bluuebunny/crossref_metadata_2025_split huggingface dataset:
Functional alterations in visual networks underlie differences in the phenomenology of visual hallucinations in Lewy body disease
Authors: D'Antonio Fabrizia , Boccia Maddalena , Di Vita Antonella , Canevelli Marco , Fabbrini Andrea , Leodori Giorgio , Caramia Francesca , Ferracuti Stefano , Guariglia Cecilia , de Lena Carlo , Aarsland Dag , Ffytche Dominic H. 
Published: December 2020

AbstractBackgroundThe phenomenology of visual hallucinations (VH) in Lewy Body Disease (LBD) is heterogenous including minor phenomena (passage, presence, illusions) and complex hallucinations. Underlying mechanisms are largely unknown and here we investigated whether distinct neural networks underpin minor (MVH) and complex VH (CVH).MethodLBD patients (n=17 DLB, n=10 PDD; mean age=76.5±6.5; mean MMSE=20.2±5.7, male=16; 59.2%) with VH underwent resting state fMRI and the North East Visual Hallucinations Interview (NEVHI) to assess the phenomenology, duration and frequency of VH. Using multiple regression models, we performed a seed‐to‐seed functional connectivity (FC) analysis to identify specific nodes associated with i) duration, ii) frequency and iii) severity of MVH (controlling for CVH and MMSE) or CVH (controlling for MVH and MMSE).ResultThe severity, frequency and duration of MVH was negatively associated with FC between early visual areas (EVA) and regions of the ventral visual stream, and positively associated with FC between EVA and regions of the dorsal visual stream that may reflect the phenomenology of passage and presence. Furthermore, the duration of MVH was negatively associated with FC between the brainstem and EVA that may be linked to LBD brainstem neuropathology and positively associated with FC between areas of the dorsal visual stream (Table 1). The severity and duration of CVH was negatively associated with FC between areas of the ventral visual stream and positively associated with FC between lingual gyrus and supramarginal gyrus, within the salience network, that may relate to the complexity of the hallucination content. The frequency of CVH was negatively associated with FC between areas of the default mode network and the salience network (i.e. supramarginal gyrus) that may reflect attentional dysregulation (Table 2).ConclusionFunctional alterations in distinct visual and attentional networks underpin VH in LBD according to their phenomenology, showing a greater involvement of the brainstem and dorsal visual stream for MVH, and of the ventral visual stream and attentional networks for CVH. These findings can be interpreted according to the hodotopic hypothesis of VH (ffytche et al. 2008) and may reflect a link between VH phenomenology and the neuropathological progression of Braak stage (ffytche et al. 2017).
Encapsulated cell biodelivery of NGF (ECB‐NGF) for AD therapy has implications from astroglial activation and amyloid‐beta toxicity
Authors: Mitra Sumonto , Turchetto Silvia , Wahlberg Lars , Linderoth Bengt , Behbahani Homira , Eriksdotter Maria 
Published: December 2020

AbstractBackgroundAlzheimer’s disease (AD) is a progressive neurodegenerative disorder characterised by loss of cholinergic neurons in the basal forebrain (BFCN). Mature Nerve growth factor (mNGF) is required for the survival of BFCN’s, but since it cannot cross blood‐brain barrier (BBB), its tissue targeted delivery via encapsulated cell biodelivery (ECB‐NGF) device has been envisaged as a potential therapeutic strategy. In our previous first‐in‐human studies, we observed some inter‐capsule differences in mNGF release among ECB‐NGF devices, when implanted in human AD patients. To address this issue, we pursued whether amyloid‐beta (Ab40/42) peptides directly or indirectly (by activating astroglial cells) can affect the NGF‐delivering (NGC‐0211) cells.MethodWe tested direct or astrocyte‐mediated (indirect) effect of Ab40 and Ab42 on the NGC‐0211 cells in‐vitro. To study the astrocyte‐mediated effects of Ab peptides, human primary astrocytes were first incubated with Ab peptides and the conditioned medium was further transferred on NGC‐0211 cells. Effects on cell survival (flowcytometry), stress markers (spectrophotometric measurements), cell proliferation (immunocytochemistry) and NGF release (ELISA) were monitored.ResultWe report that Ab‐peptides induced marginal effects on cell survival and NGF release upon direct and indirect stimulation. Astrocyte conditioned media partially modulated biochemical parameters. In both cases of stimulation method, cell proliferative ability of NGC0211 cells was significantly hampered.ConclusionOur data suggests that the survival of the NGC‐0211 cells is not affected by Ab peptides, whereas their proliferation was significantly hampered, directly as well as through astroglial activation. Overall, NGF release was not affected negatively under the conditions and time points tested in this study. This study lays the foundation for further optimization of ECB‐NGF devices for future AD therapy.
Low blood amylin delays Alzheimer’s pathology by modulating brain hypoxia and amyloid composition: A study in humans and rats
Authors: Despa Florin 
Published: December 2020

