bluuebunny/crossref_metadata_2025 huggingface dataset:
Prediction of antipsychotics use in patients with mild cognitive impairment and dementia
Authors: Söderlund Maria Elvira , Guajardo Maria Elena , Cavagna Marina , Labos Edith , Rodriguez Pablo Oscar , Schapira Marcelo , Seinhart Daniel Bernardo
Published: December 2020

Introduction

Antipsychotic medications are widely prescribed to manage neuropsychiatric symptoms (NPS) of dementia. NPS produce a negative impact on the caregiver and represent a cause of institutionalization. The benefit of antipsychotics is controversial and should be the last treatment option.

Objective

To detect potential predictors of antipsychotic drug (risperidone, quetiapine, olanzapine, clozapine, haloperidol) use in patients with mild cognitive impairment and mild dementia.

Methods

Data was collected as part of the prospective study of home‐dwelling people with cognitive impairment and their caregivers. The associations between antipsychotic medication use and cognitive‐clinical measures were analyzed using a multivariate binomial generalized linear model.

Results

228 patients were evaluated at baseline. MCI and dementia were diagnosed in 125 and 30 subjects respectively. After a median (25th to 75th percentile range) of 4.5 (4.1‐4.9) years 21 patients died. Antipsychotics were prescribed in 46 cases (16 with dementia and 30 with MCI). In the multivariate model, baseline Boston naming test (OR: 0.93, 95% confidence interval: 0.89‐0.98, p=0.004) and instrumental activities of the daily living score (OR: 0.65, 95% confidence interval: 0.47‐0.90, p=0.009) were independently related to antipsychotic use (table).

Conclusion

Within 4 years of follow‐up, thirty percent of the patients with cognitive impairment received antipsychotic drugs. Baseline instrumental activity of the daily living and Boston naming test were identified as independent predictors.
Diffusion MRI metrics of brain microstructure in Alzheimer’s disease: Boosting disease sensitivity with multi‐shell imaging and advanced pre‐processing
Authors: Thomopoulos Sophia I , Nir Talia M , Reina Julio E Villalon , Jahanshad Neda , Thompson Paul M
Published: December 2020

Background

Diffusion MRI (dMRI) provides novel measures of white matter (WM) microstructure, offering biomarkers that provide insight into brain aging and Alzheimer’s disease. As advanced acquisitions are implemented (multi‐shell/multi‐band; MB), novel models are developed to more accurately represent tissue microstructure. In its third phase, the Alzheimer’s Disease Neuroimaging Initiative (ADNI‐3) updated their acquisition protocols to include MB dMRI. As acquisition protocols are being updated, it is important to understand which processing steps consistently improve dMRI model fit and derived measure sensitivity to biological effects. Here, we compared state‐of‐the‐art processing methods for ADNI‐3 MB scans to (1) establish an updated dMRI ADNI processing pipeline, and (2) fit more sophisticated tissue parameters sensitive to clinical measures of burden.

Method

Baseline MB ADNI‐3 scans (N=137; Table 1) were downloaded and processed with both the dMRI pipeline we established during ADNI‐2 (Pipeline‐A) and the one we have updated during ADNI‐3 (Pipeline‐B; Fig. 1). We obtained scalar diffusion tensor imaging (DTI) maps from the down‐sampled preprocessed dMRI, and higher model metrics using all diffusion volumes using NODDI. Covarying for age, sex, age*sex, and modeling acquisition site as a random effect, we tested associations between regions of interest (ROI; Table 2) diffusion scalar measures and a set of standardized clinical measures (Fig. 2). We modeled effects of age in controls, covarying for sex, age*sex and modeling site as a random effect. All results were corrected for multiple comparisons (FDR). Within WM, voxel‐wise DTI model error (RMSE) was compared across pipelines with paired t‐tests in controls (Fig. 3).

Result

Fractional anisotropy measures were most affected by the different preprocessing methods, while diffusivity metrics were most strongly correlated with standard clinical measures of cognitive disease burden, such as CDR‐sob. Metrics from NODDI, such as ODI, behaved similarly to FA, showing greatest differences in effect sizes across pipelines.

Conclusion

We are currently applying Pipeline‐B to all available ADNI‐3 dMRI scans, to make the data available to the imaging community. As new preprocessing and denoising tools are available and acquisition protocols become more complex, our analyses indicate that preprocessing steps can sensitize diffusion metrics to differences in clinical disease burden.
Distinct and common biomarkers and phenotypes in cerebral palsy and mild cognitive impairment: An exploratory study
Authors: Ng Ted Kheng Siang , Tagawa Alex , Larbi Anis , Kua Ee‐Heok , Mahendran Rathi , Carollo James , Heyn Patricia C
Published: December 2020

Background

Cerebral palsy (CP) patients have accelerated aging, impairments in various pathology and anthropometry, and may develop geriatric syndromes, particularly cognitive impairment. Mild cognitive impairment (MCI) is an intermediate stage between healthy aging and dementia. Owing to their intriguingly parallel yet “inverted” disease trajectories, CP and MCI might share both distinct and similar pathology and phenotypes. Thus, we aimed to examine this hypothesis by developing a unique collaboration between two laboratories specialized in these two populations.

Method

The CP study was conducted at a clinical motion analysis laboratory at Children’s Hospital Colorado, while the MCI participants were recruited for a randomized controlled trial in Singapore. A total of eight measures, including blood biomarkers, neurocognitive and anthropometric measures were compared. Multivariate linear regressions were performed to examine the similarities and differences in these measures between the two cohorts and the associations between biomarkers and neurocognitive/ anthropometric measures, in the total and sub‐samples.

