bluuebunny/crossref_metadata_2025_split huggingface dataset:
LDL cholesterol and uridine levels in blood are potential nutritional biomarkers of AD progression: The NUDAD project
Authors: de Leeuw Francisca A. , Tijms Betty M. , Doorduijn Astrid S , Hendriksen Heleen M.A. , van de Rest Ondine , de van der Schueren Marian , Visser Marjolein , van den Heuvel Ellen G.H.M. , van Wijk Nick , Bierau Jörgen , Scheltens Philip , Kester Maartje I. , van Der Flier Wiesje , Teunissen Charlotte E. 
Published: December 2020

AbstractBackgroundSuboptimal nutritional status is considered a modifiable risk factor for Alzheimer’s disease (AD). Identification of nutritional biomarker levels that are related to clinical progression might provide targets for dietary intervention studies. Therefore, we examined associations between nutritional biomarkers and clinical progression in a prospective study with individuals with subjective cognitive decline (SCD), mild cognitive impairment (MCI) and AD‐type dementia.MethodWe included 551 participants: 219 patients with SCD (age 61±8y, F47%), 135 patients with MCI (age 66±8 y, F40%) and 197 patients with AD (age 67±8y, F50%). Mean follow‐up was 2±1 years. Main outcome was time to clinical event operationalized as presence of at least one of the following: 1) in SCD, progression to MCI or dementia; in MCI, progression to dementia; in AD an increase of ≥1 point on clinical dementia rating scale; or 2) admission to a nursing home or deceased; or 3) self‐reported progression of cognitive symptoms. Baseline levels of cholesterol, triglycerides, glucose, homocysteine, folate, vitamin A, B12, E, and uridine were measured in blood and those of S‐adenosylmethionine and S‐adenosylhomocysteine in cerebrospinal fluid. Cox proportional hazard models adjusted for sex, age, diagnosis, BMI and lipid lowering medication were used to assess associations of baseline nutritional biomarker levels with time to clinical progression, in the total cohort and stratified for baseline diagnosis (SCD/MCI/AD). We repeated analyses in the total cohort restricted to amyloid positive patients.ResultClinical progression was observed in 25 (11%) patients with SCD, 45 (33%) with MCI and 100 (51%) with AD. None of the nutritional biomarkers was associated with clinical progression in the total cohort. Higher levels of LDL cholesterol in SCD (HR (95%CI) 1.92 (1.05‐3.52)), and lower uridine levels in AD were associated with clinical progression (HR (95%CI) 0.78 (0.62‐0.99)) (Table 1). In amyloid positive patients, lower uridine levels were associated with clinical progression.ConclusionIn this large prospective memory‐clinic study, we found that higher LDL cholesterol and lower uridine levels were associated with clinical progression in SCD and AD dementia respectively. Our findings suggest that nutritional interventions should take into account clinical stage, and target uridine and cholesterol levels.
Enlightening behavioral disturbances in myotonic dystrophy type 1 through neuropsychology and imaging correlations: Insights from the frontal and temporal lobe functions
Authors: Morin Alexandre , Funkiewiez Aurélie , Routier Alexandre , Colliot Olivier , Eymard Bruno , Dubois Bruno , Stojkovic Tanja , Azuar Carole 
Published: December 2020