AbstractBackgroundDecreased amyloid‐β (Aβ)42 level in the cerebrospinal fluid (CSF) reflects Aβ42 accumulation in cerebral plaques and is a biomarker for Alzheimer’s disease (AD). Histopathological analyses of brain tissues from individuals with sporadic AD showed that Aβ forms mixed deposits with the pancreatic amylin, a satiety hormone. Here we show that high blood amylin modifies CSF‐brain Aβ balance and brain amyloid composition in both sporadic AD and in PSEN1 and APP mutation carriers (familial AD), and that pancreatic hypersecretion of amylin in AD and non‐AD model rats accelerates behavioral deficits, whereas suppression of amylin expression is protective.MethodWe investigated the relationship between amylin and Aβ42 levels in CSF from humans with early vs. late stage sAD, and between amylin and the brain in PSEN1 and APP mutation carriers, as these mutations have known biochemical effects on AD pathology; experiments in rats and cell models were used to define the mechanism. Specifically, we created transgenic AD and non‐AD rat models in which the consequences of elevated blood levels of human amylin can be directly addressed in terms of CSF‐brain Aβ balance, blood‐brain barrier (BBB) permeability to amylin, development of AD pathology and behavior deficits. To further test the mechanism, we intravenously injected human amylin in AD rats that express rat amylin. AD rats with the amylin gene deleted were generated to test effects of suppression of amylin secretion on AD pathology‐associated neurological score.ResultWe found that high circulating levels of amylin disrupts CSF‐brain Aβ balance via amylin‐Aβ cross‐seeding. Pancreatic hypersecretion of amylin in rats induced brain hypoxia signaling by amylin deposition in brain capillaries that altered neuronal metabolic pathways leading to increased Aβ synthesis and deposition in the brain. Similar mechanisms were triggered by intravenous injection of human amylin in rats. Amylin hypersecretion in APP/PS1 rats lowers neurologic score, whereas amylin gene deletion delays the development of AD pathology and behavioral changes.ConclusionOur results provide evidence of a role of amylin in modulating brain hypoxia and amyloid composition in both familial and sporadic forms of AD, and suggest that blood amylin may be a therapeutic target for early AD stage.
Barriers to dementia diagnosis in India: Effect of education, dementia subtype and age at onset
Authors: Ellajosyula Ratnavalli , Narayanan Jwala 
Published: December 2020

AbstractBackgroundEarly diagnosis in dementia is crucial for management but there is usually a time lag between symptom onset and dementia diagnosis. The prevalence and factors associated with delay in seeking help for people with dementia in India is unknown.MethodConsecutive patients with dementia (n=924) seen at a memory clinic were enrolled in the study after informed consent. All patients underwent a standard clinical assessment, neuropsychological tests and neuroimaging. The main outcome variable was time from symptom onset to diagnosis (TTD). The effect of age, education, early onset (EOD‐<65 years) and late onset (LOD‐>65 years), dementia subtype, and gender on TTD were examined using a general linear model.ResultThe mean age of the whole group was 70.15(9.1) years and the mean TTD was 32.2 (26.6) months. There was a significant effect of age at onset (EOD 37.2 months vs LOD 27 months), education [(0‐4 years‐37.9 months) vs (5‐12 years ‐27.42 months)] and dementia subtype. Patients with vascular dementia (25.4months) and dementia with Lewy bodies (23.5 months) presented earlier as compared to patients with Alzheimer’s disease (33.4 months) and Frontotemporal dementia (36.8 months).ConclusionPeople with dementia in India are diagnosed much later, approximately 3 years after symptom onset as compared to other Western and Asian studies (1‐2 years). Clinical features and low education may be barriers to seek help for dementia diagnosis.
Amyloid aggregation and subsequent memory decline over time in cognitively intact older identical twins
Authors: Tomassen Jori , den Braber Anouk , Yaqub Maqsood , Mulder Sandra D. , Teunissen Charlotte E. , Van Berckel Bart N.M. , Boomsma Dorret I. , Scheltens Philip , Tijms Betty M. , Visser Pieter Jelle 
Published: December 2020

