bluuebunny/crossref_metadata_2025_split huggingface dataset:
Analyses mutations in GSN, CST3, TTR and ITM2B genes in Chinese patients with Alzheimer’s disease
Authors: Jiang Yaling , Jiao Bin , Liao Xinxin , Xiao Xuewen , Shen Lu 
Published: December 2020

AbstractBackgroundAmyloid protein deposition is a common mechanism of hereditary amyloidosis (HA) and Alzheimer’s disease (AD). Mutations in gelsolin (GSN), cystatin C (CST3), transthyretin (TTR) and integral membrane protein 2B (ITM2B) genes can lead to HA. But the relationship is unclear between these genes and AD.MethodGenes targeted sequencing (GTS), including GSN, CST3, TTR and ITM2B, was performed in a total of 636 patients with clinical AD and 365 normal controls from China.ResultAccording to American College of Medical Genetics and Genomics (ACMG) guidelines, two novel likely pathogenic frame‐shift mutations (GSN: p.K346fs and GSN: p.P3fs) were detected in five patients with AD, whose initial symptom was memory decline, accompanied with psychological and behavioral abnormalities later. Interestingly, the patient with K346fs mutation, presented cerebral β‐amyloid protein deposition, had an early onset (48 years) and experienced rapid progression, while other four patients with P3fs mutation had a late onset ((Mean ± SD): 69.50 ± 5.20 years) and a long course of illness ((Mean ± SD): 9.24 ± 4.86 years).ConclusionTo our knowledge, we firstly report AD phenotype with GSN mutations in patients with AD in Chinese cohort. Although mutations in GSN gene are rare, it may explain a small portion of clinically diagnosed AD.
Biomarkers of agitation in moderate‐to‐severe Alzheimer's disease patients enrolled in an RCT with nabilone
Authors: Ruthirakuhan Myuri , Herrmann Nathan , Andreazza Ana C. , Verhoeff Nicolaas Paul L.G. , Gallagher Damien , Black Sandra E. , Lanctot Krista L. 
Published: December 2020

AbstractBackgroundBrain cholesterol metabolism, neuroinflammation, and oxidative stress are processes altered during Alzheimer’s disease (AD), which may impede endocannabinoid signaling, and thus worsen agitation. We assessed whether the brain cholesterol metabolite, cerebrocholesterol (Cchol), proinflammatory cytokine, tumor necrosis factor (TNF), and oxidative stress marker, 4‐hydroxynonenal (4‐HNE) were associated with agitation severity and response to nabilone.MethodSerum Cchol, TNF and 4‐HNE, were collected from AD patients enrolled in a 14‐week, double‐blind cross‐over trial comparing 6 weeks of nabilone to placebo, at the start and end of each phase. We assessed the relationship between agitation (Cohen Mansfield Agitation Inventory (CMAI)) and baseline (BL) biomarker levels; the relationship between change in agitation and BL biomarker levels within each phase; and the relationship between change in agitation and change in biomarker levels within each phase. Exploratory analyses included adjustments for BL cognition (Mini‐Mental Status Exam (MMSE)), and analyses with CMAI subtotals consistent with the International Psychogeriatric Association (IPA) definition for agitation.ResultSerum was collected from thirty‐eight participants (mean±SD age=87±10, 77% male, CMAI=68±18, MMSE=6.3±6.3). Cchol was not associated with CMAI cross‐sectionally or longitudinally, before and after adjusting for MMSE. However, BL Cchol was negatively correlated with BL CMAI IPA (F(1,36)=4.95, p=.03). In placebo only, lower BL Cchol was associated with increases in CMAI IPA (b=‐35.2, p=.02), and decreases in Cchol were associated with increases in CMAI IPA (b=‐20.94, p=.03). After adjusting for MMSE, BL TNF was positively correlated with BL CMAI (F(2,25)=3.69, p=.04), and predicted improvements in CMAI during nabilone only (b=‐1.14, p=.045). Decreases in TNF were associated with improvements in CMAI during nabilone only (b=1.12, p=.006). BL 4‐HNE was positively correlated with BL CMAI (F(1,35)=6.41, p=.02), and predicted worsening in CMAI during placebo only (b=0.01, p=.01). Changes in 4‐HNE were not associated with changes in CMAI in either phase.ConclusionCchol, TNF, and 4‐HNE may be markers of agitation severity in AD. Though neither Cchol nor 4‐HNE predicted response to nabilone and did not change over time with nabilone, these markers may be associated with changes in agitation severity. Findings with TNF suggest that this marker predicts treatment response, and decreases with nabilone treatment.
Higher digit ratio (2D:4D) associated with dementia in women
Authors: Jiang Joanne , Young Katherine , Pike Christian J 
Published: December 2020