AbstractBackgroundMyotonic Dystrophy Type 1 (MD1) is a neuromuscular disease in which subtle behavioral disturbance is often described. Few studies evaluated frontal lobe function and behavioral scales in relation with brain pathology.Method27 MD1 adult patients (mean age 46), were included. All patients performed an exhaustive neuropsychological assessment with a specific focus on cognitive and behavioral frontal functions. 18 MD1 patients and 18 healthy controls had a brain MRI with T1 and T2 Flair sequences. We performed a voxel‐based analysis with SPM12 via Clinica Software. The normalized data were smoothed with an isotropic Gaussian kernel of 8 mm. Statistical analysis was performed using general linear model with age sex and total intra cranial volume as covariates. Statistics were corrected for multiple comparisons with family‐wise error (FWE) correction at the cluster level with a height threshold of 0.001. T2 white matter lesions were segmented with VolBrain software.ResultMore than 60 % of the patients showed significant impairment in executive frontal functions (inhibition, mental flexibility, contextualization and theory of mind) with relative sparing of motivation, emotion recognition and initiation/planification.MD1 patients MRI compared to healthy controls showed grey matter atrophy in medial temporal lobe, (parahippocampus mostly) and in a smaller extent in the middle frontal gyrus and the right caudate nucleus and excessive white matter hyperintensities, mostly in temporal lobes.Frontal cognitive and behavioral impairment on neuropsychological testing was correlated with medial temporal and in a smaller extent frontal localization.ConclusionBehavioral disturbance in MD1 might be related to cognitive impairment in mental flexibility and contextualization rather than a specific social cognition deficit. This impairment might be related to white matter lesions or grey matter disease (including frontal‐subcortical network or parahippocampus, known to apprehend contextualization in emotion detection). Altogether, these findings confirm the hypothesis of a specific central nervous system involvement in MD1 patients.
Cardiovascular health metrics from mid‐ to late‐life and risk of dementia: A population‐based study
Authors: Liang Yajun , Ngandu Tiia , Laatikainen Tiina , Soininen Hilkka , Tuomilehto Jaakko , Kivipelto Miia , Qiu Chengxuan 
Published: December 2020

AbstractBackgroundCardiometabolic risk factors in middle age have been associated with late‐life risk of dementia. The associations of cardiovascular health (CVH) metrics in midlife and old age with late‐life risk of dementia need to be clarified in cohort studies. We sought to examine the associations of CVH metrics from mid‐ to late‐life with risk of incident dementia in late‐life.MethodThis population‐based cohort study used data from the Finnish Cardiovascular Risk Factors, Aging and Dementia study. A total of 1449 participants were followed from midlife (1972 to 1987, mean baseline age 50.4 years) to late‐life (1998 to 2005‐2009, mean baseline age 70.2 years, N=744). We defined six CVH metrics (smoking, blood pressure, physical activity, body mass index, fasting plasma glucose, and serum total cholesterol) following the modified American Heart Association’s recommendations. Dementia diagnosis was based on the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, criteria. Data were analysed with Cox regression models.ResultDuring the follow‐up examinations, dementia was diagnosed in 61 persons in 1998 and additional 47 persons during 2005 to 2008. The incidence of dementia (per 1000 person‐years) was 7.27, 3.76, and 2.00 for those with poor (score ≤5), intermediate (6‐7), and ideal (≥8) levels of CVH metrics in midlife, respectively. Compared with people with poor CVH metrics, those with ideal CVH metrics in midlife had a 48% lower risk of dementia in late‐life (fully‐adjusted hazard ratios, 0.52; 95% CI, 0.20‐0.92). The incidence rate of dementia (per 1000 person‐years) was 9.5, 5.5, and 8.7 for those with poor, intermediate, and ideal levels of CVH metrics in late‐life, respectively. No significant association was found between late‐life CVH metrics and risk of dementia. Compared with poor CVH metrics in both midlife and late‐life, the fully‐adjusted hazard ratio of dementia was 0.24 (95% CI, 0.06‐0.94) for having intermediate or ideal CVH metrics in either midlife or late‐life and 0.29 (0.10‐0.86) for intermediate or ideal CVH metrics in both midlife and late‐life.ConclusionHaving an intermediate or ideal level of CVH metrics in either midlife or late‐life is associated with a decreased risk of dementia.
Cognitive frailty: A pre‐dementia syndrome or a branch of healthy ageing?
Authors: Kocagoncu Ece , Nesbitt David , Hughes Laura , Henson Richard N , Can Cam , Rowe James B 
Published: December 2020

