosis or atherosclerosis based on in‐vivo MRI and basic demographic features. The model was first developed based on ex‐vivo MRI and pathology data from a large community‐based cohort of older adults and was then translated in‐vivo. The performance of the model was assessed both ex‐vivo and in‐vivo.

Method

Cerebral hemispheres were obtained from 727 participants of the Rush Memory and Aging Project (MAP) and Religious Orders Study (ROS), two longitudinal cohort studies of aging (Figure 1). A brain hemisphere from each participant was imaged ex‐vivo on a clinical 3T MRI scanner, while immersed in 4% formaldehyde solution. Following ex‐vivo MRI, all hemispheres underwent neuropathologic examination by a board‐certified neuropathologist blinded to clinical and imaging findings. The volume of white matter hyperintensities per lobe and regional white matter R2 values were extracted from the ex‐vivo MRI data and used as features in a logistic regression classifier to predict arteriolar sclerosis or small vessel atherosclerosis. The classifier was then translated to in‐vivo using linear mixed‐effects models, and was tested on in‐vivo 3T MRI of 405 ROS and MAP participants (Figure 2). In‐vivo assessment was performed by testing the association of the classification confidence score with the change in cognition two years after baseline MRI, using Pearson’s correlation.

Result

The ex‐vivo classifier of arteriolar sclerosis or small vessel atherosclerosis achieved an average area under the receiver operating characteristic curve AUC=0.73 (Figure 3). In‐vivo testing showed that the in‐vivo classification confidence score was associated with a two‐year decline in working memory (p=0.008), semantic memory (p=0.026), and perceptual speed (p=0.036) following baseline in‐vivo MRI.

Conclusion

A novel MRI‐based classifier was developed for predicting the presence of arteriolar sclerosis or small vessel atherosclerosis in‐vivo. This classifier may have broad clinical implications including refined participant selection and enhanced monitoring of the treatment response in clinical drug and prevention trials.
Evaluating pre‐screening tools for older Latino recruitment into preclinical Alzheimer’s disease studies
Authors: Muniz Martha C. , Martínez Jairo , Vila‐Castelar Clara , Pardilla‐Delgado Enmanuelle , Scott Matthew R. , Properzi Michael J. , Kirn Dylan , Rentz Dorene , Sperling Reisa A. , Quiroz Yakeel T. , Pruzin Jeremy J. , Ramirez‐Gomez Liliana A.
Published: December 2020

Background

Recruitment for preclinical Alzheimer’s disease clinical trials and observational studies in the Latino population continues to increase as researchers aim to diversify their samples. The Telephone Interview for Cognitive Status modified version (TICS‐m) is a pre‐screening tool that has shown to have high diagnostic validity for identification of dementia in mostly Caucasian samples. The TICS‐m cut‐off currently used for screening out cognitive impairment in older individuals is ≥26. We aimed to 1) determine whether currently used TICS‐m cut‐offs are appropriate for pre‐screening clinically normal older Latinos, and 2) assess the relationships among the TICS‐m score and outcome measures typically used in clinical trials, such as Mini Mental State Exam (MMSE), Logical Memory Delayed Recall, and Clinical Dementia Rating (CDR).

Methods

Twenty‐nine older Latino adults (mean age= 68.7, mean education=15.6, and mean TICS‐m= 33.4/40) from the Harvard Aging Brain Study (HABS) were included in this study. Participants completed the pre‐screening TICS‐m over the phone, followed by an in‐clinic screening neuropsychological battery, which included the MMSE, Logical Memory Delayed Recall, and CDR, administered in Spanish. Linear regression models controlling for age, sex, and education were used to assess the relationships between TICS‐m score and performance on the neuropsychological measures.

Results

TICS‐m scores were positively correlated with years of education (r=0.54, p=0.002). No significant associations were observed among TICS‐m scores and other cognitive measures, after adjusting by age, sex, and education (MMSE: r=0.04, p=0.82; Logical Memory Delayed: r=0.10, p=0.62; and CDR sum of boxes: r=‐0.03, p=0.86).

