To delineate the trajectories of A␤42 level in cerebrospinal fluid (CSF), fludeoxyglucose F18 (FDG) uptake using positron emission tomography, and hippocampal volume using magnetic resonance imaging and their relative associations with cognitive change at different stages in aging and Alzheimer disease (AD).

Objective: To investigate the vascular contribution to longitudinal changes in Alzheimer disease (AD) biomarkers. Methods:The Alzheimer's Disease Neuroimaging Initiative is a clinic based, longitudinal study with CSF, PET, and MRI biomarkers repeatedly measured in participants with normal cognition (NC), mild cognitive impairment (MCI), and mild AD. Participants with severe cerebrovascular risks were excluded. Cardiovascular risk scores and MRI white matter hyperintensities (WMHs) were treated as surrogate markers for vascular burden. Generalized estimating equations were applied, and both vascular burden and its interaction with time (vascular burden ϫ time) or timevarying WMHs were entered into regression models to assess whether biomarker rates of change were modified by vascular burden.Results: Cardiovascular risk profiles were not predictive of progression in CSF ␤ 42 -amyloid, [ 18 F]fluorodeoxyglucose (FDG) PET uptake, and MRI hippocampal atrophy. Greater baseline cardiovascular risks or WMHs were generally associated with cognitive impairment, particularly poor executive function. WMHs increased over time with a faster rate in MCI and AD than in NC. Increased time-varying WMH was associated with faster decline in executive function and lower FDG uptake in NC. Otherwise, WMH was not associated with CSF and MRI biomarkers in the 3 groups. These findings remained unchanged after accounting for APOE4. Conclusion:Increased WMHs are associated with aging, decreased glucose metabolism, and decline in executive function but do not affect AD-specific pathologic progression, suggesting that the vascular contribution to dementia is probably additive although not necessarily independent of the amyloid pathway. Neurology Both Alzheimer disease (AD) and vascular pathology are common in the elderly population, and multiple brain pathologic conditions account for most patients with dementia.1 Many cardiovascular risk factors including midlife hypertension, diabetes, dyslipidemia, and smoking seem to increase the risk of AD, suggesting a vascular contribution to the etiology of AD.2,3 Within the framework of the neurovascular unit, vascular dysfunction may reduce the clearance of ␤-amyloid (A␤) via the bloodbrain barrier or indirectly increase A␤ deposition. 4 Amyloid deposition is considered the pivotal event in the AD pathologic cascade, 5 but whether the accumulation is accelerated by vascular risks remains unclear.White matter hyperintensities (WMHs) on brain MRI reflect cardiovascular risk profiles, and greater WMH volume is associated with cerebral hypometabolism and cognitive decline.6-8 White

Background Depression is a common comorbidity in spinocerebellar ataxias (SCAs) but its association with ataxia progression is not well understood. Objectives To study the prevalence and influence of depressive symptoms in SCAs. Methods We studied 300 participants with SCA 1, 2, 3 and 6 from the Clinical Research Consortium for Spinocerebellar Ataxias (CRC-SCA) and repeatedly measured depressive symptoms by the 9-item Patient Health Questionnaire (PHQ-9) along with other clinical features including ataxia, functional status, and quality of life every 6 months for 2 years. We employed regression models to study the effects of depressive symptoms on clinical progression indexed by Scale for Assessment and Rating of Ataxia (SARA), Unified Huntington’s Disease Rating Scale Part IV (UHDRS-IV) and EQ5D after adjusting for age, sex and pathological CAG repeats. Results Comorbid depression is common in SCAs (26%). Although the baseline prevalence of depression was similar among different SCA types, suicidal ideation was more frequently reported in SCA3 (65%). Depressive symptoms were associated with SARA scores but did not significantly progress over time within 2 years or deteriorate by increased numbers of pathological CAG repeats. The effects of depression on ataxia progression varied across different SCA types. Nevertheless, depression had consistently negative and significant impact on functional status and quality of life in all SCAs, even after accounting for ataxia progression. Conclusions Depressive symptoms are not simply the consequence of motor disability in SCAs. Comorbid depression per se contributes to different health outcomes and deserves more attention when caring patients with SCAs.

To examine the association between demographic and clinical features in early Parkinson disease (PD) and length of survival in a multiethnic population.Design: Clinical features within 2 years of diagnosis were determined for an inception cohort established during 1994-1995. Vital status was determined through December 31, 2005. Predictor variables included age at diagnosis, sex, race/ethnicity, as well as clinical subtype (modified tremor dominant, postural instability gait difficulty), symmetry, cognitive impairment, depression, dysphagia, and hallucinations. Cox proportional hazards regression analysis was used to identify factors associated with shorter survival.

