bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comprehensive Alzheimer’s pathology is induced by P. gingivalis infection: COR388 and other gingipain inhibitors protect against synaptic loss
Authors: Ermini Florian , Haditsch Ursula , Roth Theresa , Rodriguez Leo , Broce Sean , Raha Debasish , Nguyen Mai , Hancock Sandy , Cecere Thomas , Detke Mike , Kapur Shirin , Holsinger Leslie J. , Lynch Casey C. , Dominy Steve 
Published: December 2020

AbstractBackgroundPorphyromonas gingivalis and its proteolytic virulence factors lysine‐gingipain (Kgp) and arginine‐gingipain (Rgp) are emerging as major etiologic agents in the pathogenesis of Alzheimer’s disease (AD). We have previously reported that gingipains colocalize with neuronal cell bodies in over 90% of AD brains studied and the presence of gingipains strongly correlates with tau pathology. We have found tau protein to be a substrate for both Kgp and Rgp and have identified over forty cleavage sites combined. Here we used iPSC‐derived neuron cultures and neuron‐astrocyte‐microglia co‐cultures to investigate the neuropathological mechanisms resulting from persistent infection with P. gingivalis and gingipain exposure and highlight the therapeutic potential of gingipain inhibitors.MethodIPSC derived neuron cultures and neuron‐astrocyte‐microglia co‐cultures were infected with P. gingivalis and analyzed by high content screening (HCS), confocal microscopy, transmission electron microscopy (TEM), protein and RNA expression analysis.ResultIntracellular P. gingivalis bacteria were observed in neurons for 3 days or longer after infection. Infection produced significant synaptic loss that was completely prevented by Kgp and Rgp inhibitors including COR388. Using electron microscopy, we found an accumulation of autophagic vacuoles in dystrophic neurites reminiscent of ultrastructural findings in AD brains. Furthermore, gingipain exposure resulted in acute fragmentation of tau and increased tau phosphorylation, resulting in destabilized microtubules and disrupted vesicle transport. Transport disruption by gingipains accounted for the accumulation of autophagic vacuoles in dystrophic neurites, as no dystrophic neurites were observed in cultures treated with gingipain inhibitors. When co‐cultures of microglia, astrocytes and neurons were infected, activated microglia displayed the highest number of internalized bacteria and responded to infection by upregulation of inflammatory markers associated with AD pathology.ConclusionWe demonstrate in an in vitro model system that P. gingivalis infection can result in a neurodegenerative phenotype consistent with pathology found in Alzheimer’s disease. With this model we show that exposure of neurons to P. gingivalis infection results in synaptic loss and dystrophic neurites which can be prevented by gingipain inhibitors.
Visit‐to‐visit heart rate variability is associated with cognitive decline in older adults: The S.AGES cohort
Authors: Rouch Laure , Vidal Jean‐Sébastien , Hanon Olivier ,   S.AGES Investigators
Published: December 2020

AbstractBackgroundVisit‐to‐visit blood pressure variability (BPV) has been increasingly recognized as a predictor of cognitive decline and dementia but the impact of long‐term heart rate variability (HRV) on cognition is unknown.Method3319 non‐institutionalized subjects from the S.AGES (elderly subjects) cohort underwent clinical examinations every 6 months during 3 years. Visit‐to‐visit HRV was evaluated using standard deviation, coefficient of variation, average real variability, successive variation, variation independent of mean and residual standard deviation. Cognition was assessed using the Mini‐Mental State Examination and incident dementia using the Diagnostic and Statistical Manual of Mental Disorders. Linear mixed models and Cox proportional hazards models were used, respectively to assess the association of HRV with cognitive function over time and incident dementia.ResultAmong the 3319 subjects (mean age, 78 years; 57% female; university level, 20%), 93 (2.8%) developed dementia. Higher HRV was significantly associated with poorer cognition (1‐sd increase of CV: β ± SE = ‐0.18 ± 0.06, p < 0.01) after adjustment for demographics, heart rate, antihypertensive drug use, coronary artery disease, diabetes, chronic heart failure, atrial fibrillation, transient ischemic attack or stroke, smoking and dyslipidemia at baseline. Similar results were observed with all other indicators of variability (p<0.01) except residual standard deviation. After adjustment, higher HRV was not associated with greater risk of dementia (1‐sd increase of CV: HR = 1.03, 95% CI [0.83‐1.28], p = 0.7).ConclusionHigher long‐term HRV is associated with cognitive decline in community‐dwelling older adults. Future research is needed to assess whether it could be a therapeutic target for preserving brain health.
A novel care model for dementia: Improving caregiver burden and depression
Authors: Manning Carol A , Boyd Elizabeth , Fields Samantha , Sperling Scott A , Tsang Siny 
Published: December 2020