Conclusion

Preliminary results suggest that in this sample of largely cognitively normal Latino adults, TICS‐m score is not associated with performance in other cognitive outcome measures typically used in clinical and observational trials for preclinical Alzheimer’s disease. These findings also suggest that the TICS‐m may not accurately reflect actual cognitive function in older Latino participants. However, we do not know if we are inadvertently screen‐failing participants using TICS‐m as a pre‐screening tool. Further research is needed to assess whether this pre‐screening tool is adequate in the pre‐screening process for preclinical Alzheimer’s disease in older Latino adults.
External validation of an MRI‐based classifier of arteriolar sclerosis
Authors: Makkinejad Nazanin , Evia Arnold M. , Tamhane Ashish A. , Bennett David A. , Schneider Julie A. , Arfanakis Konstantinos
Published: December 2020

Background

Arteriolar sclerosis is a common age‐related neuropathology that has been associated with lower cognition and higher risk of dementia. Definitive diagnosis of arteriolar sclerosis is only possible at autopsy. We recently introduced an MRI‐based classifier of arteriolar sclerosis [1]. In the present work, we tested this classifier for prediction of pathology in‐vivo, and also validated it on external datasets.

Method

In‐vivo 3T MRI and pathology data were available on participants of the Rush Memory and Aging Project (MAP) and Religious Orders Study (ROS), two longitudinal cohort studies of aging used in training of the classifier. We first assessed the performance of the classifier in predicting arteriolar sclerosis based on in‐vivo MRI of MAP and ROS participants that had not been included in the training sample. The generalizability of the classifier was then evaluated in the Minority Aging Research Study (MARS), and Alzheimer's Disease Neuroimaging Initiative (ADNI), by testing the association of the classification confidence score with change in cognition two years after baseline MRI, using Spearman’s rank correlation.

Result

The area under the receiver operating characteristic curve for in‐vivo classification of arteriolar sclerosis in MAP and ROS data not used in training of the classifier was 0.77. Also, the classification confidence score showed significant association with two‐year decline in perceptual speed (p=0.027) in the MARS dataset, and with Trail Making Test Part A (p=0.027), and Trail Making Test Part B (p=0.046) in the ADNI dataset.

Conclusion

Our previously introduced classifier of arteriolar sclerosis was shown to have a high performance in prediction of the pathology based on in‐vivo MRI, illustrating its significance. Testing in MARS and ADNI showed that the classifier generalizes to other cohorts and demonstrated its clinical utility in predicting cognitive decline two years after baseline MRI. References: [1] N. Makkinejad, A.M. Evia, A. Tamhane, D.A. Bennett, J.A. Schneider, K. Arfanakis, A Novel MRI Classifier of Arteriolar Sclerosis in Aging: Prediction of Pathology and Cognitive Decline, Proc. Int. Soc. for Magn. Reson. in Med. 2019.
Differential associations between PET and CSF Alzheimer's disease biomarkers and cognition among cognitively normal older adults
Authors: Oh Hwamee , Correia Stephen , Salloway Stephen P.
Published: December 2020

Background

The presence of brain β‐amyloid (Aβ) plaques among cognitively normal older adults has been related to steeper cognitive decline and an increased risk of Alzheimer’s disease (AD). The co‐presence of tau pathology in these individuals, however, makes it challenging to link AD pathologies to changes in specific cognitive function and brain structure. In addition, it remains unclear whether AD pathologies in the brain and their increased concentration in the cerebrospinal fluid (CSF) have similar effects on cognition.

Method

We assessed the relationship between Aβ and tau pathology, gray matter atrophy, and cognition among cognitively normal older adults in the Alzheimer's disease neuroimaging initiative whose brain Aβ deposition and tau‐protein neurofibrillary tangles were detected by 18F‐Florbetapir and 18F‐Flortaucipir, respectively. Within a subset of the sample, CSF measures of amyloid (Aβ40 and Aβ42) and tau (t‐tau and p‐tau) pathologies were assessed in relation to cognition and cortical thickness. Multiple regression models were applied to assess the relationships between AD pathologies, gray matter atrophy, and cognition using region‐of‐interest and whole‐brain surface‐based approaches.

