当前期刊: Neurobiology of Aging Go to current issue    加入关注   
显示样式:        排序: 导出
我的关注
我的收藏
您暂时未登录!
登录
  • Choroid Plexus Volume is Associated With Levels of CSF Proteins: Relevance for Alzheimer’s and Parkinson’s Disease
    Neurobiol. Aging (IF 4.398) Pub Date : 2020-01-16
    Ehsan Tadayon; Alvaro Pascual-Leone; Daniel Press; Emiliano Santarnecchi

    The Choroid plexus (ChP) is a major source of cerebrospinal fluid (CSF) production, with a direct and indirect role in protein clearance, and pathogenesis of Alzheimer’s disease (AD). Here, we tested the link between the ChP volume and levels of CSF proteins in two datasets of (i) healthy controls, mild cognitive impairment (MCI) and AD patients from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (N = 509), and (ii) healthy controls and Parkinson’s disease (PD) patients from the Parkinson’s Progression Markers Initiative (PPMI) (N=302). All subjects had baseline CSF proteins (amyloid-β, total and phosphorylated-tau and α-synuclein (only in PPMI)). ChP was automatically segmented on 3T structural T1-weighted MRIs. We found negative associations between ChP volume and CSF proteins, which was stronger in healthy controls, early-MCI and PD compared with late-MCI and AD. Further grouping of subjects into amyloid-positive and negative based on their florbetapir (AV45) PET imaging showed that the association between ChP and CSF proteins was lower in amyloid-positive group. Our findings support the possible role of ChP in the clearance of CSF proteins, provide evidence for ChP dysfunction in AD and suggest the need to account for the ChP volume in future studies of CSF-based biomarkers.

    更新日期:2020-01-16
  • Plasma amyloid is associated with rate of cognitive decline in cognitively normal elderly: the SCIENCe project
    Neurobiol. Aging (IF 4.398) Pub Date : 2020-01-15
    Inge M.W. Verberk; Heleen M.A. Hendriksen; Argonde C. van Harten; Linda M.P. Wesselman; Sander C.J. Verfaillie; Karlijn A. van den Bosch; Rosalinde E.R. Slot; Niels.D. Prins; Philip Scheltens; Charlotte E. Teunissen; Wiesje.M. Van der Flier

    Plasma biomarkers are promising, easy-to-use prognostic tools in individuals with subjective cognitive decline (SCD). We aimed to investigate the relationships of baseline plasma amyloid beta (Abeta)42/Abeta40 and total Tau (tTau) with rate of cognitive decline, in comparison to relationships of baseline cerebrospinal fluid (CSF) Abeta42, tTau and phosphorylated tau181 (pTau) with rate of cognitive decline. We included 241 SCD subjects (age=61±9, 40% female, MMSE=28±2) with follow-up (average: 2±2 years, median visits: 3 (range: 1–11)) for re-evaluation of neuropsychological test performance (covering attention, memory, language and executive functioning domains). Using linear mixed models adjusted for age, gender and education, we found that lower plasma Abeta42/Abeta40 was associated with steeper rate of decline on tests assessing attention, memory and executive functioning, but not language. Lower CSF Abeta42 was associated with steeper decline on tests covering all domains. Plasma tTau was not associated with rate of cognitive decline, whereas CSF tTau and pTau were on multiple tests covering all domains. Associations for plasma amyloid and cognitive decline mirror those of CSF amyloid.

    更新日期:2020-01-15
  • Converging patterns of ageing-associated brain volume loss and tissue microstructure differences
    Neurobiol. Aging (IF 4.398) Pub Date : 2020-01-15
    Marco Taubert; Elisabeth Roggenhofer; Lester Melie-Garcia; Sandrine Muller; Nico Lehmann; Martin Preisig; Peter Vollenweider; Pedro Marques-Vidal; Antoine Lutti; Ferath Kherif; Bogdan Draganski

    Given the worldwide increasing socio-economic burden of ageing-associated brain diseases, there is pressing need to gain in-depth knowledge about the neuro-biology of brain anatomy changes across the lifespan. Advances in quantitative magnetic resonance imaging (MRI) sensitive to brain’s myelin, iron and free water content allow for a detailed in vivo investigation of ageing-related changes whilst reducing spurious morphometry differences. Main aim of our study is to link previous morphometry findings in ageing to microstructural tissue properties in a large-scale cohort (n=966, age range 46-86y). Addressing previous controversies in the field, we present results obtained with different approaches to adjust local findings for global effects. Beyond the confirmation of age-related atrophy, myelin and free water decreases, we report proportionally steeper volume, iron and myelin decline in sensorimotor and subcortical areas paralleled by free water increase. We demonstrate ageing-related white matter volume, myelin and iron loss in fronto-striatal projections. Our findings provide robust evidence for spatial overlap between volume and tissue property differences in ageing that affect predominantly motor and executive networks.

    更新日期:2020-01-15
  • Cerebellar Dentate Nucleus functional connectivity with cerebral cortex in Alzheimer’s disease and memory: A seed-based approach
    Neurobiol. Aging (IF 4.398) Pub Date : 2020-01-15
    Giusy Olivito; Laura Serra; Camillo Marra; Carlotta Di Domenico; Carlo Caltagirone; Sofia Toniolo; Mara Cercignani; Maria Leggio; Marco Bozzali
    更新日期:2020-01-15
  • Microglial activation arises after aggregation of phosphorylated-tau in a neuron specific P301S tauopathy mouse model.
    Neurobiol. Aging (IF 4.398) Pub Date : 2020-01-10
    Lynn van Olst; Daan Verhaege; Marc Franssen; Bart Roucourt; Sofie Carmans; Ellen Ytebrouck; Alwin Kamermans; Susanne M.A. van der Pol; Dennis Wever; Marko Popovic; Roosmarijn E. Vandenbroucke; Tomás Sobrino; Marijn Schouten; Helga E. de Vries

    Alzheimer’s disease, progressive supranuclear palsy and frontotemporal dementia are characterized by neuronal expression of aberrant tau protein, tau hyper-phosphorylation (pTAU), tau aggregation and neurofibrillary tangle formation sequentially culminating into neuronal cell death, a process termed tauopathy. Our aim was to address at which tauopathy stage neuro-inflammation starts and to study the related microglial phenotype. We used Thy1-hTau.P301S (PS) mice expressing human tau with a P301S mutation specifically in neurons. Significant levels of cortical pTAU were present from 2 months onwards. Dystrophic morphological complexity of cortical microglia arose after pTAU accumulation concomitant with increased microglial lysosomal volumes and a significant loss of homeostatic marker Tmem119. Interestingly, we detected increases in neuronal pTAU and post-synaptic structures in the lysosomes of PS microglia. Moreover, the overall cortical post-synaptic density was decreased in 6-month-old PS mice. Together, our results indicate that microglia adopt a pTAU-associated phenotype, and are morphologically and functionally distinct from wild-type microglia after neuronal pTAU accumulation has initiated.

    更新日期:2020-01-11
  • Psychosis-associated DNA methylomic variation in Alzheimer’s disease cortex
    Neurobiol. Aging (IF 4.398) Pub Date : 2020-01-08
    Ehsan Pishva; Byron Creese; Adam R. Smith; Wolfgang Viechtbauer; Petroula Proitsi; Daniel L.A. van den Hove; Clive Ballard; Jonathan Mill; Katie Lunnon

    Psychotic symptoms are a common and debilitating feature of Alzheimer’s disease, associated with a more rapid course of decline. Current evidence from post-mortem and neuroimaging studies implicates frontal, temporal and parietal lobes, with reported disruptions in monoaminergic pathways. However, the molecular mechanisms underlying this remain unclear. In the present study, we investigated methylomic variation associated with AD psychosis in three key brain regions implicated in the etiology of psychosis (prefrontal cortex, entorhinal cortex and superior temporal gyrus) in post-mortem brain samples from 29 AD donors with psychosis and 18 matched AD donors without psychosis. We identified psychosis-associated methylomic changes in a number of loci, with these genes being enriched in known schizophrenia-associated genetic and epigenetic variants. One of these known loci resided in the AS3MT gene – previously implicated in schizophrenia in a large GWAS meta-analysis. We used bisulfite-pyrosequencing to confirm hypomethylation across four neighboring CpG sites in the ASM3T gene. Finally, our regional analysis nominated multiple CpG sites in TBX15 and WT1, which are genes that have been previously implicated in AD. Thus one potential implication from our study is whether psychosis-associated variation drives reported associations in AD case-control studies.

    更新日期:2020-01-09
  • The effect of aging, Parkinson’s disease, and exogenous dopamine on the neural response associated with auditory regularity processing
    Neurobiol. Aging (IF 4.398) Pub Date : 2020-01-07
    Abdullah Al Jaja; Jessica A. Grahn; Björn Herrmann; Penny A. MacDonald

    Processing regular patterns in auditory scenes is important for navigating complex environments. Electroencephalography (EEG) studies find enhancement of sustained brain activity, correlating with the emergence of a regular pattern in sounds. How aging, aging-related diseases such as Parkinson’s disease (PD), and treatment of PD with dopaminergic therapy affect this fundamental function remain unknown. We addressed this knowledge gap. Healthy younger and older adults, and PD patients listened to sounds that contained or were devoid of regular patterns. Healthy older adults and PD patients were tested twice—off and on dopaminergic medication, in counterbalanced order. Regularity-evoked, sustained EEG activity was reduced in older, compared to younger adults. PD patients and older controls evidenced comparable attenuation of the sustained response. Dopaminergic therapy further weakened the sustained response in both older controls and PD patients. These findings suggest that fundamental regularity processing is impacted by aging but not specifically by PD. The finding that dopaminergic therapy attenuates rather than improves the sustained response coheres with the dopamine overdose response and is in line with previous findings that regularity processing implicates brain regions receiving dopamine from the ventral tegmental area that is relatively spared in PD and normal aging.

    更新日期:2020-01-07
  • Whole-exome sequencing in early-onset Parkinson’s disease among ethnic Chinese
    Neurobiol. Aging (IF 4.398) Pub Date : 2020-01-07
    Nannan Li; Ling Wang; Jinhong Zhang; Eng-King Tan; Junying Li; Jiaxin Peng; Liren Duan; Chaolan Chen; Dong Zhou; Li He; Rong Peng

    Although early-onset Parkinson’s disease (EOPD) has a more penetrant genetic etiology, the genetic architecture of EOPD remains unclear. The objectives of this study were to assess the genetic and clinical features of EOPD among ethnic Chinese from mainland China. Using whole-exome sequencing (WES), we performed genetic analyses of 240 participants including 193 with sporadic and 47 with familial EOPD (age of onset < 50 years). In total, 18 patients (7.5%) harbored pathogenic or likely pathogenic variants in known PD genes. Among these variants, biallelic variants in Parkin and PINK1 were responsible for 4.2% of cases, and rare likely pathogenic variants in LRRK2 (1.7%) also appeared to be a relatively common cause of EOPD. Notably, 7.5% of patients carried risk variants in either LRRK2 or GBA, which should also be considered for EOPD. Nevertheless, 41 patients (17.1%) had rare variants of unknown significance. In conclusion, our findings provide a better understanding of the genetic architecture of PD among ethnic Chinese, and the pathogenicity of numerous rare variants should be further investigated.

