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Background: Accumulation of tau neurofibrillary tangles (NFT) in the medial temporal lobe (MTL) is an early pathological change associated with neurodegeneration in Alzheimer's Disease (AD). Current understanding of the spread of NFTs within the MTL is based on 2‐D histological sections sampled at sparse locations. Here, using human MTL specimens from donors with diagnoses spanning the AD continuum, we examine 3‐D quantitative maps of NFT burden derived from serial histology leveraging a high‐resolution, ex vivo MRI atlas, thus enabling more granular analyses. Method: We combined ex vivo MRI scans (0.2×0.2×0.2mm3, 9.4T) of 55 MTL specimens using a customized registration approach to construct a 3‐D atlas (Ravikumar et al., Acta Neuropathol Comm, 2021). MTL subregions in the atlas were labelled based on cytoarchitecture using serial Nissl histology (n = 17) (Fig.1). For 25 specimens with a primary diagnosis of AD or primary age‐related tauopathy (78.6±10.9 years; 16M/9F), quantitative NFT burden maps were derived from serial anti‐tau immunohistochemistry histology and registered to the atlas for group‐level analysis (Yushkevich et al., Brain, 2021). For quantitative comparisons, we computed the mean NFT burden and cortical thickness within each subregion. Result: Fig.2A shows average and summary frequency maps of NFT burden, computed separately for specimens with a low Braak stage (Braak0‐II; n = 11) and high Braak stage (BraakIV‐VI), that reveal a clear anterior‐to‐posterior gradient in NFT burden. At low Braak stages, we observe high levels of NFT burden in cornu ammonis (CA)1, entorhinal cortex (EC), and Brodmann area 35 (BA35;≈transentorhinal region), particularly in the outer cortical layers. CA1 and EC also show higher NFT burden relative to BA35 (Fig.2C). At high Braak stages, overall NFT burden is visibly higher and more widespread, with significant increases found across almost all subregions (Fig.2B). Moreover, significant correlations between NFT burden and cortical thinning were found in the perforant pathway (PP; molecular layer of the subiculum), dentate gyrus, EC and Areas TE, TF and TH (Fig.3). Conclusion: Building on earlier work, we provide a detailed characterization of the distribution of NFT burden in the MTL. Our findings of specific subregional involvement of early NFT pathology can help inform the development of improved in vivo neuroimaging biomarkers [ABSTRACT FROM AUTHOR]

Background: Accumulation of tau neurofibrillary tangles (NFT) in the medial temporal lobe (MTL) is an early pathological change associated with neurodegeneration in Alzheimer's Disease (AD). Current understanding of the spread of NFTs within the MTL is based on 2‐D histological sections sampled at sparse locations. Here, using human MTL specimens from donors with diagnoses spanning the AD continuum, we examine 3‐D quantitative maps of NFT burden derived from serial histology leveraging a high‐resolution, ex vivo MRI atlas, thus enabling more granular analyses. Method: We combined ex vivo MRI scans (0.2×0.2×0.2mm3, 9.4T) of 55 MTL specimens using a customized registration approach to construct a 3‐D atlas (Ravikumar et al., Acta Neuropathol Comm, 2021). MTL subregions in the atlas were labelled based on cytoarchitecture using serial Nissl histology (n = 17) (Fig.1). For 25 specimens with a primary diagnosis of AD or primary age‐related tauopathy (78.6±10.9 years; 16M/9F), quantitative NFT burden maps were derived from serial anti‐tau immunohistochemistry histology and registered to the atlas for group‐level analysis (Yushkevich et al., Brain, 2021). For quantitative comparisons, we computed the mean NFT burden and cortical thickness within each subregion. Result: Fig.2A shows average and summary frequency maps of NFT burden, computed separately for specimens with a low Braak stage (Braak0‐II; n = 11) and high Braak stage (BraakIV‐VI), that reveal a clear anterior‐to‐posterior gradient in NFT burden. At low Braak stages, we observe high levels of NFT burden in cornu ammonis (CA)1, entorhinal cortex (EC), and Brodmann area 35 (BA35;≈transentorhinal region), particularly in the outer cortical layers. CA1 and EC also show higher NFT burden relative to BA35 (Fig.2C). At high Braak stages, overall NFT burden is visibly higher and more widespread, with significant increases found across almost all subregions (Fig.2B). Moreover, significant correlations between NFT burden and cortical thinning were found in the perforant pathway (PP; molecular layer of the subiculum), dentate gyrus, EC and Areas TE, TF and TH (Fig.3). Conclusion: Building on earlier work, we provide a detailed characterization of the distribution of NFT burden in the MTL. Our findings of specific subregional involvement of early NFT pathology can help inform the development of improved in vivo neuroimaging biomarkers [ABSTRACT FROM AUTHOR]

Cyclin‐dependent kinases (CDKs), together with their cyclin partners, are the master cell cycle regulators. Remarkably, the cyclin family was extended to include atypical cyclins, characterized by distinctive structural features, but their partner CDKs remain elusive. Here, we conducted a yeast two‐hybrid screen to identify new atypical cyclin–CDK complexes. We identified 10 new complexes, including a complex between CDK6 and cyclin I (CCNI), which was found to be active against retinoblastoma protein. CCNI upregulation increased the proliferation of breast cancer cells in vitro and in vivo, with a magnitude similar to that seen upon cyclin D upregulation, an effect that was abrogated by CDK6 silencing or palbociclib treatment. In line with these findings, CCNI downregulation led to a decrease in cell number and a reduction in the percentage of cells reaching S phase. Finally, CCNI upregulation correlated with the high expression of E2F target genes in large panels of cancer cell lines and tissue samples from breast cancer patients. In conclusion, we unveil CCNI as a new player in the pathways that activate CDK6, enriching the wiring of cell cycle control. [ABSTRACT FROM AUTHOR]

Background: Falls are the most common injury faced by older adults and those with neurodegenerative diseases. Falls can result in concussion/mild traumatic brain injury(mTBI). Concussions in older adults or those with neurodegenerative disease can have a significant impact on behavior as post‐concussion symptoms include neuropsychiatric issues. We hypothesized that there is a relationship between past fall and neuropsychiatric symptoms and neuropsychiatric symptom severity. Methods: We used data on falls and Neuropsychiatric Inventory (NPI) from the Ontario Neurodegenerative Disease Research Initiative dataset for 480 individuals with neurodegenerative diseases (Alzheimer's Disease, Parkinson's Disease, Amyotrophic lateral sclerosis, frontotemporal dementia and vascular cognitive impairment). We used the Chi‐squared and Mann‐Whitney tests to compare frequency of NPI symptoms (anxiety, depression, irritability, disinhibition, apathy, delusions, hallucinations, agitation, euphoria, motor‐disturbance, night‐time behaviour, appetite), and total NPI severity and distress, respectively, between patients with and without falls in the past 12 months. Results: Comparing patients with falls (n = 169; mean‐age = 68.3±9; 36% F) to patients without falls (n = 311; mean‐age = 68.7±7; 32% F), there was a significantly higher frequency of anxiety (Chi‐squared test, X2 (df = 1, N = 480) = 12.859, P‐value = 0.0003); higher median anxiety severity (Mann‐Whitney/Wilcoxon‐test p‐value = 0.0002); and higher median partner anxiety distress (Wilcox test p‐value = 0.0006) in those who had had a previous fall compared to those who had not, even with multiple comparison correction. Depression, apathy, disinhibition, night‐time behaviours, and eating/appetite changes and total NPI severity were significantly worse in those with previous falls but did not survive multiple comparison correction. Conclusion: We found that anxiety frequency, severity and distress were much higher in patients with neurodegenerative disease who had a fall in the preceding 12 months compared to those without falls. Our study suggests that neuropsychiatric symptoms, especially anxiety are frequent and should be assessed in those with previous falls as they can be a consequence of mild brain injury and may contribute to worsening cognition or behaviors. [ABSTRACT FROM AUTHOR]

Background: The anterior portion of the medial temporal lobe (MTL) is one of the earliest regions showing tau deposition in Alzheimer's disease (AD) and hence a key focus area for AD imaging biomarkers. However, the anatomical variability of the anterior MTL presents a challenge for segmentation protocols. Leveraging a novel postmortem dataset with histology and MRI, we aimed to develop a histologically‐informed segmentation protocol for the anterior entorhinal cortex (ERC), Brodmann Area (BA) 35 (approximates transentorhinal cortex), and BA36 for in vivo 3 tesla (T) MRI. Method: Digitized 50‐µm thick MTL Nissl‐stained coronal histology sections from 20 cases (Table 1) were annotated by expert neuroanatomists. Cases with and without neurodegenerative diseases were included to ensure broad generalizability of the protocol. The histology sections were registered to same‐subject 0.2×0.2×0.2‐mm3 9.4 T postmortem MRI and were analyzed together to determine the location of the histological borders of the MTL cortices in relation to anatomical landmarks observable on MRI. Result: The distance between the anterior histological border of ERC, BA35 and BA36 was assessed in relation to different anatomical landmarks observable on MRI. The distance relative to the hippocampus was chosen, as there was relatively low between‐subject variability in distance (low SD in Table 2) and this region is easily identifiable on MRI. The ERC starts 4.75 mm (median) anterior to the hippocampus, BA35 9.25 mm and BA36 10.25 mm. There was no significant difference in distances between patients with and without neurodegenerative disease. Next, we analyzed the location of the ERC on histology sections. We determined that regardless of the depth of the collateral sulcus (CS) (contrary to more posterior regions), the inferior border of the ERC is on average at the edge of the CS and the superior border at the superior edge of the parahippocampal gyrus (Figure 1a), but at the halfway point for the first section with ERC. These segmentation rules for ERC can be applied to T1‐MRI (Figure 1b). Conclusion: Segmentation rules for anterior BA35 and BA36 are under development. This histologically‐informed segmentation protocol is expected to improve the efficacy of imaging biomarkers for tau deposition in AD. [ABSTRACT FROM AUTHOR]

