bluuebunny/crossref_metadata_2025_split huggingface dataset:
The CITIDEMAGE Study: Stressing the cholinergic hypothesis for the best outcomes in dementia patients
Authors: Gareri Pietro , Cotroneo Antonino Maria , Orsitto Giuseppe , Putignano Salvatore 
Published: December 2020

AbstractBackgroundCiticoline can have beneficial effects both in degenerative and in vascular cognitive decline; it works through an increase in acetylcholine intrasynaptic levels and by promoting phospholipid synthesis, (chiefly phosphatidylcholine), cellular function, and neuronal repair. Memantine is an N‐methyl‐D‐aspartate (NMDA) receptor antagonist used for the treatment of mild to moderate Alzheimer’s disease (AD). Acetylcholinesterase inhibitors (AchEIs) are widely used in AD patients. When co‐administered they could have a synergistic action in patients affected with AD and mixed dementia (MD) too. The aim of the present study was to show the effectiveness of oral citicoline plus AchEIs plus memantine in outpatients affected with AD.MethodThis was a retrospective study involving 4 centers in Italy between 2016 and 2018 on 169 patients aged 65 years old or older affected with AD (mean age 78.7± 4.9 years old). 84 patients were treated with AchEIs plus memantine plus citicoline 1g/day given orally (group A), 85 patients were treated with AchEIs plus memantine (group B). In both groups memantine and AchEIs were used at the highest dosage tolerated. The tests included MMSE, ADL and IADL, NPI, CIRS, GDS‐short form, the EuroQoL and the Sleep questionnaire. Tests were administered at baseline (T0), after 6 (T1), and 12 months (T2).The primary outcomes were the effects of combined treatment versus AchEIs plus memantine on cognitive functions assessed by MMSE.The secondary outcomes were the possible side effects or adverse events of combination therapy versus AchEIs plus memantine, the influence on daily life functions, behavioral symptoms, quality of life and sleep.ResultPatients of group A showed a mild increase in MMSE at six (15.85±2.86 vs 16.39±2.93) and 12 months (16.39±2.93 vs 16.43±3.08). The difference in MMSE score was significant when comparing the two groups, both at T1 (p=0.003) and T2 (p=0.011).There were also a significant improvement in GDS (p=0.000) and in EuroQoL scores (p=0.01).ConclusionThe present study encourages the role of combined treatment in disease management and for slowing down the progression of AD.
Impact of the presence of AβN3pE and AβpSer8 in Aβ aggregates on the induction of Aβ seeding and spreading in the brains of APP23 mice
Authors: Robberechts Tessa , Ronisz Alicja , Ospitalieri Simona , Koper Marta J. , Kumar Sathish , Walter Jochen , Willem Michael , Li Xiaohang , Thal Dietmar Rudolf 
Published: December 2020

AbstractBackgroundAmyloid β‐plaques are a hallmark lesion of Alzheimer’s disease (AD) and consist of aggregates of the amyloid β‐peptide (Aβ). Aβ peptides can undergo posttranslational modifications, including N‐terminal truncation with subsequent pyroglutamate formation at glutamate 3, and phosphorylation at serine 8, leading to the formation of AβN3pE and AβpSer8, respectively. These posttranslationally modified forms are present in the brain in addition to non‐modified Aβ. During disease development the composition of the Aβ aggregates changes from aggregates without detectable modified Aβ, in non‐demented individuals, into aggregates containing AβN3pE and AβSer8 in symptomatic AD cases. Brain‐derived Aβ aggregates are capable of inducing deposition and spreading of Aβ pathology when injected into the brain of APP‐transgenic mice. Therefore, the question arises whether the composition of Aβ aggregates has impact on its seeding capabilities as well as on the composition of the seeded Aβ plaques.MethodAPP23 mice were injected into the left hippocampus at two months of age. They received injections from three different brain homogenates. The first one lacked detectable Aβ (control), in a second homogenate only Aβ without detectable modifications was found (p‐preAD), and in the third homogenate both Aβ and AβN3pE were detected. Mice were sacrificed at six months and their brains were immunohistochemically analyzed for the presence and composition of the induced plaque pathology.ResultAPP23 mice injected with the AD or p‐preAD brain homogenates developed similar Aβ plaque loads and the plaques exhibited AβN3pE and AβpSer8 immunoreactivity. Mice receiving control brain homogenates developed very few plaques in the injected hemisphere, which were detectable with antibodies against Aβ and AβN3pE, but not with anti‐AβpSer8.ConclusionThe presence of Aβ seeds accelerates the accumulation of detectable amounts of AβN3pE and AβpSer8 and, thereby, promote the formation of fully mature Aβ aggregates similar to that seen in symptomatic AD patients. The acceleration of Aβ aggregate maturation, however, does not depend on the presence of posttranslationally modified Aβ forms in the seeds. Support: FWO.
Tau pathology mediates age effects on medial temporal lobe atrophy
Authors: Wisse Laura , Xie Long , Das Sandhitsu R. , De Flores Robin , Yushkevich Paul , Wolk David A. ,   the Alzheimer’s Disease Neuroimaging Initiative
Published: December 2020