AbstractBackgroundWomen have higher prevalence and risk for developing Alzheimer’s disease (AD) than men. The reason(s) underlying this sex difference in AD has not been definitively established but has been theorized to reflect sex‐specific patterns in age‐related depletion of sex steroid hormones, primarily the loss of estrogens in women. Not well considered is the possible role of developmental actions of sex steroids, which drive sexual differentiation of the brain. We investigated the hypothesis that early life differences in sex hormone exposure yield a female brain that is inherently more vulnerable to AD and related dementias.MethodRelative group differences in prenatal sex steroid hormone exposure were indirectly assessed by the ratio of the index (2nd digit) and ring (4th digit) fingers (2D:4D). The subjects were a community sample of non‐demented and demented men (N=66; 31 non‐demented, 35 demented) and women (N=73; 39 non‐demented, 34 demented) aged >65 years. Subjects’ right hands were scanned, finger length determined by caliper measurement, and 2D:4D calculated. Data were analyzed by two‐way ANOVA with sex and dementia status as the variables.ResultThere were no significant differences in age between men (age range: 65‐97 years; mean age=82.8 years) and women (age range: 65‐104 years; mean age=84.5). Men had a significantly lower mean 2D:4D than women (0.948 versus 0.964; p=0.006), which is expected since relatively higher androgen exposure in utero has been linked with lower 2D:4D. Among men, there was no significant difference in 2D:4D between non‐demented and demented subjects (0.954 versus 0.943; p=0.57). Importantly, women with dementia showed a significantly higher 2D:4D than non‐demented women (0.979 versus 0.951; p=0.005).ConclusionThe data demonstrate a higher (more feminine) 2D:4D in women with dementia in comparison to non‐demented women. Similar effects were not observed in men. These results suggest that developmental events that yield relatively more feminine phenotypes increase vulnerability of women to dementia. The findings support the hypothesis that the female bias in AD risk is due in part to developmental sex differences. (Support: RF1AG058068 [NIH] and SAGA‐17‐419408 [Alzheimer’s Association].)
Altered regional cerebral blood perfusion in mild cognitive impairment patients with dizziness
Authors: Im Jooyeon Jamie , Jeong Hyeonseok.s , Lee Eek‐Sung , Lee Tae‐Kyeong , Chung Yong‐An , Song In‐Uk , Na Seunghee 
Published: December 2020

AbstractBackgroundDizziness is a common symptom presenting with lightheadedness, vertigo, or disequilibrium. Previous studies reported that the prevalence of feeling dizziness is increased with age and chronic dizziness including vestibular vertigo and orthostatic hypotension may be associated with cognitive impairment and psychiatric illness. The aim of this study was to examine regional cerebral blood flow (rCBF) in mild cognitive impairment patients with or without dizziness using single‐photon emission computed tomography (SPECT).MethodA total of 50 patients with MCI were recruited. All participants underwent brain SPECT and completed the dizziness handicap inventory (DHI, 0‐100 points, higher scores indicating more severe handicap). Participants divided into a dizziness group (DHI ≥ 1, n = 18) and a non‐dizziness group (DHI = 0, n = 32).ResultThere were no significant differences between the two groups in terms of demographics. Patients with dizziness had a mean DHI score of 16.3 ± 14.6. SPECT analysis revealed decreased rCBF in the left superior temporal gyrus, left lateral orbital gyrus, and right middle frontal gyrus in patients with dizziness compared with those without dizziness. There were no significant clusters of increased rCBF in patients with dizziness compared with those without dizziness.ConclusionMCI patients with dizziness revealed frontal and left temporal hypoperfusion compared with the patients without dizziness. This finding is similar to those of the patients with persistent postural perceptual dizziness, the representative functional dizziness. Our result suggested that the altered rCBF in the left temporal and frontal cortices might be reflecting the negative impact of dizziness in patients with MCI.
Association of antihypertensive medications and Alzheimer’s disease neuropathology
Authors: Xu Chenjia , Apostolova Liana G. , Oblak Adrian L , Gao Sujuan 
Published: December 2020