Background: Plasma biomarkers of phosphorylated‐tau(p‐tau), astrocytosis and axonal damage offer a reliable means of identifying and measuring multiple pathological processes in‐vivo. How these biomarkers are associated with cortical brain structure and cognition within, and across, disorders is unclear. Leveraging the Ontario Neurodegenerative Disease Research Initiative, we examined the cross‐sectional association between plasma biomarkers, cortical thickness, and multi‐domain cognition. Method: 290 participants diagnosed with AD or PD (in accordance with clinical guidelines) and healthy controls (HC) were included (MeanAge = 68.96;[41% women; 35% APOE4carriers]). Four groups were formed: i)AD with mild cognitive impairment or dementia(ADMCI/ADD;N = 121), ii)PD with MCI or dementia(PDMCI/PDD;N = 78), iii)PD with normal cognition(PD‐NC;N = 43) and HC(N = 44; Table1). Plasma measures of p‐tau181‐UGOT, Neurofilament light chain (NfL) and GFAP, alongside FreeSurfer‐derived cortical thickness were included. A neuropsychological battery was administered. All models were adjusted for age, sex, and education. Result: There was an effect of diagnostic group on global cortical thickness, with PD‐NC, ADMCI/ADD and PDMCI/ADD exhibiting a significant reduction relative to HC(Fig1A). Regional patterns of brain atrophy were significantly associated in ADMCI/ADD and PDMCI/ADD(Fig1B). Across groups, p‐tau181, GFAP and to a lesser extent NfL, were associated with cortical thinning, particularly in lateral temporal and medial parietal regions (Fig2A). Unlike global thickness, ADMCI/ADD and PDMCI/PDD, but not PD‐NC, showed reduced thickness in the regions associated with p‐tau181, GFAP and NfL (Fig2B). Diagnostic group*GFAP/NfL/ptau181 interactions were not significant. Mediation analysis showed the cortical thinning in lateral temporal and medial parietal regions mediated between 33% to 40% of association between p‐tau181 and delayed memory. Similarly, thinning in these areas mediated 22% to 33% of the relationship between GFAP and executive function(Fig2C). Conclusion: We conclude that there is a similar pattern of gray matter loss in MCI/Dementia due to AD and PD. Higher concentrations of plasma p‐tau181 and GFAP are associated with poorer memory and executive function, in part through cortical thinning in lateral temporal and medial parietal regions. In conclusion, pathological processes related to the deposition of amyloid and tau, as well as astrogliosis, may co‐exist across cognitively impaired individuals with AD and PD. This is consistent with autopsy findings showing that AD pathology is present in 33‐60% of PD patients. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) and Parkinson's disease (PD) are two distinct neurodegenerative brain conditions associated with varying degrees of cognitive impairment, including an overlapping amnestic phenotype. At autopsy, APOEε4 and AD proteinopathies are associated with dementia severity in both AD and PD. The extent to which in‐vivo AD biomarkers are associated with memory and underlying regional brain volume in AD and PD patients is under‐investigation. Here, we focused on plasma biomarker associations with anterior‐temporal and posterior‐medial regions that are known to accumulate tau and Aβ in AD. Method: Neuroimaging, biomarker, genetic and cognitive data were collected from 244 patients through the Ontario Neurodegenerative Disease Research Initiative (MeanAge = 68.96; 41% women; 35%APOE‐ε4‐carriers). Based on clinical diagnostic criteria, three groups were formed: i)AD with mild cognitive impairment or dementia(ADMCI/ADD;N = 120), ii)PD with MCI or dementia(PDMCI/PDD;N = 76) and iii)PD with normal cognition(PD‐NC;N = 48). Linear regressions assessed clinical diagnosis differences in the volumetric integrity of a priori regions: anterior‐temporal(ATN; including amygdala, fusiform gyrus, and ITG) and posterior‐medial(PMN; including PCC, parahippocampal cortex and precuneus;Fig1). Differences on related item recognition memory and associative memory was examined via the FaceName Association Task. APOE(ε4‐/ε4+), p‐tau181‐UGOT and Aβ42 associations between ATN/PMN and item recognition/associative memory outcomes were estimated. Diagnostic*APOEε4*ptau181 interactions were tested. Age, sex, education and ICV were covaried. Result: Background characteristics showed that the ADMCI/ADD group exhibited the oldest age and the highest frequency of female sex and ε4‐carriership. ADMCI/ADD and PDMCI/PDD, but not PD‐NC, exhibited elevated ptau181 and Aβ42 relative to a healthy control group. Both ADMCI/ADD and PDMCI/PDD groups exhibited PMN and ATN degradation, as well as memory impairment, relative to the PD‐NC(Fig2A‐B). Plasma p‐tau181 was associated with ATN and PMN, as well as associative memory(Fig3A). APOEε4 was associated with PMN only, as well as item recognition(Fig3B). Diagnostic*APOEε4*ptau181 interactions were not significant. Post‐hoc analysis showed significant p‐tau181xAPOEε4 interactions on item recognition and total white matter hyperintensity(WMH;Fig3C). Aβ42 was not associated with outcomes. Conclusion: Volumes of the ATN and PMN are lower in cognitively impaired AD and PD patients with higher p‐tau and/or APOEε4‐carriership. P‐tau and APOEε4 may work synergistically to promote domain‐specific memory impairment and WMH burden in both AD and PD. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) and Parkinson's disease (PD) are two distinct neurodegenerative brain conditions associated with varying degrees of cognitive impairment, including an overlapping amnestic phenotype. At autopsy, APOEe4 and AD proteinopathies are associated with dementia severity in both AD and PD. The extent to which in‐vivo AD biomarkers are associated with memory and underlying regional brain volume in AD and PD patients is under‐investigation. Here, we focused on plasma biomarker associations with anterior‐temporal and posterior‐medial regions that are known to accumulate tau and Aß in AD. Method: Neuroimaging, biomarker, genetic and cognitive data were collected from 244 patients through the Ontario Neurodegenerative Disease Research Initiative (MeanAge = 68.96; 41% women; 35%APOE‐e4‐carriers). Based on clinical diagnostic criteria, three groups were formed: i)AD with mild cognitive impairment or dementia(ADMCI/ADD;N = 120), ii)PD with MCI or dementia(PDMCI/PDD;N = 76) and iii)PD with normal cognition(PD‐NC;N = 48). Linear regressions assessed clinical diagnosis differences in the volumetric integrity of a priori regions: anterior‐temporal(ATN; including amygdala, fusiform gyrus, and ITG) and posterior‐medial(PMN; including PCC, parahippocampal cortex and precuneus;Fig1). Differences on related item recognition memory and associative memory was examined via the FaceName Association Task. APOE(e4‐/e4+), p‐tau181‐UGOT and Aß42 associations between ATN/PMN and item recognition/associative memory outcomes were estimated. Diagnostic*APOEe4*ptau181 interactions were tested. Age, sex, education and ICV were covaried. Result: Background characteristics showed that the ADMCI/ADD group exhibited the oldest age and the highest frequency of female sex and e4‐carriership. ADMCI/ADD and PDMCI/PDD, but not PD‐NC, exhibited elevated ptau181 and Aß42 relative to a healthy control group. Both ADMCI/ADD and PDMCI/PDD groups exhibited PMN and ATN degradation, as well as memory impairment, relative to the PD‐NC(Fig2A‐B). Plasma p‐tau181 was associated with ATN and PMN, as well as associative memory(Fig3A). APOEe4 was associated with PMN only, as well as item recognition(Fig3B). Diagnostic*APOEe4*ptau181 interactions were not significant. Post‐hoc analysis showed significant p‐tau181xAPOEe4 interactions on item recognition and total white matter hyperintensity(WMH;Fig3C). Aß42 was not associated with outcomes. Conclusion: Volumes of the ATN and PMN are lower in cognitively impaired AD and PD patients with higher p‐tau and/or APOEe4‐carriership. P‐tau and APOEe4 may work synergistically to promote domain‐specific memory impairment and WMH burden in both AD and PD. [ABSTRACT FROM AUTHOR]

Background: Plasma biomarkers of phosphorylated‐tau(p‐tau), astrocytosis and axonal damage offer a reliable means of identifying and measuring multiple pathological processes in‐vivo. How these biomarkers are associated with cortical brain structure and cognition within, and across, disorders is unclear. Leveraging the Ontario Neurodegenerative Disease Research Initiative, we examined the cross‐sectional association between plasma biomarkers, cortical thickness, and multi‐domain cognition. Method: 290 participants diagnosed with AD or PD (in accordance with clinical guidelines) and healthy controls (HC) were included (MeanAge = 68.96;[41% women; 35% APOE4carriers]). Four groups were formed: i)AD with mild cognitive impairment or dementia(ADMCI/ADD;N = 121), ii)PD with MCI or dementia(PDMCI/PDD;N = 78), iii)PD with normal cognition(PD‐NC;N = 43) and HC(N = 44; Table1). Plasma measures of p‐tau181‐UGOT, Neurofilament light chain (NfL) and GFAP, alongside FreeSurfer‐derived cortical thickness were included. A neuropsychological battery was administered. All models were adjusted for age, sex, and education. Result: There was an effect of diagnostic group on global cortical thickness, with PD‐NC, ADMCI/ADD and PDMCI/ADD exhibiting a significant reduction relative to HC(Fig1A). Regional patterns of brain atrophy were significantly associated in ADMCI/ADD and PDMCI/ADD(Fig1B). Across groups, p‐tau181, GFAP and to a lesser extent NfL, were associated with cortical thinning, particularly in lateral temporal and medial parietal regions (Fig2A). Unlike global thickness, ADMCI/ADD and PDMCI/PDD, but not PD‐NC, showed reduced thickness in the regions associated with p‐tau181, GFAP and NfL (Fig2B). Diagnostic group*GFAP/NfL/ptau181 interactions were not significant. Mediation analysis showed the cortical thinning in lateral temporal and medial parietal regions mediated between 33% to 40% of association between p‐tau181 and delayed memory. Similarly, thinning in these areas mediated 22% to 33% of the relationship between GFAP and executive function(Fig2C). Conclusion: We conclude that there is a similar pattern of gray matter loss in MCI/Dementia due to AD and PD. Higher concentrations of plasma p‐tau181 and GFAP are associated with poorer memory and executive function, in part through cortical thinning in lateral temporal and medial parietal regions. In conclusion, pathological processes related to the deposition of amyloid and tau, as well as astrogliosis, may co‐exist across cognitively impaired individuals with AD and PD. This is consistent with autopsy findings showing that AD pathology is present in 33‐60% of PD patients. [ABSTRACT FROM AUTHOR]

Background: According to data from the Alzheimer's Association, more than two‐thirds of patients living with Alzheimer's disease (AD) in the United States are women. The interplay between aging and hormone depletion during menopause has been proposed as a leading cause, but the molecular underpinnings of this vulnerability are not fully understood. On the one hand, approaches that seek to supplement estrogens to rescue pre‐menopausal hormonal levels have had contradictory outcomes in clinical trials. On the other hand, androgen effects in women in a neurodegeneration context are dramatically understudied. Furthermore, the number of XX chromosome individuals using androgens for sex‐reassignment purposes has steadily increased. Whether androgens can regulate tau pathology and how is poorly understood, especially in the context of female physiology. Method: We performed a dihydrotestosterone (DHT) supplementation paradigm in 5‐6 month old P301S female mice and harvested brain tissue at 9 months of age. Pathological and biochemical tau markers, as well as androgen receptor content were evaluated in the hippocampus and cortex. Result: Here, we report an exacerbation of tau pathology in tauP301S female mice treated with DHT, an androgen receptor (AR)‐specific ligand, in the hippocampus, as evaluated by AT8 and MC‐1 immunostaining. Furthermore, we report upregulation of AR almost exclusively in neurons upon DHT treatment, potentially mediating our observations. Conclusion: Our results implicate AR activation in females as a potential risk factor for tau pathology. Overall, the AD field will benefit from a more thorough understanding of neurodegeneration in women and transmasculine individuals, facilitating the identification of different risk and protection factor, paving the way to the development of novel and targeted therapies, and better addressing the health issues of our diverse society. [ABSTRACT FROM AUTHOR]

Background: Tau pathology in the medial temporal lobe (MTL) is closely linked to neurodegeneration, and is an early pathological change associated with Alzheimer's disease (AD). MRI measures of MTL neurodegeneration have proven to be sensitive to change during preclinical AD. Current measures are confounded by the presence of non‐AD pathologies (e.g., TDP‐43, ageing). Here, we combine ex vivo imaging with histopathological ratings of tau and TDP‐43 to identify fine‐grained MTL atrophy patterns specific to tau. Such an analysis could be used to define MTL "hotspots" where in vivo measures of neurodegeneration are expected to be strongly associated with tau, potentially enabling the development of biomarkers that are more effective during early AD clinical trials. Method: Ex vivo MRI scans (0.2x0.2x0.2mm3, 9.4T) of human MTL specimens were combined using a customized registration approach to construct a 3D atlas. Using serial histology available in a subset of specimens (n = 11), MTL subregions in the atlas were labelled based on cytoarchitecture (Ravikumar et al., 2021) (Figure 1A). To perform thickness analysis, 29 specimens containing a primary diagnosis of AD or primary age‐related tauopathy were registered to the atlas (13 specimens were registered to the atlas during atlas construction, and 16 were registered to the atlas after it was constructed) (Figure 1B, Table 1). Using histopathology measures of tau and TDP‐43 pathology (based on contralateral sampling), we investigated the association between tau and thickness by fitting a linear model (with age/TDP‐43 as covariates) at each point along the MTL and SRLM surface. Result: Pointwise thickness analysis reveals significant atrophy patterns in the transentorhinal region and SRLM. When excluding age from the model, stronger tau associations are observed in the SRLM, entorhinal cortex, and extending further towards Brodmann Area 35 (Figure 2). Conclusion: Our findings are consistent with early Braak stages but suggest that covarying for age may be obscuring some associations due to tau since age and tau burden have a highly correlated relationship (Figure 3). In future work, quantitative maps of NFT burden will be mapped from serial pathology images into atlas space, allowing us to characterize NFT distribution in 3D (Yushkevich et al., 2021). [ABSTRACT FROM AUTHOR]