AbstractBackgroundIn the United States, people with dementia are cared for by 16,000,000 unpaid caregivers (Alz. Association, 2019). Dementia caregivers have increased morbidity and poorer health than non‐caregivers. Negative biopsychosocial impacts related to caregiving undermine the capacity to provide care, and lead to increased institutional placement, increasing burden on public systems (de Vugt, Verhey, 2013).MethodThis study investigated the efficacy of a novel care model in which participants were assigned care coordinators who provided education, support, guidance and access to existing resources. Participants were 105 people with dementia (54.3% women) and their caregivers (67.3% women). Depression (CES‐D), caregiver burden (Zarit), and healthcare utilization were measured at baseline and twelve months. We used Linear Effects Modeling and the Actor‐Partner Interdependence Model (APIM; Kashy & Kenny, 2000) to examine the extent to which patient/caregiver’s depression at 12 months was affected by their own and partner’s depression at baseline.ResultCare coordination satisfaction was high. There were significant decreases in caregiver burden and depression over time (both p’s < 0.001). Regarding health care utilization, there was a decrease in the number of nights in the hospital with care coordination relative to before study onset. Most people had no change in the number of doctor visits relative to prior to the study, but of those who had a change, most had fewer visits with care coordination. APIM results showed patients’ and caregivers’ depression at baseline were positively correlated (p < .001). Patients’ depression at baseline predicted their depression at 12‐months (p < .01), taking into account the correlation of depression between patients and caregivers, and the effect of caregivers’ depression at baseline. Caregivers’ depression at 12‐months was not affected by their own nor patients’ depression at baseline.ConclusionPatients and caregivers participating in a novel caregiving model involving care coordination showed decreased caregiver burden, depression and hospitalization. Caregiver depression at twelve months was unrelated to caregiver and patient baseline depression, controlling for correlations between caregiver and patient depression at baseline. Care coordination may help alleviate negative impacts related to caregiving, suggesting that this model may improve important elements of dementia care.
Depressive symptoms and risk of dementia in non‐depressed older adults
Authors: Fitzpatrick Annette L. , Lopez Oscar L. , Leary Cindy S. , Semmens Erin O. , Adam Claire , Park Christina , Senter Camilla , Hajat Anjum 
Published: December 2020

AbstractBackgroundThe relationship between depression and dementia is complex. Whether depression serves as a risk factor, prodromal symptom, or comorbidity of dementia remains unclear. Longitudinal studies that establish temporality of these conditions in late life may shed light on their relationship.MethodWe analyzed data from the Ginkgo Evaluation of Memory Study (GEMS) initiated in 2000 and followed for 8 years to determine incident dementia and its subtypes Alzheimer’s disease (AD) and vascular dementia (VaD). Inclusion criteria for enrollment in GEMS required participants to have a Center for Epidemiology Studies Depression score (CES‐D) <16 or to be on treatment for depression. Dementia was determined by consensus of study neurologists based on standardized criteria using neuropsychiatric testing, MRI imaging, and comorbidities. Cox Proportional Hazards Regression was used to evaluate the associations of dementia (n=515), AD (without VaD, n=348) and VaD (with or without AD, n=145) with number of depressive symptoms at baseline. We determined the optimum cutpoint for depressive symptoms to predict dementia using Receiver Operating Characteristic (ROC) curves. Adjustments for age, gender, race, education, area level income, and study site were included in models.Result3,042 participants mean age 78.6 (SD 3.3), 46% women, mean follow‐up time 5.5 (SD 1.6) person‐years, were included in analyses. Mean number of CES‐D depressive symptoms at baseline was 3.5 (SD 3.2) with 525 participants reporting none. Number of depressive symptoms was associated with an increased risk of dementia (HR:1.09, 95% CI:1.06‐1.12, p<0.001), AD (HR:1.10, 95% CI:1.07‐1.13, p<0.001) and VaD (HR:1.05, 95% CI:1.00‐1.10, p=0.04). The optimum cutpoint based on the ROC curve was 2.6 with sensitivity of 0.64 and specificity of 0.49. Participants who reported > 3 depressive symptoms had a 45% increased risk of dementia compared to those with fewer symptoms (HR: 1.45, 95% CI:1.04‐2.04, p=0.03). Effect modification by presence of mild cognitive impairment (MCI) was found (p interaction = 0.008). Results were only significant for those without MCI.ConclusionReporting just a few depressive symptoms in late life may indicate future onset of dementia. These results suggest the need for close clinical follow‐up of cognitive impairment in these non‐depressed older adults.
Genetic context and aging influence anxiety‐like behavior in diverse mouse models of Alzheimer’s disease
Authors: Korgan Austin C. , Doyle Patricia H. , Neuner Sarah M. , Kaczorowski Catherine C. , O'Connell Kristen M.S. 
Published: December 2020