Result

Higher entorhinal tau PET counts corresponded to greater gray matter atrophy in the entorhinal cortex and hippocampus and poorer executive function performance, controlling for age, sex, and whole‐brain amyloid load. In the subset of the sample, whole‐brain amyloid load related to poorer memory and executive function performance, controlling for age, sex, and CSF total tau. Age was associated with memory and executive function performance, independent of entorhinal tau PET counts, CSF total tau, and whole‐brain amyloid load. Entorhinal tau PET counts did not correlate with CSF total tau or p‐tau among cognitively normal older adults.

Conclusion

Amyloid and tau pathology differentially influence cognition and brain structure. A low correlation between tau PET and CSF total tau measures in cognitively normal older adults may warrant further investigation on the source of discordance in these measures.
Decreased complexity and increased variability in systolic blood pressure are associated with elevated long‐term risk of dementia: The Rotterdam Study
Authors: Ma Yuan , Zhou Junhong , Kavousi Maryam , Lipsitz Lewis A , Raso Francesco US Mattace , Westerhof Berend E , Wolters Frank J , Wu Julia W , Manor Brad , Ikram M Kamran , Goudsmit Jaap , Hofman Albert , Ikram M Arfan
Published: December 2020

Background

Blood pressure (BP) is a key player in the vascular etiology of dementia, but their relationship is not fully elucidated. The current BP control paradigm focuses on BP levels, but real‐time BP is highly dynamic, involving simultaneous interactions of numerous neural and vascular feedback mechanisms. We hypothesized that early subclinical disruption in BP dynamics, captured by decreased complexity and increased variability, contributes to dementia risk, above and beyond BP levels.

Method

In a prospective cohort study since 1997 involving 1,877 dementia‐free community‐based older adults, we investigated whether BP variability and complexity were associated with the risk of dementia. The primary exposures were BP complexity (quantified by sample entropy) and BP variability (quantified by coefficient of variation) derived from continuous beat‐to‐beat BP series of 300 beats. The primary outcome was incident dementia during follow‐up until January 1, 2016.

Result

Of 1,877 participants (59% women; mean [SD] age, 70.9 [6.3] years), 333 developed dementia over 20 years. Reduced systolic BP (SBP) complexity was associated with a higher dementia risk (HR comparing extreme quintiles: 1.53 [95%CI: 1.08, 2.17], P=0.008). Increased SBP variability was also associated with a higher risk of dementia (HR comparing extreme quintiles: 1.57 [95% CI: 1.11, 2.22]; P=0.017). When considered jointly, individuals with both high variability (within the top quintile) and low complexity (within the bottom quintile) had a significantly higher risk of developing dementia compared with those with both high complexity and low variability in SBP (HR: 2.16; 95%CI: 1.28‐3.65, P=0.003). These findings were observed after adjusting for age, sex, APOE genotype, mean SBP, and traditional vascular risk factors. Consistent findings were observed for variability but not complexity of diastolic BP.

Conclusion

Decreased complexity and increased variability of beat‐to‐beat systolic blood pressure are potential novel risk factors for dementia. Our findings suggest that maintaining complexity and limiting variability in systolic blood pressure may provide new opportunities to prevent dementia.
Serum NFL as a predictor of disease progression in dementia with Lewy bodies
Authors: Pilotto Andrea , Imarisio Alberto , Conforti Francesca , Lupini Alessandro , Giannì Giuliana , Gipponi Stefano , Cottini Elisabetta , Masciocchi Stefano , Nocivelli Sara , Grasso Roberto , Turrone Rosanna , Borroni Barbara , Rizzetti Maria Cristina , Bonanni Laura , Pizzi Marina , Bellucci Arianna , Garrafa Emirena , Zetterberg Henrik , Hye Abdul , Ashton Nicholas J. , Padovani Alessandro
Published: December 2020

Background

CSF and plasma neurofilament light chain (NfL) levels have been consistently proposed as reliable markers of neurodegeneration able to discriminate between Parkinson’s disease (PD) and atypical parkinsonisms. Increased Serum NfL might predict worse motor and cognitive progression in PD patients at single subject level.

