Progression of neuropsychiatric symptoms in young-onset versus late-onset Alzheimer's disease.
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ABSTRACT:
SUBMITTER: Gumus M
PROVIDER: S-EPMC8050126 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Neuropsychiatric symptoms, previously denominated as behavioural and psychological symptoms of dementia, are common features of Alzheimer's disease (AD) and are one of the major risk factors for institutionalization. At present, the role of the apolipoprotein E (APOE) gene in the development of neuropsychiatric symptoms in AD patients is unclear. In this paper, we summarized the findings of the studies of neuropsychiatric symptoms and neuropsychiatric syndromes/endophenotypes in AD in relation to APOE genotypes, with special attention to the possible underlying mechanisms. While some studies failed to find a significant association between APOE and neuropsychiatric symptoms in late-onset AD, other studies reported a significant association between the APOE ε4 allele and an increase in agitation/aggression, hallucinations, delusions, and late-life depression or anxiety. Furthermore, some negative studies that focused on the distribution of APOE genotypes between AD patients with or without neuropsychiatric symptoms further emphasized the importance of subgrouping neuropsychiatric symptoms in distinct neuropsychiatric syndromes. Explanations for the variable findings in the existing studies included differences in patient populations, differences in the assessment of neuropsychiatric symptomatology, and possible lack of statistical power to detect associations in the negative studies.
| S-EPMC3090058 | biostudies-literature
Project description:Investigators report greater parietal tau deposition and alternate frontoparietal network involvement in early onset Alzheimer's Disease (EOAD) with onset <65 years as compared with typical late onset AD (LOAD). To determine whether clinical brain MRI volumes reflect these differences in EOAD compared with LOAD. This study investigated the clinical MRI scans of 45 persons with Clinically Probable AD with onset <65 years, and compared them to 32 with Clinically Probable AD with onset ≥65 years. Brain volumes on their T1 MRI scans were quantified with a volumetric program. Receiver operating curve analyses were performed. Persons with EOAD had significantly smaller parietal lobes (volumetric percentiles) than LOAD. Late onset Alzheimer's Disease had a smaller left putamen and hippocampus. Area Under the Curve was 96.5% with brain region delineation of EOAD compared to LOAD. This study indicates parietal atrophy less than 30% of normal on clinical MRI scans is suggestive of EOAD compared to LOAD.
| S-EPMC10623969 | biostudies-literature
Project description:Co-pathologies play an important role in the expression of the Alzheimer's disease clinical phenotype and may influence treatment efficacy. Early-onset Alzheimer's disease, defined as manifesting before age 65, is viewed as a relatively pure form of Alzheimer's disease with a more homogeneous neuropathological substrate. We sought to compare the frequency of common neuropathological diagnoses in a consecutive autopsy series of 96 patients with early-onset Alzheimer's disease (median age of onset = 55 years, 44 females) and 48 with late-onset Alzheimer's disease (median age of onset = 73 years, 14 females). The UCSF Neurodegenerative Disease Brain Bank database was reviewed to identify patients with a primary pathological diagnosis of Alzheimer's disease. Prevalence and stage of Lewy body disease, limbic age-related TDP-43 encephalopathy (LATE), argyrophilic grain disease, hippocampal sclerosis, cerebral amyloid angiopathy, and vascular brain injury were compared between the two cohorts. We found at least one non-Alzheimer's disease pathological diagnosis in 98% of patients with early-onset Alzheimer's disease (versus 100% of late onset), and the number of comorbid diagnoses per patient was lower in early-onset than in late-onset Alzheimer's disease (median = 2 versus 3, Mann-Whitney Z = 3.00, P = 0.002). Lewy body disease and cerebral amyloid angiopathy were common in both early and late onset Alzheimer's disease (cerebral amyloid angiopathy: 86% versus 79%, Fisher exact P = 0.33; Lewy body disease: 49% versus 42%, P = 0.48, respectively), although amygdala-predominant Lewy body disease was more common in early than late onset Alzheimer's disease (22% versus 6%, P = 0.02). In contrast, LATE (35% versus 8%, P < 0.001), hippocampal sclerosis (15% versus 3%, P = 0.02), argyrophilic grain disease (58% versus 41%, P = 0.052), and vascular brain injury (65% versus 39%, P = 0.004) were more common in late than in early onset Alzheimer's disease, respectively. The number of co-pathologies predicted worse cognitive performance at the time of death on Mini-Mental State Examination [1.4 points/pathology (95% confidence interval, CI -2.5 to -0.2) and Clinical Dementia Rating-Sum of Boxes (1.15 point/pathology, 95% CI 0.45 to 1.84)], across early and late onset cohorts. The effect of sex on the number of co-pathologies was not significant (P = 0.17). Prevalence of at least one APOE ε4 allele was similar across the two cohorts (52% and 54%) and was associated with a greater number of co-pathologies (+0.40, 95% CI 0.01 to 0.79, P = 0.047), independent of age of symptom onset, sex, and disease duration. Females showed higher density of neurofibrillary tangles compared to males, controlling for age of onset, APOE ε4, and disease duration. Our findings suggest that non-Alzheimer's disease pathological diagnoses play an important role in the clinical phenotype of early onset Alzheimer's disease with potentially significant implications for clinical practice and clinical trials design.