AbstractBackgroundMany neuropsychiatric symptoms have been observed in humans with Alzheimer’s disease (AD). Significant changes in anxiety, depression, agitation, and apathy are present in AD patients relative to age‐matched controls, often occurring prior to the onset of cognitive deficits.MethodHere, we used the elevated plus maze (EPM) to examine anxiety‐like behavior in our AD‐BXD genetic reference panel to determine if sex, age (6 and 14m), or genetic background (28 BXD strains) influence anxiety in 5XFAD carrier (AD‐BXD) and non‐carrier (Ntg‐BXD) mice.ResultAt 6m of age, AD‐BXD strains spent significantly more time in the open arms (anxiolytic) compared to Ntg‐BXD controls, despite no differences in cognitive abilities (presymptomatic). The effect of the 5XFAD transgene on time spent in the open arms was exacerbated with aging, 14m AD‐BXD strains spent significantly more time in the open arms compared to both 6m 5XFAD carriers and non‐transgenic mice at either age. We also found a significant main effect of background strain and a strain by genotype interaction; indicating that the degree to which the transgene increased the time spent in open arms was dependent on individual genetic context. Interestingly, the anxiolytic response in these mice was mirrored by a decrease in locomotor activity (distance traveled).ConclusionContrary to increased anxiety described in human AD patients, we observed a decrease in anxiety‐like behaviors in the AD‐BXDs that exacerbated by age. However, circadian influence on anxiety may limit the translational relevance of this data set, especially considering the impact of strain, age, and genotype on locomotor activity. Ongoing work will investigate non‐anxiety‐like behavior in the EPM (risk‐taking), circadian‐dependent (i.e. morning vs. evening) changes in anxiety‐like behaviors, and gene expression in the hypothalamus as a function of anxiety‐like behavior.
Are early stage tau depositions associated with pyroglutamylated Aβ in Alzheimer’s disease?
Authors: Walker Lauren , Johnson Mary , Thomas Alan J. , Attems Johannes 
Published: December 2020

AbstractBackgroundHallmark lesions observed Alzheimer’s disease (AD) include neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau protein (HP‐
T
) and amyloid β plaques. Pyroglutamylated Aβ (pAβ) is a sub‐species of Aβ, and we have previously demonstrated an association between (pAβ) and HP‐T in human post‐mortem brains, and observed that pAβ predicts the severity of clinical dementia. Several studies in transgenic mouse models have demonstrated Aβ inducing HP‐T pathology and anti‐Aβ antibody treatment eliminated not only parenchymal Aβ deposits but also early stage HP‐T deposits while mature NFTs remained unaltered suggesting that Aβ ‐ HP‐T interaction takes place at an early stage of NFT development. However, these studies did not specifically look for the proportion of pAβ within Aβ and hence data on the interaction between pAβ and stages of NFT development are lacking. We now aim to investigate whether pAβ is associated with tau conformations that represent earlier stages of tangle development, measured by MC1 and CP13 antibodies in human post‐mortem tissue.MethodTissue from frontal, temporal, parietal, occipital and entorhinal cortices from 70 post‐mortem brains (35 AD and 35 aged controls) were processed into a tissue microarray blocks for high throughput analysis, and stained for pAβ, MC1, and CP13. Percentage area of immunopositivity calculated using an automated image analysis system.ResultpAβ, MC1, and CP13 loads were higher in AD cases compared to controls in all regions (all p < 0.05). The burden of pAβ positively correlated with the burden of MC1 and CP13 in all regions (all p < 0.05).ConclusionThis study provides the first set of results from a larger screening study to determine at which point the interaction between pAβ and tau takes place. Our results suggests pAβ is associated with conformational states of tau that represent early stage tau depositions. Therefore studies investigating whether immunisation using pAβ is capable of removing early stage tau depositions, precluding excessive mature NFT tau accumulations, and attenuating cognitive decline in AD are warranted.
Adverse lipid profiles in older people are associated with lower dementia risk
Authors: van Dalen Jan Willem , Hoevenaar‐Blom Marieke P , van Gool Willem A , van Charante Eric P Moll , Richard Edo 
Published: December 2020