    更新日期:2020-01-07
  • C9orf72 Hexanucleotide repeat expansion in Indian ALS patients: A common founder and its geographical predilection.
    Neurobiol. Aging (IF 4.398) Pub Date : 2020-01-03
    Uzma Shamim; Sakshi Ambawat; Jyotsna Singh; Aneesa Thomas; Chevula Pradeep-Chandra-Reddy; Varun Suroliya; Bharathram Uppilli; Shaista Parveen; Pooja Sharma; Shankar Chanchal; Saraswati Nashi; Veeramani Preethish-Kumar; Seena Vengalil; Kiran Polavarapu; Muddasu Keerthipriya; Niranjan Prakash Mahajan; Neeraja Reddy; Priya Treesa Thomas; Mohammed Faruq

    Hexanucleotide repeat expansion in C9orf72 is defined as a major causative factor for familial Amyotrophic Lateral Sclerosis (ALS). The mutation frequency varies dramatically among populations of different ethnicity, however in majority of cases, C9orf72 mutant has been described on a common founder haplotype. We assessed its frequency in a study cohort involving 593 clinically and electro-physiologically defined ALS cases. We also investigated the presence of reported Finnish haplotype among the mutation carriers. The identified common haplotype region was further screened in 192 (carrying 2-6 G4C2 repeats) and 96 (≥7 repeats) control chromosomes. The G4C2 expansion was observed in 3.2% (19/593) of total cases where 9/19 (47.4%) positive cases belonged to Eastern region of India. Haplotype analysis revealed 11 G4C2-Ex carriers shared the common haplotype (haplo-A) background spanning a region of ∼90kbp (SNP895021-rs11789520) including rs3849942 (a well-known global at-risk allele for G4C2 expansion). The other three G4C2-Ex cases had a different haplotype (haplo-B) with core difference from haplo-A at G4C2-Ex flanking 31 kbp region between rs3849942 and rs11789520 SNPs (allele 'C' of rs3849942 which is a non-risk allele). This study establishes the prevalence of C9orf72 expansion in Indian ALS cases providing further evidence for geographical predilection. The global core risk haplotype predominated C9orf72 expansion positive ALS cases yet the existence of a different haplotype suggests a second lineage (haplo B) which may have arisen from the TCT haplotype background or may imply a unique haplotype among Asians. The association of risk haplotype with normal intermediate C9orf72 alleles reinforced its role in conferring instability to C9orf72- G4C2 region. We thus present an effective support to interpret future burden of ALS cases in India.

    更新日期:2020-01-04
  • Cognitive reserve predicts future executive function decline in older adults with Alzheimer’s Disease pathology but not age-associated pathology
    Neurobiol. Aging (IF 4.398) Pub Date : 2020-01-03
    Cathryn McKenzie; Romola S. Bucks; Michael Weinborn; Pierrick Bourgeat; Olivier Salvado; Brandon E. Gavett

    Cognitive reserve has been described as offering protection against Alzheimer’s disease (AD) and other neurodegenerative conditions, but also against age-associated brain changes. Using data from the Alzheimer’s Disease Neuroimaging Initiative, we defined cognitive reserve using the residual reserve index: episodic memory performance residualized for 3T MRI-derived brain volumes and demographics. We examined whether cognitive reserve predicted executive function (EF) decline equally across two groups of older adults – AD biomarker positive (n=468) and negative (n=402) – defined by the tau-to-amyloid ratio in cerebrospinal fluid. A significant interaction between the residual reserve index and biomarker group revealed that the effect of cognitive reserve on EF decline was dependent on pathology status. In the biomarker positive group, higher cognitive reserve predicted EF decline over five years. However, cognitive reserve did not predict EF decline in the biomarker negative group. These results suggest a certain level of AD pathology may be needed before cognitive reserve exerts its protective effects on future cognition; however, further research that tracks cognitive reserve longitudinally is needed.

    更新日期:2020-01-04
  • The geriatric pain experience in mice: intact cutaneous thresholds but altered responses to tonic and chronic pain
    Neurobiol. Aging (IF 4.398) Pub Date : 2019-12-31
    Magali Millecamps; Xiang Qun Shi; Marjo Piltonen; Stefania Echeverry; Luda Diatchenko; Ji Zhang; Laura S. Stone

    Older individuals have an elevated risk for chronic pain as half of all individuals over 65 years old have at least one chronic pain condition. Unfortunately, relevant assessment tools and recommendations for chronic pain management targeting older adults are lacking. This study explores changes in response to pain between young (2-3-month-old) and geriatric (20-24-month-old) ages using mice. While cutaneous thresholds to brisk stimuli (von Frey and radiant heat assays) were not affected, behavioural responses to tonic stimuli (acetone and capsaicin assays) were more pronounced in geriatric animals. After nerve injury, geriatric mice present an altered neuropathic pain profile with hypersensitivity to mechanical stimuli but not acetone and an impairment in conditioned noxious stimuli avoidance. This altered behavioural response pattern was associated with an abnormal monoaminergic signature in the medial prefrontal cortex, suggesting decreased COMT function. We conclude that young and geriatric mice exhibit different behavioural and physiological responses to the experience of pain, suggesting that knowledge and practices must be adjusted for geriatric populations.

    更新日期:2019-12-31
  • Patterns of olfactory functional networks in Parkinson’s disease dementia and Alzheimer’s dementia
    Neurobiol. Aging (IF 4.398) Pub Date : 2019-12-30
    Yang Hyun Lee; Yunjin Bak; Chang-hyun Park; Seok Jong Chung; Han Soo Yoo; Kyoungwon Baik; Jin Ho Jung; Young H. Sohn; Na-Young Shin; Phil Hyu Lee

    Hyposmia is common in Alzheimer’s dementia (AD) and Parkinson’s disease dementia (PDD). We evaluated the pattern of olfactory functional connectivity (FC) in AD and PDD to uncover neural correlates that are related to olfactory dysfunction. This study enrolled 57 AD and PDD patients, and 25 control subjects. Using a seed-based approach, we compared the resting-state network from the seed-region-of-interest in the olfactory bulb (OB), olfactory tract, piriform cortex, and orbitofrontal cortex (OFC) between groups. The PDD group showed lower FC with striatal-thalamic-frontal regions from the OB than the AD group. The PDD group showed lower FC from left OFC with striatal-frontal regions and lower FC from right OFC with left fronto-temporal areas than the AD group. In a correlation analysis, the FC from left OFC with right insula that differed between the PDD and control groups was positively correlated with olfactory function. The present study demonstrated that this distinct olfactory functional network pattern may represent different neural mechanisms for olfactory dysfunction in AD and PDD.

    更新日期:2019-12-30
  • CSF cut-offs for MCI due to AD depend on APOEε4 carrier status
    Neurobiol. Aging (IF 4.398) Pub Date : 2019-12-30
    Moira Marizzoni; Clarissa Ferrari; Claudio Babiloni; Diego Albani; Frederik Barkhof; Libera Cavaliere; Mira Didic; Gianluigi Forloni; Federica Fusco; Samantha Galluzzi; Tilman Hensch; Jorge Jovicich; Camillo Marra; José Luis Molinuevo; Flavio Nobili; Lucilla Parnetti; Pierre Payoux; Jean-Philippe Ranjeva; Giovanni B. Frisoni

    Amyloid and tau pathological accumulation should be considered for AD definition and before subjects enrolment in disease-modifying trials. Although age, APOEε4 and sex influence CSF biomarker levels, none of these variables are considered by current normality/abnormality cut-offs. Using baseline CSF data from two independent cohorts (PharmaCOG/European ADNI and ADNI), we investigated the effect of age, APOEε4 status and sex on CSF Aβ42/P-tau distribution and cut-off extraction by applying mixture models with covariates. The Aβ42/P-tau distribution revealed the presence of 3 subgroups (AD-like, intermediate, control-like) and 2 cut-offs. The identification of the intermediate subgroup and of the higher cut-off were APOEε4-dependent in both cohorts. APOE-specific classification (higher cut-off for APOEε4+, lower cut-off for APOEε4-) showed higher diagnostic accuracy in identifying MCI due to AD compared to single Aβ42 and Aβ42/P-tau cut-offs. APOEε4 influences amyloid and tau CSF markers and AD progression in MCI patients supporting i) the use of APOE specific cut-offs to identify MCI due to AD and, ii) the utility of considering APOE genotype for early AD diagnosis.

    更新日期:2019-12-30
  • Neural correlates of auditory sensory memory dynamics in the aging brain
    Neurobiol. Aging (IF 4.398) Pub Date : 2019-12-30
    Sandeepa Sur; Edward J. Golob

    The auditory system allows us to monitor background environmental sound patterns and recognizes deviations that may indicate opportunities or threats. The mismatch negativity (MMN) and P3a potentials have generators in auditory and inferior frontal cortex, and index expected sound-patterns (standards) and any aberrations (deviants). The MMN and P3a waveforms show increased positivity for consecutive standards and deviants preceded by more standards. We hypothesized attenuated repetition effects in older participants, potentially due to differences in prefrontal functions. Young (23 ± 5 yrs.) and older (75 ± 5 yrs.) adults were tested in two oddball paradigms with pitch or location deviants. Significant repetition effects were observed in the young standard and deviant waveforms at multiple time windows. Except the earliest time window (30-100ms), repetition effects were absent in the older group. Repetition effects were significant at frontal but not temporal lobe sites, and did not differ among pitch and location deviants. However, P3a repetition was evident in both ages. Findings suggest age differences in the dynamic updating of sensory memory for background sound patterns.

    更新日期:2019-12-30
  • Impact of BDNF and sex on maintaining intact memory function in early midlife
    Neurobiol. Aging (IF 4.398) Pub Date : 2019-12-24
    Kyoko Konishi; Sara Cherkerzian; Sarah Aroner; Emily G. Jacobs; Dorene M. Rentz; Anne Remington; Harlyn Aizley; Mady Hornig; Anne Klibanski; Jill M. Goldstein

    Sex steroid hormones and neurotrophic factors, such as brain-derived neurotrophic factor (BDNF), play a significant neuroprotective role in memory circuitry aging. Here, we present findings characterizing the neuroprotective effects of BDNF on memory performance, as a function of sex and reproductive status in women. Participants (N=191; mean age=50.03±2.10) underwent clinical and cognitive testing, fMRI scanning, and hormonal assessments of menopausal staging. Memory performance was assessed with the 6-Trial Selective Reminding Test and the Face-Name Associative Memory Exam. Participants also performed a working memory (WM) N-back task during fMRI scanning. Results revealed significant interactions between menopausal status and BDNF levels. Only in postmenopausal women, lower plasma BDNF levels were associated with significantly worse memory performance and altered function in the WM circuitry. BDNF had no significant impact on memory performance or WM function in pre/perimenopausal women or men. These results suggest that in postmenopausal women, BDNF is associated with memory performance and memory circuitry function, thus providing evidence of potential sex-dependent factors of risk and resilience for early intervention.