AbstractBackgroundOlder individuals with intact cognition and pathological amyloid depositions are at increased risk for memory decline. At this point the precise biological processes leading to cognitive decline are unclear. We tested the role of genetic influences on the relationship between amyloid pathology and subsequent memory decline over time using a monozygotic twin approach, and whether these relationships were dependent on the methodology used to determine amyloid aggregation.MethodWe selected 78 monozygotic twins with at baseline normal cognition from the EMIF‐AD PreclinAD study (Table 1), who had completed 4 years of follow‐up. We defined baseline amyloid status using either visual read of dynamic [18F]flutemetamol PET images or CSF amyloid‐β 1‐42/1‐40 (Aβ42/40) ratio (ADx Neurosciences/Euroimmun assays) <0.066 (based on Gaussian mixture modelling). Memory was tested at baseline, 2‐year and 4‐year, with six tests combined into one composite score. Associations between baseline amyloid status and subsequent decline on memory was tested using linear mixed models with main effect amyloid status, time and amyloid*time, adjusted for age, sex, education and genetic relatedness. We repeated analyses taking continuous CSF Aβ42/40 ratio and PET binding potential (BPND) values as predictors. To examine the role of genetic influences on observed associations we performed cross‐twin cross‐trait analysis.ResultNine individuals had abnormal Aβ at baseline and did not differ in age, sex and education from Aβ‐ subjects. They had a faster decline in memory than Aβ‐ subjects (ß=‐0.127(SE=0.041), pamyloid*time=0.002, Figure 1). Continuous measures of amyloid burden also predicted memory decline at follow‐up (CSF Aβ42/40 ratio ß=0.055(SE=0.016), PET BPND ß=‐0.040(SE=0.014), both p<0.005). Baseline CSF Aβ42/40 ratio in one twin could predict memory decline in its co‐twin (r=0.31,p=0.04), which suggests similar genetic factors underlie these processes, however this relation did not reach significance when using amyloid‐PET BPND (r=‐0.12,p=0.35).ConclusionIn our study CSF Aβ42/40 ratio was more sensitive for detecting early pathophysiological changes compared to PET BPND. A larger sample is needed to confirm this finding. Our twin approach suggests that in preclinical AD amyloid burden and memory performance may share common genetic pathways. The next step will be to identify what these underlying shared biological mechanisms are.
Late‐onset epilepsy with unknown etiology: A pilot study on neuropsychological profile, cerebrospinal fluid biomarkers, and quantitative EEG characteristics
Authors: Farotti Lucia , Cesarini Elena Nardi , Babiloni Claudio , Salvadori Nicola , Percio Claudio Del , Pascarelli Maria Teresa , Noce Giuseppe , Lizio Roberta , Da Re Fulvio , Isella Valeria , Tremolizzo Lucio , Romoli Michele , Francesco Jacopo C Di , Parnetti Lucilla , Costa Cinzia 
Published: December 2020