Method

plasma NfL was assessed in a longitudinal study including 93 patients with Parkinson’s disease and 27 patients with DLB who underwent an extensive motor and cognitive assessment and after 2 years of follow‐up. The study evaluated the correlation between NfL plasma levels and motor, non‐motor symptoms, cognitive and behavioral abnormalities in the two cohorts, as well as benignant/malignant phenotypes and motor/cognitive progression in PD after 2 years of follow‐up.

Result

Serum NfL correlated with age and age at onset in the cohort. In DLB, NfL correlated with disease duration, hyposmia and neuropsychiatric symptoms, but not with motor function assessed by UPDRS‐III. We found no significant associations between NfL and disease progression in DLB patients. In PD, higher NfL levels correlated with hyposmia (p=0.01), total UPDRS‐II and UPDRS‐III scores (0.001), gait speed (0.04) and several disability milestones, including mild cognitive impairment (0.001), symptomatic dysautonomia (0.001), loss of independency in activities of daily living (p=0.01) and instrumental daily living (p=0.001). At two years of follow‐up, NfL was the best marker in multivariate regression analyses for both motor and cognitive progression beyond malignant/benignant phenotypes.

Conclusion

Elevated serum NfL levels are associated with fast progression in PD patients and could thus represent target of interventions in specific subpopulation of patients.
Magnetic nanoparticles as MRI contrast agents for the diagnosis of Alzheimer’s disease
Authors: Ulanova Marina , Gloag Lucy , Bongers Andre , Gooding Justin , Biazik Joanna , Tilley Richard , Sachdev Perminder S. , Braidy Nady
Published: December 2020

Background

Nanoparticle‐based magnetic contrast agents have opened the potential for Magnetic Resonance Imaging (MRI) to be used for early non‐invasive diagnosis of Alzheimer’s disease (AD). Current methods for clinical diagnosis in the early stages of the disease, such as Positron Emission Tomography imaging of amyloid build‐up, are limited by their availability and cost. The aim of this research is to develop a novel non‐toxic amyloid targeted nanoparticle which can successfully permeate the blood brain barrier and bind amyloid plaques resulting in enhanced contrast in the MR image and improved diagnostic sensitivity.

Methods

Targeted iron nanoparticles were assessed using a U‐251 cell line to determine their in vitro toxicity. Transmission electron microscopy was used to determine the movement of the nanoparticles within the cell and in vitro binding to amyloid fibrils. APPSwe/PSEN1 mice were treated with increasing doses of targeted and non‐targeted nanoparticles to evaluate acute in vivo toxicity, in addition to nanoparticle biodistribution and MRI contrast enhancement.

Results

The novel targeted nanoparticles have demonstrated no significant in vitro toxicity and electron microscopy results show their movement through the endocytic cycle within the cell, demonstrating an effective degradation and clearance pathway (Figure). No acute toxicity was observed in the animal model. In addition, immunohistochemistry demonstrated nanoparticles to co‐localise with plaques on ex vivo brain sections.

Conclusion

The present work shows promising preliminary results in the development of a targeted non‐invasive method of early AD diagnosis using contrast enhanced MRI.
Study design and clinical characteristics of the LEADS cohort
Authors: Apostolova Liana G.
Published: December 2020

Background

The Longitudinal Early‐Onset Alzheimer's Disease Study (LEADS) is a 2‐year observational study designed to look at disease progression in adults with early‐onset Alzheimer's disease (EOAD). To move toward more effective treatments, scientists need to understand the genetic, biological and clinical processes involved in EOAD. Compared to LOAD, patients with sporadic EOAD are believed to show more rapid clinical decline, higher prevalence non‐amnestic phenotypes, greater impairment in non‐memory domains, as well as more severe and widespread neurodegeneration.

Method

The over‐arching goals of the LEADS are to: (1) Compare the baseline and longitudinal cognitive, functional imaging and fluid biomarker characteristics of EOAD vs. LOAD; (2) Develop sensitive clinical and biomarker measures for future clinical and research use; (3) Develop composite clinical and biomarker outcome measures for implementation in clinical trials; (4) Establish a network of EOAD sites ready to launch interventional studies in this population; and (5) Explore possible genetic susceptibility factors through WGS. LEADS will recruit and longitudinally follow approximately 400 EOAD, 200 amyloid‐negative cognitively impaired subjects (EOnonAD) and 100 age‐matched controls. Participants will undergo clinical and psychometric assessments, MRI, amyloid ([18F]Florbetaben) and tau ([18F]AV1451) PET, CSF, DNA, RNA, plasma, serum and peripheral blood mononuclear cells collection at three time points. Methods are harmonized with ADNI and DIAN to facilitate scientific comparisons.