AbstractBackgroundThere is a pressing need for new therapeutic strategies to arrest Alzheimer’s disease (AD) at its prodromal stage. MTL pathology at this stage causes widespread synaptic dysfunction, before any cognitive decline and atrophy. We propose that neurophysiological biomarkers sensitive to this early synaptic dysfunction could be recorded using electro‐magnetoencephalography (E/MEG). Cam‐CAN Frail study, investigates neurophysiological changes that occur in cognitively frail individuals, who show cognitive decline in the absence of a clinical diagnosis.MethodWe collected E/MEG data from healthy controls, cognitively frail, MCI and early AD patients (N=90). Frail and MCI groups performed similarly on MMSE or ACER. Frail group had lower education levels than the other groups. Participants were presented fractals followed by sounds. The stimuli consisted of standard and deviant pairs. Deviants were pairs with shuffled sounds (associative deviants) or novel sounds (novelty deviants). We extracted the signal from inferior frontal (IFG), superior temporal (STG) and Heschl’s gyri (HG). We tested the relationship between the mismatch response, hippocampal grey matter volumes (GMV), neuropsychological scores and education.ResultNovelty response was found in control and frail groups, with larger clusters in bilateral IFG. MCI and AD groups showed weaker novelty effects only in the RHG and RSTG respectively. The associative deviant response was observed only in the bilateral IFG across the groups. Novelty deviant response in LHG negatively correlated with MMSE and ACER. Education level was not significant correlated with mismatch responses. Hippocampal and entorhinal GMVs of the controls and the cognitively frail were significantly higher than the MCI/AD groups. The difference in GMVs between controls and the frail was not significant. Hippocampal, entorhinal GMV and education levels positively correlated with MMSE and ACER scores.ConclusionCognitively frail do not show the neurophysiological or structural profile, characteristic of AD. Cognitive frailty might be reflecting an extreme of the normal spectrum of cognition, but not AD. The underperformance could instead be explained by lower education levels. Secondly, we showed that E/MEG identifies the loss of response to novelty deviance in MCI and AD; and E/MEG tasks that are automatic, easy and require minimal training can be used to develop biomarkers in AD.
Slowed processing speed contributes to cognitive deficits in amnestic and non‐amnestic mild cognitive impairment
Authors: Daugherty Ana M. , Shair Sarah , Kavcic Voyko , Giordani Bruno 
Published: December 2020

AbstractBackgroundMild cognitive impairment (MCI) is characterized by deficits across functional domains, with pronounced memory impairment among amnestic (aMCI) patients. The mixture of cognitive complaints is a challenge in diagnosis and is further complicated by interactions between cognitive domains that are typical for neuropsychological performance.MethodWe aim to examine if slow processing speed may convey MCI‐related deficits across cognitive domains in a sample of African American adults (ages 56‐90): 61 cognitively typical, 28 aMCI, and 14 non‐amnestic MCI. Working memory, executive function, declarative memory and processing speed indices were estimated in structural equation modeling, including indirect effects with bootstrapped 95% confidence intervals (CI).ResultMCI diagnosis predicted deficits in processing speed (b=‐0.53, p=0.02), executive function (b=‐0.37, p=0.03), working memory (b=‐0.62, p=0.001), and episodic memory (b=‐0.61, p<0.001). Slow processing speed predicted low function across domains and in turn partially accounted for effects of diagnosis on executive function (‐0.21, CI:‐0.37/‐0.10), working memory (‐0.12, CI: ‐0.24/‐0.05) and a non‐significant trend for declarative memory (‐0.05, CI: ‐0.15/0.01). Slow processing speed explained approximately 36% of MCI‐related deficits in executive function, 16% in working memory and 8% in declarative memory. In comparison between typical aging and specifically aMCI, processing speed explained deficits in executive function (‐0.19, CI: ‐0.39/‐0.06; 37% indirect) and working memory (‐0.09, CI: ‐0.22/‐0.01; 13%), and a non‐significant trend in declarative memory (‐0.06, CI: ‐0.19/0.00; 8%).ConclusionSlowed processing speed contributes to typical cognitive aging and conveys MCI‐related deficits across domains. Identification of deficits in processing speed may provide insight into MCI progression and opportunities for clinical intervention.
Neuropsychiatric symptoms and cognitive trajectories in older adults free of dementia: The Mayo Clinic Study of Aging
Authors: Krell‐Roesch Janina , Vassilaki Maria , Syrjanen Jeremy , Machulda Mary M. , Christianson Teresa J. , Kremers Walter K. , Mielke Michelle M. , Knopman David S. , Petersen Ronald C. , Geda Yonas E. 
Published: December 2020