| S-EPMC8502474 | biostudies-literature
Project description:Late-onset Alzheimer's disease (LOAD) is an age-related neurodegenerative disorder characterized by gradual loss of synapses and neurons, but its pathogenesis remains to be clarified. Neurons live in an environment constituted by neurons themselves and glial cells. In this review, we propose that the neuronal degeneration in the AD brain is partially caused by diverse environmental factors. We first discuss various environmental stresses and the corresponding responses at different levels. Then we propose some mechanisms underlying the specific pathological changes, in particular, hypothalamic-pituitary adrenal axis dysfunction at the systemic level; cerebrovascular dysfunction, metal toxicity, glial activation, and Aβ toxicity at the intercellular level; and kinase-phosphatase imbalance and epigenetic modification at the intracellular level. Finally, we discuss the possibility of developing new strategies for the prevention and treatment of LOAD from the perspective of environmental stress. We conclude that environmental factors play a significant role in the development of LOAD through multiple pathological mechanisms.
| S-EPMC5562669 | biostudies-other
Project description:BackgroundAlzheimer's disease is a neurodegenerative syndrome characterized by multiple dimensions including cognitive decline, decreased daily functioning and psychiatric symptoms. This systematic review aims to investigate the relation between somatic comorbidity burden and progression in late-onset Alzheimer's disease (LOAD).MethodsWe searched four databases for observational studies that examined cross-sectional or longitudinal associations of cognitive or functional or neuropsychiatric outcomes with comorbidity in individuals with LOAD. From the 7966 articles identified originally, 11 studies were included in this review. The Newcastle-Ottawa quality assessment was used. The large variation in progression measures, comorbidity indexes and study designs hampered the ability to perform a meta-analysis. This review was registered with PROSPERO under DIO: 10.15124/CRD42015027046.ResultsNine studies indicated that comorbidity burden was associated with deterioration in at least one of the three dimensions of LOAD examined. Seven out of ten studies investigating cognition found comorbidities to be related to decreased cognitive performance. Five out of the seven studies investigating daily functioning showed an association between comorbidity burden and decreased daily functioning. Neuropsychiatric symptoms (NPS) increased with increasing comorbidity burden in two out of three studies investigating NPS. Associations were predominantly found in studies analyzing the association cross-sectionally, in a time-varying manner or across short follow-up (≤2 years). Rarely baseline comorbidity burden appeared to be associated with outcomes in studies analyzing progression over longer follow-up periods (>2 years).ConclusionThis review provides evidence of an association between somatic comorbidities and multifaceted LOAD progression. Given that time-varying comorbidity burden, but much less so baseline comorbidity burden, was associated with the three dimensions prospectively, this relationship cannot be reduced to a simple cause-effect relation and is more likely to be dynamic. Therefore, both future studies and clinical practice may benefit from regarding comorbidity as a modifiable factor with a possibly fluctuating influence on LOAD.
| S-EPMC5417646 | biostudies-literature
Project description:The term early-onset Alzheimer's disease (EOAD) identifies patients who meet criteria for AD, but show onset of symptoms before the age of 65. We map progression of gray matter atrophy in EOAD patients compared to late-onset AD (LOAD). T1-weighted MRI scans were obtained at diagnosis and one-year follow-up from 15 EOAD, 10 LOAD, and 38 age-matched controls. Voxel-based and tensor-based morphometry were used, respectively, to assess the baseline and progression of atrophy. At baseline, EOAD patients already showed a widespread atrophy in temporal, parietal, occipital, and frontal cortices. After one year, EOAD had atrophy progression in medial temporal and medial parietal cortices. At baseline, LOAD patients showed atrophy in the medial temporal regions only, and, after one year, an extensive pattern of atrophy progression in the same neocortical cortices of EOAD. Although atrophy mainly involved different lateral neocortical or medial temporal hubs at baseline, it eventually progressed along the same brain default-network regions in both groups. The cortical region showing a significant progression in both groups was the medial precuneus/posterior cingulate.