Result

Compared to MCI, brain‐derived neurotrophic factor (BDNF) levels and diastolic blood pressure were significantly lower in CP, upon controlling for covariates. In CP, BDNF was significantly correlated with hs‐CRP and BMI. Furthermore, the variance of diastolic blood pressure in CP could be explained largely by chronological age. The other six measures, including impaired neurocognitive functions, were similar between CP and MCI.

Conclusion

These findings supported our hypothesis on both distinct and common pathology between CP and MCI, which could be partly attributed to either aging or pathophysiology. In CP, BDNF levels were lower than MCI, and it plays significant roles in inflammation and weight, whereas aging effect contributed mainly to the variability in diastolic blood pressure. Future studies using longitudinal follow‐up with larger sample sizes and examining accelerated biological aging is warranted.
Brain imaging data quality and denoising: Impact on the study of sex differences in Alzheimer’s disease
Authors: Caldwell Jessica ZK , Yang Zhengshi , Kaplan Nikki , Leavitt MacKenzie , Miller Justin , Mishra Virendra R , Shan Guogen , Cordes Dietmar
Published: December 2020

Background

Recent research highlights sex effects in Alzheimer’s disease (AD). However, examining sex effects presents challenges, for example due to Magnetic Resonance Imaging (MRI) methodological differences and effects of sex on resting state functional MRI (rsfMRI) being small compared to effects of factors like age. Attention to data processing methodology may help to address this challenge. The present discussion will highlight the results of our recent examinations of the effect of sex on success of automated MRI volumetric analysis with clinically‐obtained MRI, and the role of rsfMRI data denoising on measuring sex effects in AD.

Method

Volumetric quality was assessed in 438 patients seen in an outpatient neurology clinic specializing in diagnosis and treatment for neurodegenerative diseases (47.7% women), and rsfMRI in 168 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI: 49 Cognitively Normal (CN); 67 early Mild Cognitive Impairment (eMCI); 52 AD; 52% women). MRI data were processed using Freesurfer 6.0, with in‐house quality assessment. Resting state data were preprocessed with realignment, slice‐time correction, coregistration and normalization to standard MNI space, and then denoised using traditional nuisance regression methods with global signal, mean white matter and cerebrospinal fluid time series, and motion parameters; Compcor; and a novel in‐house developed, deep neural network approach.

Result

In‐house quality assessment resulted in discarding 43% of segmented images. Individuals whose images were discarded were significantly older than individuals with retained images, but sex did not impact retention. In contrast, using our novel rsfMRI denoising technique, CN women showed significantly lower degree centrality, global efficiency, local efficiency, and clustering coefficient, and significantly longer path length. Differences were less significant in MCI and not significant in AD. Traditional denoising approaches revealed weak differences or no differences by sex.

Conclusion

These findings suggest that quality control approaches to clinical imaging processing may be important to the study of AD generally, but that data denoising techniques in rsfMRI may have impact specifically on the study of AD‐related sex differences.
Secondary tauopathy in a genetic synucleinopathy, mitochondrial protein–associated neurodegeneration (MPAN)
Authors: Nguyen Vy , Garcia Daphne , Setthavongsack Naly , Shirley Kristen , Krajbich Victoria , Clark David , van der Weijden Marlous , Zhen Dolly , Wakeman Katrina , Jeong Suh Young , Freed Alison , Gregory Allison , Hogarth Penelope , Hayflick Susan , Woltjer Randall
Published: December 2020

Background

Tauopathy and α‐synucleinopathy often occur together in human brain diseases but most commonly in the context of β‐amyloidosis. Tauopathy induced by α‐synucleinopathy in the absence of β‐amyloid has been demonstrated in vitro and in cultured cells but compelling examples of this in human disease rarely occur, most commonly in familial Parkinson's disease due to mutations in the α‐synuclein gene. Mitochondrial protein‐associated neurodegeneration (MPAN) due to mutations in C19orf12 produces neurodegeneration with brain iron accumulation as well as widespread α‐synucleinopathy. We report here on the findings and significance of associated tauopathy in MPAN.

Method

Four patients with genetically confirmed MPAN were referred for brain autopsy and a complete histologic and immunohistochemical evaluation was undertaken for lesions and proteinopathies of common neurodegenerative diseases as well as the specific reported lesions of MPAN.

Result

All patients had hallmark pathologic features of MPAN including atrophy, gliosis, and iron accumulation involving the globus pallidus as well as abundant α‐synucleinopathy manifest as Lewy bodies and neurites thoughout the brain. Tauopathy was present in each case with neurofibrillary tangles distributed in Braak stages I to V with pretangles and more widely distributed tau‐positive dystrophic neurites. The distribution and regional burden of tauopathy was less than that of α‐synucleinopathy in each case. β‐amyloid or TDP‐43 abnormalities were not identified in any case.