Background: Individuals with the APOE ε4 allele (ApoE4) have an increased risk of developing Alzheimer's disease (AD) compared to individuals with the more common ε2 or ε3 alleles. Previous work by our group found that female ApoE4 homozygotes with Lewy body (LB) pathology were more likely to experience psychosis compared to female ApoE4 non‐carriers, whereas in males there was no dose‐dependent difference (Kim et al., 2017). The objective of this study was to refine our previous findings by adjusting for covariates (age, education, MMSE scores). Method: The patient cohort was obtained from the National Alzheimer's Coordinating Center (NACC). Demographics, APOE genotype, LB pathology, and Neuropsychiatric Inventory (NPI) data was gathered in individuals with neuropathologically‐confirmed AD (n = 1,241). Patients were considered psychotic if they scored positively for delusions and/or hallucinations on the NPI. Two cohorts were extracted, those with LB pathology (LB(+)) and those without (LB(‐)). Within each cohort, patients were classified as E4(‐), E4, or E44 based on the number of APOE ε4 alleles they carried (0, 1, 2, respectively), and stratified by sex. Binary logistic regression was used to predict the relationship between ApoE4 status and sex on presence of psychosis. Result: In the LB(+) group, female ApoE4 homozygotes were significantly more likely to experience psychosis compared to female ApoE4 non‐carriers (p =.003). The significant effect remained after adjusting for covariates (p =.027). There was no significant association between ApoE4 and presence of psychosis in males. In the LB(‐) group, there was no significant association between ApoE4 and presence of psychosis in either sex. There was no significant effect in female nor male ApoE4 heterozygotes, with or without LB pathology. Conclusion: Sex and zygosity modulate the effect of ApoE4 on psychosis in a cohort of neuropathologically‐confirmed AD patients, specifically, that the effect of having 2 ApoE4 alleles on presence of psychosis is limited to female ApoE4 homozygotes with LB pathology. These findings reveal a cohort of AD patients that appear to be particularly vulnerable to developing psychosis. References: Kim, J., Fischer, C.E., Schweizer, T.A., & Munoz, D.G. (2017). Gender and pathology‐specific effect of Apolipoprotein E genotype on psychosis in Alzheimer's disease. Current Alzheimer Research, 14(8), 834‐840. [ABSTRACT FROM AUTHOR]

Background: Quantitative three‐dimensional maps of tau neurofibrillary tangles (NFT) burden derived from dense serial histology have potential application for in‐vivo biomarker studies. We constructed a group‐level NFT burden map from 15 medial temporal lobe (MTL) specimens, majority with Primary Age‐Related Tauopathy (PART) or low‐level Alzheimer’s disease neuropathologic change, and showed relatively greater NFT burden in the anterior vs. posterior MTL. We investigated whether in‐vivo MRI and PET measures in ROIs derived from this map show meaningful biological relationships. Method: Multimodal in‐vivo imaging data from 292 participants in the Aging Brain Cohort were used. The group‐level NFT burden map was mapped to each participant’s MRI to define an ROI mask, further divided into anterior (aMTL) and posterior (pMTL) ROIs. Cortical thickness (N=292) and 18F‐Flortaucipir SUVR maps (N=86) were computed. Participants’ age was correlated with average thickness in the aMTL, pMTL, and anatomically defined MTL ROIs. 18F‐Flortaucipir uptake was compared between aMTL and pMTL. The analyses were repeated in subsets of cognitive normal participants, and those with negative amyloid PET scans. Result: Cortical thickness in the aMTL ROI showed stronger correlation with age than pMTL and anatomically defined MTL subregional thickness. A polynomial fit provided the best age regression, with older participants showing a parabolic decline in thickness around age 60, when substantial NFT accumulation begins in MTL. Further, tau tracer uptake in aMTL was slightly but significantly higher than in pMTL (SUVR 1.19 vs. 1.18, p=0.02). Conclusion: We demonstrate the potential use of ex‐vivo NFT burden maps for in‐vivo image analysis. NFT deposition is particularly prominent in the anterior MTL in cases without or with low amyloid burden and at early Braak stage. Prior work suggests that even in the absence of amyloid, this tangle pathology may drive neurodegeneration in the aging population. Here we show that cortical thickness, a biormarker for neurodegeneration, when measured within a histopathologically‐defined region enriched for PART NFTs in the aMTL, is better correlated with age than when measured within anatomically defined subregions, suggesting that the relationship may be driven by PART. Greater tau tracer uptake in the aMTL ROI further supports this notion. [ABSTRACT FROM AUTHOR]

Background: Despite the increase in Alzheimer's disease (AD) research among ethnic and racial minority populations, they are underrepresented in research and successful recruitment of diverse cohorts remains challenging. Culturally specific recruitment strategies and community engagement are needed to increase diverse participant enrollment in aging research. In 2020, we designed and implemented a strategy to recruit 1,000 African Americans (AA), 50 years and older into the Health & Aging Brain Study‐ Health Disparities (HABS‐HD) project. In this study, we examined the effectiveness of recruitment strategies among this group. Method: HABS‐HD is an epidemiological study of cognitive aging among diverse communities. The team recruited an initial cohort of 1,000 non‐Hispanic whites and 1,000 Mexican Americans using a community‐based approach. This foundation was expanded to reach the AA community through the engagement of key stakeholders and the use of an integrated marketing and outreach strategy. Recruitment methods included an integrated approach combining traditional marketing (print, radio); social media (influencers and online ads), and in person community recruitment and education events at local churches, barbershops, health fairs, etc. The reach and enrollment data were collected and analyzed. Result: Out of 4066 participants that were interested in HABS‐HD, 1362 (33.5%) identified as AA. While recruiting the AA cohort outreach team participated in over 140 community events, ranging from state fairs, barbershops, and church events. Enrollment data indicated participants heard of us through word of mouth (35%); community events (21.6%); news (12.7%); refer a friend program (6.8%); print media (6.4%) radio (4%); and social media (3.6%). In terms of traditional marketing and overall general study awareness, the social media approach reached 179,200 individuals. Of this number12.1% of people interacted with the landing site and then a further 747 clicked to sign up. The reach of our radio advertising was 2,200,000 listeners. Conclusion: Recruiting diverse communities into research involves targeting the recruitment techniques and materials to the target population. The creation of a culturally appropriate media campaign and utilizing community based methods such as outreach, engagement, and collaboration between the research team and key stakeholders in the community led to the successful recruitment of AA into our study. [ABSTRACT FROM AUTHOR]

Background: Neuroinflammation (NI) has been implicated in both the pathogenesis of and neuroprotection against neurodegenerative diseases (NDs)(Psenicka et al., 2021). Plasma glial fibrillary acidic protein (GFAP), and Neurofilament light (NFL) are measures of astrogliosis and neurodegeneration, respectively. Amyloid beta (Aβ)42/40 ratio (Aβ42 concentration to total Aβ concentration) below 0.068 is associated with AD pathology (Baldeiras et al., 2018). Neuroimaging‐based inflammatory biomarkers have been proposed, including free‐water diffusion (FWD)(Pasternak et al., 2009). Here we investigated FWD as a candidate biomarker for NI in AD compared to non‐AD dementia using Aβ42/40 ratio in a subset of data from the Ontario Neurodegenerative Disease Research Initiative (ONDRI). Method: FWD maps were generated in 370 subjects (126 non‐AD and 244 AD). MRI processing included ICVmapp3r for brain extraction and bias field correction, Synb0, Topup and Eddy for dMRI preprocessing and MATLAB for freewater mapping. Plasma Aβ42, Aβ40, GFAP and NFL were measured using the Simoa Human Neurology 4‐Plex E assay, and cognition was estimated using the Montreal Cognitive Assessment (MoCA). Linear regression was used to estimate the ability for FWD in the left (LcGM) and right (RcGM) cortical grey matter to predict GFAP, NFL and MoCA score in AD and nonAD based on Aβ42/40 threshold of 0.068. Result: FWD correlated with GFAP (LcGM; R = 0.4, p = 0.0013 and RcGM; R = 0.37, p = 0.0069), and MoCA total score (LcGM; R = ‐0.29, p = 0.001 and RcGM; R = ‐0.27, p = 0.001), but not with NFL across the whole group. This relationship was largely driven by the AD group wherein FWD predicted GFAP (LcGM: R = 0.12, p = 0.02, RcGM approaching significance R = 0.1, p = 0.06), and MoCA Total score (LcGM: R = ‐0.33, p<0.0001), RcGM: R = ‐0.25, p<0.0001). The nonAD group did not show this relationship. FWD did not predict NFL in the AD and nonAD group. Conclusion: In patients with Aβ42/40<0.068, suggestive of AD, FWD in cGM was more strongly related to GFAP than NFL, and predicted cognition, a pattern that was not observed in nonAD patients. Our results suggest distinct patterns of NI in AD compared with nonAD that can be detected with FWD and with a multi‐modal approach could further understanding of differences in pathophysiology across NDs. [ABSTRACT FROM AUTHOR]

Background: Due to low success rates in clinical trials for Alzheimer's disease (AD), there is a need to apply precision medicine approaches, such as stratifying based on APOE genotype, in order to assess its effects on outcome measures. Herein, we aim to better understand how plasma biomarkers of AD and neurodegenerative pathology are associated with cognition and neurodegeneration in APOE E4 carriers compared to non‐carriers. Method: Patients from the Ontario Neurodegenerative Disease Research Initiative (ONDRI) diagnosed with AD were included (n = 126, age = 71.0±8.2, 55%M). Plasma concentrations of Aβ40 and Aβ42 (Aβ42/40 ratio), glial fibrillary acidic protein (GFAP), neurofilament light (NfL) and phosphorylated‐tau181 (p‐tau181) were measured using Simoa assays. Composite cognitive domain scores (attention & working memory, executive function, language, memory, and visuospatial function) were computed from a comprehensive neuropsychological assessment. Volumes of regional grey matter, ventricular cerebrospinal fluid, white matter hyperintensities, perivascular spaces, lacunes and strokes were extracted from 3T structural MRI sequences using the SABRE pipeline. Linear regression models with an interaction term, controlling for age, sex and education were used to test the moderating effect of the APOE E4 allele on the association of plasma biomarkers with cognitive and MRI variables. When interaction effects were significant, post‐hoc models stratified by APOE E4 carrier status and controlling for age, sex and education were assessed. Result: The APOE E4 allele moderated the association of GFAP, NfL and p‐tau181 with memory. Further stratification revealed that higher levels of GFAP, NfL and p‐tau181 were all associated with worse memory only in APOE E4 carriers. APOE E4 was also found to moderate the association of GFAP and p‐tau181 with many imaging markers. Further stratification revealed that higher levels of GFAP were associated with increased white matter hyperintensities, ventricular expansion and grey matter atrophy (temporal lobe, occipital lobe, hippocampus, basal ganglia and thalamus) only in APOE E4 carriers. Higher levels of p‐tau181 were also associated with increased temporal, parietal, and hippocampal atrophy only in APOE E4 carriers. Conclusion: Plasma biomarkers, especially GFAP and p‐tau181, appear to be significantly more predictive of memory deficits and brain neurodegeneration in APOE E4 carriers compared to non‐carriers in AD. [ABSTRACT FROM AUTHOR]