AbstractBackgroundNeuropsychiatric symptoms (NPS) are associated with the risk of incident mild cognitive impairment (MCI) and dementia. However, the association between NPS and global and domain‐specific cognitive trajectories among older adults free of dementia remains unclear.MethodWe conducted a longitudinal study derived from the population‐based Mayo Clinic Study of Aging, including individuals aged ≥ 50 years who were free of dementia. Participants completed the Neuropsychiatric Inventory Questionnaire at baseline and underwent neuropsychological testing assessing four cognitive domains (i.e., memory, language, attention, visuospatial skills) every 15 months. We calculated linear mixed‐effect models with random subject‐specific intercepts and slopes to examine the association between presence of twelve different NPS (i.e., delusions, hallucinations, agitation, depression, anxiety, euphoria, apathy, disinhibition, irritability, motor behavior, nighttime behavior, appetite) at baseline and trajectories for individual yearly change in global and domain‐specific cognitive z‐scores. The models were adjusted for age, sex, education, and whether or not this was the first time the cognitive battery had been administered.ResultThe sample included 5081 persons (51% males; 4439 cognitively unimpaired, 642 with MCI). The median [IQR] age was 74 [67, 81] years, and the median [IQR] education was 14 [12, 16] years. Regardless of NPS status, participants declined in cognition over time, on average. However, presence of NPS was significantly associated with an increased decline in cognition, i.e., the annualized change in global cognition z‐scores for participants with compared to without the given NPS ranged from ‐0.018 (p = 0.011) for irritability to ‐0.16 (p = 0.001) for hallucinations. These associations between NPS and annual decline in global cognition were significant for all NPS except euphoria and disinhibition. Similar results were seen for the individual cognitive domains, e.g., participants with depression, apathy and nighttime behavior had a greater longitudinal decline in all domain specific z‐scores, whereas presence of delusions and anxiety was associated with a more pronounced decline in language, attention and visuospatial skills.ConclusionNeuropsychiatric symptoms are associated with greater longitudinal decline of both global and domain‐specific cognitive functions in community‐dwelling older adults free of dementia. More research is needed to confirm these preliminary findings.
Protein levels of APP, ADAM10 and BACE1 in aging adults with Down syndrome: Preliminary findings
Authors: Bram Jessyka Maria de França , Talib Leda Leme , Joaquim Helena Passarelli Giroud , Gattaz Wagner Farid , Forlenza Orestes Vicente 
Published: December 2020

AbstractBackgroundDown syndrome (DS) is associated with high prevalence of dementia, with onset in late adulthood. Given the pathological similarities, dementia in DS is regarded as a variant of early‐onset Alzheimer’s disease (AD). The genetic causality of dementia in DS is attributed to the overexpression of the amyloid precursor protein (APP) gene located on chromosome 21. Abnormalities in the regulation of APP metabolism cause the overproduction of the amyloid‐beta peptide (Aβ) and subsequent effects on the amyloid cascade, which ultimately lead to the formation of neuritic plaques and neurofibrillary tangles. To compare protein levels of secreted APP metabolites (sAPP) and APP‐secretases (ADAM10, BACE1, PSEN1) in platelets from adults and elders with DS compared to controls, and to determine whether these findings correlate with global cognitive state.MethodThe study group comprises 21 aging adults with DS, and the comparison group comprises a similar number of age/gender‐matched healthy subjects with normal karyotype (controls). DS subjects were subdivided according to age stratification (20‐34 years, n=8; 35‐49 years, n=4; ≥50 years, n=9). Global cognitive state of participants was ascertained with the CAMCOG schedule (controls) or its adapted version for DS (CAMCOG‐DS). Protein levels of APP‐related biomarkers were determined by Western Blotting.ResultCAMCOG‐DS scores were significantly different in DS subgroups (clinical evidence of cognitive impairment/dementia, DSd; normal cognitive function, DSnc). DSd subjects achieving lower scores (43.8, SD20.7) than DSnc (66.4, SD16.1) p=0.001. Low levels of APP130 have been found among DS as age increased (1.71, SD0.99; 0.76, SD0.46; 0.48, SD0.16, respectively; p=0,013), and higher BACE1 levels was found between aged 35‐49 years old DS (0.44, SD0.77) compared with aged 20‐34 years old DS (0.70, DS0.20), p=0,048. No statistically significant differences were found in platelet levels of ADAM10.ConclusionIn this preliminary analysis, APP‐related platelet biomarkers was able to show significant differences among DS age groups.
Connectivity between serotonin and dopamine systems is altered in Alzheimer’s disease
Authors: Ceyzériat Kelly , Gloria Yesica , Millet Philippe , Tournier Benjamin 
Published: December 2020