Conclusion

The lesional burden and distribution in MPAN are consistent with a pathogenetic model in which dysmetabolism of α‐synuclein is sufficient, in the absence of other common neurodegenerative pathologies, to induce tauopathy. Study of rare familial diseases such as MPAN may enhance our understanding of the pathogenesis of more common idiopathic neurodegenerative diseases.
Subjective memory ability correlates with functional connectivity between the medial temporal lobe and posterior default mode network in cognitively normal older adults
Authors: Mah Linda , Murari Geetanjali , Vandermorris Susan , Verhoeff Nicolaas Paul L.G. , Herrmann Nathan
Published: December 2020

Background

Subjective cognitive decline (SCD) increases the risk of developing Alzheimer's disease (AD) but the neural mechanisms underlying this association remain unclear. Multimodal neuroimaging studies suggest that large‐scale network disruptions occur before amyloid plaques appear in the brain, beginning with alterations in the posterior default mode network (DMN). Here we investigated the association between subjective report of memory ability and functional connectivity between the posterior DMN and medial temporal lobe structures. We hypothesized that self‐report of greater memory ability would be positively correlated with functional connectivity between the posterior DMN and the medial temporal lobe.

Methods

Participants were 46 older adults [27 females, mean age=71.2 (6.5)] free of psychiatric or neurological illnesses, and normal cognition based on neuropsychological assessment. Subjective memory was evaluated using the Memory Functioning Questionnaire (MFQ). Resting state functional magnetic resonance imaging was acquired using gradient‐echo EPI BOLD at 3T and processed using CONN toolbox. A seed‐based analysis using the posterior cingulate cortex, a key node within the posterior DMN (x=‐6, y=‐52, z=40), as the seed was conducted to measure functional connectivity between the PCC and the hippocampus and parahippocampal regions. Correlations between functional connectivity measures and subjective memory [MFQ Frequency of Forgeting (MFQ‐FF)] as well as objective memory (California Verbal Learning Test‐II delayed recall) were performed.

Results

MFQ‐FF scores were significantly correlated with functional connectivity between the PCC and left parahippocampal gyrus (r = .52, p < .001). MFQ‐FF scores were similarly correlated with functional connectivity between the PCC and hippocampus (r=.34, p=.02) but this finding was not statistically significantly after applying a Bonferroni correction. In contrast, CVLT delayed recall scores were not correlated with functional connectivity of the posterior DMN and the medial temporal lobe.

Conclusions

Disruption of functional connectivity between the posterior DMN and the medial temporal lobe may mediate the association between SCD and AD risk.
Inclusive support: Addressing the needs of black family caregivers of persons with dementia
Authors: Robinson‐Lane Sheria G , Zhang Xingyu (Mark)
Published: December 2020

Background

Family caregivers of Black older adults with Alzheimer’s disease and/or related dementias (ADRD) have an increased risk, compared to White family caregivers, for developing ADRD themselves and premature death. An effective minority family caregiver support intervention may be designed, or current program appropriately modified, by understanding the relationships between family caregiver support needs, health challenges, and predominantly used coping strengths.

Method

A cross‐sectional sample of Black family caregivers living in southeastern Michigan (n=56) completed a survey comprised of a demographic tool, and multiple assessment measures including, the Promise Global Health Scale, the Personal Resource questionnaire, the Revised Scale for Caregiving Self‐Efficacy, and the Coping and Adaptation Processing Scale. Descriptive statistics and Spearman correlation coefficients were used to identify the prevalence of population health concerns and the relationships between particular health outcomes and caregiving strengths.

Result

More than 90% of the sample were educated Black women over the age 50 caring for parents (36%), grandparents (5%), Spouses (20%), children (14%), and other relatives (18%). The most common care recipient diagnoses included dementia non‐specified (52%), Alzheimer’s disease (20%), and vascular dementia (13%). The average body mass index for the caregivers was 31.7 indicating a high prevalence of obesity. Related caregiver health concerns included hypertension (70%) and diabetes (22%). Adaptive coping by caregivers was significantly associated with positive physical health (p = 0.000), mental health (p=0.001), perceived social support (p=0.001) and self‐efficacy for controlling upsetting thoughts (p=0.014). The predominant coping strategies used by the sample were spiritual coping, information gathering, and drawing upon past experiences.

Conclusion

Family caregiver support programs that are designed to target Black adults may be enhanced through an increased focus on health promotion—particularly weight and disease management. Programs should also consider supporting caregivers in developing effective coping strategies in alignment with their preferred ways of coping, including an increased focus on spirituality, optimizing information sourcing, and utilizing effective past strategies.
Stages of tau aggregation associated with amyloidosis reflected in non‐negative matrix factorization components
Authors: Srinivasan Dhivya , Truelove‐Hill Monica , Erus Guray , Sotiras Aristeidis , Doshi Jimit , Wolk David A. , Davatzikos Christos , Nasrallah Ilya M. ,   Alzheimer’s Disease Neuroimaging Initiative
Published: December 2020

Background

Tau aggregation, when accompanied by amyloid deposition, is a key neuropathological signature of Alzheimer’s disease (AD). The regional distribution of tau may be a more sensitive marker of AD pathology than total tau level, however the spread of disease is unlikely to conform to common atlas‐based regions of interest. As such, methods for evaluating tau’s regional distribution could be useful for predicting AD staging or disease progression. In this analysis, we derive regional patterns of tau aggregation in AD using nonnegative matrix factorization (NNMF), a data‐driven method of identifying areas of the brain that consistently covary across individuals.

Method

We used data from 269 ‐amyloid (A) positive subjects with 18F‐flortaucipir‐PET data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database and the AVID study (138 females, mean age = 73.09; 110 healthy controls, 118 MCI, and 41 AD). PET data were registered to Standard Montreal Neurological Institute (MNI152) 182x218x182 grid with 1mm resolution. SUVR maps were computed with a cerebellar gray matter reference and NNMF was used to estimate common patterns of tau aggregation. Once these patterns were identified, mean SUVR for each component computed for each participant. We performed Gaussian mixture modeling for each component to determine optimal tau positivity cutpoint, and subjects were classified as positive or negative for each component. Components were ordered by frequency of appearance in subjects in order to determine staging.