Background: It is necessary to better understand the value of plasma biomarkers in reflecting ongoing neurodegenerative processes before widespread use as diagnostic and prognostic tools in specialized clinics and as markers of disease progression in trials. Herein, we investigate their association with imaging markers of brain atrophy and white matter disease across three common neurodegenerative diseases and cerebrovascular disease. Method: Patients from the curated multi‐site Ontario Neurodegenerative Disease Research Initiative (ONDRI) were included in this study, classified by diagnostic group: Alzheimer's disease/Mild cognitive impairment (AD/MCI, n = 126, age = 71.0±8.2, 55%M), frontotemporal dementia (FTD, n = 53, age = 67.8±7.1, 64%M), Parkinson's disease (PD, n = 140, age = 67.9±6.3, 78%M) and cerebrovascular disease (CVD, n = 161, age = 69.2±7.4, 68%M). Plasma concentrations of Aβ40 and Aβ42 (Aβ42/40 ratio), glial fibrillary acidic protein (GFAP), neurofilament light (NfL) and phosphorylated‐tau181 (p‐tau181) were measured using high‐sensitivity Simoa assays. Volumes of regional grey matter, ventricular cerebrospinal fluid, white matter hyperintensities, perivascular spaces, lacunes and strokes were extracted using the semi‐automated SABRE pipeline on 3T structural MRI sequences harmonized across sites. Fractions of supratentorial total intracranial volume were used when appropriate. Linear regression models controlling for age and sex were used to test the association between plasma biomarkers and MRI variables in each group separately. Result: In AD/MCI, higher levels of GFAP, NfL and p‐tau181 were all associated with extensive grey matter atrophy, ventricular expansion and, excluding p‐tau181, with increased white matter hyperintensities. In FTD, increased Aβ42/40 ratio was associated with frontal grey matter atrophy, and higher levels of NfL were associated with ventricular expansion. In PD, higher levels of NfL were associated with frontal, temporal and hippocampal grey matter atrophy. In CVD, higher levels of GFAP and NfL were associated with temporal and subcortical grey matter atrophy and ventricular expansion. Higher levels of GFAP were also associated with enlarged perivascular spaces, while higher levels of NfL were associated with increased lacunes. Finally, still in CVD, higher levels of GFAP and p‐tau181 were associated with increased stroke volumes. Conclusion: Excluding Aβ42/40, plasma biomarkers appear to reflect various levels of brain atrophy in all neurodegenerative diseases studied, but reflect markers of white matter disease only in AD/MCI and CVD. [ABSTRACT FROM AUTHOR]

Background: It is critical to better understand the value of plasma biomarkers in predicting cognitive deficits before widespread use as diagnostic and prognostic tools in specialized clinics and as markers of neurodegenerative disease progression in trials. Herein, we investigate their association with five cognitive domains across three common neurodegenerative diseases and cerebrovascular disease. Method: Patients from the curated multi‐site Ontario Neurodegenerative Disease Research Initiative (ONDRI) were included in this study, classified by diagnostic group: Alzheimer's disease/Mild cognitive impairment (AD/MCI, n = 126, age = 71.0±8.2, 55%M), frontotemporal dementia spectrum disorders (FTD, n = 53, age = 67.8±7.1, 64%M), Parkinson's disease (PD, n = 140, age = 67.9±6.3, 78%M) and cerebrovascular disease (CVD, n = 161, age = 69.2±7.4, 68%M). Plasma concentrations of Aβ40 and Aβ42 (Aβ42/40 ratio), glial fibrillary acidic protein (GFAP), neurofilament light (NfL) and phosphorylated‐tau181 (p‐tau181) were measured using high‐sensitivity Simoa assays. Scores from a 26‐test comprehensive neuropsychological assessment were used to compute composite z‐scores for five cognitive domains: attention & working memory, executive function, language, memory, and visuospatial function. Linear regression models controlling for age, sex, education and APOE E4 allele were used to test the association between plasma biomarkers and cognitive domains in each group separately. Result: In AD/MCI, higher levels of GFAP, NfL and p‐tau181 were all associated with worse attention & working memory, executive function, and memory. In PD, higher levels of NfL were associated with worse attention & working memory, executive function, and visuospatial function; higher levels of GFAP were also associated with worse executive function. In CVD, higher levels of GFAP were associated with worse executive function, memory and visuospatial function; higher levels of p‐tau181 were also associated with worse memory. In FTD, no associations were found. Conclusion: Plasma biomarkers indicative of neuronal and glial pathology are useful to predict the severity of widespread cognitive deficits in AD/MCI, PD, and CVD. Interestingly, p‐tau181 predicted memory deficits in both AD/MCI and CVD, suggesting potential mixed disease or pathological overlap. Plasma Aβ42/40 does not appear to predict any cognitive deficits in any of the neurodegenerative diseases studied. As FTD is highly heterogeneous and had the least number of patients, we are possibly lacking power to detect effects in this group. [ABSTRACT FROM AUTHOR]

Background: The APOE ε4 (APOE4) allele is a genetic risk factor for Alzheimer's disease (AD). Prior work by our group found a significant association between the APOE4 allele and presence of psychosis as well as overall increased neuropsychiatric symptom (NPS) burden in female APOE4 homozygote AD patients, with no effect present in males. In this study, we sought to examine the relationship between APOE4 carrier status and sex on NPS burden from a neuroimaging perspective, with the aim to determine what brain regions may be driving this effect. Method: A cohort of 752 AD patients were selected from the National Alzheimer's Coordinating Center (NACC) database: 104 APOE4 homozygotes (40F|64M), 304 APOE4 heterozygotes (160F|144M) and 310 APOE4 non‐carriers (131F|179M). Presence of NPS was identified using the Neuropsychiatric Inventory (NPI). Structural T1‐weighted images were downloaded from the NACC imaging dataset and cortical thickness measures corresponding to frontal, cingulate, temporal and parietal regions were assessed. Statistical analysis included a Bayesian multilevel regression where cortical thickness was modeled as an outcome variable against an interaction between sex and APOE4 homozygote status (0|1), while controlling for heterozygote status, APOE4 non‐carrier status, age, sex and MMSE as predictor variables. Within‐ and between‐groups mean differences in thickness were measured as a probability density estimate (Highest Density interval), and partial correlation was used to examine NPI correlates to thickness. Result: Female APOE4 homozygotes displayed a high probability (>90%HDI) of greater cortical thickness in the posterior cingulate and isthmus cingulate regions bilaterally and reduced cortical thickness in temporal regions (Figure 1). Cortical thickness in the fusiform cortex was positively correlated to greater NPI burden (p<0.05) among female homozygotes, and negatively correlated to NPI burden among female heterozygotes. Cortical thickness in males, regardless of carrier status, did not correlate to NPI burden in any region. Conclusion: This study highlights an important relationship between the fusiform cortex and NPI burden in female APOE4 carriers, marking a female‐specific effect. Future work should further disentangle sex differences in APOE4 status and psychosis with a focus on the fusiform cortex as a potential region of interest. [ABSTRACT FROM AUTHOR]

Background: Neuroinflammation (NI) has been implicated in both the pathogenesis of and neuroprotection against neurodegenerative diseases (NDs)(Psenicka et al., 2021). Plasma glial fibrillary acidic protein (GFAP), and Neurofilament light (NFL) are measures of astrogliosis and neurodegeneration, respectively. Amyloid beta (Aß)42/40 ratio (Aß42 concentration to total Aß concentration) below 0.068 is associated with AD pathology (Baldeiras et al., 2018). Neuroimaging‐based inflammatory biomarkers have been proposed, including free‐water diffusion (FWD)(Pasternak et al., 2009). Here we investigated FWD as a candidate biomarker for NI in AD compared to non‐AD dementia using Aß42/40 ratio in a subset of data from the Ontario Neurodegenerative Disease Research Initiative (ONDRI). Method: FWD maps were generated in 370 subjects (126 non‐AD and 244 AD). MRI processing included ICVmapp3r for brain extraction and bias field correction, Synb0, Topup and Eddy for dMRI preprocessing and MATLAB for freewater mapping. Plasma Aß42, Aß40, GFAP and NFL were measured using the Simoa Human Neurology 4‐Plex E assay, and cognition was estimated using the Montreal Cognitive Assessment (MoCA). Linear regression was used to estimate the ability for FWD in the left (LcGM) and right (RcGM) cortical grey matter to predict GFAP, NFL and MoCA score in AD and nonAD based on Aß42/40 threshold of 0.068. Result: FWD correlated with GFAP (LcGM; R = 0.4, p = 0.0013 and RcGM; R = 0.37, p = 0.0069), and MoCA total score (LcGM; R = ‐0.29, p = 0.001 and RcGM; R = ‐0.27, p = 0.001), but not with NFL across the whole group. This relationship was largely driven by the AD group wherein FWD predicted GFAP (LcGM: R = 0.12, p = 0.02, RcGM approaching significance R = 0.1, p = 0.06), and MoCA Total score (LcGM: R = ‐0.33, p<0.0001), RcGM: R = ‐0.25, p<0.0001). The nonAD group did not show this relationship. FWD did not predict NFL in the AD and nonAD group. Conclusion: In patients with Aß42/40<0.068, suggestive of AD, FWD in cGM was more strongly related to GFAP than NFL, and predicted cognition, a pattern that was not observed in nonAD patients. Our results suggest distinct patterns of NI in AD compared with nonAD that can be detected with FWD and with a multi‐modal approach could further understanding of differences in pathophysiology across NDs. [ABSTRACT FROM AUTHOR]

Background: It has been shown that gout is associated with left atrium remodeling and a pro‐inflammatory state leading to the development of atrial fibrillation (AF). There is limited evidence whether gout increases the risk of stroke in patients with AF. We assessed the incidence of gout and the risk of stroke in patients with AF. Methods: This is a retrospective cohort study using the 2016 US National Inpatient Sample (NIS) based on ICD‐10 codes. The outcomes of the study were the risk and severity of new stroke in patients with pre‐existing AF and gout. Results: In 2016, we identified 3 844 057 patients admitted to the hospitals in NIS with history of AF, of which 240 875 had history of gout. Patients with AF and gout have higher risk of new stroke (OR 2.07 [1.97‐2.19], P <.001), and this risk remains significantly elevated after adjusting for CHADS2VASC score variables, chronic kidney disease, dyslipidemia, obesity, and race (OR 1.10 [1.01‐1.11], P =.041). However, presence of gout in patients with AF was not associated with all‐cause in‐hospital mortality, need for mechanical ventilation, percutaneous gastrostomy tube insertion, or discharge to skilled nursing facility. Conclusion: Subjects with AF and gout compared to AF alone had an increased risk of new stroke, but presence of gout was not associated with stroke severity. There is a potential role of gout as a risk factor or a risk marker for stroke in subjects with AF. [ABSTRACT FROM AUTHOR]

Background: The medial temporal lobe (MTL) is a hotspot of different neurodegenerative pathologies, and recent studies have shown associations of severity of pathology with atrophy measured on antemortem MRI. However, these studies are limited by the interval between time of scan and death and the relatively low resolution of the commonly acquired in vivo MRI scans, limiting the granularity of the regions being measured. We investigate the association of different neurodegenerative pathologies, particularly TDP‐43, and the thickness of different MTL subregions measured on high‐resolution postmortem MRI. As prior work suggests an anterior‐to‐posterior gradient of atrophy for TDP‐43 in frontotemporal dementia spectrum disorders and Limbic‐predominant Age‐related TDP‐43 Encephalopathy (LATE), we also examined differences along the long axis of the MTL. Method: Tau, TDP‐43, β‐amyloid and α‐synuclein pathology were rated (0‐absent – 3‐frequent) in the hippocampus and entorhinal cortex (ERC) of 35 individuals with and without neurodegenerative diseases (Table 1). Thickness measurements were obtained from 0.2x0.2x0.2 mm3 post‐mortem MRI scans of excised MTL specimens from the contralateral hemisphere (Figure 1) in the ERC, Brodmann Area 35 and 36, parahippocampal cortex, subiculum, cornu ammonis (CA)1 and the stratum radiatum lacunosum moleculare. For each region, thickness was measured at an anterior and posterior location using a semi‐automated approach (Figure 2). Spearman's rank correlations were performed, correcting for age, sex and hemisphere, including all four proteinopathies in the model. Result: We find strong negative associations of TDP‐43 with thickness in all cortical MTL regions (Table 2, Figure 3) and with CA1, averaged over the two locations. We repeated the analyses for the thickness measurements separately in the anterior and posterior locations, but did not find a clear difference along the longitudinal axis. This is potentially due to the severity of the TDP‐43 pathology. Conclusion: In this unique dataset with neurodegenerative pathologies and high‐resolution scans of the MTL, preliminary results show strong associations between TDP‐43 pathology and atrophy in several MTL subregions. As this dataset continues to grow, we will be able to tease apart the effects of multiple MTL pathologies at a subregional level. [ABSTRACT FROM AUTHOR]