AbstractBackgroundDyslipidaemia in mid‐life is associated with incident dementia but evidence is conflicting on whether dyslipidaemia in late‐life increases dementia risk. This may be due to the large heterogeneity in cholesterol measures and study designs employed. We used detailed data from a large prospective cohort of older people to comprehensively assess the relation between a broad range of cholesterol measures and incident dementia, addressing potential biases, confounders and modifiers.MethodIn 3392 community‐dwelling individuals, without dementia, aged 70‐78 years, total cholesterol, low‐density lipoprotein cholesterol (LDL‐C), high‐density lipoprotein cholesterol (HDL‐C), triglycerides and apolipoprotein A1 and B were assessed. Over a median of 6.7 years follow‐up, dementia was established by clinical diagnosis confirmed by independent outcome adjudication. Hazard ratios (HR) for dementia and mortality were calculated using Cox regression.ResultDementia occurred in 231 (7%) participants. Dyslipidaemia, particularly high LDL‐C/HDL‐C, was associated with lower dementia risk, independent of age, cardiovascular risk factors, cognitive function, apolipoprotein E genotype and cholesterol lowering drugs. This association was not influenced by the competing risk of mortality. One SD increase in LDL/HDL conveyed a 19% lower dementia risk (HR=0.81, 95%CI=0.69‐0.96) and a 10% lower risk of dementia/mortality combined (HR=0.90, 95%CI=0.82‐0.98). Strong and consistent interactions suggested these associations were predominant in individuals with low BMI and education and potentially reversed in high BMI and education subgroups.ConclusionDyslipidaemia in older individuals conveyed a lower risk of dementia. Differentiating between subgroups seems essential when assessing the risk of poor outcome associated with dyslipidaemia. This may have important implications for dementia risk prediction.
Sensory function, cognition, and brain structure in SCD, MCI, and AD: Initial findings from the COMPASS‐ND Study
Authors: Phillips Natalie , Al‐Yawer Faisal , Giroud Nathalie , Rehan Sana , Pappadatos Zoe , Mick Paul , Wittich Walter , Pichora‐Fuller M. Kathleen 
Published: December 2020

AbstractBackgroundThere is a strong relationship between sensory and cognitive function in older adults and impairment in hearing, vision, and olfaction are each independently associated with dementia. However, these have rarely been examined together in persons with dementia, nor their concurrent relationship with cognitive function and brain structure. The Comprehensive Assessment of Neurodegeneration and Dementia (COMPASS‐ND) study is a large‐scale study of older Canadians who are living with, or are at risk for, dementia, including those with subjective cognitive decline (SCD), mild cognitive impairment (MCI), Alzheimer’s disease (AD), other causes of dementia, and normal controls. We collect clinical and cognitive data, structural brain imaging, and measures of sensory function.MethodComplete sensory, cognitive, and brain imaging data have been released on participants with study diagnoses of SCD (n=35; 74% women, mean age = 69.4 years; mean education = 16.6 years), MCI (n=79; 49% women, mean age = 73.5 years; mean education = 15.5 years), and AD (n=21; 10% women, mean age = 75.9 years; mean education = 15.5 years).Hearing function was assessed by pure tone screening at 25 and 40 dB and with a computerized speech in noise perception task. Vision function was assessed by measuring reading acuity and contrast sensitivity. Olfaction was assessed with a 16‐item olfactory recognition test.ResultControlling for age, sex, and education, cognitive performance measures decreased over the groups (SCI>MCI>AD), as expected. The groups differed in contrast sensitivity and olfaction, but not hearing (audiometric category, perceiving digits in noise) or visual reading acuity. Poorer olfaction was associated with poorer auditory episodic memory and lower hippocampal volume. Poorer hearing thresholds were associated with lower right hippocampal volume in SCD participants. Within MCI participants, poorer hearing was associated with a disruption in the relationship between auditory episodic memory and a number of variables, including visual episodic memory and lateralized hippocampal volume.ConclusionThese results illustrate a complex interplay between sensory‐cognitive‐brain measures in older adults with or at risk for dementia and suggest that sensory status has important implications for brain structure and clinical status.
Identification of dysregulated lipid metabolic pathways in mouse embryonic derived neurons and in a mouse model of Alzheimer's disease
Authors: Costa Ana Paula , Menon Vilas , McIntire Laura Beth 
Published: December 2020