Result

12 regional patterns of tau binding were identified (Figure 1). The patterns most commonly expressed among subjects reflected regions of the temporal lobe (Figure 2a). This was particularly noted in those with AD (Figure 2b). These components were followed by a component including the lingual gyrus, and then by components involving frontal lobes, precuneus, and parietal lobes.

Conclusion

NNMF‐derived tau PET components provide a data‐driven method for identifying common patterns of tau aggregation, producing stages that are consistent with previous research on tau pathology in AD. These components may provide a more sensitive method for identifying disease progression in AD.
Microglial sex dimorphism poses greater vulnerability to Alzheimer’s disease in females: A cross‐species study
Authors: Kang Min Su , Ottoy Julie , Aliaga Arturo Aliaga , Mathotaarachchi Sulantha , Savard Mélissa , Chamoun Mira , Stevenson Jenna , Rahmouni Nesrine , Thomas Emilie , Benedet Andréa Lessa , Tissot Cécile , Therriault Joseph , Lussier Firoza Z , Wang Yi‐Ting , Arias Jaime Fernandez , Massarweh Gassan , Soucy Jean‐Paul , Gauthier Serge , Rosa‐Neto Pedro , Terada Tatsuhiro
Published: December 2020

Background

Understanding sex dimorphism in neurodevelopment and neurodegeneration is imperative for therapeutic strategy, clinical trial enrichment, and personalized medicine. However, the cellular underpinning of sex dimorphism in Alzheimer’s disease (AD) pathophysiology is still poorly understood. Here, we aimed to investigate the effect of sex on microglial activation and its effect on cognition using the major targets of AD clinical trials – amyloid ([18F]AZD4694), tau ([18F]MK6240), and neuroinflammation ([11C]PBR28) – through a multimodal PET study in humans and rats.

Method

A total of 108 participants (70 CN, 25 MCI, and 13 AD; 36 M, 72 F) with a high‐affinity binder for TSPO from the TRIAD cohort underwent 3 PET scans and MMSE for cognitive assessment. Static [18F]AZD4694, [18F]MK6240, and [11C]PBR28 SUVR images were generated. All PET images were normalized to the ADNI template, used cerebellar grey as a reference region. Furthermore, 29 rats (8 WT, 21 Tg; 13 M, 16 F) underwent a 60‐min dynamic [18F]AZD4694 and [11C]PBR28 PET scans. All PET images were normalized to the average template. [18F]AZD4694 and [11C]PBR28 BPND were quantified based on SRTM method using Pons and midbrain as a reference region, respectively. The sex effect on neuroinflammation is evaluated based on a linear regression model in humans and rats. Consequently, sex dimorphism induced neuroinflammation effect on cognition was assessed using MMSE. All the models were corrected for age, APOE, education, amyloid and tau status.

Result

In this study, females showed greater [11C]PBR28 binding in basal temporal regions in humans and parietotemporal cortex, hippocampus, and basal forebrain in rats. Consequently, greater neuroinflammation in females showed negative effects on MMSE but not in males, p = 0.033.

Conclusion

This study demonstrated the greater microglia activation in females compared to males. Considering the difference in the microglia reaction to amyloidosis in rodents compared to humans, the increased microglial activation effect on cognition was only assessed in humans. Here, microglial sex dimorphism showed deleterious effects on cognition only in females. This study highlights the difference in microglial reactivity leading to greater vulnerability to cognitive decline in females. As such, it is imperative to explore a sex‐specific therapeutic strategy for AD clinical trial.
Neuroimaging and neuropsychological findings in MAPT N279K mutation phenoconverters
Authors: Forsberg Leah K. , Fields Julie A. , Brushaber Danielle , Chen Qin , Kantarci Kejal , Senjem Matthew L. , Jack Clifford R. , Gavrilova Ralitza H. , Graff‐Radford Jonathan , Graff‐Radford Neill R. , Jones David T. , Knopman David S. , Kremers Walter K. , Petersen Ronald C. , Savica Rodolfo , Syrjanen Jeremy , Rademakers Rosa , Wszolek Zbigniew , Boeve Bradley F.
Published: December 2020

Background

Characterization of the changes that occur throughout the transition from asymptomatic to symptomatic for those with familial frontotemporal dementia is essential for planning future disease‐modifying trials.

Method

We identified four related microtubule associated protein tau (MAPT) N279K mutation carriers who have phenoconverted from the asymptomatic to the symptomatic state. Key features were as follows: Case 1 (female) initial exam age 36, onset age 44, current age 49; Case 2 (male) initial exam age 39, onset age 43, current age 48; Case 3 (female) initial exam age 41, onset age 47, current age 53; Case 4 (male) initial exam age 36, onset age 37, current age 46. MRI and neuropsychological data were analyzed.

Result

Structural MRI was analyzed using Tensor Based Morphometry Symmetric Diffeomorphic Image Normalization (TBM‐SyN) methodology to quantify lobar volumes, which was then analyzed using a Mixed Effects Model to determine the annual change in lobar volumes. The phenoconverters had a greater estimated annual rate of cortical atrophy in temporal (p <0.001), frontal (p <0.01) and parietal (p <0.05) lobes compared to non‐carriers, with the rate of annual change in symptomatic individuals double that of asymptomatic individuals. Annual change in the parietal and occipital lobes was also analyzed and found to be similar to healthy controls of a similar age. Raw scores on neuropsychological measures were converted to z‐scores for analysis. Category fluency, letter fluency, and Trails A and B were all impaired (z‐score <‐1.5) following phenoconversion, but performance on these and other measures was variable across these four in the late asymptomatic state.