Background: Structural magnetic resonance imaging (MRI) biomarkers are important for early detection of Alzheimer's Disease (AD). However, atrophy measures can be confounded by changes due to aging and comorbid non‐AD neurodegenerative pathologies. Linking postmortem MRI of the medial temporal lobe (MTL) to histopathology may identify focal patterns of change associated specifically with early AD. We implemented a pipeline of high‐resolution MRI of MTL specimens and serial histopathology imaging [REF]. However, the task of extracting the intact MTL specimen such that it fits into the MRI coil requires anatomical expertise and has proven error prone. Here we present an algorithm to automatically create 3D printed molds guiding MTL extraction. Method: INPUTS: 7T MRI scan of a formalin‐fixed hemisphere in which the hemisphere, MTL ROI and optional second ROI to be spared during cutting (e.g. frontal lobe) have been segmented using ITK‐SNAP semi‐automatic segmentation tools. OUTPUTS: Two 3D printed molds with slits that guide cutting. Mold 1 holds the whole hemisphere, guiding four cuts orthogonal to the midsagittal plane (Figure 1). Mold 2 holds the extracted tissue block, guiding three subsequent longitudinal cuts that trim the tissue to fit into a 50mm cylindrical holder (Figure 2). The positioning of the cuts can be specified interactively by the user using ITK‐SNAP (translating and rotating 3D images representing cutting planes) or automatically by optimizing (using Powell's method) energy functions that minimize the volume of the final piece of tissue under multiple constraints (see Figures 3 and 4). Result: The algorithm with interactively positioned cut planes was used in four hemispheres; the automated version in one (Figure 5). For each MRI scan, the MTL was intact. By contrast, retrospective review revealed cutting errors in 48% of manually cut specimens. Conclusion: Our image‐guided approach reduces errors and dependence on anatomical expertise; allows more tissue to be spared from each brain donation; and enables postmortem imaging at a larger scale. It is not limited to the MTL and could be of interest to brain banks and AD research centers involved in postmortem imaging. [ABSTRACT FROM AUTHOR]

Background: Finding effective biomarkers that can support early‐stage clinical trials is a major challenge in Alzheimer's Disease (AD). MRI measures of structural change in the medial temporal lobe (MTL) have proven to be sensitive to change in the early stages of AD. However, other frequently comorbid non‐AD factors (e.g. cerebrovascular disease, TDP‐43 pathology) also cause changes in the MTL. For MRI biomarkers to detect changes specifically linked to AD pathology, patterns of structural change must be linked to the underlying neuropathology. To provide this linkage, we use ex vivo imaging with pathologically derived ratings of AD and non‐AD pathology to study the localized effects of the disease on MTL structure. We hypothesize that such an analysis can be used to define MTL "hotspots" where in vivo measures will be more sensitive to disease progression in preclinical AD than current state of the art biomarkers. Method: Ex vivo MTL specimens from 24 donors were scanned at 0.2x0.2x0.2mm3 on 9.4T MRI. The specimens contain varying degrees of pathology spanning the spectrum of AD and common co‐morbid non‐AD pathologies. For 21 specimens, a pathologist provided semi‐quantitative ratings of tau and TDP‐43 severity (Table 1). Extending on techniques developed in our prior work, a computational atlas of the MTL was built via groupwise registration of all specimens' MRI scans (Adler et al, 2018; Ravikumar et al, 2020). The atlas was used to investigate the correlation between tau pathology and cortical thickness. Result: The developed atlas achieves excellent groupwise alignment and captures anatomical variability in the MTL despite its complex geometry (Figure 1). Correlation analysis between tau pathology and atrophy (correcting for age and TDP‐43) reveals significant clusters near the transentorhinal region and subiculum (Figure 2). Conclusion: These correlation patterns are consistent with the early Braak stages and resemble results from a previous study which looked at the association between in vivo tau PET measures and atrophy (Das et al, 2019) (Figure 3). In future work, our novel ex vivo atlas will be leveraged to study variability in the distribution of tau pathology in 3D, by mapping quantitative serial pathology images into the atlas space (Figure 4). [ABSTRACT FROM AUTHOR]

Parameter estimation is needed for process management, design, and reactor scaling when values from the literature vary tremendously or are unavailable. A Bayesian approach, implemented via Markov chain Monte Carlo (MCMC) simulations using SAS software, was used to estimate the kinetic parameters of toluene and trichloroethylene (TCE) biodegradation by the microorganism Pseudomonas putida F1 in batch cultures. The prediction capabilities of Bayesian estimation were illustrated by comparing predicted and observed data and reported in goodness‐of‐fit statistics. The sensitivity analysis showed that the parameters obtained using this approach were consistent under the designated toluene and TCE concentration range. Moreover, the impact of TCE on toluene degradation kinetics was numerically exhibited, verifying the fact that TCE was able to stimulate toluene degradation; hence, TCE's presence increased the apparent maximum toluene‐specific rate. Various kinetic models were explored at different degrees of complexity. At a low TCE concentration range (e.g., <2 mg L−1), a simplified Michaelis–Menten model (i.e., substrate half‐saturation parameters approximated the inhibition parameters) was adequate to describe the reaction kinetics. However, at a higher TCE range (e.g., 5 mg L−1), a full‐scale Michaelis–Menten model was needed to discriminate among the inhibition parameters in the model. The results demonstrated that a Bayesian estimation method is particularly useful for determining complex bioreaction kinetic parameters in the presence of a small volume of experimental data. [ABSTRACT FROM AUTHOR]

Background: Recently, there has been debate for the suitability of statins for geriatric populations and patients with dementia as there is evidence suggesting improved quality of life following discontinuation of therapy in these groups, as well as conflicting evidence surrounding its potential to both prevent and potentiate downstream cognitive deficits. Despite large scale studies being conducted in the past regarding statins and cognition, there is a paucity of literature investigating its interaction with sex, as well as possible associations with other variables such as subjective complaints, neuropsychiatric symptoms, and function. Methods: Analysis was done on patients assessed at a Memory Disorders Clinic at St. Michael's Hospital between 2012 and 2017, comprising a population of 348 patients divided into groups taking daily atorvastatin (N = 45), rosuvastatin (N = 40), and controls (N = 263) (Table 1). Data form the Mini‐Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Behavioural Neurology Assessment‐Revised (BNA‐R), Neuropsychological Impairment Scale (NIS), The Older Americans Resources and Services (OARS) Activities of Daily Living (ADL) Scale and Neuropsychiatric Inventory Questionnaire (NPI‐Q) were analyzed. Results: Two‐way ANOVA demonstrated a significant interaction between sex, cognitive performance, and statin use in which female statin users scored significantly lower on multiple subdomains of the BNA‐R (p < 0.05) (Table 2). Patients taking atorvastatin additionally scored lower on CERAD delayed recall, delayed recognition, and in the cumulative recognition domain than other groups (p < 0.05). Atorvastatin and rosuvastatin were additionally associated with higher frequency of dysphoria and disinhibition, respectively (p < 0.05). No significant results were found in other measures investigated. Conclusions: In addition to minor associations between atorvastatin usage and lower memory performance, findings from this investigation suggest a possible interaction between sex, cognition and statin use that has not been well documented in literature. Though these findings were not reflected in other measures such as subjective complaint or function, further research may be warranted to provide insight into the relationship between sex, statin usage and neurological effects. [ABSTRACT FROM AUTHOR]

Background: Why some individuals with significant Alzheimer's disease(AD) lesions in their brain retain their cognitive abilities while others with the same level of pathology manifest symptoms of dementia remains incompletely understood. The term cognitive resilience refers to this phenomenon. With limited success in pharmacological interventions that prevent the onset of AD pathology, more efforts are aiming toward developing strategies to delay the clinical expression of AD; acetylcholinesterase inhibitors serve as an example, and compounds with similar pharmacodynamics such as nicotine may play a similar role. Here we sought to identify demographic, clinical, genetic, and neuropathological features associated with cognitive resilience in participants with severe AD neuropathology. Method: Data for this retrospective cohort was collected from the datasets developed by the National Alzheimer's Coordinating Centre (NACC). Individuals with severe AD pathology and no other primary neuropathology diagnoses who had their last visit within 2 years of their time of death were included. Severe AD pathology definition was based on National Institute on Aging–Reagan (NIA‐Reagan) criteria pathology, i.e., frequent neuritic plaques and Braak & Braak stage V/VI pathology. Cognition was assessed using the Mini‐Mental Status Examination (MMSE) score at their last visit and cases with scores ≥24 were defined as being cognitively intact, and thus resilient. Following bivariate analysis to compare resilient with non‐resilient groups, significantly different variables were adjusted for demographics using logistic regression analysis. Subsequently, statistically significant characteristics were entered in a multivariable model. Results: We classified 59(9%) individuals as resilient and 595(91%) as non‐resilient. The binary logistic regression model showed that resilient subjects were older (odds ratio[OR] = 1.03;95% confidence interval[CI] = 1–1.07), had more years of education (OR = 1.16;95%CI = 1.04‐1.29), had lower BMI (OR = 0.91;95%CI = 0.85‐0.99), were more likely to be a smoker (OR = 2.78;95% CI = 1.45‐5.34), and were more likely to use an anticoagulant/antiplatelet at last visit compared with subjects with impaired cognition (OR = 1.87;95%CI = 1.01‐3.48). Conclusions: Our results corroborated previous findings that lower BMI and higher education are associated with AD cognitive resilience, and additionally demonstrated that the level of smoking and usage of anticoagulant/antiplatelet medication have a direct relationship with cognitive resilience to AD severe pathology. Nicotine mimetics could be explored as a potential option for preventing AD clinical expression. [ABSTRACT FROM AUTHOR]

Background: The relationship between delusional severity and structural brain changes in patients with cognitive decline is unclear. In prior work by our group, we conducted texture and volume analysis of Normal Appearing Brain Matter (NABM) using FLAIR MRI sequences in a cognitively impaired delusional cohort. Our results demonstrated that with more severe delusions, greater global brain disease burden and tissue degeneration in NABM is apparent. In this study we examined the relationship between our findings and neurodegenerative biomarkers, ApoE4 and plasma tau. Methods: A total of 42 patients with Alzhiemer's disease (AD) or Mild Cognitive Impairment (MCI) with delusions as identified by the Neuropsychiatric Inventory‐Quick version (NPI‐Q) were selected from the Alzheimer's Disease Neuroimaging Initiative (ADNI). From fluid‐attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) images, Brain extraction and intensity standardization alghorthims were applied to extract the normal‐appearing brain matter (NABM). Three biomarkers were measured from the NABM region, which included volume and two texture features called integrity and damage that measure the structural integrity of tissue and tissue damage. Statistical analysis included a multivariable stepwise regression of each biomarker as a dependent variable across delusional severity groups 1 (lowest severity) to 3 (highest severity) and the inclusion of sex, age, education, ApoE4 and plasma tau as co‐variates. Results: Data were gathered on the 42 participants representing 164 MRI scans. Significant associations were found between baseline plasma tau, delusional severity group 3 for the NABM integrity and volume biomarkers (p<.05). Additionally, ApoE4 homozygotes were signficantly associated to NABM volume, integrity and damage, though no association was found with delusional severity. Conclusion: These findings suggest that plasma tau may be linked to both delusional severity and structural alterations within the NABM while ApoE4 status is more strongly associated with structural alterations in the NABM with no effect on delusional severity. Further longitudinal studies are required to establish plasma tau associated mechanisms of delusional severity. [ABSTRACT FROM AUTHOR]