AbstractBackgroundPrevious research has reported that antihypertensive medications are associated with reduced risk of Alzheimer’s disease (AD). The objective of this study is to determine the association between antihypertensive medication use and its subclasses of medications with AD neuropathological measures.MethodsAutopsy data were obtained from National Alzheimer's Coordinating Center (NACC). This analysis included data from 4,368 individuals. Braak stage for neurofibrillary degeneration, CERAD score for neuritic and diffuse plaques, and cerebral amyloid angiopathy were used as separate outcomes in proportional odds models. Vascular pathology, defined as the total of vascular conditions noted on autopsy forms was also used an outcome in proportional odds models. Any antihypertensive medication use and seven antihypertensive subclasses of medications (antiadrenergic agents, ACE inhibitors, angiotensin II inhibitors, beta‐blockers, calcium channel blocking agents, diuretics, and vasodilators) were independent variables in separate models for each neuropathological outcome while adjusting for age, sex, education, race and other vascular conditions (hypertension, heart disease, diabetes and stroke), blood pressure measures and APOE status.ResultsMean age at death for this sample was 80.6 (SD=11.6) and 54.0% were male. Sixty percent reported a history of hypertension, 91% of whom were on antihypertensive medications. Any antihypertensive medication use was associated with lower Braak stage of neurofibrillary tangles (proportional OR=0.82, p=0.0085) and lower cerebral amyloid angiopathy (OR=0.80, p=0.0063) while adjusting for demographic variables and other vascular conditions. Among antihypertensive subclass of medications, diuretics were associated with lower Braak stage (OR=0.71, p<0.0001), lower CERAD neuritic plaque density (OR=0.77, p=0.0007), lower CERAD diffused plaque (OR=0.74, p<0.0001), and cerebral amyloid angiopathy (OR=0.75, p<0.0001) while adjusting for demographic variables, other vascular conditions, blood pressure, and APOE. The associations between diuretics and lower pathological measures were unchanged after further adjusting for vascular pathology.ConclusionsAntihypertensive medication use is associated with decreased AD neuropathology in this large sample of individuals with autopsy. In particular, individuals on diuretics were associated with lower AD pathology after adjusting for blood pressure and APOE. This association appears to be independent of other vascular conditions and is not mediated by vascular neuropathology findings. The mechanism underlying these associations requires further investigation.
Exacerbation of tau pathology by pre‐existing amyloidosis in novel transgenic mice
Authors: Lewis Jada , Xu Guilian , Ulm Brittany , Howard John , Fromholt Susan , Borchelt David R. 
Published: December 2020

AbstractBackgroundNumerous mouse models have been created to recapitulation of AD pathology; however, mouse models featuring Aβ‐related transgenes and mutations has been imperfect, resulting in Aβ plaques, synaptic and other AD‐related changes, but failing to fully recapitulate the downstream tau pathology. Conversely, mouse models with mutant tau demonstrate neurofibrillary tangle formation and neurodegeneration, while failing to demonstrate amyloid β pathology. While we and others have created model systems in which APP and tau pathologies were driven by concurrent expression of amyloid and tau transgenes or through the use of proteinaceous seeds, those systems failed to test the age‐associated, sequential nature of amyloidosis, and tauopathy as is suggested by the amyloid cascade hypothesis. In the current study, we have introduced late stage tau expression onto a background of pre‐existing amyloidosis to determine if this accelerated the development secondary tauopathy.MethodWe crossed APPswe/PS1dE9 amyloidosis mice with rTg4510 conditional tauopathy mice to determine if inducing mutant human tau expression in aged brains of APPswe/PS1dE9/rTg4510 mice with pre‐existing amyloidosis accelerates “secondary” tauopathy. Mice were raised on doxycycline (to suppress transgenic tau expression) until ∼14 months of age, at which time transgenic tau expression was induced through the withdrawal of doxycycline in the diet. We evaluated the aggregation of phosphorylated tau and the activation of glia through immunohistochemistry.ResultWe found that inducing mutant tau expression at 14‐15 months of age, in a background of substantial amyloid deposition, produced robust tau pathology by 20‐21 months of age as compared to rTg4510 transgenic mice lacking the amyloid pathology. In the triple transgenic model, neurofibrillary tangle pathology was evident throughout the cortex and hippocampus. Unexpectedly, the level of glial activation between triple transgenic and APPswe/PS1dE9 mice was similar with no obvious increase by the combination of amyloid and tau pathology.ConclusionThese data demonstrate that pre‐existing amyloidosis can exacerbate tauopathy and highlights the utility of delayed tau expression in modeling the amyloid cascade hypothesis.
Development of [18F]SNFT‐1, a novel tau PET tracer with little off‐target binding
Authors: Ishiki Aiko , Harada Ryuichi , Lerdsirisuk Pradith , Yiqing Du , Michinori Ezura , Yanai Kazuhiko , Furumoto Shozo , Kudo Yukitsuka , Arai Hiroyuki , Okamura Nobuyuki 
Published: December 2020