Conclusion

For each of the four phenoconverters, structural MRI changes preceded symptom onset, whereas neuropsychological performance was more variable and occurred in closer proximity to the time of phenoconversion. Decrements in verbal fluency and cognitive flexibility were observed earlier than other cognitive domains. These findings suggest that changes in frontal and temporal volume on MRI precede symptom onset, with regional brain volumes most consistently tracking the evolution from the asymptomatic to symptomatic state in N279K MAPT mutation carriers. Supported by: AG063911, AG045390, NS092089, AG016976, AG016574, AG062677.
Amygdala tau in preclinical Alzheimer’s disease
Authors: Abiose Olamide , Deters Kacie D , Young Christina , Mormino Elizabeth C
Published: December 2020

Background

Post‐mortem and neuroimaging studies have established the amygdala as one of the earliest sites of tau deposition and neurofibrillary tangles. We investigated the cognitive and anatomical consequences of amygdala tau levels in healthy, older adults.

Method

We examined 226 cognitively unimpaired ADNI participants who underwent AV‐1451 PET imaging (Aß‐ = 145, Aß+ = 81). We identified cognitive (memory, executive functioning) and MMSE scores — as well as neuroanatomical measures — closest in proximity to participants’ respective AV‐1451 PET scans (average time differences = 1.87 months, 2.04 months, and 11.05 months respectively). We used a series of linear regression models to explore the cross‐sectional relationships between amygdala and entorhinal tau/volume and cognition, as well as that between tau and volume. In a smaller set of 177 individuals, we also examined the extent to which neuropsychiatric symptoms (average time from AV‐1451 PET scan = 2.71 years) predicted amygdala tau and volume measures. All models controlled for age, sex, education level, and amyloid status. Models with volumetric measures also controlled for intracranial volume.

Result

Amyloid‐beta positive participants had higher tau levels in both the amygdala and entorhinal cortex (p < 0.001); they also had smaller amygdala volumes than Aß‐ participants (p < 0.05). Within the Aß+ groups, elevated amygdala tau (only) was associated with lower amygdala volumes (ß=‐445.198, p=0.01). Both amygdala (ß=‐2.908, p=0.02) and entorhinal tau (ß=‐3.347, p=0.02) were significant predictors of MMSE scores, but only in Aß+ participants. Amygdala volume was a significant predictor of memory among Aß+ participants (ß=0.001, p=0.01), and there was a trend towards significance between amygdala volume and executive function (ß=0.001, p=0.07). There were no other significant effects on memory or executive functioning measures. Additionally, we found trend‐level inverse relationships between NPI anxiety and amygdala tau (ß= ‐0.073, p=0.1), as well as NPI anxiety and amygdala volume (ß= ‐104.975, p=0.06).

Conclusion

Early amygdala tau is associated with reduced volume as well as worse overall global cognition in individuals thought to be in the preclinical stage of AD (Aß+ normal controls). Anxiety may possibly have a relationship with amygdala tau and volume (suggestively associated with less tau and less volume).
Comparison of deep learning methods for brain age prediction
Authors: Lam Pradeep , Zhu Alyssa , Salminen Lauren , Thomopoulos Sophia I , Bright Joanna , Jahanshad Neda , Thompson Paul M
Published: December 2020

Background

BrainAge ‐ an estimate of a person’s age predicted from their structural MRI ‐ is a biomarker used to quantify age‐related neurodegeneration. The deviation of BrainAge from chronological age (Predicted Age Difference ‐ PAD) is of interest for prognostic research. Here we evaluated the accuracy of several deep learning methods (convolutional neural networks; CNNs) in predicting brain age.

Method

All experiments were conducted with a subset of 10,801 neurologically healthy participants from the UK Biobank. Of these, 9,301 were scanned at a single site; an additional 1,500 were from auxiliary sites with the same calibration standards. Participants’ age range was 48.9‐76.6 years. The primary site data had a mean age of 62.4 (SD, 7.5; 47% women/53% men). The auxiliary site scanned subjects with a mean age of 63.9 (SD, 7.3; 55% women/45% men). From the 9,301 single‐site scans, 7,153 were used to train the models; the rest were split into validation and testing sets. All auxiliary site data was used for out‐of‐site testing. Each model was trained using a different divergence penalty. In addition, a single model was evaluated on 25,756 participants from the UK Biobank dataset. K‐fold Cross‐Validation was used to prevent overlap between train, validation, and test sets. For each training instance, 12,365 subjects were used for the training set; the rest were split evenly between validation and test sets. For this experiment, subjects were not filtered out based on neurological health.

Result

All models performed well on both the in‐site and out‐of‐site test sets with an average mean absolute error (MAE) of 2.98 and 2.94 years, respectively. The model evaluated on 25,756 subjects received a MAE of 2.85 (R 0.845) with a residual correlation of 0.432 between PAD and true age.