Education, occupation, premorbid intelligence and brain size are surrogate markers for cognitive reserve. Whether these markers have biological influence on Alzheimer disease (AD) pathology is not known. We thus aimed to investigate the effect of cognitive reserve proxies on longitudinal change of AD biomarkers. A total of 819 participants with normal cognition (NC), mild cognitive impairment (MCI) and mild AD were enrolled in the Alzheimer’s Disease Neuroimaging Initiative and followed up with repeated measures of CSF, PET and MRI biomarkers. Generalized estimating equations were employed to assess whether biomarker rates of change were modified by reserve proxies. CSF Aβ42 decline was slower in NC participants with higher cognitive reserve indexed by education, occupation and American National Adult Reading Test (ANART). The decline of [18F] fluorodeoxyglucose PET uptake was slower in AD participants with better performance on the ANART. Education, occupation and ANART did not modify the rates of MRI hippocampal atrophy in any group. These findings remained unchanged after accounting for APOE 4, longitudinal missing data and baseline cognitive performance. Higher levels of reserve markers may slow the rate of amyloid deposition before cognitive impairment and preserve glucose metabolism at the dementia stage over the course of AD pathological progression.

Multimorbidity is common in AD. Depression, CVD, osteoporosis, and DM are associated with incident AD, supporting that their co-existence is a typical feature of AD at old age. Comorbidity care should be integrated into current management for patients with AD.

The aim of this article was to evaluate cancer occurrence before and after diagnosis of Parkinson's disease (PD). We investigated 692 patients newly diagnosed with PD and 761 age- and sex-matched control subjects identified during two periods (1994-1995 and 2000-2003) within Kaiser Permanente Medical Care Program of Northern California. Primary cancers were searched and dated, and all participants were followed up until the end of membership, death, or December 31, 2008. We used unconditional logistic regression to evaluate the PD-cancer association before the date of PD diagnosis or the index date and Cox proportional hazards regression to evaluate the PD-cancer association after the index date. Nearly 20% (140 of 692) of the PD patients and 25% (188 of 761) of the non-PD controls had ever had a cancer diagnosis. Before the index date, the prevalence of cancer was not significantly lower in patients with PD (8.1% PD vs. 9.2% controls; OR = 0.83; 95% CI 0.54-1.3). After the index date, the risk of developing a cancer did not differ between PD cases and controls (relative risk [RR] = 0.94; 95% CI 0.70-1.3). Among specific cancers, melanoma was more common among PD cases (before PD, OR = 1.5; 95% CI 0.40-5.2; after PD, RR = 1.6; 95% CI 0.71-3.6), but independent of dopaminergic therapy. Cancer occurrence is not significantly lower among patients with PD. The positive association between PD and subsequent melanoma merits further investigation, as it does not seem to be attributable to dopaminergic therapy, pigmentation, or confounding by smoking.

Apolipoprotein E (APOE) ε4 carriers and patients with amnestic mild cognitive impairment (MCI) have high risk of developing Alzheimer's disease (AD). The Scaffolding Theory of Aging and Cognition proposes that recruitment of additional frontal brain regions can protect cognition against aging. This thesis has yet to be fully tested in older adults at high risk for AD. In the present study, 75 older participants (mean age: 74 years) were included. Applying a voxel-wise approach, fractional amplitude of low-frequency fluctuations (fALFF) in resting-state functional neuroimaging data were analyzed as a function of APOEε4 status (carrier vs. noncarrier) and clinical status (healthy control [HC] vs. MCI) using a 2×2 analysis of covariance (ANCOVA). Measures of cognition and cerebrospinal fluid levels of amyloid-beta were also obtained. Three frontal regions were identified with significant interaction effects using ANCOVA (corrected p < .01): left-insula, left-inferior frontal gyrus (IFG), and right-precentral gyrus. The HC/APOEε4 carrier group had significantly higher fALFF in all three regions than other groups. In the entire sample, for two regions (left insula and left IFG), a significant positive relationship between β-amyloid and memory was only observed among individuals with low fALFF. Our results suggest higher activity in frontal regions may explain being cognitively normal among a subgroup of APOEε4 carriers and protect against the negative impact of AD-associated pathology on memory. This is an observation with potential implications for AD therapeutics.