    更新日期:2019-12-25
  • Association of brain network dynamics with plasma biomarkers in subjective memory complainers
    Neurobiol. Aging (IF 4.398) Pub Date : 2019-12-23
    Patrizia A. Chiesa; Marion Houot; Andrea Vergallo; Enrica Cavedo; Simone Lista; Marie Claude Potier; Henrik Zetterberg; Kaj Blennow; Eugeen Vanmechelen; Ann De Vos; Bruno Dubois; Harald Hampel

    Using a single integrated analysis, we examined the relationship between brain networks and molecular pathways in a cohort of elderly individuals at-risk for Alzheimer’s disease (AD). In 205 subjective memory complainers (124 females, mean age: 75.7±3.4), individual functional connectome was computed for a total of 3,081 functional connections (Set A) and six core plasma biomarkers of AD (Set B) were assessed. Partial least squares correlation analysis identified one dimension of population co-variation between the two sets (p<.006), that we named bio-neural mode. Five core plasma biomarkers and 190 functional connections presented bootstrap ratios greater than the critical value |1.96|. T-tau protein showed a trend towards significance (BR=1.64). The salience, the language, the visuospatial and the default mode networks were the strongest significant networks. We detected a strong association between network dynamics and core pathophysiological blood biomarkers. Innovative composite biomarkers, such as the bio-neural mode, are promising to provide outcomes and better inform drug development and clinical practice for neurodegenerative diseases.

    更新日期:2019-12-23
  • Excess Brain Age in the Sleep Electroencephalogram Predicts Reduced Life Expectancy
    Neurobiol. Aging (IF 4.398) Pub Date : 2019-12-23
    Luis Paixao; Pooja Sikka; Haoqi Sun; Aayushee Jain; Jacob Hogan; Robert Thomas; M. Brandon Westover

    The Brain Age Index (BAI) measures the difference between an individual’s apparent “brain age” (BA; estimated by comparing EEG features during sleep from an individual with age norms), and their chronological age (CA); that is BAI = BA – CA. Here, we evaluate whether BAI predicts life expectancy. Brain age was quantified using a previously published machine learning algorithm for a cohort of participants > 40 years old who underwent an overnight sleep electroencephalogram (EEG) as part of the Sleep Heart Health Study (n = 4,877). Excess brain age (BAI > 0) was associated with reduced life expectancy (adjusted hazard ratio (aHR) 1.12, [1.03, 1.21], p = 0.002). Life expectancy decreased by -0.81 [-1.44, -0.24] years per standard-deviation increase in BAI. Our findings show that BAI, a sleep EEG-based biomarker of the deviation of sleep microstructure from patterns normal-for-age, is an independent predictor of life expectancy.

    更新日期:2019-12-23
  • Modulation of neuroinflammation by cysteinyl leukotriene 1 and 2 receptors: Implications for cerebral ischemia and neurodegenerative diseases
    Neurobiol. Aging (IF 4.398) Pub Date : 2019-12-20
    Yuxi Wang; Yi Yang; Siran Zhang; Chengtan Li; Lihui Zhang

    Neuroinflammation is a complex biological process and has been known to play an important role in age-related cerebrovascular and neurodegenerative disorders, such as cerebral ischemia, Alzheimer's disease (AD) and Parkinson's disease (PD). Cysteinyl leukotrienes (CysLTs) are potent inflammatory lipid mediators that exhibit actions mainly through activating type 1 and type 2 CysLT receptors (CysLT1 and CysLT2). Accumulating evidence shows that CysLT1 and CysLT2 are activated at different stages of pathological process in various cell types in the brain such as vascular endothelial cells, astrocytes, microglia and neurons in response to insults. However, the precise roles and mechanisms of CysLT1 and CysLT2 in regulating the pathogenesis of cerebral ischemia, AD and PD are not fully understood. In this article, we focus on current advances that link activation of CysLT1 and CysLT2 to the pathological process during brain ischemia and neurodegeneration, and discuss mechanisms by which CysLT1 and CysLT2 mediate inflammatory process and brain injury. Multitarget antiinflammatory potentials of CysLT1 and CysLT2 antagonism for neuroinflammation and brain injury will also be reviewed.

    更新日期:2019-12-20
  • Screening of the glucocerebrosidase (GBA) gene in South Africans of African ancestry with Parkinson’s disease
    Neurobiol. Aging (IF 4.398) Pub Date : 2019-12-20
    Amokelani C. Mahungu; David G. Anderson; Anastasia C. Rossouw; Riaan van Coller; Jonathan A. Carr; Owen A. Ross; Soraya Bardien

    Sequence variants in glucocerebrosidase (GBA) are a major genetic risk factor for Parkinson’s disease (PD), and display ethnic-dependent frequencies, e.g. variants such as p.N370S and 84insGG are common in Ashkenazi Jewish patients. Notably, there are limited studies on Black patients from the African continent; hence, we conducted a study on 30 South African Black PD patients. All 11 exons of GBA were screened using a nested PCR approach to avoid pseudogene contamination. We identified previously described Gaucher’s disease-associated variants, p.R120W in one patient [age-at-onset (AAO) of 35 years], and p.R131L in another patient (AAO 3O years) and in her affected sibling (AAO 45 years). Also, we found three previously-identified [p.K(-27)R, p.T36del, and p.Q497*], and two novel (p.F216L and p.G478R) variants. Screening of ethnic-matched controls for the novel variants revealed that the allele frequency of p.F216L was 9.9%, whereas p.G478R was not found in the controls. Studies such as these are important and necessary to reveal the genetic architecture underlying PD in the understudied patients of African ancestry.

    更新日期:2019-12-20
  • Cerebrospinal fluid progranulin is associated with increased cortical thickness in early stages of Alzheimer’s disease
    Neurobiol. Aging (IF 4.398) Pub Date : 2019-12-20
    Lucia Batzu; Eric Westman; Joana B. Pereira

    Progranulin plays an important role in neuroinflammation in Alzheimer’s disease (AD) pathophysiology, being upregulated by activated microglia. This study assessed whether cerebrospinal fluid levels of progranulin correlated with structural neuroimaging measures and cognition in 122 cognitively normal individuals, 81 mild cognitive impairment (MCI) and 70 AD patients from the Alzheimer’s Disease Neuroimaging Initiative. Cognitively normal subjects were classified into 3 groups using the AT(N) system, whereas all MCI and AD patients were A+/TN+. Correlations between progranulin with neuroanatomical measures and cognitive decline were performed within each group. Progranulin was associated with cortical thickening in parietal, occipital and frontal regions in cognitively normal individuals with amyloid pathology. These subjects also showed cortical thickening compared to A-/TN- subjects, an effect that was partially mediated by progranulin. In addition, higher progranulin correlated with longitudinal cognitive decline. The association between progranulin and cortical thickening, together with regional “brain swelling” in A+/TN- subjects, suggests progranulin contributes to the neuroinflammatory structural changes in preclinical AD.

    更新日期:2019-12-20
  • Multivariate analysis reveals anatomical correlates of naming errors in Primary Progressive Aphasia
    Neurobiol. Aging (IF 4.398) Pub Date : 2019-12-20
    Rose Bruffaerts; Jolien Schaeverbeke; An-Sofie De Weer; Natalie Nelissen; Eva Dries; Karen Van Bouwel; Anne Sieben; Bruno Bergmans; Charlotte Swinnen; Yolande Pijnenburg; Stefan Sunaert; Mathieu Vandenbulcke; Rik Vandenberghe

    Primary Progressive Aphasia (PPA) is an overarching term for a heterogeneous group of neurodegenerative diseases which affect language processing. Impaired picture naming has been linked to atrophy of the anterior temporal lobe in the semantic variant of PPA. While atrophy of the anterior temporal lobe proposedly impairs picture naming by undermining access to semantic knowledge, picture naming also entails object recognition and lexical retrieval. Using multivariate analysis, we investigated whether cortical atrophy relates to different types of naming errors generated during picture naming in 43 PPA patients (13 semantic, 9 logopenic, 11 nonfluent and 10 mixed variant). Omissions were associated with atrophy of the anterior temporal lobes. Semantic errors, e.g. mistaking a rhinoceros for a hippopotamus, were associated with atrophy of the left mid and posterior fusiform cortex and the posterior middle and inferior temporal gyrus. Semantic errors and atrophy in these regions occurred in each PPA subtype, without major between-subtype differences. We propose that pathological changes to neural mechanisms associated with semantic errors occur across the PPA spectrum.

    更新日期:2019-12-20
  • Reelin in the Years: decline in the number of reelin immunoreactive neurons in layer II of the entorhinal cortex in aged monkeys with memory impairment
    Neurobiol. Aging (IF 4.398) Pub Date : 2019-12-19
    Jeffrey M. Long; Evelyn J. Perez; Jeffrey A. Roberts; Mary T. Roberts; Peter R. Rapp

    The glycoprotein reelin has been implicated in both memory-related synaptic plasticity and Alzheimer’s disease pathogenesis. Aged rats with memory impairment display decreased reelin expression in layer II of the entorhinal cortex (EC) relative to memory-intact subjects, and here we tested whether this effect extends to the primate brain. Seven young adult (8-10 years) and 14 aged (27-38 years) rhesus monkeys (Macaca mulatta) were examined, including 7 old animals classified as impaired based on their scores from a delayed nonmatching-to-sample recognition memory test. Histological sections spanning the rostrocaudal extent of the intermediate and caudal divisions of EC were processed by immunohistochemistry and the total number of reelin-positive neurons in layer II was estimated using design-based stereological techniques. The main finding was that the number of reelin expressing neurons in EC layer II is decreased selectively in aged monkeys with memory deficits relative to young adult and aged subjects with intact memory. The results add to evidence implicating EC-hippocampal integrity in neurocognitive aging, and they suggest that disrupted reelin signaling may be among the mechanisms that mediate the associated vulnerability of this circuitry in Alzheimer’s disease.