Background: Atrial fibrillation (AF) among patients with heart failure with reduced ejection fraction (HFrEF) is associated with adverse clinical outcomes. Our primary aim was to evaluate patient‐centered outcomes and surrogate outcomes following catheter ablation (CA) of AF among patients with HFrEF compared to standard medical therapy with or without device therapy (atrioventricular node ablation and cardiac resynchronization therapy). Methods: A systematic literature review was performed limiting our searches to randomized control trials reporting outcomes of CA compared to standard medical therapy with or without device therapy were included. Patient‐centered outcomes were relative reduction in all‐cause mortality, heart failure readmissions, and recurrence of AF. Surrogate outcomes of interest were change in ejection fraction, change in peak oxygen consumption, reduction in brain natriuretic peptide levels, change in 6‐minute walk distance, and change in Minnesota living with heart failure score. Results: Seven randomized control trials (Patient n = 721) met our inclusion criteria. All trials used radiofrequency energy for CA of AF. CA for AF was associated with significantly lower all‐cause mortality (Risk ratio [RR] = 0.52, 95% confidence interval [CI] = 0.35‐0.76, P = 0.001, I2 = 0%), lower rate of heart failure readmission (RR = 0.58, 95% CI = 0.46‐0.74, P < 0.001, I2 = 0%) and lower rate of AF recurrence (RR = 0.33, 95% CI = 0.22‐0.50, P < 0.001, I2 = 68%) as compared to standard medical therapy. Surrogate outcomes showed a similar benefit favoring CA. Conclusion and Relevance: Catheter ablation for AF in HFrEF is associated with improvement in patient‐centered outcomes and surrogate outcomes when compared to standard medical therapy with or without device therapy. [ABSTRACT FROM AUTHOR]

Introduction: The relative contributions of vascular and degenerative pathology to dementia are unknown. We aim to quantify the proportion of dementia explained by potentially preventable vascular lesions. Methods: We systematically searched for population‐based cohorts before February 2017 reporting clinicopathological data for individuals with and without dementia. We calculated the summary proportion and absolute risk of dementia comparing subjects with and without the pathology. Results: We identified 10 studies comprising 2856 subjects. Vascular‐type pathology and mixed pathology are respectively two and three times more likely in demented patients. The summary proportion of dementia is 77%–86% in subjects with mixed degenerative and vascular pathology and 45% in subjects with pure Alzheimer‐type pathology. Discussion: Patients with mixed pathologies have nearly twice the incremental risk of dementia compared with patients with only Alzheimer‐type lesions. Consequently, many cases of dementia could be prevented or delayed by targeting the vascular component. Highlights: Vascular lesions were the most frequent types of brain lesions (44%) in the elderly.Vascular‐type pathology is two‐times more likely in demented vs. nondemented subjects.Mixed pathology doubles the risk of dementia compared with only degenerative lesions.Mixed pathology is three‐times more likely in demented vs. nondemented subjects.Many cases of dementia could be prevented or delayed by targeting vascular component. [ABSTRACT FROM AUTHOR]

Background: Many lifestyle factors have been associated with lower rates of cognitive decline in AD and MCI patients, however the effect of tobacco smoking remains unclear. This study examined how longitudinal cognitive performance in AD and MCI patients varied for those with versus without smoking history. Method: The study included all 126 patients from the Ontario Neurodegenerative Disease Research Initiative (ONDRI) AD/MCI cohort. The patients were divided into those with a history of cigarette smoking (n = 67) vs without (n = 59), defined as greater than two years of daily smoking. To measure longitudinal cognition, MoCA scores were taken three times with one year elapsing between assessments. Result: Linear mixed effects models were performed, with MoCA score as the dependent variable. Time point, smoking history, sex, education, age, clinical diagnosis (AD vs MCI) and number of languages spoken were fixed effects and subject was a random effect. The presence of smoking history had a significant effect on MoCA score (χ2(1) = 4.5, p = 0.034), improving the average score by 1.37 points ± 0.66 (standard errors). A strong interaction was also found between smoking history and time point (χ2(1) = 8.2, p = 0.0042), as the positive effect of smoking history on MoCA score increased with time. No other significant interactions were found. Conclusion: Our findings indicate that smoking history may improve longitudinal cognition in AD and MCI patients. It is unclear whether smoking history is simply a mediating variable for another protective factor, or whether these results arise from cigarette smoking itself affecting some stage of disease progression. Smoking has been consistently associated with a lower risk of developing Parkinson's disease (PD), however the mechanism for such protection remains unclear. Further research into any association between smoking history and longitudinal cognition in AD and MCI might indicate whether a similar protective association is found in AD and MCI as exists in PD. However, it must be remembered that smoking is associated with many serious diseases, particularly lung cancer, and remains one of the biggest causes of preventable death worldwide. [ABSTRACT FROM AUTHOR]

Background: Why some individuals with significant Alzheimer's disease(AD) lesions in their brain retain their cognitive abilities while others with the same level of pathology manifest symptoms of dementia remains incompletely understood. The term cognitive resilience refers to this phenomenon. With limited success in pharmacological interventions that prevent the onset of AD pathology, more efforts are aiming toward developing strategies to delay the clinical expression of AD; acetylcholinesterase inhibitors serve as an example, and compounds with similar pharmacodynamics such as nicotine may play a similar role. Here we sought to identify demographic, clinical, genetic, and neuropathological features associated with cognitive resilience in participants with severe AD neuropathology. Method: Data for this retrospective cohort was collected from the datasets developed by the National Alzheimer's Coordinating Centre (NACC). Individuals with severe AD pathology and no other primary neuropathology diagnoses who had their last visit within 2 years of their time of death were included. Severe AD pathology definition was based on National Institute on Aging–Reagan (NIA‐Reagan) criteria pathology, i.e., frequent neuritic plaques and Braak & Braak stage V/VI pathology. Cognition was assessed using the Mini‐Mental Status Examination (MMSE) score at their last visit and cases with scores ≥24 were defined as being cognitively intact, and thus resilient. Following bivariate analysis to compare resilient with non‐resilient groups, significantly different variables were adjusted for demographics using logistic regression analysis. Subsequently, statistically significant characteristics were entered in a multivariable model. Results: We classified 59(9%) individuals as resilient and 595(91%) as non‐resilient. The binary logistic regression model showed that resilient subjects were older (odds ratio[OR] = 1.03;95% confidence interval[CI] = 1–1.07), had more years of education (OR = 1.16;95%CI = 1.04‐1.29), had lower BMI (OR = 0.91;95%CI = 0.85‐0.99), were more likely to be a smoker (OR = 2.78;95% CI = 1.45‐5.34), and were more likely to use an anticoagulant/antiplatelet at last visit compared with subjects with impaired cognition (OR = 1.87;95%CI = 1.01‐3.48). Conclusions: Our results corroborated previous findings that lower BMI and higher education are associated with AD cognitive resilience, and additionally demonstrated that the level of smoking and usage of anticoagulant/antiplatelet medication have a direct relationship with cognitive resilience to AD severe pathology. Nicotine mimetics could be explored as a potential option for preventing AD clinical expression. [ABSTRACT FROM AUTHOR]

Person-centered or patient-centered care (PCC) focuses on the individual's needs and concerns. Although PCC is widely acknowledged as a core value of modern medicine, there has been a lack of research on how dental curricula could engage future dentists in PCC approaches. The aim of this study was to assess the impact of a PCC course on empathy in dental students. A controlled study was conducted with fourth-year dental students in four dental faculties in France in 2014-15. The test group (n=63) received 20 hours of PCC training including arts-based approaches, narrative dentistry activities, and workshops on communication based on the Calgary-Cambridge guide. There was no change in the curriculum of the control group (n=217). Pretest and posttest measures with the Toronto Empathy Questionnaire (TEQ) and Jefferson Scale of Physician Empathy (JSPE) were compared for the two groups. The comparisons showed no significant differences on the TEQ or JSPE (p=0.25 and p=0.08, respectively). However, there was a higher proportion of students with more than an eight-point decrease in TEQ values in the control group (p=0.02). The stabilization of empathic ability in the test group may have counteracted the tendency for natural erosion of empathy among students during their clinical activities. These results suggest that PCC training constitutes a promising approach to developing dental students' empathic ability, but there is a need to assess the effects of such training over longer periods. [ABSTRACT FROM AUTHOR]

Background: The Apolipoprotein E (APOE) ε4 allele is a well‐established genetic risk factor of Alzheimer's disease (AD). While sex may play an important modulatory role in the association between APOε4 and certain neuropsychiatric symptoms (NPS) in AD1, it is unclear whether or not this risk extends to cognitively at‐risk populations with Mild Cognitive Impairment (MCI) or a history of Major Depressive Disorder (MDD). This cross‐sectional analysis compared NPS burden between males and females in a cohort of APOε4 carriers with at‐risk cognitive conditions of AD. Method: We analyzed the Neuropsychiatric Inventory Questionnaire (NPI‐Q) data of 51 symptomatic APOε4 carriers (age = 71.9 ± 5.2) from the PACt‐MD cohort which was comprised of older persons from three at‐risk groups of AD: MCI; MDD without MCI; and MDD with MCI. We stratified participants by sex to compare their NPS severity. We tested whether there was a significant association between sex and i) NPI‐Q total score, and ii) NPI‐Q severity score. We chose not to stratify by zygosity or diagnosis due to the sample size. Result: Female APOε4 carriers (n = 33, MNPI Total= 2.27, MNPI Severity = 3.55) had significantly higher NPI‐Q total scores(t = 2.15, df = 43.67, p = 0.037, d = 0.50) and significantly higher NPI‐Q severity scores (t = 2.06, df = 45.37, p = 0.044, d = 0.48) than male carriers (n = 18 , MNPI Total = 1.72, MNPI Severity = 2.44). There were no significant differences in the prevalence of certain NPS between male and female carriers. Conclusion: Our findings support the need to further investigate whether sex influences the effect of APOε4 on NPS burden. Although female carriers showed significantly higher levels of NPS burden, aligning with previous findings1, our analysis was limited by the small number of symptomatic male carriers (n = 18). Thus, further studies with larger samples are needed to elucidate the interaction between sex and APOε4 status on NPS burden. References: Kim, J., Fischer, C. E., Schweizer, T. A., & Munoz, D. G. (2017). Gender and Pathology‐ Specific Effect of Apolipoprotein E Genotype on Psychosis in Alzheimer's Disease. Current Alzheimer research, 8, 834–840. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's Disease (AD) clinical trials often lack diversity in study participants. Older Black adults are nearly twice as likely as their White peers to have Alzheimer's disease or other dementias, but are underrepresented in AD clinical trials. Social media recruitment may help improve diversity in AD clinical trials. Methods: Recruitment data from Facebook advertisements and physician referrals for anti‐amyloid clinical trials at a Boston‐based research site between April and December 2021 were examined. 2,838 potential participants contacted the site through Facebook advertisements, of which 476 completed a phone screen interview with a recruiter. Of the 143 participants who passed the phone screen and attended an in‐person prescreening visit with a clinician, 69 screened for an industry‐sponsored clinical trial. Referrals from local neurologists resulted in 19 participants attending prescreening, 13 eventually screening for a trial. Demographics for participants were compared to census data for the Boston Metropolitan Area. Results: Of the 143 participants recruited from Facebook who completed a prescreening visit, 87.4% identified as White, 9.8% as Black, and 2.8% as Asian or other. 3.5% were White Hispanic and 2.1% were Non‐White Hispanic. 100% of physician referrals identified as White, non‐Hispanic. The Facebook‐recruited sample was stratified into three age groups: 55‐64, 65‐74, and 75‐86. All age groups recruited from Facebook had an equal or higher percentage of Black participants than would be expected based on census data. While 6.5% of the local age 55‐64 population are Black, 13% of Facebook‐recruited participants in that age group identified as Black. Similarly, while 5.5% of the age 65‐74 population are Black, 12.3% of Facebook‐recruited participants in that age group identified as Black. Finally, 5.5% of the oldest cohort (75+) of Facebook‐recruited participants identified as Black, closely matching census data for that age group (5.2%). Conclusion: Social media advertising may be an effective way to recruit a more diverse population of participants for AD clinical trials. In this sample, Facebook recruitment overrepresented some minority groups, which is meaningful given the prevalence of dementia in Black adults. Expanding study recruitment tactics represents an important step towards clinical trial populations that more accurately represents the real‐world AD patient population. [ABSTRACT FROM AUTHOR]