Result

The latest enrollment data including the demographic, clinical and biomarker characteristics of the LEADS cohort to date will be presented at the meeting. We will include data on disease subtypes, biomarker collection, genetic screening and counseling and results disclosure.

Conclusion

LEADS will develop a publicly available natural history biomarker and clinical dataset in EOAD and will enable future planning and implementation of clinical trials in EOAD. Successful completion of this project will address several substantial gaps in our understanding of EOAD and AD research in general.
Network‐level relationships between cortical neurodegeneration and FDG‐PET hypometabolism across clinical and A/T/N subgroups in AD
Authors: Stocks Jane , Karteek Popuri , Martersteck Adam , Beg Mirza Faisal , Wang Lei
Published: December 2020

Background

Converging evidence suggests that Alzheimer’s disease (AD) affects multiple large‐scale brain networks. Determining the relationship between network‐level alterations in neuroimaging‐derived metrics of brain structure and function and whether concordance between metrics varies by clinical presentation or pathological status can increase our understanding of the disease process in AD. To this aim, we evaluated the relationship between cortical thinning (neurodegeneration) and cortical glucose hypometabolism within distributed brain networks in individuals across clinical (AD, MCI who later progress to AD, MCI who remain stable, and normal controls) and CSF‐defined A/T/N subgroups.

Method

T1‐MPRAGE and FDG‐PET scans were downloaded from the Alzheimer’s Disease Neuroimaging Initiative website (cohorts ADNI‐1&2 at baseline only). Regional W‐score maps were computed for each patient and each imaging modality, to adjust for the effect of normal aging. Using a well‐validated atlas from the Human Connectome Project/Glasser et al. (2016) and the corresponding cortical network solution by Ji et al. (2019), network‐level Pearson correlations were computed between cortical thickness and FDG metabolism, for each participant, reflecting individual consistency in the degree of atrophy and hypometabolism at each network. Multivariate analysis of variance models assessing the effects of clinic diagnostic category and, separately, A/T/N status, on correlations while accounting for age, education and APOE‐4 status were examined.

Results

Among clinical diagnostic groups, atrophy‐hypometabolism correlations showed significant differences in 11 of 12 networks (Table 1), with correlations increasing by disease severity specifically within networks known to be affected by AD (e.g., frontoparietal, default mode, ventral multimodal; Figures 1 and 2). Among A/T/N subgroups, significant differences in correlation scores were found only within select networks including frontoparietal and default mode networks (Table 2; Figure 3).

Conclusion

With increased disease severity, cortical atrophy is increasingly related to cortical FDG hypometabolism across brain networks. In the A/T/N framework, our findings suggest that both amyloid and tau increase this structure‐function relationship. However, considerable heterogeneity was present among all A/T/N subgroups, warranting further exploration. Multimodal neuroimaging analyses can unravel the structure‐function relationships that contribute to clinical outcomes and diagnostic uncertainty in AD.
Evaluation of polygenic risk scores for 17 cancer types in relation to cognitive decline in the UK Biobank
Authors: Graff Rebecca E , Ackley Sarah F , Romero Monica Ospina , Zimmerman Scott C , Elahi Fanny M , Lu Kun Ping , Witte John S , Glymour M Maria
Published: December 2020

Background

Accumulating evidence suggests that cancer and dementia are inversely associated, wherein cancer survivors have a roughly 40% reduced dementia incidence and vice versa. Survival and diagnostic bias cannot seemingly account for the relationship fully, but causal explanations have not been adequately investigated. We thus considered a possible inverse shared genetic basis in a large population‐based cohort with extensive individual‐level genotypic and phenotypic data.