    更新日期:2019-12-19
  • Cognitive reserve and rate of change in Alzheimer’s and cerebrovascular disease biomarkers among cognitively normal individuals
    Neurobiol. Aging (IF 4.398) Pub Date : 2019-12-17
    Corinne Pettigrew; Anja Soldan; Yuxin Zhu; Qing Cai; Mei-Cheng Wang; Abhay Moghekar; Michael I. Miller; Baljeet Singh; Oliver Martinez; Evan Fletcher; Charles DeCarli; Marilyn Albert

    We examined whether cognitive reserve (CR) impacts level of, or rate of change in, biomarkers of Alzheimer’s disease (AD) and small vessel cerebrovascular disease in >250 individuals who were cognitively normal and middle-aged and older at baseline. The four primary biomarker categories commonly examined in studies of AD were measured longitudinally: cerebrospinal fluid (CSF) measures of amyloid (A) and tau (T); CSF and neuroimaging measures of neuronal injury (N); and neuroimaging measures of white matter hyperintensities (WMH) to assess cerebrovascular pathology (V). CR was indexed by a composite score including years of education, reading, and vocabulary test performance. Higher CR was associated with lower levels of WMH, particularly among those who subsequently progressed from normal cognition to MCI. CR was not associated with WMH trajectories. Additionally, CR was not associated with either levels of, or rate of change in, A/T/N biomarkers. This may suggest that higher CR is associated with lifestyle factors that reduce levels of cerebrovascular disease, allowing individuals with higher CR to better tolerate other types of pathology.

    更新日期:2019-12-18
  • Estimating age-related changes in in-vivo cerebral magnetic resonance angiography using convolutional neural network
    Neurobiol. Aging (IF 4.398) Pub Date : 2019-12-16
    Yoonho Nam; Jinhee Jang; Hea Yon Lee; Yangsean Choi; Na Young Shin; Kang-Hyun Ryu; Dong Hyun Kim; So-Lyung Jung; Kook-jin Ahn; Bum-soo Kim

    While age-related changes of cerebral arteries were observed in in-vivo MR angiography (MRA), standard tools or methods measuring those changes were limited. In this study, we developed and evaluated a model to measure age-related changes in the cerebral arteries from 3D MRA using a 3D deep convolutional neural network (CNN). From participants without any medical abnormality, training (n=800) and validation sets (n=88) of 3D MRA were built. After preprocessing and data augmentation, a 3D CNN was trained to estimate each subject’s chronological age from in-vivo MRA data. There was good correlation between chronological age and predicted age (r=0.83) in an independent test set (n=354). The predicted age difference (PAD) of the test set was 2.41 ± 6.22. Interaction term between age and sex was significant for PAD (P=0.008). After correcting for age and interaction term, men showed higher PAD (P<0.001). Hypertension was associated with higher PAD with marginal significance (P=0.073). We suggested that PAD might be a potential measurement of cerebral vascular aging.

    更新日期:2019-12-17
  • Rho-kinase ROCK Inhibitors Reduce Oligomeric Tau Protein
    Neurobiol. Aging (IF 4.398) Pub Date : 2019-12-16
    Tadanori Hamano; Norimichi Shirafuji; Shu-Hui Yen; Hirotaka Yoshida; Nicholas M. Kanaan; Kouji Hayashi; Masamichi Ikawa; Osamu Yamamura; Youshi Fujita; Masaru Kuriyama; Yasunari Nakamoto

    Neurofibrillary tangles (NFTs), one of the pathological hallmarks of Alzheimer’s disease (AD), consist of highly phosphorylated tau proteins. Tau protein binds to microtubules, and is best known for its role in regulating microtubule dynamics. However, if tau protein is phosphorylated by activated major tau kinases, including glycogen synthase kinase 3β (GSK3β) or cyclin dependent kinase 5 (Cdk5), or inactivated tau phosphatase, including protein phosphatase 2A (PP2A), its affinity for microtubules is reduced, and the free tau is believed to aggregate, thereby forming NFTs. We previously reported that pitavastatin decreases the total and phosphorylated tau protein using a cellular model of tauopathy. The reduction of tau was considered to be due to Rho-associated coiled coil protein kinase (ROCK) inhibition by pitavastatin (Hamano et al., 2012). ROCK plays important roles to organize the actin cytoskeleton, an expected therapeutic target of human disorders. Several ROCK inhibitors are clinically applied to prevent vasospasm post-subarachnoidal hemorrhage (fasudil) and for the treatment of glaucoma (ripasudil). We have examined the effects of ROCK inhibitors (H 1152, Y-27632, and fasudil (HA-1077)) on tau protein phosphorylation in detail. A human neuroblastoma cell line (M1C cells) that expresses wild-type tau protein (4R0N) by tetracycline-off (TetOff) induction, primary cultured mouse neurons, and a mouse model of tauopathy (rTG4510 line) were used. The levels of phosphorylated tau and caspase-cleaved tau were reduced by the ROCK inhibitors. Oligomeric tau levels were also reduced by ROCK inhibitors. Following ROCK inhibitor treatment, GSK3β, Cdk5, and caspase were inactivated, PP2A was activated, and the levels of IFN-γ were reduced. ROCK inhibitors activated autophagy and proteasome pathways, which are considered important for the degradation of tau protein. Collectively, these results suggest that ROCK inhibitors represent a viable therapeutic route to reduce the pathogenic forms of tau protein in tauopathies, including AD.

    更新日期:2019-12-17
  • Distance Disintegration Delineates the Brain Connectivity Failure of Alzheimer’s Disease
    Neurobiol. Aging (IF 4.398) Pub Date : 2019-12-14
    Victor Costumero; Federico d'Oleire Uquillas; Ibai Diez; Magi Andorrà; Silvia Basaia; Elisenda Bueichekú; Laura Ortiz-Terán; Vicente Belloch; Joaquin Escudero; César Ávila; Jorge Sepulcre

    Alzheimer disease (AD) is associated with brain network dysfunction. Network-based investigations of brain connectivity have mainly focused on alterations in the strength of connectivity, however, the network breakdown in AD spectrum is a complex scenario in which multiple pathways of connectivity are affected. In order to integrate connectivity changes that occur under AD-related conditions, here we developed a novel metric that computes the connectivity distance between cortical regions at the voxel-level (or nodes). We studied 114 individuals with mild cognitive impairment, 24 with AD and 27 healthy controls. Results showed that areas of the default mode network, salience network, and fronto-parietal network, display a remarkable network separation, or greater connectivity distances, from the rest of the brain. Furthermore, this greater connectivity distance was associated with lower global cognition. Overall, the investigation of AD-related changes in paths and distances of connectivity provides a novel framework for characterizing subjects with cognitive impairment; a framework that integrates the overall network topology changes of the brain and avoids biases toward unreferenced connectivity effects.

    更新日期:2019-12-17
  • Age differences in the fronto-striato-parietal network underlying serial ordering
    Neurobiol. Aging (IF 4.398) Pub Date : 2019-12-13
    Zheng Ye; Guanyu Zhang; Shuaiqi Li; Yingshuang Zhang; Weizhong Xiao; Xiaolin Zhou; Thomas F. Münte

    Maintaining the ability to arrange thoughts and actions in an appropriate serial order is crucial for complex behavior. We aimed to investigate age differences in the fronto-striato-parietal network underlying serial ordering using functional magnetic resonance imaging. We exposed 25 young and 27 older healthy adults to a digit ordering task where they had to reorder and recall sequential digits or simply to recall them. We detected a network comprising of the lateral and medial prefrontal, posterior parietal, and striatal regions. In young adults, the prefrontal and parietal regions were more activated and more strongly connected with the supplementary motor area for ‘reorder & recall’ than ‘pure recall’ trials (psychophysiological interaction, PPI). In older adults, the prefrontal and parietal activations were elevated, but the PPI was attenuated. Individual adults who had a stronger PPI performed more accurately in ‘reorder & recall’ trials. The decreased PPI appeared to be compensated by increased physiological correlations between the prefrontal/parietal cortex and the striatum, and by that between the striatum and the supplementary motor area.

    更新日期:2019-12-13
  • Neurophysiological alterations in the nucleus reuniens of a mouse model of Alzheimer’s disease
    Neurobiol. Aging (IF 4.398) Pub Date : 2019-12-12
    D.A. Walsh; J.T. Brown; A.D. Randall

    Recently, increased neuronal activity in nucleus reuniens (Re), has been linked to hyperexcitability within hippocampal-thalamo-cortical networks in the J20 mouse model of amyloidopathy. Here in vitro whole-cell patch clamp recordings were used to compare old pathology-bearing J20 mice and wild-type controls to examine whether altered intrinsic electrophysiological properties could contribute to the amyloidopathy-associated Re hyperactivity. A greater proportion of Re neurons display hyperpolarised membrane potentials in J20 mice without changes to the incidence or frequency of spontaneous action potentials (AP). Re neurons recorded from J20 mice did not exhibit increased AP generation in response to depolarising current stimuli but an increased propensity to rebound burst following hyperpolarising current stimuli. Increased rebound firing did not appear to result from alterations to T-type calcium channels. Finally, in J20 mice there was an ∼8% reduction in spike width, similar to what has been reported in CA1 pyramidal neurons from multiple amyloidopathy mice. We conclude that alterations to the intrinsic properties of Re neurons may contribute to hippocampal-thalmo-cortical hyperexcitability observed under pathological Aβ load.

    更新日期:2019-12-13
  • Trajectory of Lobar Atrophy in Asymptomatic and Symptomatic GRN Mutation Carriers: a Longitudinal MRI Study
    Neurobiol. Aging (IF 4.398) Pub Date : 2019-12-12
    Qin Chen; Bradley F. Boeve; Matthew Senjem; Nirubol Tosakulwong; Timothy Lesnick; Danielle Brushaber; Christina Dheel; Julie Fields; Leah Forsberg; Ralitza Gavrilova; Debra Gearhart; Jonathan Graff-Radford; Neill Graff-Radford; Clifford R. Jack; David Jones; David Knopman; Walter K. Kremers; Maria Lapid; Kejal Kantarci

    Loss-of-function mutations in the progranulin gene (GRN) are one of the major causes of familial frontotemporal lobar degeneration (FTLD). Our objective was to determine the rates and trajectories of lobar cortical atrophy from longitudinal structural MRI in both asymptomatic and symptomatic GRN mutation carriers. Individuals in this study were from the ADRC and LEFFTDS studies at the Mayo Clinic. We identified 13 GRN mutation carriers (8 asymptomatic, 5 symptomatic) and non-carriers (n=10) who had at least 2 serial T1-weighted structural MRIs and were followed annually with a median of 3 years (range 1.0 to 9.8 years). Longitudinal changes in lobar cortical volume were analyzed using the tensor-based morphometry with symmetric normalization (TBM-SyN) algorithm. Linear mixed effect models were used to model cortical volume change over time among 3 groups. The annual rates of frontal (p<0.05) and parietal (p<0.01) lobe cortical atrophy were higher in asymptomatic GRN mutation carriers than non-carriers. The symptomatic GRN mutation carriers also had increased rates of atrophy in the frontal (p<0.01) and parietal lobe (p<0.01) cortices than non-carriers. In addition, greater rates of cortical atrophy were observed in the temporal lobe cortices of symptomatic GRN mutation carriers than non-carriers (p<0.001). We found that a decline in frontal and parietal lobar cortical volume occurs in asymptomatic GRN mutation carriers and continues in the symptomatic GRN mutation carriers, while an increased rate of temporal lobe cortical atrophy is observed only in symptomatic GRN mutation carriers. This sequential pattern of cortical involvement in GRN mutation carriers has important implications for utilizing imaging biomarkers of neurodegeneration as an outcome measure in potential treatment trials involving GRN mutation carriers.