AbstractBackgroundDespite epilepsy has been associated with cognitive decline, neuropsychological, neurobiological and neurophysiological features in patients with late‐onset epilepsy of unknown etiology (LOEU) are still unknown. This cross‐sectional study aims at investigating neuropsychological profile, cerebrospinal fluid (CSF) biomarkers of Alzheimer’s disease (AD), and resting‐state quantitative electroencephalographic (qEEG) cortical rhythms in LOEU patients with mild cognitive impairment (LOEU‐MCI) and with normal cognition (LOEU‐CN), compared to non‐epileptic MCI (NE‐MCI) and cognitively normal (CN) controls.MethodConsecutive patients in two clinical Units diagnosed with LOEU‐CN (19), LOEU‐MCI (27), and NE‐MCI (21) were enrolled, and compared to age and sex‐matched cognitively normal subjects (CN, 11). Patients underwent standardized comprehensive neuropsychological evaluation and CSF core AD biomarkers assessment (i.e., CSF Aβ42, phospho‐tau and total tau, classified through A/T/(N) system). Recordings of resting‐state eyes‐closed electroencephalographic (EEG) rhythms were collected and cortical source estimation of delta (<4 Hz) to gamma (>30 Hz) bands with exact Low Resolution Electromagnetic Tomography (eLORETA) was performed.ResultMost of LOEU patients had MCI status at seizure onset (59%). Patients with LOEU‐MCI performed significantly worse on measures of global cognition, visuo‐spatial abilities and executive functions compared to NE‐MCI patients (p<0.05). Regarding MCI subtype, multiple‐domain MCI was 3‐fold more frequent in the LOEU‐MCI than in the NE‐MCI patients (OR 3.14, 95%CI 0.93‐10.58, p=0.06). CSF Aβ42 levels were lower in the LOEU‐MCI compared with the LOEU‐CN group. Finally, parietal and occipital sources of alpha (8‐12 Hz) rhythms were less active in the LOEU‐MCI than NE‐MCI and CN groups, and the opposite was true for frontal and temporal cortical delta sources.ConclusionMCI status was relatively frequent in LOEU patients, involved multiple cognitive domains, and might have been driven by amyloidosis according to CSF biomarkers. LOEU‐MCI status was associated with abnormalities in cortical sources of EEG rhythms related to quiet vigilance. Future longitudinal studies should cross‐validate our findings and test the predictive value of CSF and EEG variables.
Long‐term dietary intervention adherence among individuals with elevated risk of dementia: The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER)
Authors: Lehtisalo Jenni , Lindstrom Jaana , Ngandu Tiia , Solomon Alina , Laatikainen Tiina , Strandberg Timo , Antikainen Riitta , Tuomilehto Jaakko , Hänninen Tuomo , Soininen Hilkka , Kivipelto Miia ,   FINGER Study Group
Published: December 2020

AbstractBackgroundFinnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) is a multi‐center, randomized trial that showed beneficial effect on cognition with a multi‐domain lifestyle intervention including nutritional guidance. The aim here is to investigate how dietary changes are maintained after the active intervention period, and if baseline cognitive performance modifies the intervention effect.MethodIndividuals aged 60‐77 years and at risk of dementia were randomly allocated into intervention (n=631) or control (n=629) group for 2 years, with post‐intervention follow‐up visit at 5 and 7 years. Neuropsychological Test Battery was executed and a z‐score for global cognition calculated (14 tests). Three food records during the intervention and one at 7 years were used to calculate FINGER dietary adherence score based on national recommendations (9 goals, higher indicating better adherence). A linear mixed model was used to evaluate association between dietary change, group allocation and baseline cognition dichotomized at the median, adjusting for age, education, sex, study area, BMI, and total energy intake.ResultAltogether 783 participated at the 7‐year visits. Better baseline cognition predicted 7‐year participation (p<0.01) and food record completion (p<0.01), which was lower than at earlier visits (73%; n=572). Dietary quality improved more in the intervention group compared with the control over the 7‐year period (p<0.01). Baseline cognitive function did not modify the intervention effect on diet during the first years of the study (p<0.05 for the intervention effect in both cognition groups at the 1st and the 2nd year, respectively). On longer term the interaction between baseline cognition and intervention group became significant (p=0.03 at the 7‐year follow‐up), and the intervention effect was especially seen with lower baseline cognition. Dietary quality declined only in the control group participants with lower baseline cognition.ConclusionThe FINGER dietary intervention showed that beneficial dietary changes are achieved by older individuals and also maintained after the active intervention period. These results indicate that while dietary changes during the intervention are achieved regardless of baseline cognition, people with lower baseline cognition may benefit more in long term, because their dietary quality is more likely to worsen without an intervention.
Looking at competing events through a different lens in dementia research: Examples from the Rotterdam Study
Authors: Rojas‐Saunero Liliana Paloma , Ikram M Arfan , Swanson Sonja 
Published: December 2020