AbstractBackgroundAge effects on the hippocampus are well established, but age‐effects on adjacent cortical regions less so. Moreover, aging has often been investigated using cross‐sectional designs, seldomly separating aging effects from the effects of β‐amyloid. We investigate the effect of aging on medial temporal lobe (MTL) subregions cross‐sectionally and longitudinally in β‐amyloid‐negative (A‐) cognitively normal (CN) older adults and the role of tau pathology, a potential mediator.MethodT1‐MRI scans of 191 A‐ CN adults (71.7±6.0 years, 52.4% male) from ADNI‐GO/2 were segmented using a specialized method for MTL morphometry to obtain anterior/posterior hippocampus volumes, entorhinal cortex (ERC), Brodmann areas (BA) 35/36 and parahippocampal cortex thickness. Annualized atrophy rates were estimated with an unbiased deformation‐based morphometry method using follow‐up MRI scans within 2.1±0.1 years. All MTL subregions were corrected for sex and hippocampal volume also for intracranial volume. Cerebrospinal fluid levels of phosphorylated tau (p‐tau) were logtransformed. β‐amyloid status (A+/‐) was determined using a standard cutoff for amyloid PET.ResultCross‐sectionally age was significantly associated with hippocampal volumes and BA35 (Figure 1‐2). Longitudinally, MTL subregions showed atrophy rates significantly smaller than 0, and paired t‐tests revealed a significantly faster atrophy rate for BA35 than the other cortical regions (Figure 1). Older age was associated with increased atrophy rates in hippocampal volumes, ERC and BA35 (Table 1, Figure 3). A significant association was found for p‐tau levels with anterior and posterior hippocampus (trend) and with anterior and posterior hippocampal atrophy rates (Figure 4), which remained similar after a correction for age. Since the association for anterior/posterior hippocampus was similar, we performed a mediation analysis for total hippocampus, showing that aging leads to smaller hippocampal volumes (p<0.05) and faster hippocampal atrophy rates (p<0.10) through higher p‐tau levels (Figure 5), while covarying for β‐amyloid levels.ConclusionThe cross‐sectional age effects on the MTL roughly matched longitudinal atrophy rates in A‐CN older adults, with most pronounced atrophy in the hippocampus and BA35, early sites of neurofibrillary pathology. The mediation analyses further supported an important role for tau pathology suggesting that Primary Age‐Related Tauopathy may partly mediate the observed age effects on the MTL.
Semantic impairment in very early Alzheimer disease
Authors: Liu Yi‐Chien ,   CTH MCI Research Group
Published: December 2020

AbstractBackgroundComparing to episodic memory, semantic memory is less likely to be impaired in normal aging. Investigation of semantic memory may give us a better chance on detecting Alzheimer disease in early stage.MethodIn 2019, we collected 20 patients from our memory clinic. Half of them were diagnosed as amnesic MCI (mild cognitive impairment), half of them were their spouse. All of them received amyloid PET (florbetaben), brain MRI, ERP (evoked related potential) studies and detailed language evaluation. According to their clinical symptoms and status of amyloid deposition, they were grouping as normal, preclinical and prodromal stage.ResultIn picture description test, participants of prodromal group expressed fewer semantic contents and more filler words compared to others. No significant difference was found between preclinical and normal group. However, N400 (component of ERP, indicating semantic mismatch) showed difference between preclinical and normal group.ConclusionSemantic network impairment begins from preclinical stage of AD. Through detailed spoken language analysis, we could use it as early biomarker and trace disease progression.
Multimorbidity as a correlate of dementia among older people in Central Africa: The EPIDEMCA study
Authors: Guerchet Maëlenn M , Gbessemehlan Antoine , Mbelesso Pascal , Bandzouzi Bebene Ndamba , Yaffe Kristine , Clement Jean‐Pierre , Dartigues Jean‐François , Preux Pierre‐Marie ,   EPIDEMCA
Published: December 2020