| S-EPMC4559486 | biostudies-literature
Project description:Background: Neuropsychiatric symptoms due to Alzheimer's disease (AD) and mild cognitive impairment (MCI) can decrease quality of life for patients and increase caregiver burden. Better characterization of neuropsychiatric symptoms and methods of analysis are needed to identify effective treatment targets. The current investigation leveraged the National Alzheimer's Coordinating Center (NACC) Uniform Data Set (UDS) to examine the network structure of neuropsychiatric symptoms among symptomatic older adults with cognitive impairment. Methods: The network relationships of behavioral symptoms was estimated from Neuropsychiatric Inventory Questionnaire (NPI-Q) data acquired from 12,494 older adults with MCI and AD during their initial visit. Network analysis provides insight into the relationships among sets of symptoms and allows calculation of the strengths of the relationships. Nodes represented individual NPI-Q symptoms and edges represented the pairwise dependency between symptoms. Node centrality was calculated to determine the relative importance of each symptom in the network. Results: The analysis showed patterns of connectivity among the symptoms of the NPI-Q. The network ( M =.28) consisted of mostly positive edges. The strongest edges connected nodes within symptom domain. Disinhibition and agitation/aggression were the most central symptoms in the network. Depression/dysphoria was the most frequently endorsed symptom, but it was not central in the network. Conclusions: Neuropsychiatric symptoms in MCI and AD are highly comorbid and mutually reinforcing. The presence of disinhibition and agitation/aggression yielded a higher probability of additional neuropsychiatric symptoms. Interventions targeting these symptoms may lead to greater neuropsychiatric symptom improvement overall. Future work will compare neuropsychiatric symptom networks across dementia etiologies, informant relationships, and ethnic/racial groups, and will explore the utility of network analysis as a means of interrogating treatment effects.
| S-EPMC10168435 | biostudies-literature
Project description:Objective:To study associations of cerebrovascular metabolism genotypes and haplotypes with age at Alzheimer's disease dementia (AD) onset and with neuropsychiatric symptoms according to each dementia stage.Methods:Consecutive outpatients with late-onset AD were assessed for age at dementia onset and Neuropsychiatric Inventory scores according to Clinical Dementia Rating scores, apolipoprotein E gene (APOE) haplotypes, angiotensin-converting enzyme gene (ACE) variants rs1800764 and rs4291, low-density lipoprotein cholesterol receptor gene (LDLR) variants rs11669576 and rs5930, cholesteryl ester transfer protein gene (CETP) variants I422V and TaqIB, and liver X receptor beta gene (NR1H2) polymorphism rs2695121.Results:Considering 201 patients, only APOE-ɛ4 carriers had earlier dementia onset in multiple correlations, as well as less apathy, more delusions, and more aberrant motor behavior. Both ACE polymorphisms were associated with less intense frontally mediated behaviors. Regarding LDLR variants, carriers of the A allele of rs11669576 had less anxiety and more aberrant motor behavior, whereas carriers of the A allele of rs5930 had less delusions, less anxiety, more apathy, and more irritability. CETP variants that included G alleles of I422V and TaqIB were mostly associated with less intense frontally mediated behaviors, while severely impaired carriers of the T allele of rs2695121 had more anxiety and more aberrant motor behavior.Conclusion:Though only APOE haplotypes affected AD onset, cerebrovascular metabolism genotypes were associated with differences in several neuropsychiatric manifestations of AD.
| S-EPMC7111454 | biostudies-literature
Project description:Sporadic late-onset Alzheimer's disease (LOAD), the most common form of dementia in the elderly, causes progressive and severe loss of cognitive abilities. With greater numbers of people living to advanced ages, LOAD will increasingly burden both the healthcare system and society. There are currently no available disease-modifying therapies, and the failure of several recent pathology-based strategies has highlighted the urgent need for effective therapeutic targets. With aging as the greatest risk factor for LOAD, targeting mechanisms by which aging contributes to disease could prove an effective strategy to delay progression to clinical dementia by intervention in elderly individuals in an early prodromal stage of disease. Excess neural activity in the hippocampus, a recently described phenomenon associated with age-dependent memory loss, was first identified in animal models of aging and subsequently translated to clinical conditions of aging and early-stage LOAD. Critically, elevated activity was similarly localized to specific circuits within the hippocampal formation in aged animals and humans. Here we review evidence for hippocampal hyperactivity as a significant contributor to age-dependent cognitive decline and the progressive accumulation of pathology in LOAD. We also describe studies demonstrating the efficacy of reducing hyperactivity with an initial test therapy, levetiracetam (Keppra), an atypical antiepileptic. By targeting excess neural activity, levetiracetam may improve cognition and attenuate the accumulation of pathology contributing to progression to the dementia phase of LOAD.
| S-EPMC5509635 | biostudies-literature
Project description:Objective: We investigated whether "late-onset" ADHD that emerges in adolescence/adulthood is similar in risk factor profile to: (1) child-onset ADHD, but emerges later because of scaffolding/compensation from childhood resources; and (2) depression, because it typically onsets in adolescence/adulthood and shows symptom and genetic overlaps with ADHD. Methods: We examined associations between late-onset ADHD and ADHD risk factors, cognitive tasks, childhood resources and depression risk factors in a population-based cohort followed-up to age 25 years (N=4224-9764). Results: Parent-rated late-onset ADHD was like child-onset persistent ADHD in associations with ADHD polygenic risk scores and cognitive task performance, although self-rated late-onset ADHD was not. Late-onset ADHD was associated with higher levels of childhood resources than child-onset ADHD and did not show strong evidence of association with depression risk factors. Conclusions: Late-onset ADHD shares characteristics with child-onset ADHD when parent-rated, but differences for self-reports require investigation. Childhood resources may delay the onset of ADHD.
| S-EPMC7612898 | biostudies-literature