AbstractBackgroundLipidomic data from autopsy brain, human plasma and animal models highlights severe lipid dyshomeostasis in Alzheimer’s disease (AD). The importance of lipid metabolism in AD is supported by GWAS studies which have identified multiple lipid modifying enzymes and interacting proteins. Further, mouse genetic studies have shown benefit of genetic disruption of synaptojanin1 (Synj1), phospholipase A2 (PLA2), and phospholipase D2 (PLD2).MethodWe used high‐content screening for Aß‐triggered synapse loss in mouse embryonic stem cell derived neurons to identify phospholipid modifying enzymes which contributed to synapse loss. In an orthogonal approach we used DESI Imaging Mass Spectrometry to identify lipid metabolic pathways which are dysregulated in brain of a mouse model of AD.ResultWe showed that haploinsufficiency of Synj1, a phosphoinositide phosphatase, and concurrent maintenance of phosphoinositide levels, ameliorated behavioral deficits in a mouse model of AD in spite of pathological amyloid accumulation. Similarly, disruption of phospholipid modifying enzymes PLD2 and PLA2 resulted in rescue of behavioral deficits despite the pathological accumulation of amyloid. It is likely then that specific pathways in lipid metabolism underlie AD disease mechanisms leading to behavioral impairment. Specifically, the loss of polyunsaturated fatty acids among multiple phospholipid classes is common in AD affected human brain and mouse models. Our lipidomic studies show that lipid species are dramatically altered in mouse brain in a regionally specific manner determined by imaging mass spectrometry.ConclusionSynthesis of these findings and the fact that disruption of phospholipid modifying enzymes Synj1, PLA2 and PLD2 rescue behavioral deficits in spite of pathological accumulation of amyloid, implicate acyl chain remodeling as a candidate therapeutic target in AD.
Histopathological assessment and staging of large and small vessel disease associated with normal brain aging
Authors: Dallaire‐Théroux Caroline , Saikali Stephan , Duchesne Simon 
Published: December 2020

AbstractBackgroundVascular cognitive impairment is the manifestation of diffuse underlying cerebrovascular disease (CVD) that can be assessed at postmortem examination. However, CVD is nonspecific and therefore common in cognitively intact individuals, as prevalence increases with age. There is also an important overlap between CVD and other neurodegenerative conditions, especially Alzheimer’s disease, with more than 40% of cases being mixed aetiologies. We aimed to validate a histological scale able to assess the natural progression of small and large vessel lesions associated with normal brain aging, and further understand their potential contribution to cognitive impairment.MethodBrain specimens from 63 cognitively intact participants aged 19 to 84 were examined and rated by two blinded and independent observers using a modified version of the Vascular Cognitive Impairment Neuropathology Guidelines (VCING; Skrobot et al. 2016). The scale focuses on nine anatomical regions and ten histological changes, including vascular wall lesions and secondary tissue damages. Weighted Kappa coefficients were calculated to estimate interrater reliability, and Spearman’s rank correlation test was used to calculate regional gradients of vascular load associated with age.ResultPreliminary analyses suggest an inter‐observer agreement ranging from 0.39 to 1.00. Atherosclerosis, arteriolosclerosis, cerebral amyloid angiopathy and perivascular hemosiderin deposits were significantly correlated with age (ρ = 0.76, 0.74, 0.44 and 0.39, respectively; p < 0.005). There was also a trend in the severity of perivascular retraction and myelin loss associated with age (ρ = 0.26 and 0.31, p = 0.04 and 0.01). In arteriolosclerosis, the strongest regional gradients were observed in deeper brain structures (i.e., basal ganglia and thalamus).ConclusionThese results suggest an existing cerebrovascular pathology that accumulates with normal aging, the burden of which can be reproducibly estimated with a modified version of the VCING scale. Our results can be used as normative benchmarks to assess the severity of occurrence. While large vessel pathology is a well‐known risk factor for vascular dementia, the contribution of small vessel disease to cognitive impairment has yet to be established. The use of a dedicated standardized histological staging scale is crucially needed to better understand its clinical implications and identify thresholds of pathological states associated with cognitive decline.