AbstractBackgroundWith global ageing, multimorbidity becomes a priority for global health research. Multimorbidity prevalence increases with age and is associated with poorer health outcomes. As people live longer, chronic conditions, including dementia, are rising in low‐ and middle‐income countries (LMIC) but the relationship between multimorbidity and dementia is not well studied despite its importance for dementia prevention. The aim of this study is to investigate the association between multimorbidity and dementia among older people in Central African countries.MethodsA multicentre population‐based study was carried out in Central African Republic and Republic of Congo between 2011 and 2012 including both urban and rural sites. Participants aged ≥65 years old were interviewed using a structured questionnaire (sociodemographic data, clinical history) and underwent a physical examination. Multimorbidity (ie. the presence of two or more chronic diseases in the same individual) was ascertained as a count of up to 12 mental, cognitive and physical health conditions. Conditions were either collected through self‐report or assessed during the physical exam. DSM‐IV criteria were required for dementia diagnoses. The association of multimorbidity with dementia was assessed using logistic regression models.ResultsAt baseline, 2002 participants were included across the two countries (mean age 73.3 ± 6.7 years, sex‐ratio M/F = 0.62) and 135 were diagnosed with dementia. Overall 55.3% of the participants had 2 or more chronic diseases, with hypertension, depression, heart disease, pulmonary conditions, and visual impairment as the most common comorbidities. A higher prevalence of multimorbidity was found in Congo than in Central African Republic. Dementia was significantly associated with the presence of multimorbidity (OR=1.45, 95%CI 1.01‐2.00), however the effect disappeared after adjustment on age, sex and study site. There was a non‐significant trend of greater odds of dementia with an increasing number of comorbidities.ConclusionsThe results support a high prevalence of multimorbidity among these older populations, especially among people with dementia. However, odds of dementia seemed to not be significantly impacted by multimorbidity in this context. Due to its high prevalence and low access to healthcare, this evidence remains of importance for medical care of comorbidities in older populations of sub‐Saharan Africa.
Impact of disease severity on quality of life, activities of daily living, and medical costs for people living with dementia in Japanese nursing home
Authors: Ashizawa Takumi 
Published: December 2020

AbstractBackgroundJapan has the highest proportion of elderly aged 65 and over in the world, which accounts for 28.1% in 2018, and expected to reach 30.0% in 2025 and over 20% of those will suffer from dementia. This study aimed to evaluate the impact of severity of dementia on quality of life (QoL), activity of daily living (ADL), medical costs and caregiving costs in Japan.MethodPeople living in nursing home under the Life Company Limited (N=2,114) were enrolled. Their QoL, ADL, and the severity of dementia were assessed by staff working in the facilities by using Euro‐QoL 5 dimension (EQ‐5D), Barthel Index (BI) and Mini‐Mental State Examination (MMSE), respectively. The medical and caregiving costs were derived from payment records and claim data between December 2018 and September 2019, respectively. All participants were sub‐categorized by MMSE score into three dementia groups of mild (21≦MMSE≦30), moderate (11≦MMSE≦20), and severe (0≦MMSE≦10). All results were assessed by using Shirley‐Williams test.ResultSurvey was conducted on Mar. 2019 and 1,491 people completed the entire questionnaires, of which, 592 used medical cares and 1,424 records for caregiving activities. Using MMSE scores, 561 were classified to mild group with mean age (SD) 84.9±8.7 years old and 67.7% accounted for women, 491 to moderate (87.3±6.9y, 73.9%) and 439 to severe (87.4±7.7y, 73.1%). Mean EQ‐5D scores for three groups were 0.75, 0.63 and 0.40, respectively. Mean BI scores were 78.5, 62.4, and 24.9, respectively. Significant decrements for both EQ‐5D and BI scores were observed for severe against mild or moderate groups. Annual out‐of‐pocket medical costs were not statistically differed by severity, or JPY11,445, 12,548 and 10,764 for mild, moderate and severe patients, respectively(not significant), while annual caregiving costs were increased as dementia becomes severer, or JPY2.1Mil, 2.4Mil and 2.8Mil for mild, moderate and severe patients, respectively (p<0.05)ConclusionSeverity of dementia significantly impairs QoL and ADL, as observed from score decrements in EQ‐5D, BI and caregiving costs when severity worsened, while no significant difference was observed for medical costs.
iPSCs from Alzheimer’s disease patients display neuronal differentiation impairment of neural progenitor cells
Authors: Le Weidong 
Published: December 2020