    更新日期:2019-12-13
  • Determinants of mesial temporal lobe volume loss in older individuals with preserved cognition: a longitudinal PET amyloid study
    Neurobiol. Aging (IF 4.398) Pub Date : 2019-12-11
    Marie-Louise Montandon, François R. Herrmann, Valentina Garibotto, Cristelle Rodriguez, Sven Haller, Panteleimon Giannakopoulos

    Mesial temporal lobe (MTL) is prominently affected in normal aging and associated with neurodegeneration in AD. Whether or not MTL atrophy is dependent on increasing amyloid load prior to the emergence of cognitive deficits is still disputed. We performed a 4.5-year longitudinal study in 75 older community dwellers (48 women, mean age: 79.3 years) including MRI at baseline and follow-up, PET amyloid during follow-up, neuropsychological assessment at 18 and 55 months, and APOE genotyping. Linear regression models were used to identify predictors of the MTL volume loss. Amyloid load was negatively associated with bilateral MTL volume at baseline explaining almost 10.5% of its variability. In multivariate models including time of follow-up as well as demographic variables (older age, male gender) this percentage exceeded 35%. The APOE4 allele independently contributed another 6%. Cognitive changes had a modest but still significant negative association with MTL volume loss. Our data support a multifactorial model including amyloid deposition, older age, male gender, APOE4 allele and slight decline of cognitive abilities as independent predictors of MTL volume loss in brain aging.

    更新日期:2019-12-11
  • Delivery of exogenous proteins by mesenchymal stem cells attenuates early memory deficits in a murine model of Alzheimer's disease
    Neurobiol. Aging (IF 4.398) Pub Date : 2019-12-11
    An Li, Jiayi Zhao, Chongzhu Fan, Lihong Zhu, Cuiqin Huang, Qin Li, Danhui Gan, Caiyan Wen, Mengfei Chen, Daxiang Lu
    更新日期:2019-12-11
  • Dysregulated Fc gamma receptor-mediated phagocytosis pathway in Alzheimer's disease: network-based gene expression analysis
    Neurobiol. Aging (IF 4.398) Pub Date : 2019-12-10
    Young Ho Park, Angela Hodges, Shannon L. Risacher, Kuang Lin, Jae-Won Jang, Soyeon Ahn, SangYun Kim, Simon Lovestone, Andrew Simmons, Michael W. Weiner, Andrew J. Saykin, Kwangsik Nho

    Transcriptomics has become an important tool for identification of biological pathways dysregulated in Alzheimer’s disease (AD). We performed a network-based gene expression analysis of blood-based microarray gene expression profiles using two independent cohorts, Alzheimer’s Disease Neuroimaging Initiative (ADNI; N=661) and AddNeuroMed (N=674). Weighted gene co-expression network analysis identified 17 modules from ADNI and 13 from AddNeuroMed. Four of the modules derived in ADNI were significantly related to AD; 5 modules in AddNeuroMed were significant. Gene-set enrichment analysis of the AD-related modules identified and replicated three biological pathways including the Fc gamma receptor-mediated phagocytosis pathway. Module-based association analysis showed the AD-related module, which has the three pathways, to be associated with cognitive function and neuroimaging biomarkers. Gene-based association analysis identified PRKCD in the Fc gamma receptor-mediated phagocytosis pathway as being significantly associated with cognitive function and CSF biomarkers. The identification of the Fc gamma receptor-mediated phagocytosis pathway implicates the peripheral innate immune system in the pathophysiology of AD. PRKCD is known to be related to neurodegeneration induced by amyloid-β.

    更新日期:2019-12-11
  • Effect of a 24-month physical activity program on brain changes in older adults at risk of Alzheimer's disease: the AIBL active trial
    Neurobiol. Aging (IF 4.398) Pub Date : 2019-05-27
    Vijay K. Venkatraman, Andrew Sanderson, Kay L. Cox, Kathryn A. Ellis, Christopher Steward, Pramit M. Phal, Alexandra Gorelik, Matthew J. Sharman, Victor L. Villemagne, Michelle Lai, Elizabeth V. Cyarto, Bernd Merkel, David Ames, Cassandra Szoeke, Christopher C. Rowe, Colin L. Masters, Nicola T. Lautenschlager, Patricia M. Desmond

    White matter hyperintensities (WMHs) are a risk factor for cognitive decline. Physical activity (PA) is associated with lower WMH. Whether long-term exposure to PA programs has beneficial effects on WMH progression in older adults with memory complaints and comorbid conditions has had limited exploration. This study explored whether a 24-month moderate-intensity PA intervention can delay the progression of WMH and hippocampus loss in older adults at risk for cognitive decline. Data acquired on magnetic resonance imaging were used to measure the progression of WMH and hippocampus loss. The results of this study showed no effect of intervention on either the primary outcome measure “WMH” or the secondary outcome measure “hippocampal volume.” In addition, neither beta amyloid status nor the adherence to the intervention had any effect on the outcome. In this cohort of subjective memory complaints and mild cognitive impairment participants with vascular risk factors, there was no effect of long-term moderate-intensity PA on WMH or hippocampal loss.

    更新日期:2019-12-11
  • Rare, low-frequency and common coding variants of ARHGEF28 gene and their association with sporadic amyotrophic lateral sclerosis
    Neurobiol. Aging (IF 4.398) Pub Date : 2019-03-26
    Yang Song, Feng Lin, Cheng-hui Ye, Huaping Huang, Xuying Li, Xiaoli Yao, Yanming Xu, Chaodong Wang

    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. Over 90% of cases are sporadic (sALS) and 5%–10% are familial (fALS). So far, more than 20 genes/loci have been linked to ALS. C9orf72, SOD1, TARDBP, and FUS are noted as the most common ALS genes; however, mutations of these genes explain <10% of sALS cases. Recently, Rho guanine nucleotide exchange factor, encoded by ARHGEF28, has been linked to the ALS pathogenesis, possibly by binding low-molecular-weight neurofilament mRNA and affects its stability. However, a systemic screening of ARHGEF28 mutations in ALS is lacking. In this study, we sequenced the entire coding sequence of ARHGEF28 in a Chinese cohort of 399 sporadic ALS and 327 elderly controls. A total of 73 coding variants were identified, including 26 synonymous and 47 nonsynonymous. Among the nonsynonymous variants, 33 were rare (minor allele frequency [MAF]<0.01), in which 18 were only identified in cases and 12 were only in controls. Three loss-of-function mutations were identified, including 2 truncations (p.Arg231Ter and p.Ser561Ter) and a frameshift deletion (p.Lys1070fs) in 2 cases and 1 control subject. The frequency of total and case-only rare variants was 7.5% (30/399) and 5.0% (20/399), respectively, in the patients. SKAT-O test suggested that the novel coding variants were marginally enriched in the cases (p = 0.049). Single-variant analysis suggested that the p.Asn1046Ser variant had a higher frequency in cases (8/399, 0.02) than in controls (1/327, 0.003) (OR: 6.67, 95% CI: 0.83–53.61; p = 0.046). By contrast, none of the low-frequency (MAF: 0.01–0.05) or common (MAF > 0.05) variants was associated with ALS (p > 0.05). Among all patients, 9 (2.3%) carried rare variants predicted to be deleterious, and the age at onset of these carriers (45.6 ± 10.9 years) was marginally younger than noncarriers (51.9 ± 10.7 years) (p = 0.11). Our results supported a possible genetic contribution of rare but not low-frequency and common coding variants to ALS. These data may have implications in the mechanisms and genetic counseling of the disease.

    更新日期:2019-12-11
  • ITPKB and ZNF184 are associated with Parkinson's disease risk in East Asians
    Neurobiol. Aging (IF 4.398) Pub Date : 2019-02-02
    Elaine Guo Yan Chew, Louis C.S. Tan, Wing-Lok Au, Kumar-M. Prakash, Jianjun Liu, Jia Nee Foo, Eng-King Tan

    A recent meta-analysis of Parkinson's disease (PD) genome-wide association studies has identified 17 novel risk loci in the European population. We aim to assess if these reported novel risk loci are similarly implicated in PD risk within the East Asian population by analyzing the reported risk single nucleotide polymorphism or proxy single nucleotide polymorphism in 14,006 East Asian samples (779 patients and 13,227 controls). We found that 9 of the 17 reported novel PD risk loci showed very similar effects in Europeans and East Asians (I2 = 0 to 10.7%), of which 2 loci ITPKB and ZNF184 were significantly associated with PD in our samples. Two of the reported risk loci, ANK2/CAMK2D and CTSB, were non-polymorphic in East Asians and therefore not implicated in PD risk in the East Asian population. Given the small effect sizes of these risk loci, further validation is needed in additional Asian samples.

    更新日期:2019-12-11
  • Genetic screening in early-onset Alzheimer's disease identified three novel presenilin mutations
    Neurobiol. Aging (IF 4.398) Pub Date : 2019-01-29
    Tsz Hang Wong, Harro Seelaar, Shamiram Melhem, Annemieke J.M. Rozemuller, John C. van Swieten

    Mutations in presenilin 1 (PSEN1), presenilin 2 (PSEN2), and amyloid precursor protein (APP) are major genetic causes of early-onset Alzheimer's disease (EOAD). Clinical heterogeneity is frequently observed in patients with PSEN1 and PSEN2 mutations. Using whole exome sequencing, we screened a Dutch cohort of 68 patients with EOAD for rare variants in Mendelian Alzheimer's disease, frontotemporal dementia, and prion disease genes. We identified 3 PSEN1 and 2 PSEN2 variants. Three variants, 1 in PSEN1 (p.H21Profs*2) and both PSEN2 (p.A415S and p.M174I), were novel and absent in control exomes. These novel variants can be classified as probable pathogenic, except for PSEN1 (p.H21Profs*2) in which the pathogenicity is uncertain. The initial clinical symptoms between mutation carriers varied from behavioral problems to memory impairment. Our findings extend the mutation spectrum of EOAD and underline the clinical heterogeneity among PSEN1 and PSEN2 mutation carriers. Screening for Alzheimer's disease–causing genes is indicated in presenile dementia with an overlapping clinical diagnosis.