Conclusion

Good accuracy achieved by all models suggests the value of BrainAge as a holistic biomarker of brain aging.
Endophenotype driven polygenic risk scores for Alzheimer’s disease
Authors: Chasioti Danai , Jacobson Tanner Y. , Nho Kwangsik , Risacher Shannon L. , Gao Sujuan , Yan Jingwen , Saykin Andrew J.
Published: December 2020

Background

Precision medicine is designed to resolve heterogeneity in complex diseases such as Alzheimer’s (AD) to deliver timely and tailored treatment. Using ADNI data, we developed profiling based on genetically driven endophenotype‐specific polygenic risk scores (PRS) and assessed participant clustering on these profiles.

Method

We used ADNI genetic, clinical and biomarker data for PRS development. We performed cross‐sectional and longitudinal analysis in order to identify individual profiles at the baseline and to track disease progression. We derived four ADRD endophenotype components including Amyloid (A), Tau (T), Neurodegeneration (N) and Vascular (V), by applying PCA on 10 phenotypic variables. Bootstrapping was used for SNP selection and weight re‐estimation. APOE SNPs (rs429358, rs7412) and nearby genes were excluded. We performed K‐means clustering on the 4 derived A/T/N/V PRSs and cluster assignment was computed for 839 individuals of the validation set (excluding AD at the baseline). Baseline levels of cognition and biomarkers were estimated using linear regression adjusting for age, sex, education and (ICV when necessary) (Table 1, Figure 2). Longitudinal trajectories were estimated using linear mixed models (LMM) (Table 2, Figure 3). The performance of the LMM was assessed using marginal R2 (Table 3).

Result

Cluster assignment placed 306 individuals in Cluster1 and 533 in Cluster2. Both were balanced in terms of APOE e4 status, and demographics. Cluster1 showed elevated genetic risk (Figure 1) that was manifest at baseline by higher levels of amyloid (PET, CSF) and reduced temporal lobe thickness and memory (Table 1, Figure 2). Longitudinally, significant effect differences among the clusters were observed in angular gyrus, temporal lobe, white mater hyperintensity (WMHI), and clinical/cognitive measures (ADNI_EF and FAQ) (Table 2, Figure 3). Among APOE e4 non‐carriers, Cluster1 had significantly worse scores compared to Cluster2 (ADNI_EF and WMHI).

Conclusion

Using clusters derived from endophenotype specific genetic information we were able to identify distinct progression profiles with predictive value beyond APOE alone. Endophenotype‐based PRS may be useful for therapeutic enrichment and targeting strategies in development of personalized therapeutics. Validation in independent samples is a critical next step.
Efficacy of structured cognitive stimulation therapy program for older adults with dementia
Authors: Sanchez Cintia P
Published: December 2020

Background

Cognitive stimulation therapy (CST) is an evidence‐based psychosocial intervention for people with mild‐to‐moderate dementia due to various etiological factors.

Objective

The aim of the present study was to assess the efficacy of a structured group CST program, in individuals who have vascular or Alzheimer dementia.

Methods

Older adults with mild vascular or Alzheimer dementia (N = 20) were assigned to one of two programs: one group (N = 10) attended during one year, two sessions per week program of the group structured CST program, while the other, active control group (N = 10) took part in alternative activities. The following domains were examined: cognitive functioning, quality of life, mood, behavior, functional activities of daily living.

Results

Compared with the active controls, the structured group CST program showed a greater improvement in general cognitive functioning after the intervention (i.e. score increase on the Mini‐Mental State Examination and clock test score). A trend towards improvement was also identified in short term/working memory and perceived quality of life (Quality of life (QoL) of elderly with dementia). No significant differences emerged between the two groups for the other domains considered.

Conclusion

The present results support the efficacy of structured group CST program in people with dementia. Key Words: Cognitive stimulation therapy (CST), Minimental State Examination (MMSE), Quality of life of elderly with dementia (QoL).
Experimental design for evaluating the effect of lighting interventions on patients with Alzheimer's: A review
Authors: Mathur Pegah , Rider Traci Rose , Place Wayne
Published: December 2020

Background

Alzheimer’s disease is expected to become a major public health problem in the U.S. for the aging population. It is projected that in 2050, 65% of the aging population will die of Alzheimer’s. This raises the questions of whether and how we are prepared to provide care for this growing population. In this regard, the built environment can have a crucial role in supporting care and cure processes for the disease. Among the environmental variables that impact the provision of care for Alzheimer patients, lighting is especially consequential as it is known as a non‐invasive cure method that can stimulate the circadian rhythm and mitigate the issues of sleeping disturbance and agitation. Nevertheless, previous experimental research on this topic is inconclusive since many studies failed to present important variables and strategies used in their experimental designs (e.g. characteristics of the lighting device, exposing light intensity and spectral quantity, time‐series design and frequency of the interventions, the amount of light entered into the subject’s eyes).

Method

This paper reviews the existing research on lighting and Alzheimer’s to develop a framework that gives structure to the design of experimental research on the effect of lighting interventions on Alzheimer’s patients (e.g. variables, contextual factors, control strategies).

Result

This framework can facilitate future research on this topic as it enables the researchers to improve the internal validity of their results by improving their research design. Furthermore, this proposed framework can lead to a consistency in defining and using variables, control factors, and applicable findings across different studies to facilitate replication of experimental studies and inform the researcher on the generalizability of the findings.