AbstractBackgroundAlzheimer’s disease (AD) is the most common age‐related dementia associated with progressive neuronal loss. However, the cause of the disease is still unknown. Induced pluripotent stem cells (iPSCs) derived from somatic cells of AD patients provide unique opportunities to model the early development of AD.ObjectiveThe objective of this study is to use iPSCs system to determine the molecular mechanisms of neuronal loss in AD.MethodsWe used iPSC lines generated from fibroblasts of two familial AD (FAD) patients with autosomal dominant mutations in presenilin 1 (PSEN1) (S169del) or (A246E). We characterized the AD‐iPSCs characteristic properties of human pluripotent stem cells and differentiate them into functional neurons.ResultWe found abnormally enhanced neuronal differentiation in AD iPSC‐derived neural progenitor cells (AD‐NPCs), and a reduction in the number of NPCs in AD‐NPCs during differentiation. Consistently, we detected a decreased proliferation and an increased apoptosis in differentiating AD‐NPCs. In addition, we identified the same phenotypes when PSEN1 with the mutation of A246E was introduced into control iPSCs. Furthermore, knockdown of mutated PSEN1 in AD‐NPCs significantly attenuated the premature neuronal differentiation. Our results suggest that PSEN1 mutation causes reduction in the NPC pool, which might be relevant to the neuronal loss in the brain of AD patients. Additionally, our genome‐wide transcript analyses identified differentially expressed genes relevant to neuronal differentiation and cell cycle in differentiating AD‐NPCs.ConclusionCollectively, our study uncovers previously unappreciated early NPC dysfunctions in FAD‐NPCs and provides new cues to elucidate molecular mechanisms underlying AD development.
U.S. POINTER Imaging: Study design and launch
Authors: Lockhart Samuel N. , Baker Laura D. , Carrillo Maria C. , DeCarli Charles , Espeland Mark A. , Harvey Danielle J. , Jack Clifford R. , Jagust William J. , Jung Youngkyoo , Koeppe Robert A. , Lovato Laura , Snyder Heather M. , Toga Arthur W. , Vemuri Prashanthi , Woolard Nancy , Landau Susan M. ,   the U.S. POINTER Study Group
Published: December 2020

AbstractBackgroundRecent studies suggest that lifestyle changes (physical exercise, Mediterranean diet adherence, cognitive stimulation, vascular risk management) may protect against cognitive decline and reduce AD pathophysiology. The U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) is a 2‐year randomized controlled trial to evaluate whether lifestyle interventions can protect cognitive function in older adults (60‐79 years) who are at increased risk for cognitive impairment and dementia. The POINTER Imaging ancillary study will assess effects of the POINTER lifestyle interventions on neuroimaging biomarkers of AD and cerebrovascular pathophysiology, and whether baseline neuroimaging measures predict cognitive responses to the interventions.MethodThe POINTER Imaging ancillary study aims to enroll 1250 participants from the five U.S. POINTER sites. Ancillary study participants will undergo PET imaging (Baseline, Month 24) to measure Aβ ([18F]Florbetaben) and tau ([18F]MK‐6240) burden, and MRI (Baseline, Months 12 & 24) to measure brain morphometry, white matter (WM) hyperintensities and microstructure, and cerebral blood flow. U.S. POINTER provides standardized cognitive, clinical, genetic (e.g. APOE), and lifestyle activity assessments, and demographics for integration with neuroimaging data.ResultThe study design and methods for the POINTER Imaging ancillary study will be presented. The study will examine whether: (1) neuroimaging biomarkers at baseline (Aβ, tau, hippocampal volume, WM hyperintensities) predict intervention‐related cognitive changes and (2) biomarker outcomes are differentially modified by participation in lifestyle interventions. It will also examine changes in exploratory biomarkers (tensor‐based morphometry, microstructural integrity, microbleeds, cerebral blood flow).ConclusionThe POINTER Imaging study aims to address gaps in our understanding of how a variety of lifestyle practices (diet, exercise, cognitive stimulation and vascular risk management) influence brain health. In particular, the study will determine whether imaging measurements of AD and cerebrovascular pathophysiology are amenable to improvement with the POINTER lifestyle interventions. It also aims to determine pathological profiles of individuals who benefit most from such interventions.
Severe systemic inflammation promotes persistent brain metabolic abnormalities
Authors: Bellaver Bruna , da Silva Eduarda J.F. , da Rocha Andreia Silva , Ferreira Pamela C.L. , Fontella Fernanda U. , Vasconcellos Alessandra Amaral , das Ros Lucas U. , Venturin Gianina Teribele , Greggio Samuel , da Costa Jaderson Costa , Souza Diogo O. , Zimmer Eduardo R. 
Published: December 2020