Background: Nearly half of all Alzheimer's Disease (AD) patients experiences psychosis at some point in their disease trajectory. Kim et al. (2017) found a sexual dimorphism in AD psychosis where the ε4 allele may play a larger role in influencing psychosis development in females with Lewy body (LB) pathology. Method: We investigated the effect of sex and ApoE‐4 status on age, presence and severity of psychotic symptoms on a clinical cohort using data from the National Alzheimer's Disease Coordinating Centre (Figure 1). The non‐psychotic group (AD‐P) was compared against each of the overlapping diagnostic groups – psychotic (AD+P), delusion (AD+D) and hallucination (AD+H). Result: We found a significant association between ε4 homozygotes and AD+P (OR = 1.08, p =. 017) and AD+D (OR = 1.09, p =.007). There was also a significant association between ε4 heterozygotes and AD+P (OR = 1.09, p =.004) and AD+D (OR = 1.08, p =.012). In males, the likelihood of having two copies of ε4 was increased in AD+P (OR = 1.10, p =.034) and AD+D (OR = 1.13, p =.006). The likelihood of having one copy of ε4 was also increased in AD+P (OR = 1.10, p =.030) and AD+D (OR = 1.10, p =.028). In females, the likelihood of having one copy of ε4 was increased in AD+H (OR = 1.10, p =.033). Participants who were female and homozygous for ε4 had a predicted increase of 0.388 in the log‐odds of being in a more severe category for delusions (95% CI: 0.016 ‐ 0.759, p =.041) and hallucinations (95% CI: 0.011 ‐ 1.264, p =.046). Conclusion: Our findings show that the presence of ApoE‐4 increases the risk of psychosis in clinically diagnosed AD patients. Moreover, there are differential associations between sex, ApoE‐4 status and psychotic manifestations. The fact that we did not find an increase risk of psychosis among female homozygous ApoE‐4 carriers may be explained by the fact that we did not stratify by Lewy body pathology (Tsuang et al., 2005). [ABSTRACT FROM AUTHOR]

Background: Astrocytes contribute to the normal function and maintenance of the health of the central nervous system (CNS). The abnormal behavior of astrocytes can lead to a major alteration in neuronal function contributing to the pathogenesis of several neurological diseases, including Alzheimer's disease (AD). Dysfunctional astrocytes have been linked to the onset and development of overreacting inflammation in CNS tissue which is a major contributing factor to the onset and progression of AD. We hypothesize that by modulating mitochondrial activity and cell metabolism using antioxidants, key characteristics of astrogliosis could be regulated. Mainly, we believe that some antioxidants can help to regulate astrocyte response and promote their return back to a quiescent state. Methods: In this work, we explored the use of two antioxidant molecules (A1 and A2) as a way to regulate the metabolic activity, proliferation, and overreactive behavior of glial cells. Human astrocytes were cultured for five days in growth media supplemented with 0, 25, or 50 μM A1 or A2. Changes in DNA levels were used to calculate the doubling time of the cell population. DNA levels were quantified using PicoGreen dsDNA quantitation assay. Astrocytes were stained with JC‐1 and fluorescence readings were taken to evaluate mitochondrial activity. Changes in metabolic activity were evaluated using the Vibrant Metabolic Assay and Adenosine Triphosphate (ATP) production. Results: Quantitative assessments demonstrate that increasing levels of A1 significantly reduce human astrocyte proliferation while the addition of A2 at the chosen concentrations does not appear to have a significant effect on cell proliferation. The preliminary data for ATP production and metabolic activity illustrates that A1 appears to decrease cell metabolic activity which may lead to lower cell proliferation. In addition, quantitative analysis of the JC‐1 mitochondrial staining suggests that the addition of A1 does not significantly impact mitochondrial membrane potential while increasing levels of A2 enhanced the polarization of the mitochondrial membrane. Conclusion: The modulation of mitochondrial and metabolic activity using antioxidant molecules may be used as a viable strategy to regulate the overreactive proliferative response of human astrocytes during astrogliosis. [ABSTRACT FROM AUTHOR]

Triticale (x Triticosecale Wittmack) is a promising cereal for malting and brewing owing to its high levels of a-amylase and proteolytic activity and low gelatinization temperatures. However, almost no investigation about its protein modifications during malting has been conducted. In this work, triticale proteins during the malting process were separated and analyzed, first, according to their isoelectric point and molecular weight (MW) and, second, according to their solubility and MW. Moreover, the composition of free amino acids was determined. The results describe the modification changes of the different protein fractions during malting. Triticale proteins were found between 4,700 and 64,000. The majority of the proteins were characterized as having an isoelectric point between 5.08 and 6.63. The Osborne fractionation revealed an albumin band pattern of between 13,400 and 153,800, globulin from 12,700 to 152,300, gliadin from 14,500 to 230,100, and glutenin from 11,200 to 102,200. Free amino acids increased in concentration during malting except for asparagine, which decreased. Asparagine exhibited varying trends during malting. This paper contributes to the understanding of the protein modifications and metabolic changes during the malting process of triticale and indicates the potential of this cereal for the production of cereal-based products. [ABSTRACT FROM AUTHOR]

Although spelt has promising aptitudes for beer and beverage production, almost no investigation about its protein modifications during malting has been conducted. Spelt proteins during the malting process were separated and analyzed, first, according to the isoelectric point and molecular weight (MW) and, second, according to solubility and MW. Moreover, the composition of the free amino acid was determined. Spelt proteins could be divided into a total of 13 zones according to their isoelectric point and MW. Most of the present proteins (90%) had a MW between 35,000 and 60,000 and an isoelectric point between 5.84 and 9.52. The most prominent protein fraction was defined by an isoelectric point between 5.84 and 6.89 and a MW between 35,000 and 55,000. Generally, a protein degradation process during malting was found. The Osborne fractionation revealed an albumin band pattern between 14,000 and 131,700, globulin ranging from 13,400 to 130,500, gliadin from 14,500 to 220,800, and glutenin from 19,800 to 215,300. The free amino acid composition increased in concentration except for asparagine, which decreased during malting. This paper contributes to the understanding of the protein modifications and metabolic changes during the malting process of spelt and facilitates the determination of the potential of this cereal for the production of cereal-based products. [ABSTRACT FROM AUTHOR]

Rapid and ongoing change creates novelty in ecosystems everywhere, both when comparing contemporary systems to their historical baselines, and predicted future systems to the present. However, the level of novelty varies greatly among places. Here we propose a formal and quantifiable definition of abiotic and biotic novelty in ecosystems, map abiotic novelty globally, and discuss the implications of novelty for the science of ecology and for biodiversity conservation. We define novelty as the degree of dissimilarity of a system, measured in one or more dimensions relative to a reference baseline, usually defined as either the present or a time window in the past. In this conceptualization, novelty varies in degree, it is multidimensional, can be measured, and requires a temporal and spatial reference. This definition moves beyond prior categorical definitions of novel ecosystems, and does not include human agency, self-perpetuation, or irreversibility as criteria. Our global assessment of novelty was based on abiotic factors (temperature, precipitation, and nitrogen deposition) plus human population, and shows that there are already large areas with high novelty today relative to the early 20th century, and that there will even be more such areas by 2050. Interestingly, the places that are most novel are often not the places where absolute changes are largest; highlighting that novelty is inherently different from change. For the ecological sciences, highly novel ecosystems present new opportunities to test ecological theories, but also challenge the predictive ability of ecological models and their validation. For biodiversity conservation, increasing novelty presents some opportunities, but largely challenges. Conservation action is necessary along the entire continuum of novelty, by redoubling efforts to protect areas where novelty is low, identifying conservation opportunities where novelty is high, developing flexible yet strong regulations and policies, and establishing long-term experiments to test management approaches. Meeting the challenge of novelty will require advances in the science of ecology, and new and creative conservation approaches. [ABSTRACT FROM AUTHOR]

The article discusses the management of air embolism in the operating room. It mentions the preoperative and intraoperative phases of venous and arterial air embolism which demand prompt coordinated interventions by all perioperative team members. It notes the required critical skills of perioperative nurses. It also emphasizes the importance to return the patient to a stable hemodynamic state by restoration of a normal oxygen level and prevention of further air entry into the vascular system.

Mechanical periodontal therapy is widely used for a variety of periodontal conditions. While the clinical efficacy of this treatment has been validated, the radiographic response has not been studied in depth. The purpose of the present study was to examine the clinical and radiographic response to mechanical periodontal therapy, and assess the factors associated with these changes. One hundred and eight patients, with established periodontitis, received oral hygiene instruction and mechanical periodontal therapy for a period of 4 to 5 weeks. Scheduled maintenance visits were performed at 3, 6, 9, and 15 months. Probing depth (PD) and attachment level (AL) measurements were performed at baseline, and at 3 and 15 months. Intraoral radiographs were taken at baseline and 12 to 15 months postsurgery using a Rinn alignment system. Alveolar crestal height (ACH) measurements were performed on a pair of digitized images of the previously taken radiographs. An overall mean of patients' changes for PD, AL, and ACH was initially computed. Active sites (gainers and losers) were determined using a threshold method, and expressed as patient's percentage of active sites (number of active sites of the total sites measured in each patient). Mean overall probing reduction and AL gain was 0.5 mm and 0.44 mm, respectively. Of all sites measured, 16.6% exhibited AL gain, while only 6.2% of all sites exhibited AL loss. Mean overall change in ACH was -0.07 mm, of which 11.8% of all sites exhibited ACH gain, while 15.1% exhibited loss beyond the threshold. Non-smokers presented no change in bone loss, while smokers continued to lose bone at an annual rate of 0.17 mm, despite treatment (P <0.005). Likewise, the average percent of sites per patients showing attachment gain beyond the threshold were much greater in non-smokers (13.9%) compared to 9.0% in smokers (P <0.01). Mean probing reduction was 50% greater among non-smokers (0.6 mm) when compared to smokers (0.4 mm), which was also statistically significant (P <0.05). A positive and significant correlation was established between the percentage of sites with AL gain and sites with ACH gain (Rho =0.40; P=0.0001). It is suggested that monitoring sites for AL and ACH gain expressed as changes beyond a selective threshold is an important outcome variable in treatment studies. [ABSTRACT FROM AUTHOR]

The article presents a study on ten polycyclic aromatic hydrocarbons' (PAHs) mass balances in the New York-New Jersey Harbor. It mentions that PAH's are a concern in urban watersheds due to its potential hazardous effects to health. The study aims to approximate loads and losses of ten PAH compounds from several transmission routes to the harbor to determine the key loading pathways and inform authorities designed to reduce these loadings. Among the PAHs studied are fluorene, perylene, and indeno. It notes that the study found the need for a comprehensive monitoring of flow and PAH concentrations in stormwater and combine sewer overflows.

This article discusses the concentrations of nitrogen and nitrate in groundwater beneath seepage-irrigated potato cropping systems in the Saint Johns River Watershed in northeast Florida. Soil solution from the root zone was sampled by lysimeters and water from the perched groundwater was sampled in wells. According to the authors, fertilization at planting increased the nitrogen-nitrate concentration in the perched groundwater unless legumes were in the rotation. In the perched groundwater after potato planting, nitrate-nitrogen concentration was proportional to rainfall magnitude. They concluded elevated concentrations under sorghum in perched groundwater were not significant.