Conclusion

Furthermore, this proposed framework can lead to a consistency in defining and using variables, control factors, and applicable findings across different studies to facilitate replication of experimental studies and inform the researcher on the generalizability of the findings.
U.S. POINTER (USA)
Authors: Baker Laura D. , Espeland Mark A. , Kivipelto Miia , Whitmer Rachel A. , Snyder Heather M. , Carrillo Maria C. , Antkowiak Susan , Chavin Melanie , Cleveland Maryjo , Day Claire E. , Desai Pankaja , Elbein Richard , Farias Sarah Tomaszewski , Gitelman Darren , Katula Jeffrey A. , Lambert Katherine , Leng Xiaoyan Iris , Lovato Laura , Morris Martha Clare , Ngandu Tiia , Papp Kathryn V. , Pavlik Valory N , Raman Rema , Robertson Julie , Rushing Scott , Salloway Stephen , Solomon Alina , Su Jing , Ventrelle Jennifer , Williams Benjamin J. , Williamson Jeff D. , Woolard Nancy , Yu Melissa
Published: December 2020

Background

U.S. POINTER aims to test whether a multidomain lifestyle intervention focused on physical and cognitive activity, nutrition, and risk factor management reduces risk of cognitive decline in a heterogeneous population of older adults in the U.S. The study adapts the FINGER (Finnish Intervention Geriatric Study to Prevent Cognitive Impairment and Disability) interventions to fit American culture and works with community partners at 5 sites across the country to develop sustainable community‐based intervention programs.

Methods

U.S. POINTER is a 2‐year RCT that is enrolling 2000 cognitively normal older adults (60‐79 years) who are at risk for decline due sedentary lifestyle, poor diet and other factors such as family history of memory impairment and suboptimum cardiovascular health. Recruitment utilizes electronic health records, as well as grassroots approaches to engage traditionally underrepresented groups. Participants are randomized to one of two lifestyle intervention groups – Self‐Guided or Structured Lifestyle Intervention – that differ in format, intensity and accountability. U.S. POINTER includes partnerships with local chapters of the Alzheimer's Association and lifestyle specialists to assist with intervention delivery. The primary outcome is 2‐year change in cognitive function measured with a composite score that permits harmonization with FINGER.

Results

Recruitment began in 2019 at the vanguard site in North Carolina. Study progress at all 5 participating sites will be presented. Progress toward harmonization with FINGER and other international study teams in the WW‐FINGERS network will also be discussed.

Conclusion

As a member of the WW‐FINGERS network of trials, U.S. POINTER provides an unprecedented opportunity to leverage lessons learned in FINGER and expand this work to test the generalizability of the findings to a heterogeneous American cohort with different cultural needs and practices. The results, in combination with those from other WW‐FINGERS studies, have the potential to identify a strategy to slow cognitive decline on a global scale.
Contrasting alterations between cortical and subcortical myelin across age, AD diagnosis, and amyloid and tau pathology as assessed by quantitative R1 mapping
Authors: Kohli Akshay , Kecskemeti Steven , Adluru Nagesh , Jonaitis Erin M , Asthana Sanjay , Blennow Kaj , Zetterberg Henrik , Carlsson Cynthia M , Alexander Andrew L , Johnson Sterling C , Bendlin Barbara B
Published: December 2020

Background

Accumulation of pathology in cortical tissue are early pathological hallmarks of Alzheimer’s disease. High resolution T1w/T2w ratio maps from structural MRI may reflect tissue microstructure with sensitivity to myelin, iron, and dendritic density. Few studies have investigated this in AD with conflicting reports of directionality of T1w/T2w ratios in individuals with AD diagnosis and pathology. However, these ratios will be sensitive to pulse sequences, protocols and bias field inhomogeneities, limiting their utility in clinical and research contexts. Here we employ R1 (=1/T1) relaxometry mapping, a quantitative imaging measure that is sensitive to myelin, to investigate relationships between cortical and subcortical tissue microstructure, age, AD diagnosis, and amyloid and tau pathology.

Method

Participants from the Wisconsin Alzheimer’s Disease Research Center and Wisconsin Registry for Alzheimer’s Prevention underwent 3T MRI with whole‐brain, 1mm isotropic MPnRAGE T1 relaxometry with motion correction (Kecskemeti et al., 2016) (N=605/CN, 39/AD; age = 65.49 +/‐ 7.89 yrs) with a subset undergoing lumbar puncture for CSF Aß42/Tau biomarker classification (N = 141/A‐T‐, 26/A+T‐, 22/A‐T+, 18/A+T+). T1‐weighted images were processed using ANTS and CAT12, and transformation warps were applied to produce subcortical R1 maps in MNI space (6mm smoothing) and cortical R1 surface meshes (164k mesh, 5mm smoothing). Vertex‐wise (GM) and voxel‐wise (WM) ANCOVA were performed (p<0.05 FWE corrected). Covariates included age, sex, study protocol, and AD diagnosis in model 1, and age, sex, years between CSF collection and MRI, study protocol, and A/T biomarker group in model 2.

Result

Significant associations between R1 and age, clinical AD diagnosis, and A/T pathology were found (Figure 1A‐C). Post‐hoc tests revealed increased R1 due to A/T pathology driven by A+T+ individuals. In contrast, significant widespread decreases in subcortical R1 were found with age and AD diagnosis (Figure 1D&E), with no significant alterations in subcortical R1 due to biomarker status.