AbstractBackgroundSevere systemic inflammation can spread to the central nervous system, promoting neuronal dysfunction. Individuals who survive to a severe inflammatory episode, have greater chances to develop cognitive impairment. In this context, brain inflammatory changes have been considered a risk factor for Alzheimer’s disease (AD). We previously demonstrated, a significant [18F]FDG hypometabolism 24 h after the induction of severe systemic inflammation by cecal ligation and perforation (CLP), a sepsis model. However, whether severe systemic inflammation causes long‐term effects on brain energy metabolism remains unclear. Here, we aim at Investigating persistent consequences of a severe systemic inflammatory episode on brain energy metabolism. We hypothesized that brain energetic metabolism does not completely recover from a systemic inflammatory episode, which could be a trigger for neurodegeneration.MethodWistar rats (90 days old) were submitted to CLP and, examined in vivo via Micro‐PET [18F]FDG imaging 30 days later. Albumin and cellularity in the cerebrospinal fluid (CSF) were assessed by HPLC and flow cytometry, respectively, as an index of blood brain barrier (BBB) integrity. HPLC was also used for evaluating glutamate levels in CSF and glutamate uptake was evaluated in hippocampal and cortical slices using a radioactive assay.ResultWe found a persistent brain [18F]FDG hypometabolism in the CLP group. A 4‐fold increase in albumin levels was observed, along with a prominent increase in cellularity in the CSF of CLP animals. Additionally, decreased glutamate uptake in cortex (32%) and hippocampus (16%) along with increased levels of glutamate in CSF was found in the CLP group (Figure 1).ConclusionThese results that an episode of severe systemic inflammatory causes persistent brain metabolic disturbances and BBB damage. It is very likely that the long period of BBB disruption, allowing for communication between peripheral mediators/cells and the brain, compromises brain energy metabolism. Together, these findings suggest a link between peripheral inflammation and neurodegeneration.
Repetitive negative thinking is associated with subjective cognitive decline in older adults
Authors: Schlosser Marco , Demnitz‐King Harriet , Whitfield Tim , Marchant Natalie L. 
Published: December 2020

AbstractBackgroundSubjectively experienced cognitive decline (SCD), particularly when accompanied by worries, has been associated with an increased risk for dementia. Repetitive negative thinking (RNT) is a transdiagnostic process that manifests across several mental health disorders previously associated with increased vulnerability to dementia. RNT has thus been proposed as a candidate psychological risk factor for dementia and, relatedly, could contribute to the manifestation of SCD.MethodIn a cross‐sectional online survey, 491 older adults (mean age = 64.9 years) completed measures of RNT and other theoretically informed psychological risk/protective factors for dementia, namely, personality (including neuroticism), purpose in life, worry, rumination, and meditation practice. SCD was assessed continuously via the Cognition Function Short Form and categorically via endorsement (yes/no) of worries about memory.Regression models, using a stepwise backwards elimination, were built to assess associations between SCD and all psychological risk and protective factors. Final prediction models retained all explanatory variables associated with SCD at p < 0.01. Age, sex and education were retained in all models.ResultRNT was the only psychological variable associated with SCD (SE = ‐0.52; 95% CI: ‐0.59 to ‐0.44; p<0.001), with higher RNT levels associated with worse self‐perceived cognitive function. A total of 16.1% of participants reported feeling worried about their memory. RNT was the only variable associated with worries about memory (OR = 2.20; 95% CI: 1.70 to 2.86; p<0.001).ConclusionThis study empirically corroborates the theoretical relationship between SCD and RNT. SCD is a relatively newly defined clinical stage, and thus requires more research to better understand the clinical characteristics of the group. SCD has been associated with elevated anxiety and neuroticism (Jessen et al., 2014), but we show that neither worry (a core symptom of anxiety) nor neuroticism add explanatory power to predict SCD symptoms over and above RNT. The relationship between RNT and SCD therefore appears not to be based on the time orientation of negative thoughts (worry being future‐directed and RNT time‐independent). RNT, whether it be a prodromal symptom or independent risk factor, is a promising marker of dementia risk given its association with SCD.