AbstractBackgroundApproximatively half of Alzheimer’s disease (AD) patients shows dysfunctions of the dopaminergic (DA) and serotoninergic (5HT) systems, in addition to cognitive impairment. However, the relationships between AD and the time of onset of monoaminergic disorders and their course remain poorly understood. In the present study, we characterized the DA system and the links between the 5HT and the DA systems in the TgF344‐AD rat model of AD.MethodLocomotor activity tests were performed in response to the dopamine receptor 2 (D2R) agonist quinpirole. Quinpirole decreases and activates locomotion according to the dose used, which is attributable to an effect at the pre‐ and post‐synaptic D2R, respectively. The impact of the serotonin receptor 2A (5HT2AR) antagonist MDL100.907 on the quinpirole‐induced locomotion changes was also tested. In vivo SPECT molecular imaging with [123I]IBZM was used for the indirect measurement of DA release in the striatum in response to MDL100.907. The densities of D2R and 5HT2AR receptors were evaluated by in situ autoradiography.ResultQuinpirole stimulated locomotion in wild type (WT, +114, +170 and +65%, at 6‐, 12‐ and 18‐months) and this effect is increased in TgF344‐AD rats at all ages (+340, +300 and +103%). TgF344‐AD rats also showed an increased response to pre‐synaptic dose of quinpirole, at both 6‐ and 12‐months old. These data demonstrated a hypersensitivity of the D2R. The administration of MDL100.907 significantly exacerbated the quinpirole‐induced locomotion in WT (+40%) but not in TgF344‐AD rats, indicating a hypo‐sensitivity of the 5HT2AR. The striatal dopamine release in response to MDL100.907 was significantly higher in WT (25.6%) than in TgF344‐AD rats (10.3%), showing a reduction of the DA system control by the 5HT2AR. This effect was measured at an early stage of the disease (6 months‐old), when amyloid plaques and cognitive disorders were still slight. In addition, the density of 5HT2A receptors was decreased in DA system‐related regions (‐27% in striatum and ‐40% in subtancia nigra), without any modifications on the D2R.ConclusionTgF344‐AD rats showed functional DA system alterations and a reduction in the connectivity between the 5HT2AR and the DA system that appears early in the course of the disease.
Investigation of herpesviruses in dementia patients and associated inflammatory gene modulation
Authors: Seaks Charles E. , Kloske Courtney M. , Salmeron Kathleen , Nelson Peter T. , Wilcock Donna M. 
Published: December 2020

AbstractBackgroundAlzheimer’s disease (AD) and vascular contributions to cognitive impairment and dementia (VCID) are the leading causes of dementia worldwide, with the two frequently found co‐morbid in dementia patients at autopsy. Studies have connected multiple herpesviruses to the development and pathogenesis of AD. The goal of this study was to determine the prevalence of four common herpesviruses in a cohort of AD and VCID patients, and to identify differential gene expression as a function of viral presence. We hypothesize AD and VCID cases will possess more latent virus than control cases, and cases with latent virus present will show a down‐regulation of innate immune related genes, and an upregulation of cell survival genes and transcriptional suppressors.MethodUsing droplet‐based PCR, we quantified the prevalence of four herpesviruses (herpes simplex virus 1, herpes simplex virus 2, cytomegalovirus, and human herpes virus 6) in a subset of brain autopsy tissue obtained from the Sanders‐Brown Center on Aging Alzheimer’s Disease Center (UK‐ADC). RNA and genomic DNA was extracted from the superior medial temporal gyrus and cerebellum of 49 cases (n=18 control, n=10 vascular pathology, n=20 AD, n=1 mixed AD+VCI). Genomic DNA was used to determine the presence of latent virus and cDNA to determine actively replicating virus. The RNA from these regions was run on the NanoString neuroinflammatory panel which quantifies a number of genes, ranging from neuroinflammatory markers to cell specific functional genes.ResultWe identified an increased amount of latent viral populations in the AD patients relative to control patients. NanoString analysis supported our initial hypothesis regarding gene regulation relating to innate immunity and cell survival, but we also observed downregulation of insulin‐like growth factor, synapse‐associated protein 97, and cell death‐inducing DFFA‐like effector b in the presence of certain latent viral populations.ConclusionOur results demonstrate the prevalence of herpesviruses within an AD cohort, supporting research suggesting a link between the two. Further, it shows alterations in the expression of neuroinflammatory genes as a function of latent virus presence.