AbstractBackground[18F]THK‐5351, which was originally designed to detect tau aggregates, bound to monoamine oxidase B (MAO‐B) with high affinity. Lead optimization toward selective binding profiles to tau has resulted in the development of novel selective tau PET tracer named [18F]SNFT‐1 (THK‐5562). Here we present the preclinical characteristics of this tracer.MethodIn vitro competitive binding assays against MAO‐A, MAO‐B, amyloid, and tau were performed. In vitro autoradiography of the human brain tissues of various neurodegenerative diseases was performed. Receptor panel screen was performed to confirm the binding selectivity of this compound. Biodistribution study was performed in mice. In addition, an acute toxicity with intravenous administration of a single dose of this compound in mice was also investigated.ResultSNFT‐1 showed high affinity (K
d = 0.47 nM) and selectivity for tau aggregates over other misfolding proteins as well as MAO enzymes. In vitro autoradiography demonstrated the intense laminar binding of [18F]SNFT‐1 to tau pathology in AD and less off‐target binding than currently available tau PET tracers. No remarkable binding inhibition on various receptors ion channels, and transporters was observed at 1 μM concentration. [18F]SNFT‐1 showed good initial brain uptake and rapid washout without defluorination and troublesome radiolabeled metabolites in mice. In acute toxicity study, no drug‐related changes were noted after intravenous administration of this compound in mice.Conclusion[18F]SNFT‐1 is highly selective tau PET tracer, which will enable accurate monitoring of abnormal tau pathology in AD brain.
Effect of disproportionately enlarged subarachnoid space hydrocephalus (DESH) on cognition
Authors: Cogswell Petrice M. , Weigand Stephen D. , Gunter Jeffrey L. , Graff‐Radford Jonathan , Jones David T. , Schwarz Christopher G. , Senjem Matthew L. , Knopman David S. , Petersen Ronald C. , Jack Clifford R. 
Published: December 2020

AbstractBackgroundDisproportionately enlarged subarachnoid‐space hydrocephalus (DESH), characterized by tight high convexity CSF spaces, ventriculomegaly, and enlarged Sylvian fissures, is thought to be an indirect marker of a CSF dynamics disorder. Although this imaging phenotype was originally described in normal pressure hydrocephalus (NPH), it has since been more widely recognized in the aging population with a prevalence of 6‐7% in the Mayo Clinic Study of Aging (MCSA) 1. The clinical significance of DESH with regards to cognitive decline outside of NPH is not yet well‐defined. The goal of this work is to determine if DESH is associated with risk of cognitive impairment.MethodParticipants in the population‐based MCSA who met the following criteria were included: age ≥ 65 years, 3T MRI, cognitively unimpaired at enrollment, and at least one follow‐up visit. A support vector machine based method to detect the DESH imaging features on T1‐weighted MRI was used to calculate “computational DESH” or CDESH scores2 (Figure 1). Cox proportional hazard models were fit with events defined as progression from cognitively unimpaired to mild cognitive impairment or dementia. Time was defined as years from MCSA enrollment to the first visit with cognitive impairment with censoring at last follow‐up. CDESH was modelled as a spline to allow for non‐linear effects. Covariates included age, sex, education, APOE status, cortical thickness, white matter hyperintensity (WMH) volume, and total intracranial volume.ResultParticipant demographics are summarized in Table 1. The model including the above co‐variates showed a significant CDESH effect (p=0.02) with an approximately 20% greater hazard of progression for a CDESH score of +1 versus −1 (HR 1.2, 95% CI 1.0‐1.4) (Figure 2).ConclusionImaging features of disordered CSF dynamics are an independent predictor of subsequent cognitive decline in the MCSA, among other well‐known factors including age, cortical thickness, and APOE status. Therefore, since DESH contributes to cognitive decline and is present in the general population, identifying individuals with DESH features may be important clinically and also used as a selection stratification variable for clinical trials. References: (1) Graff‐Radford et al doi:10.1212/WNL.0000000000008616; (2) N. Gunter et al doi:10.1016/j.nicl.2018.11.015.
Untangling neuropathological changes in a large clinicopathological population younger than 65: Correlations with clinical scores
Authors: Socher Karen L.R. , Rodriguez Roberta Diehl , Suemoto Claudia K. , Brucki Sonia M.D. , Leite Renata Elaine Paraizo , Ferretti‐Rebustini Renata Eloah de Lucena , Jacob‐Filho Wilson , Pasqualucci Carlos Augusto , Grinberg Lea Tenenholz , Nitrini Ricardo 
Published: December 2020