Conclusion

Cortical and subcortical tissue exhibit differential tissue microstructural changes in response to aging, AD diagnosis and pathology. Importantly, increases in cortical R1 in unimpaired A+T+ individuals may reflect increased remyelination prior to the development of cognitive impairment. Future research will assess longitudinal relationships of R1 with age, cognition and markers of neurodegeneration.
Imaging ketone metabolism in the brain in Alzheimer's disease using hyperpolarized 13C spectroscopy
Authors: Page Lydia M Le , Shin Soo Hyun , Qiao Kai , Chaumeil Myriam M
Published: December 2020

Background

After a ketogenic diet (KD), some cognitive improvements have been seen in Alzheimer’s disease (AD) patients. In vivo measurement of cerebral BHB metabolism is critically needed to properly assess patient response, as blood ketone level (especially beta‐hydroxybutyrate (BHB)) is not always coupled to brain ketone metabolism. Here, we evaluate a new imaging method, 13C magnetic resonance spectroscopy (MRS) of hyperpolarized (HP) [1‐13C]BHB, for in vivo assessment of ketone metabolism.

Method

[1‐13C]BHB was hyperpolarized and injected with BDH at 11.7T or in a C57BL/6J mouse at 3T, and dynamic 13C MRS acquired. Non‐HP [1‐13C]BHB was injected in a C57BL/6J mouse, brain metabolites extracted using chloroform/methanol, and 13C data acquired (11.7T). C57BL/6J (n=6‐8) or AD hAPP‐J20 mice (n=3) received either a KD (TD.160153, Envigo) or control diet (TD.150345, Envigo). Serum BHB levels (Precision Xtra) and brain BDH activity (BMR) were measured. Ex vivo data were analyzed using Mestrenova; in vivo data in jMRUI.

Result

T1 was 41s (1.5T); 37s (3T); 28s (11.7T) (Fig.1A). Metabolism of HP [1‐13C]BHB (181ppm) to HP 13C AcAc (175ppm) by BDH was detected (Fig.1B‐C). [1‐13C]BHB and 13C AcAc were seen in brain extracts after [1‐13C]BHB injection (Fig.1D). Serum BHB and BDH activity were significantly elevated, but not correlated, in both healthy KD mice (Fig.2A‐C), and hAPP‐J20 KD mice (Fig.2D‐F). Following intravenous injection, HP [1‐13C]BHB and product HP 13C AcAc were observed in the live mouse brain (Fig.3). We believe this is the first observation of HP [1‐13C]BHB metabolism in the mouse brain.

Conclusion

KD increased BHB serum levels and brain BDH activity in healthy and AD mice. These two values were not correlated, confirming the necessity of an in vivo marker of ketone metabolism. Detection of conversion of HP [1‐13C]BHB to AcAc is feasible both ex vivo and in vivo. Future studies will image KD‐fed hAPP‐J20 mice. References: 1) Taylor, M.K., et al. Alzheimer’s Dement. Transl. Res. Clin. Interv. 4, 28–36 (2018). 2) Laffel, L. Diabetes. Metab. Res. Rev. 15, 412–426 (1999). 3) Grabacka, M., et al. Int. J. Mol. Sci. 17, 2093 (2016). 4) Najac, C. et al. Sci. Rep. 9, 3402 (2019).
Sovateltide (IRL‐1620) promotes neural regeneration and protects mitochondrial function in APP/PS1 transgenic mouse model of Alzheimer’s disease
Authors: Briyal Seema , Voshtina Ralf , Gulati Anil
Published: December 2020

Background

Mitochondrial dysfunction plays a central role in a common pathophysiology causing neuronal cell death in Alzheimer’s disease (AD). Endothelin B (ETB) receptor agonist, sovateltide, is being investigated as a potential therapeutic agent for AD, however, its mechanism of action of sovateltide is not yet established. The present study was undertaken to investigate whether sovateltide enhances neural regeneration by regulating mitochondrial function.

Method

APP/PS1 transgenic mice and C57BL/6 control mice were divided into two groups (vehicle and sovateltide). Sovateltide (5 μg/kg) was intravenously injected, three times at 2 hour intervals on days 1, 3 and 6 of every month until study end points (3, 6 and 12 months age). Control mice received equal volume of saline. Memory deficit was conducted using morris water maze test. Separate sets of mice were sacrificed at the end of 3, 6 and 12 months and brain harvested to determine the expression of markers for mitochondrial dysfunction, neuro‐ and synapto‐genesis using both western blot and immunofluorescence techniques.

Result

APP/PS1 transgenic mice showed significant (p<0.001) impairment in spatial memory. Sovateltide treatment significantly reduced learning and memory deficit in 6 months (40%) and 12 months (46%) aged transgenic mice. We found that sovateltide enhanced the expression of neuronal differentiation marker, NeuroD1 (p<0.0001) and DoubleCortin (p<0.0001) compared to vehicle group at 6 and 12 months. Expression of neural marker for mature neurons, NeuN (p<0.0001), was enhanced along with an upregulation of synaptic proteins (synapsin‐1, synaptophysin, and postsynaptic density‐95) compared to vehicle at 6 and 12 months of APP/PS1 transgenic mice. Furthermore, we found a shift in dynamics from fission to fusion proteins in sovateltide treated mice. An upregulation (p<0.0001) of mitochondrial fusion‐related proteins, Mfn1, Mfn2, Opa1, and downregulation of fission proteins, Drp1 and Fis1, in sovateltide group compared to vehicle at 6 and 12 months was observed. There were no changes in the expression of any markers at 3 months.

Conclusion

Sovateltide has shown neural protective and regenerative effect by attenuating mitochondrial dysfunction impaired memory deficits, and supports the use of sovateltide as a possible pharmaceutical intervention for the treatment of Alzheimer’s disease.