AbstractBackgroundOur ability to both ask clear questions and obtain clear answers in dementia research is always challenged by the competing risk of death. For example, we might ask at least two questions: (1) what is the risk of dementia, regardless of risk of death, and (2) what is the risk of dementia if we were able to prevent death during the study period? We aim to demonstrate estimating these quantities in three comparisons: higher vs. lower education, women vs. men, and apoe4 carriers vs non‐carriers.MethodWe used data from individuals over 55 years with no prior history of dementia or cognitive impairment within the Rotterdam Study, a population‐based cohort followed since 1990. To estimate risk of dementia we used inverse probability weighting (IPW) for lost to follow‐up (LTFU) to answer question (1), and for the risk of death, and IPW for death and LTFU for question (2), with our models including time‐updating covariates (systolic blood pressure, body max index, smoking status, development of heart disease, diabetes and cancer). We calculated the risks at each time‐point using pooled logistic regression.ResultOver 20 years of follow up, 4869 individuals where followed, 657 developed dementia, 1540 died and 1029 were lost to follow up. Regardless of whether we estimated risks for question (1) or (2), individuals with higher education had a lower risk of dementia compared to lower education. In contrast, women had an increased risk of dementia compared to men only when we approached question (2) rather than (1). Apoe4 carriers had an increased risk of dementia compared to the non‐carriers, though risks were lower for question (2) rather than (1).ConclusionEstimates for the risk of dementia will always be affected by how we include death in our research question, as demonstrated in our three examples. We will discuss the implications of these research questions, including whether they represent realistic scenarios of clinical or public health interest, and the considerations when conducting such analyses in the presence of competing events.
Harmony: Demographic and baseline characteristics from the 12‐week, open‐label treatment phase
Authors: Foff Erin P. , McEvoy Bradley , Erten‐Lyons Deniz , Sultzer David L. , Stankovic Srdjan 
Published: December 2020

AbstractBackgroundApproximately 2.4 million patients in the U.S. experience delusions and hallucinations associated with dementia‐related psychosis (DRP) with no approved therapies. Pimavanserin is a 5HT2A inverse agonist/antagonist approved in the U.S. for treating hallucinations and delusions associated with Parkinson’s disease psychosis. The objective is to examine baseline characteristics from patients with DRP enrolled in the HARMONY study, a pivotal Phase 3, placebo‐controlled, randomized withdrawal study.MethodEligible patients with dementia due to Alzheimer’s disease (AD), Parkinson’s disease dementia (PDD), dementia with Lewy bodies (DLB), frontotemporal dementia (FTD) or vascular dementia (VaD) with moderate to severe psychosis (SAPS H+D total score ≥10 AND a CGI‐S score ≥4 AND a SAPS H+D global item (H7 or D13) score ≥4) were enrolled into the 12‐week open‐label (OL) period where they received pimavanserin 34 mg once daily. Patients with sustained response to pimavanserin during the OL were randomized into the double‐blind portion of the trial where they received pimavanserin or placebo and were assessed for relapse of psychosis. Demographic and baseline characteristics of the population were summarized.ResultOf 392 patients enrolled, 66.3% of patients had a most likely clinical diagnosis of AD,15.1% PDD, 9.7% VaD, 7.1% DLB, and 1.8% FTD. A non‐specific dementia diagnosis had been given in the past to 110/390 (28.2%) subjects, and 46.9% had previously used an off‐label antipsychotic for DRP. Most patients had moderate dementia (70.2%), and the mean (SE) duration of cognitive impairment was 4.3 (0.1) years. The population was expectedly frail: at baseline, mean age was 74.5 (0.4) years, 46.4% of patients were taking >5 concomitant medications, and 70.4% had at least 3 comorbid medical conditions. At baseline, mean (SE) scores for SAPS‐H+D, SAPS‐H, SAPS‐D, and CGI‐S were 24.4 (0.47), 14.2 (0.32), 10.2 (0.33), and 4.7 (0.03), respectively; mean (SE) MMSE score was 16.7 (0.24), and 84% had delusions and 79% visual hallucinations. Baseline and disease characteristics by clinical subtype will be summarized.ConclusionBaseline characteristics in the open‐label phase of HARMONY indicate target enrollment of patients with the most common neurodegenerative dementias and moderate to severe psychosis consisting mostly of elderly patients with multiple co‐morbidities.