    更新日期:2019-12-11
  • A novel homozygous mutation in TREM2 found in a Chinese early-onset dementia family with mild bone involvement
    Neurobiol. Aging (IF 4.398) Pub Date : 2019-01-24
    Xiantao Li, Yimin Sun, Lingyun Gong, Li Zheng, Keliang Chen, Yan Zhou, Yuehua Gu, Yao Xu, Qihao Guo, Zhen Hong, Ding Ding, Jianhui Fu, Qianhua Zhao

    Variants in triggering receptor expressed on myeloid cells 2 (TREM2) are associated with both behavioral variant frontotemporal lobar degeneration and Alzheimer's disease. TREM2 homozygous mutations cause Nasu-Hakola disease, an early-onset recessive form of dementia preceded by bone cysts and fractures. The same type of mutations has been shown to cause frontotemporal dementia without the presence of any bone phenotype. Herein, we report a Chinese Han consanguineous family carrying a novel TREM2 mutation, presenting with early-onset dementia similar to behavioral variant frontotemporal dementia with mild radiological bone involvement. Minigene reporter assay showed the variant disturbed splicing by preservation of intron 2 in transcription. In our investigation, the clinical and genetic spectra of Chinese early-onset dementia patients were expanded; TREM2 mutations should be screened in familial and Chinese early-onset dementia patients.

    更新日期:2019-12-11
  • Genetic risk for coronary heart disease alters the influence of Alzheimer's genetic risk on mild cognitive impairment
    Neurobiol. Aging (IF 4.398) Pub Date : 2019-06-08
    Jeremy A. Elman, Matthew S. Panizzon, Mark W. Logue, Nathan A. Gillespie, Michael C. Neale, Chandra A. Reynolds, Daniel E. Gustavson, Brinda K. Rana, Ole A. Andreassen, Anders M. Dale, Carol E. Franz, Michael J. Lyons, William S. Kremen

    Understanding genetic influences on Alzheimer's disease (AD) may improve early identification. AD polygenic risk scores (AD-PRSs) are associated with increased odds of AD and mild cognitive impairment (MCI). Additional sources of genetic risk may also contribute to disease outcomes. Coronary artery disease (CAD) is a risk factor for AD, interacts with AD pathology, and is also heritable. We showed that incidence-based and prevalence-based CAD-PRSs moderate the association between the AD-PRS and MCI, but in opposing directions. Higher incidence-based CAD-PRSs interacted with the AD-PRS to further increase MCI risk. Conversely, the AD-PRS was predictive of MCI when prevalence-based CAD-PRSs were low. The latter finding is likely due to prevalent CAD cases being biased toward longer postevent survival times, perhaps selecting for protective loci that offset AD risk. These results demonstrate (1) the importance of examining multiple PRSs and their interactions; (2) how genetic risk for one disease can modify the impact of genetic risk for another; and (3) the importance of considering ascertainment procedures of GWAS used for genetic risk prediction.

    更新日期:2019-12-07
  • c-fos revealed lower hippocampal participation in older homing pigeons when challenged with a spatial memory task
    Neurobiol. Aging (IF 4.398) Pub Date : 2019-12-05
    Vincent J. Coppola, Verner P. Bingman

    Homing pigeons experience age-related spatial-cognitive decline similar to that seen in mammals. In contrast to mammals, however, previous studies have shown the hippocampal formation (HF) of old, cognitively-impaired pigeons to be greater in volume and neuron number compared to young pigeons. As a partial explanation of the cognitive decline in older birds, it was hypothesized that older pigeons have reduced HF activation during spatial learning. The current study compared HF activation (via the activity-dependent expression of the immediate early gene c-Fos) between younger and older pigeons during learning of a spatial, delayed non-match-to-sample task. On the last day of training, c-Fos activation significantly correlated with behavioral performance in the young, but not old, pigeons suggesting more HF engagement by the young pigeons in solving the task. The behavioral correlation was additionally associated with consistently higher, but insignificant c-Fos activation across practically every HF subdivision in the young compared to the old pigeons. In sum, the results of the current study are consistent with the hypothesis that age-related decline in the spatial cognitive ability of homing pigeons is in part a result of an older HF being less responsive to the processing of spatial information. However, alternative interpretations of the data are discussed.

    更新日期:2019-12-05
  • Education does not Protect Cognitive Function from Brain Pathology in the ADNI 2 Cohort
    Neurobiol. Aging (IF 4.398) Pub Date : 2019-12-05
    Christopher E. Bauer, Christopher A. Brown, Brian T. Gold

    Educational attainment is widely accepted as a cognitive reserve variable. However, few studies have demonstrated that education statistically moderates the effects of pathology on cognition. Here, we explored this issue in a sample of 441 Alzheimer’s disease (AD) and mild cognitive impairment (MCI) participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI2) cohort who had AD markers (Aβ42, tau, structural brain volumes) at baseline and underwent cognitive testing at baseline and at 6-month, 12-month, and 24-month timepoints. An AD-related biomarker (atrophy/pathology) composite at baseline was developed using stepwise backward linear regression. Potential moderation effects of education on the relationship between AD biomarkers and memory and executive function were explored using linear mixed models. Education was positively correlated with cognition, and biomarkers were negatively correlated with cognition, across domains and diagnostic groups. However, education generally did not moderate the effects of biomarkers on baseline or longitudinal cognition. Our results do not support the hypothesis that education protects cognitive function from brain pathology in the ADNI 2 cohort, questioning its accepted status as a reserve variable.

    更新日期:2019-12-05
  • Characterization of Age-related Microstructural Changes in Locus Coeruleus and Substantia Nigra Pars Compacta
    Neurobiol. Aging (IF 4.398) Pub Date : 2019-11-29
    Jason Langley, Sana Hussain, Justino J. Flores, Ilana J. Bennett, Xiaoping Hu

    Locus coeruleus (LC) and substantia nigra pars compacta (SNpc) degrade with normal aging, but not much is known regarding how these changes manifest in MRI images, or whether these markers predict aspects of cognition. Here, we use high-resolution diffusion-weighted MRI to investigate microstructural and compositional changes in LC and SNpc in young and older adult cohorts, as well as their relationship with cognition. In LC, the older cohort exhibited a significant reduction in mean and radial diffusivity, but a significant increase in fractional anisotropy compared to the young cohort. We observed a significant correlation between the decrease in LC mean, axial, and radial diffusivities and measures examining cognition (Rey Auditory Verbal Learning Test delayed recall) in the older adult cohort. This observation suggests that LC is involved in retaining cognitive abilities. In addition, we observed that iron deposition in SNpc occurs early in life and continues during normal aging.

    更新日期:2019-11-29
  • Voluntary exercise increases brain tissue oxygenation and spatially homogenizes oxygen delivery in a mouse model of Alzheimer's Disease
    Neurobiol. Aging (IF 4.398) Pub Date : 2019-11-27
    Xuecong Lu, Mohammad Moeini, Baoqiang Li, Olivia de Montgolfier, Yuankang Lu, Samuel Bélanger, Éric Thorin, Frédéric Lesage

    While vascular contributions to dementia and Alzheimer’s Disease (AD) are increasingly recognized, the potential brain oxygenation disruption associated with AD and whether preventive strategies to maintain tissue oxygenation are beneficial remain largely unknown. This study aimed to examine 1) whether brain oxygenation is compromised by the onset of AD and 2) how voluntary exercise modulates the influence of AD on brain oxygenation. In vivo two-photon phosphorescence lifetime microscopy was used to investigate local changes of brain tissue oxygenation with the progression of AD and its modulation by exercise in the barrel cortex of awake transgenic AD mice. Our results show that cerebral tissue oxygen partial pressure (PO2) decreased with the onset of AD. Reduced PO2 was associated with the presence of small near-hypoxic areas, an increased oxygen extraction fraction, and reduced blood flow, observations that were all reverted by exercise. AD and age also increased the spatial heterogeneity of brain tissue oxygenation, which was normalized by exercise. Ex vivo staining also showed fewer amyloid-β (Aβ) deposits in the exercise group. Finally, we observed correlations between voluntary running distance and cerebral tissue oxygenation/blood flow, suggesting a dose-response relationship of exercise on the brain. Overall, this study suggests that compromised brain oxygenation is an indicator of the onset of AD, with the emergence of potential deleterious mechanisms associated with hypoxia. Furthermore, voluntary exercise enhanced the neurovascular oxygenation process, potentially offering a means to delay these changes.

    更新日期:2019-11-28
  • A high-sucrose diet aggravates Alzheimer's disease pathology, attenuates hypothalamic leptin signaling, and impairs food-anticipatory activity in APPswe/PS1dE9 mice
    Neurobiol. Aging (IF 4.398) Pub Date : 2019-11-27
    Skye Hsin-Hsien Yeh, Feng-Shiun Shie, Hui-Kang Liu, Heng-Hsiang Yao, Pei-Chen Kao, Yi-Heng Lee, Li-Min Chen, Shu-Meng Hsu, Li-Jung Chao, Kuan-Wei Wu, Young-Ji Shiao, Huey-Jen Tsay
    更新日期:2019-11-28
  • Multi-shell diffusion imaging reveals sex-specific trajectories of early white matter degeneration in normal aging
    Neurobiol. Aging (IF 4.398) Pub Date : 2019-11-27
    Nicola Toschi, Rebeca Arrais Gisbert, Luca Passamonti, Santiago Canals, Silvia De Santis

    During aging, human white matter (WM) is subject to dynamic structural changes which have a deep impact on healthy and pathological evolution of the brain through the lifespan; characterizing this pattern is of key importance for understanding brain development, maturation and aging as well as for studying its pathological alterations. Diffusion Magnetic Resonance Imaging (MRI) can provide a quantitative assessment of the white-matter microstructural organization that characterizes these trajectories. Here, we use both conventional and advanced diffusion MRI in a cohort of 91 individuals (age range: 13-62) to study region- and sex-specific features of WM micro-structural integrity in healthy aging. We focus on the age at which microstructural imaging parameters invert their development trend as the timepoint which marks the onset of microstructural decline in WM. Importantly, our results indicate that age-related brain changes begin earlier in males than females and affect more frontal regions - in accordance with evolutionary theories and numerous evidences across non-MRI domains. Advanced diffusion MRI reveals age-related WM modifications patterns which cannot be detected using conventional DTI.

    更新日期:2019-11-28
  • Basal forebrain metabolism in Alzheimer’s Disease continuum: relationship with education
    Neurobiol. Aging (IF 4.398) Pub Date : 2019-11-27
    Brandt Nicolas, Dodich Alessandra, Perani Daniela, Ratib Osman, Trombella Sara, Frisoni Giovanni B, Garibotto Valentina

    We analyzed education, as a proxy of cognitive reserve (CR), and the cholinergic pathway in Alzheimer’s disease (AD), to test the hypothesis that education might modulate the relationship between clinical symptoms and metabolic and structural changes in AD. We included 84 subjects and compared between diagnostic groups and different educational levels the glucose metabolism and volume of basal forebrain (BFM and BFV), the major cholinergic structure, and hippocampus (HM and HV), a relevant projection site for the BF. Correlations with the global cognitive status and education in the whole sample were also performed. AD dementia patients showed reduced BFV, HV and HM compared to controls. In the whole group, the global cognitive status was positively correlated with BFM and HM. Among high-educated subjects, mild cognitive impairment (MCI) showed higher BFM and HM in comparison to other diagnostic groups. Our results suggest that in MCI subjects with a higher educational level cholinergic activity is upregulated and this appears to have a compensatory effect, which may be lost in later symptomatic stages.