AbstractBackgroundClinical symptoms in early‐onset dementia occurs before than 65 years of age and represents around 10% of the dementia cases. The evidence of tau lesions in young individuals from nonselected autopsy studies supports that AD‐type pathology can start much earlier than previously thought. However, the majority of studies in dementia are focused in caucasians older than 60 years. Here we analyze demographics and neuropathological features of individuals between 30 to 65 years of age.MethodThe Biobank for aging studies has a unique collection of brain samples of a large mixed population spanning all AD‐Braak stages. To explore the presence of AD‐type pathology, we analyzed 275 younger individuals. All cases have a complete semistructured interview performed to obtain data about sociodemographic, lifestyle, past medical history, and cognitive and neuropsychiatric symptoms (NPS). Presence of cognitive impairment (CI) was defined according the Clinical Dementia Rating Scale (CDR≥0.5) and the Neuropsychiatric inventory was used to evaluate the presence of NPS. Internationally accepted neuropathological criteria were used for pathological staging and diagnosis.ResultThe mean age at death was 58 ± 5.4 years, 58% were men and 67.3% white. The mean education was 5.1 ± 4.1 years. High frequency of cerebrovascular risk factors such as hypertension (63.9%), smoking (58.5%) and alcohol intake (27.5%) was noted. Presence of CI was found in 22.5%, while some degree of NPS was noted in 59%. The most prevalent NPS was anxiety (25.5%) followed by appetite changes (24.4%). Some degree of cortical neurofibrillary tau pathology was observed in 53.5% (147), while neuritic plaques was found only in 9.5% (26). There were no significant differences in AD‐type pathology burden between individuals with and without CI. Vascular lesions were observed in 5.1% of all individuals, and those with CI and NPS showed more vascular pathology (p < 0.001 and <0.005 respectively). In addition, CI individuals had more history of alcohol abuse (p = 0.02), meanwhile the same association was not noted with the presence of NPS (p = 0.13).ConclusionIn younger individuals vascular pathology seems to play an important role in cognitive and neuropsychiatric symptoms. The high frequency of cerebrovascular risk factors highlights the importance of early prevention strategies.
Influence of social networks on Alzheimer’s disease biomarkers and subjective cognitive decline among elders without dementia: A CABLE study
Authors: Ma Ya‐Hui , Wang Ya‐Yu , Tan Lan , Yu Jin‐Tai , Xu Wei 
Published: December 2020

AbstractBackgroundThe social networks has been recommended as a moderator of incident Alzheimer’s disease (AD) and aggravated cognitive deficits. Still few data are available about the effect of social networks on cerebrospinal fluid (CSF) AD biomarkers.MethodParticipants without dementia were recruited from the Chinese Alzheimer’s disease Biomarker and Lifestyle (CABLE) study. Multiple‐adjusted analyses were performed to explore the association of social networks with CSF biomarkers, pre‐AD stage and subjective cognitive decline (SCD).ResultTotal eight hundred and twenty‐two individuals without dementia were included in current study. Moderate to high social network scores were significantly associated with CSF low levels of β‐amyloid (Aβ)40 (moderate, β=‐0.198; close, β=‐0.127), Aβ42/Aβ40 (moderate, β=0.227; close, β=0.184) and phosphorylated tau (p‐tau)/Aβ42 (moderate, β=‐0.106; close, β=‐0.1). In addition, moderate and high scores associated with low p‐tau (β=‐0.076) and total‐tau(t‐tau)/Aβ42 (β=‐0.111) respectively. Mostly significant associations of social network scores with biomarkers persisted in advanced age group, males and SCD group after stratified analyses. Moderate to high social network scores decreased risk for A+ (moderate:odds ratio (OR)=0.519, 95% confidence intervals (CI)=0.302‐0.890; high: OR=0.516, 95%CI=0.305‐0.874), A+T+ (moderate: OR=0.208, 95% CI=0.089‐0.488; high: OR=0.228, 95%CI=0.098‐0.528) and A+T+N+ (moderate: OR=0.144, 95% CI=0.055‐0.378; high: OR=0.141, 95%CI=0.054‐0.370)). In addition, close social ties and high social network scores decreased the risk of SCD (p < 0.05). There were no significant associations of moderate social ties and social network scores with SCD (p > 0.05).ConclusionSocial networks weaken the deleterious effect of AD neurodegenerative biomarkers. Furthermore, favorable influences of social networks on early neurobiological alterations of preclinical stage of AD and self‐reported SCD were suggested.