Background: Delusions in older adults correlate with white matter lesion burden [1], though the relationship with white matter texture (WMT) is unclear. White matter texture is the tissue organization in normal‐appearing brain matter (NABM) related to overall diffusion capabilities. Method: Using NPI‐Q scores from the ADNI data set, a cognitively mixed sample of patients with delusions was extracted. Delusional severity was ranked from 1‐3 (1 being the lowest severity) based on the NPI‐Q scores along with downloads of FLAIR MRI volumes for each subject. Subjects and volumes were analyzed in each severity group. Normal‐appearing brain matter of FLAIR images were extracted with validated in‐house brain extraction and intensity standardization algorithms [2]. Volume texture maps representing the correlation in the NABM for each FLAIR image were generated as per Khademi et. al [3]. Result: Boxplots for the NABM texture measures are shown for groups 1, 2 and 3 in Figure 1. Subjects with high delusional severity (group 3) had the most noticeable change in WMT relative to lowest delusional severity (group 1). Group 3 had a higher spatial correlation value of 6.0947 e+03 +/‐ 592.6178 than group 1 with values of 5.7630 e+03 +/‐ 832.5040. A higher value indicates more spatial correlation among pixels. This suggests that there are larger regions that are smooth in Group 3 compared to Group 1, indicating less WM "structure" in the more severe delusion group. Conclusion: The severity of delusions in a cognitively diverse sample of older adults correlates with abnormalities in white matter texture, though further research is required to further validate our findings. References: [1] K. Misquitta, M. Dadar, D. L. Collins and M. C. Tartaglia and Alzheimer's Disease Neuroimaging Initiative, White matter hyperintensities and neuropsychiatric symptoms in Alzheimer's disease and mild cognitive impairment, bioRxiv, 2019. [2] A. Khademi, B. Reiche, G. Arezza, Method and System for Standardized Processing of MR Images, PCT Patent Application No. PCT/CA2018/051606, Filed.US. December 2018. [3] A. Khademi, D. Hosseinzadeh, A. Venetsanopoulos and A. Moody, "Nonparametric statistical tests for exploration of correlation and nonstationarity in images," 2009 16th International Conference on Digital Signal Processing, Santorini‐Hellas, 2009, pp 1‐6. [ABSTRACT FROM AUTHOR]

Background: Body mass index (BMI) is a known risk factor for Alzheimer's disease (AD). Research with autosomal dominant Alzheimer's disease (ADAD) has shown a relationship between lower BMI, greater amyloid burden and worse memory performance in presymptomatic mutation carriers. Women have a higher incidence of AD, and may be more susceptible to AD‐ related pathology. However, little is known about the effects of sex/gender on BMI in individuals at increased risk for AD. As carriers of ADAD mutations are destined to develop early‐onset dementia, they allow us to investigate sex differences without aging confounds known to vary by sex (i.e., life expectancy, menopause). We sought to examine sex differences in BMI in non‐demented mutation carriers and non‐carriers from a Colombian kindred with ADAD. Method: 191 carriers of the Presenilin‐1 E280A mutation (104 females; age range: 18‐55 years) and 261 age‐matched non‐carriers (165 females) were included. All participants completed clinical and cognitive assessments, including BMI (kg/m2) measures, MMSE and CERAD Word List tests. Mann‐Whitney‐U test was used to examine sex differences on BMI. General linear models were used to examine the associations between BMI, MMSE and memory, controlling for age and education. Result: Compared to non‐carriers, carriers had lower BMI (carriers: 23.05 +/‐ 3.65; non‐carriers: 24.26 +/‐ 3.92, p=0.002). In carriers, lower BMI was associated with worse performance on MMSE (r=0.49, p=0.001). Compared to male carriers, female carriers had greater BMI (males: 22.4 +/‐ 3.3, females: 23.5 +/‐ 3.7, p=0.04), and performed worse on the MMSE (males: 28.19 +/‐1.8, females: 27.91 +/‐1.91, p=0.04). There was a trend for female carriers to also have worse memory performance (p=0.06). Sex differences were not observed in non‐carriers. There were no associations between BMI and memory. Conclusion: There are sex differences in body composition in carriers of ADAD without dementia. These findings suggest that changes in BMI may reflect early signs of abnormal systemic responses to AD‐related pathology. Future studies should examine longitudinal changes in BMI, from preclinical to clinical stages, and other contributing factors (e.g. vascular risk factors and sex hormones) to determine the potential role of BMI as a risk factor for dementia. [ABSTRACT FROM AUTHOR]

Background: Numerous recent studies have focused on the role of microglia in the onset and progression of neurodegenerative diseases including Alzheimer's disease (AD) (Lee et al. 2015). One of the areas of interest is the study of the physiological changes microglia elicit in response to neural damage. Macromolecules such as collagen type IV, laminin, and hyaluronic acid (HA) characterize the extracellular matrix (ECM) landscape of the central nervous system (CNS). These components contribute to the regulation of microglia activation and phenotype modulation. In response to tissue injury or trauma, the normal composition of the ECM can be altered to induce microglia activation. Methods: In this work, we modeled and evaluated the effects of HA molecular weight (MW) on human microglial cells (HMC3) under in vitro conditions using multi‐interpenetrating polymer networks (mIPNs). We fabricated and characterized a family of mIPNs comprised of poly(ethylene glycol) diacrylate (PEGDA), collagen type I (Col I), and HA of high (HAH, ∼1.5 MDa) or low (HAL, ∼40 kDa) MW via sequential infiltration (Van Drunnen et al. 2019). The viscoelastic properties of mIPNs were evaluated using dynamic mechanical analysis (DMA). In these scaffolds, the effects of HA MW on microglia activation were studied independently of scaffold mechanical performance. After 3 days in culture, changes in the expression of microglia pro‐inflammatory (M1) markers TNFα, IL‐1β, iNOS, and CD86, and the alternatively activated (M2) marker CD206 were measured at the protein level using immunofluorescence. Cell phenotypic expression at the protein level was quantified using confocal microscopy imaging and the ImageJ 2 (FIJI) program. Cell morphology was assessed using confocal microscopy. Results: The overall HMC3 viability in the mIPNs exceeded 85%. Microglia morphology appears to be modulated by HA MW. On day 3, the reduction in HA MW in the mIPN formulations promoted a significant increase in the expression of the M1 and M2 markers iNOS, IL‐1β, and CD206 respectively. Conclusion: With the proposed engineered scaffolds, we demonstrated that the reduction in the MW of HA — which is normally associated with tissue degradation — is a significant contributing factor for human microglia activation. [ABSTRACT FROM AUTHOR]

Background: Delusions in older adults correlate with white matter lesion burden [1], though the relationship with white matter texture (WMT) is unclear. White matter texture is the tissue organization in normal‐appearing brain matter (NABM) related to overall diffusion capabilities. Method: Using NPI‐Q scores from the ADNI data set, a cognitively mixed sample of patients with delusions was extracted. Delusional severity was ranked from 1‐3 (1 being the lowest severity) based on the NPI‐Q scores along with downloads of FLAIR MRI volumes for each subject. Subjects and volumes were analyzed in each severity group. Normal‐appearing brain matter of FLAIR images were extracted with validated in‐house brain extraction and intensity standardization algorithms [2]. Volume texture maps representing the correlation in the NABM for each FLAIR image were generated as per Khademi et. al [3]. Result: Boxplots for the NABM texture measures are shown for groups 1, 2 and 3 in Figure 1. Subjects with high delusional severity (group 3) had the most noticeable change in WMT relative to lowest delusional severity (group 1). Group 3 had a higher spatial correlation value of 6.0947 e+03 +/‐ 592.6178 than group 1 with values of 5.7630 e+03 +/‐ 832.5040. A higher value indicates more spatial correlation among pixels. This suggests that there are larger regions that are smooth in Group 3 compared to Group 1, indicating less WM "structure" in the more severe delusion group. Conclusion: The severity of delusions in a cognitively diverse sample of older adults correlates with abnormalities in white matter texture, though further research is required to further validate our findings. References: [1] K. Misquitta, M. Dadar, D. L. Collins and M. C. Tartaglia and Alzheimer's Disease Neuroimaging Initiative, White matter hyperintensities and neuropsychiatric symptoms in Alzheimer's disease and mild cognitive impairment, bioRxiv, 2019. [2] A. Khademi, B. Reiche, G. Arezza, Method and System for Standardized Processing of MR Images, PCT Patent Application No. PCT/CA2018/051606, Filed.US. December 2018. [3] A. Khademi, D. Hosseinzadeh, A. Venetsanopoulos and A. Moody, "Nonparametric statistical tests for exploration of correlation and nonstationarity in images," 2009 16th International Conference on Digital Signal Processing, Santorini‐Hellas, 2009, pp 1‐6. [ABSTRACT FROM AUTHOR]

Background: Bone loss in periodontitis results from inflammatory reactions that stimulate osteoclastic bone resorption. Bisphosphonates inhibit bone resorption and increase bone mass. This study evaluated the effect of bisphosphonate therapy as an adjunct to non-surgical periodontal treatment in patients with moderate to severe chronic periodontitis. Methods: Patients were randomized (2:1) to one of two bisphosphonate therapies or placebo for 1 year. All patients received non-surgical periodontal treatment (scaling, root planing) and periodontal maintenance therapy every 3 months. Clinical assessments at baseline and 6 and 12 months included clinical attachment level (CAL), probing depth (PD), and bleeding on probing (BOP). Periodontal bone mass was assessed by dental radiographs at baseline and 12 months using fractal analysis and digital subtraction radiography (DSR). Results: Seventy patients were randomized, 43 to the bisphosphonate group and 27 to the placebo group. Bisphosphonate therapy significantly improved CAL, PD, and BOP relative to the placebo group during the 6- to 12-month period (CAL, P = 0.0002; PD, P = 0.0156; BOP, P = 0.0079). There was no difference in the change in periodontal bone mass between the bisphosphonate and placebo groups as measured by fractal analysis and DSR. Conclusion: These data suggest that bisphosphonate treatment improves the clinical outcome of non-surgical periodontal therapy and may be an appropriate adjunctive treatment to preserve periodontal bone mass. [ABSTRACT FROM AUTHOR]

Background: Recruitment of older adults into aging research is a challenge. Several research studies and clinical trials have failed due to low participant enrollment. Older adults face many barriers to study participation (mistrust of research, lack of transportation, health status, etc.), so special efforts must be made to recruit them into research. We created a recruitment questionnaire with the goal of understanding how to better promote the study and to obtain participant suggestions of groups and locations where the study team could recruit new participants. Method: The Health and Aging Brain Study: Health Disparities (HABS‐HD) is a community based research study of cognitive aging in diverse communities. We designed a voluntary exit questionnaire for current study participants regarding their recruitment preferences. The questionnaire included the following questions: 1) How did you find out about the study? 2) How can we promote the study to someone similar to you? 3)Which of the following advertising methods do you prefer? 4) Do you know any organization/group that would benefit from the study information? Questionnaire data was compiled and analyzed to assess recruitment preferences and suggestions. Result: The total number of participants who responded to the questionnaire was 413. 26.9% of respondents stated that they would prefer TV as their main advertising method, followed by the internet (23%) and postal service (mail) (22.7%). Word of mouth was listed as the best way to promote the study (26.9%) followed by community engagement (16.2%) and church (8.2%). When asked for names of organizations, participants recommended tradition groups such as churches, senior centers, and retirement homes. Participants also recommended groups such as rotary clubs, veterans associations, libraries, and the community college senior education program. Conclusion: Participants can assist in recruitment efforts through suggesting organizations that study personnel may not have reached out to. The input allows for assessment of recruitment and the suggestions can broaden the study's reach. [ABSTRACT FROM AUTHOR]