    更新日期:2019-11-27
  • Differences in neuroimaging features of early- versus late-onset nonfluent/agrammatic primary progressive aphasia
    Neurobiol. Aging (IF 4.398) Pub Date : 2019-11-26
    Jin San Lee, Sole Yoo, Seongbeom Park, Hee Jin Kim, Key-Chung Park, Joon-Kyung Seong, Mee Kyung Suh, Juyoun Lee, Hyemin Jang, Ko Woon Kim, Yeshin Kim, Soo Hyun Cho, Seung Joo Kim, Jun Pyo Kim, Young Hee Jung, Eun-Joo Kim, Yeon-Lim Suh, Samuel N. Lockhart, Sang Won Seo

    This study investigated distinct neuroimaging features measured by cortical thickness and subcortical structural shape abnormality in early-onset (EO, onset age <65 years) and late-onset (LO, onset age ≥65 years) nonfluent/agrammatic variant of primary progressive aphasia (nfvPPA) patients. Cortical thickness and subcortical structural shape analyses were performed using a surface-based method from 38 patients with nfvPPA and 76 cognitively normal individuals. To minimize the effects of physiological aging, we used W-scores in comparisons between the groups. The EO-nfvPPA group exhibited more extensive cortical thickness reductions predominantly in the left perisylvian, lateral and medial prefrontal, temporal, posterior cingulate, and precuneus regions than the LO-nfvPPA group. The EO-nfvPPA group also exhibited significantly greater subcortical structural shape abnormality than the LO-nfvPPA group, mainly in the left striatum, hippocampus, and amygdala. Our findings suggested that there were differences in neuroimaging features between these groups by the age of symptom onset, which might be explained by underlying heterogeneous neuropathological differences or the age-related brain reserve hypothesis.

    更新日期:2019-11-27
  • Normal brain aging and Alzheimer’s disease are associated with lower cerebral pH: an in vivo histidine 1H-MR spectroscopy study
    Neurobiol. Aging (IF 4.398) Pub Date : 2019-11-22
    Epameinondas Lyros, Andreas Ragoschke-Schumm, Panagiotis Kostopoulos, Alexandra Sehr, Martin Backens, Stefania Kalampokini, Yann Decker, Martin Lesmeister, Yang Liu, Wolfgang Reith, Klaus Fassbender

    It is unclear whether alterations in cerebral pH underlie Alzheimer’s disease (AD) and other dementias. We performed proton spectroscopy after oral administration of histidine in healthy young and elderly persons and in patients with mild cognitive impairment (MCI) and dementia (total N=147). We measured cerebral tissue pH and ratios of common brain metabolites in relation to phosphocreatine and creatine (Cr) in spectra acquired from the hippocampus, the white matter of the centrum semiovale (WM) and the cerebellum. Hippocampal pH was inversely associated with age in healthy participants, but did not differ between patients and controls. WM pH was low in AD and, to a lesser extent, MCI but not in frontotemporal dementia spectrum disorders and pure vascular dementia. Furthermore, WM pH provided incremental diagnostic value in addition to N-acetylaspartate to Cr ratio. Our study suggests that in vivo assessment of pH may be a useful marker for the differentiation between AD and other types of dementia.

    更新日期:2019-11-22
  • Serum Pro-Bdnf Levels Correlate With Phospho-Tau Staining In Alzheimer’s Disease
    Neurobiol. Aging (IF 4.398) Pub Date : 2019-11-22
    Krishna L. Bharani, Aurélie Ledreux, Anah Gilmore, Steven L. Carroll, Ann-Charlotte Granholm

    Disruption of brain-derived neurotrophic factor (BDNF) biosynthesis and/or signaling has been implicated in the pathogenesis of Alzheimer’s disease (AD). We utilized post mortem brain and fluid samples from 20 patients with variable severity of AD and 11 controls to investigate whether BDNF levels in serum and brain tissue correlated with hippocampal pathology. Total BDNF (tBDNF), proBDNF, and mature BDNF (mBDNF) were measured in cranial spinal fluid (CSF), serum, and three post mortem brain regions. Histological markers for AD pathology, BDNF cognate receptor (TrkB), and glia were measured in the hippocampus (HIP). Lower proBDNF levels were observed in the entorhinal and frontal cortices in AD cases compared to controls. AD cases also exhibited significantly lower staining densities of the cognate BDNF receptor TrkB in the HIP compared to controls, and TrkB staining was inversely correlated with both Amylo-Glo and pTau staining in the same region, suggesting a relationship between the density of the cognate BDNF receptor and accumulation of AD pathology. In addition, higher serum proBDNF levels correlated with lower HIP proBDNF levels and higher pTau staining in the HIP. Total BDNF levels in cortical regions were also negatively correlated with Amylo-Glo staining in the hippocampus suggesting that reduced BDNF cortical levels might influence hippocampal amyloid accumulation. These results strongly suggest that altered BDNF and TrkB receptors are involved in AD pathology and therefore warrant investigations into therapies involving the BDNF pathway.

    更新日期:2019-11-22
  • Medial Temporal Lobe White Matter Pathway Variability is Associated with Individual Differences in Episodic Memory in Cognitively Normal Older Adults
    Neurobiol. Aging (IF 4.398) Pub Date : 2019-11-21
    Kylie H. Alm, Andreia V. Faria, Abhay Moghekar, Corinne Pettigrew, Anja Soldan, Susumu Mori, Marilyn Albert, Arnold Bakker

    Significant evidence demonstrates that aging is associated with variability in cognitive performance, even among individuals who are cognitively normal. In this study, we examined measures from magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) to investigate which measures, alone or in combination, were associated with individual differences in episodic memory performance. Using hierarchical linear regressions, we compared the ability of diffusion tensor imaging (DTI) metrics, CSF measures of amyloid and tau, and gray matter volumes to explain variability in memory performance in a cohort of cognitively normal older adults. Measures of DTI microstructure were significantly associated with variance in memory performance, even after accounting for the contribution of the measures of CSF and MRI gray matter volume. Significant associations were found between DTI measures of the hippocampal cingulum and fornix with individual differences in memory. No such relationships were found between memory performance and CSF markers or gray matter volumes. These findings suggest that DTI metrics may be useful in identifying changes associated with aging or age-related diseases.

    更新日期:2019-11-22
  • Two pathologically confirmed cases of novel mutations in the MAPT gene causing frontotemporal dementia
    Neurobiol. Aging (IF 4.398) Pub Date : 2019-11-20
    Rachelle Shafei, Ione O.C. Woollacott, Catherine J. Mummery, Martina Bocchetta, Rita Guerreiro, Jose Bras, Jason D. Warren, Tammaryn Lashley, Zane Jaunmuktane, Jonathan D. Rohrer

    MAPT mutations were the first discovered genetic cause of frontotemporal dementia (FTD) in 1998. Since that time, over 60 MAPT mutations have been identified, usually causing behavioural variant FTD (bvFTD) and/or parkinsonism clinically. We describe two novel MAPT mutations, D252V and G389_I392del, each presenting in a patient with bvFTD and associated language and cognitive deficits. Neuroimaging revealed asymmetrical left greater than right temporal lobe atrophy in the first case, and bifrontal atrophy in the second case. Disease duration was 8 years and 5 years respectively. Post mortem examination in both patients revealed a 3-repeat predominant tauopathy, similar in appearance to Pick's disease. These two mutations add to the literature on genetic FTD, both presenting with similar clinical and imaging features to previously described cases, and pathologically showing a primary tauopathy similar to a number of other MAPT mutations.

    更新日期:2019-11-20
  • Profile of pathogenic proteins in total circulating extracellular vesicles in mild cognitive impairment and during the progression of Alzheimer’s disease
    Neurobiol. Aging (IF 4.398) Pub Date : 2019-11-15
    Morgane Perrotte, Mohamed Haddad, Aurélie Le Page, Eric H. Frost, Tamàs Fulöp, Charles Ramassamy

    Accumulating evidence suggests that the propagation of hyperphosphorylation of Tau protein and β-amyloid peptide (Aβ) can be mediated by extracellular vesicles (EVs) and be associated with the onset and the progression of Alzheimer disease (AD). As EVs may transfer between the brain and the blood, we have thus hypothesized that the total plasma EVs (pEVs) may contain potential markers to predict the mild cognitive impairment (MCI) and AD progression. We have thus quantified AD-related proteins in isolated pEVs from controls, MCI and AD subjects. In pEVs, we observed early changes of tTau, APP levels and pTau-T181/tTau ratio from MCI subjects and late increases of Aβ42 and pTau-T181 levels from moderate AD patients. Interestingly, abnormal APP levels and pTau-T181/tTau ratio in pEVs demonstrated a high accuracy to define MCI and AD staging. Although larger samples sizes will be needed to generate well-powered investigations, these preliminary results highlighted the potential of AD-related proteins enriched in pEVs as a sensitive tool for differentiating MCI to AD patients and monitoring AD progression.

    更新日期:2019-11-18
  • Presenilin 1 Increases Association with Synaptotagmin 1 During Normal Aging
    Neurobiol. Aging (IF 4.398) Pub Date : 2019-11-15
    Laura J. Keller, Nicole M. Sekula, Sarah Svirsky, Masato Maesako, Katarzyna M. Zoltowska, Oksana Berezovska

    Presenilin 1 (PS1), the catalytic component of gamma secretase, associates with Synaptotagmin 1 (Syt-1). This interaction is decreased in the brains of sporadic Alzheimer’s disease (AD) patients. However, it remains unclear how this interaction changes during normal aging. Because aging is a risk factor for AD, we sought to identify changes in PS1 and Syt-1 association during aging in primary neurons in vitro and mouse brain sections ex vivo. We also tested the effect of aging on the calcium dependence of the interaction by treating neurons aged in vitro with KCl. We found that PS1 and Syt-1 increase their association with age, an effect that is more robust in neuronal processes than cell bodies. Treatment with KCl triggered the interaction in both young and old neurons. Baseline calcium levels as well as calcium influx in response to KCl treatment were significantly higher in older neurons, which can partially explain the increase in PS1/Syt-1 binding with age. These results suggest a compensatory mechanism during normal aging to offset detrimental age-associated effects.