Methods

The study population included European ancestry individuals from the UK Biobank who 1) were age 60 or over at baseline assessment (incident dementia analyses; n=190,230 individuals, including 1,887 dementia diagnoses after baseline), or 2) had completed at least one test of fluid intelligence – the capacity to solve problems that require logic and reasoning ability, independent of acquired knowledge – at age 60 or over (fluid intelligence analyses; n=127,529 individuals with 163,266 total measures). We selected known independent genetic risk variants to construct polygenic risk scores (PRS) for cancer overall and each of 17 cancer types. We used multivariable logistic regression and random intercept linear mixed models to evaluate per standard deviation increases of each PRS with respect to dementia status and fluid intelligence, respectively. Bonferroni corrected p‐values were used to evaluate statistical significance.

Results

None of the cancer PRS were significantly associated with dementia (p>0.05/17=0.0029). The directionality of the overall cancer PRS (856 variants) was consistent with improved cognitive outcomes (p
dementia=0.20; p
fluid intelligence=0.052). Among PRS for individual cancers, only that for lung cancer (113 variants) was significantly positively associated with fluid intelligence (p=5.9x10‐4). Among variants comprising the various cancer PRS, four independent variants in the human leukocyte antigen (HLA) complex were significantly positively associated with fluid intelligence (p<0.05/856=5.84x10‐5). All were expression quantitative trait loci for major histocompatibility complex class I genes.

Conclusions

A PRS for lung cancer was positively associated with fluid intelligence (i.e., decreasing cognitive decline). The association pattern with HLA‐related variants, which code for proteins involved in antigen presentation to stimulate immune response, suggests potential relevance of immune surveillance for the inverse association between dementia and cancer. Further teasing apart their genetic similarities and differences has the potential to clarify mechanisms of dementia pathogenesis.
Cognition‐related structure in the progression of Alzheimer’s disease
Authors: Mao Chenhui , Li Jie , Huang Xinying , Lei Dan , Liu Caiyan , Dong Liling , Peng Bin , Cui Liying , Gao Jing
Published: December 2020

Background

Typical Alzheimer’s disease (AD) presented with memory loss, followed by global involvement of cognitive domains in the progression of the disease. Bilateral medial temporal lobe and posterior atrophy was most common structure imaging changes.

Method

111 patients diagnosed probable AD based on 2011 NIA‐AA guideline were enrolled. All of them had systemic cognitive evaluation including MMSE, MOCA, CDR, ADL and domain specific batteries. The severity of the disease was defined by MMSE score: 1‐10 severe, 11‐20 moderate, 21‐30 mild. 3D‐T1 MRI data were analyzed using voxel based morphometry supported by DR. BRAIN platform. The volumes of bilateral hippocampus, superior temporal gyrus, superior parietal lobe, posterior cingulate gyrus as well as total grey matter and white matter were calculated.

Result

The male: female ratio was 38:73. The average age was 70.8. The mild: moderate: severe ratio was 48:38:25. The volume of left hippocampus was 2127.8, 1973.2, 1757.6mm3 in mild, moderate and severe group respectively. The volume of right hippocampus was 2426.8, 2275.9, 2101.3mm3. The volume of left superior temporal gyrus was 5354.9, 4888.8, 4358.1mm3. The volume of right superior temporal gyrus was 5690.6, 5139.5, 4872.8mm3. The volume of left superior parietal lobe was 8663.0, 7873.0, 7065.6mm3. The volume of right superior parietal lobe was 8533.1, 7858.9, 7227.1mm3. The volume of left posterior cingulate gyrus was 3364.7, 3028.5, 2816.3mm3. The volume of right posterior cingulate gyrus was 3071.3, 2779.2, 2612.0mm3. Atrophy of all the above area was significantly associated with progression of AD, while posterior area more prominent. The volume of total grey matter was 549373.9, 514908.9, 488812.2mm3. The volume of total white matter was 435153.6, 422331.1, 423894.8mm3. Grey matter volume was significant related to cognition while white matter not, which was in consistent with previous knowledge.

Conclusion

Cognition deterioration was associated with structure atrophy in the progression of AD. Bilateral hippocampus, superior temporal gyrus, superior parietal lobe, posterior cingulate gyrus were all closely related. Besides hippocampus, we reported diffuse cortex including lateral temporal lobe and posterior areas structure change was important.