    更新日期:2019-11-18
  • C9orf72 and intracerebral hemorrhage
    Neurobiol. Aging (IF 4.398) Pub Date : 2019-07-18
    Isabel C. Hostettler, Manuel Bernal-Quiros, Andrew Wong, Nikhil Sharma, Duncan Wilson, David J. Seiffge, Clare Shakeshaft, Hans R. Jäger, Hannah Cohen, Tarek Yousry, Rustam Al-Shahi Salman, Gregory Y.H. Lip, Martin M. Brown, Keith W. Muir, David J. Werring, Henry Houlden

    The chromosome 9 open reading frame 72 (C9orf72) GGGGCC repeat expansion has been associated with several diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. It has also been associated with increased white matter changes in frontotemporal dementia and risk of cognitive impairment in ALS. Dementia is common both before and after intracerebral hemorrhage (ICH). Because the mechanisms of cognitive impairment in patients with ICH are uncertain, we investigated whether C9orf72 could influence dementia risk in this patient group. Therefore, we genotyped 1010 clinically characterized ICH cases and 2147 population controls in comparison with prior data of dementia and ALS cases. We did not find any association between C9orf72 repeat expansion and repeat size with ICH compared with controls or with dementia when assessing ICH patients only. The frequency of C9orf72 expansions in our series of individuals born in 1946 (2/2147) and other U.K. controls was age dependent, decreasing with increasing age, highlighting the high age-dependent penetrance of this expansion.

    更新日期:2019-11-18
  • A patient with early-onset Alzheimer's disease with a novel PSEN1 p.Leu424Pro mutation
    Neurobiol. Aging (IF 4.398) Pub Date : 2019-06-13
    Gamze Guven, Nihan Erginel-Unaltuna, Bedia Samanci, Cagri Gulec, Hasmet Hanagasi, Basar Bilgic

    “Presenilin 1” (PSEN1) gene mutations are the major known genetic cause of early-onset Alzheimer's disease. Herein, we report a novel heterozygous PSEN1 mutation (p.Leu424Pro) in a Turkish patient presenting with deterioration of short-term memory and visuospatial skills starting at the age of 47 years. This novel mutation is located in the conserved residue of transmembrane domain 8 coded by exon 12. At the protein level, this mutation caused a disruption in the alpha helix structure of PSEN1. The structural and possible functional consequences of the mutation suggest that it has probably a pathogenic effect, which in turns had a potential role in the development of Alzheimer's disease in our patient.

    更新日期:2019-11-18
  • Improving Brain Age Prediction Models: Incorporation of Amyloid Status in Alzheimer’s Disease
    Neurobiol. Aging (IF 4.398) Pub Date : 2019-11-14
    Maria Ly, Gary Z. Yu, Helmet T. Karim, Nishita R. Muppidi, Akiko Mizuno, William E. Klunk, Howard J. Aizenstein

    Brain age prediction is a machine learning method that estimates an individual’s chronological age from their neuroimaging scans. Brain age indicates whether an individual’s brain appears “older” than age-matched healthy peers, suggesting that they may have experienced a higher cumulative exposure to brain insults or were more impacted by those pathological insults. However, contemporary brain age models include older participants with amyloid pathology in their training sets and thus may be confounded when studying Alzheimer’s disease (AD). We showed that amyloid status is a critical feature for brain age prediction models. We trained a model on T1-weighted MRI images participants without amyloid pathology. MRI data were processed to estimate gray matter density voxel-wise, which were then used to predict chronological age. Our model performed accurately comparable to previous models. Notably, we demonstrated more significant differences between AD diagnostic groups than other models. Additionally, our model was able to delineate significant differences in brain age relative to chronological age between cognitively normal individuals with and without amyloid. Incorporation of amyloid status in brain age prediction models ultimately improves the utility of brain age as a biomarker for AD.

    更新日期:2019-11-14
  • No genetic evidence for involvement of alcohol dehydrogenase genes in risk for Parkinson’s disease
    Neurobiol. Aging (IF 4.398) Pub Date : 2019-11-14
    Jonggeol Jeffrey Kim, Sara Bandres-Ciga, Cornelis Blauwendraat

    Multiple genes have been implicated in Parkinson’s disease (PD), including causal gene variants and risk variants typically identified using genome-wide association studies (GWAS). Variants in the alcohol dehydrogenase genes ADH1C and ADH1B are among the genes that have been associated with PD, suggesting that this family of genes may be important in PD. As part of the International Parkinson’s Disease Genomics Consortium’s (IPDGC) efforts to scrutinize previously reported risk factors for PD, we explored genetic variation in the alcohol dehydrogenase genes ADH1A, ADH1B, ADH1C, ADH4, ADH5, ADH6, and ADH7 using imputed GWAS data from 15,097 cases and 17,337 healthy controls. Rare-variant association tests and single-variant score tests did not show any statistically significant association of alcohol dehydrogenase genetic variation with the risk for PD.

    更新日期:2019-11-14
  • One novel GRN null mutation, two different aphasia phenotypes
    Neurobiol. Aging (IF 4.398) Pub Date : 2019-11-12
    Cinzia Coppola, Mariano Oliva, Dario Saracino, Sabina Pappatà, Emilia Zampella, Sara Cimini, Martina Ricci, Giorgio Giaccone, Giuseppe Di Iorio, Giacomina Rossi

    Progranulin gene (GRN) mutations are among the leading causes of Fronto-temporal lobar degeneration (FTLD), a group of neurodegenerative diseases characterized by remarkable clinical heterogeneity. In this paper we report the new GRN 708+4A>T splicing mutation, identified in two siblings of a family with several members affected by cognitive, behavioral and motor disorders. Plasma progranulin dosage and GRN expression analysis, together with in silico prediction studies, supported the pathogenicity of the mutation. Both the patients displayed a clinical syndrome in which language impairment was largely predominant. However, motor speech deficits were the major feature in one case, diagnosed as progressive non fluent aphasia, whereas marked semantic alterations were present in the other, whose clinical phenotype was in favor of a mixed aphasia. The profile of neuroanatomical alterations from imaging studies was in line with the clinical phenotypes. Therefore, also this novel GRN mutation is associated with haploinsufficiency and phenotypic heterogeneity, which are both typical features of progranulinopathies.

    更新日期:2019-11-13
  • APOE region molecular signatures of Alzheimer’s disease across races/ethnicities
    Neurobiol. Aging (IF 4.398) Pub Date : 2019-11-11
    Alexander M. Kulminski, Leonardo Shu, Yury Loika, Alireza Nazarian, Konstantin Arbeev, Svetlana Ukraintseva, Anatoliy Yashin, Irina Culminskaya

    The role of even the strongest genetic risk factor for Alzheimer’s disease (AD), the APOE ε4 allele, in its etiology remains poorly understood. We examined molecular signatures of AD defined as differences in linkage disequilibrium patterns between AD-affected and unaffected Whites (2,673/16,246), Hispanics (392/867), and African Americans (285/1,789), separately. We focused on 29 polymorphisms from five genes in the APOE region emphasizing beneficial and adverse effects of the APOE ε2- and ε4-coding SNPs, respectively, and the differences in the linkage disequilibrium structures involving these alleles between AD-affected and unaffected subjects. Susceptibility to AD is likely the result of complex interactions of the ε2 and ε4 alleles with other polymorphisms in the APOE region, and these interactions differ across races/ethnicities corroborating differences in the adverse and beneficial effects of the ε4 and ε2 alleles. Our findings support complex race/ethnicity-specific haplotypes promoting and protecting against AD in this region. They contribute to better understanding of polygenic and resilient mechanisms, which can explain why even homozygous ε4 carriers may not develop AD.

    更新日期:2019-11-13
  • Fear Acquisition and Extinction Deficits in Amnestic Mild Cognitive Impairment and Early Alzheimer’s Disease
    Neurobiol. Aging (IF 4.398) Pub Date : 2019-11-11
    Sarah Nasrouei, Julina A. Rattel, Michael Liedlgruber, Josef Marksteiner, Frank H. Wilhelm

    Impaired learning and memory functioning are prime markers for Alzheimer’s disease (AD). Although initial evidence points to impaired fear acquisition in later AD, no study has investigated fear conditioning in early stages and amnestic Mild Cognitive Impairment (aMCI), a condition often preceding AD. The present study examined if fear conditioning gradually decays from healthy elderly to aMCI, to AD. AD (n=43), aMCI (n=43), and matched healthy controls (HC, n=40) underwent a classical fear conditioning paradigm. During acquisition, a neutral face (conditioned stimulus, CS+) was paired with an electrical stimulus, whereas another face (unconditioned stimulus, CS-) was unpaired. Conditioned responses were measured by US-expectancy, valence, and skin conductance. Compared to HC, both patient groups showed less differential (CS+ vs. CS-) fear acquisition across all measures. Patients further displayed slowed extinction indexed by higher US-expectancy and reduced positive valence for CS+, declining from aMCI to AD. Groups did not differ in responses during a pre-conditioning habituation phase and in unconditioned responding. Diminished differential fear acquisition and slowed extinction could represent prognostic markers for AD onset.

    更新日期:2019-11-11
  • Gut microbiota manipulation through probiotics oral administration restores glucose homeostasis in a mouse model of Alzheimer’s disease
    Neurobiol. Aging (IF 4.398) Pub Date : 2019-11-11
    Laura Bonfili, Valentina Cecarini, Olee Gogoi, Sara Berardi, Silvia Scarpona, Mauro Angeletti, Giacomo Rossi, Anna Maria Eleuteri

    Cerebral glucose homeostasis deregulation has a role in the pathogenesis and the progression of Alzheimer’s disease (AD). Current therapies delay symptoms without definitively curing AD. We have previously shown that probiotics counteract AD progression in 3xTg-AD mice modifying gut microbiota and inducing energy metabolism and glycolysis-gluconeogenesis. Ameliorated cognition is based on higher neuroprotective gut hormones concentrations, reduced amyloid-β burden and restored proteolytic pathways. Here, we demonstrate that probiotics oral administration improves glucose uptake in 3xTg-AD mice by restoring the brain expression levels of key glucose transporters (GLUT3, GLUT1) and insulin-like growth factor receptor β (IGF-IRβ), in accordance with the diminished phosphorylation of AMP-activated protein kinase (AMPK) and protein-kinase B (Akt). In parallel, phosphorylated tau aggregates decrease in treated mice. Probiotics counteract the time-dependent increase of glycated hemoglobin and the accumulation of advanced glycation end-products (AGE) in AD mice, consistently with memory improvement. Collectively, our data elucidate the mechanism through which gut microbiota manipulation ameliorates impaired glucose metabolism in AD, finally delaying the disease progression.

    更新日期:2019-11-11
Contents have been reproduced by permission of the publishers.
导出
全部期刊列表>>
2020新春特辑
限时免费阅读临床医学内容
ACS材料视界
科学报告最新纳米科学与技术研究
清华大学化学系段昊泓
自然科研论文编辑服务
中国科学院大学楚甲祥
中国科学院微生物研究所潘国辉
中国科学院化学研究所
课题组网站
X-MOL
北京大学分子工程苏南研究院
华东师范大学分子机器及功能材料
中山大学化学工程与技术学院
试剂库存
天合科研
down
wechat
bug