We collected MRI diffusion tensor imaging data from 80 younger (20–32 years) and 63 older (60–71 years) healthy adults. Tract-based spatial statistics (TBSS) analysis revealed that white matter ...integrity, as indicated by decreased fractional anisotropy (FA), was disrupted in numerous structures in older compared to younger adults. These regions displayed five distinct region-specific patterns of age-related differences in other diffusivity properties: (1) increases in both radial and mean diffusivity; (2) increases in radial diffusivity; (3) no differences in parameters other than FA; (4) a decrease in axial and an increase in radial diffusivity; and (5) a decrease in axial and mean diffusivity. These patterns suggest different biological underpinnings of age-related decline in FA, such as demyelination, Wallerian degeneration, gliosis, and severe fiber loss, and may represent stages in a cascade of age-related degeneration in white matter microstructure. This first simultaneous description of age-related differences in FA, mean, axial, and radial diffusivity requires histological and functional validation as well as analyses of intermediate age groups and longitudinal samples.
Aerobic exercise in young adults can induce vascular plasticity in the hippocampus, a critical region for recall and recognition memory. In a mechanistic proof-of-concept intervention over 3 months, ...we investigated whether healthy older adults (60-77 years) also show such plasticity. Regional cerebral blood flow (rCBF) and volume (rCBV) were measured with gadolinium-based perfusion imaging (3 Tesla magnetic resonance image (MRI)). Hippocampal volumes were assessed by high-resolution 7 Tesla MRI. Fitness improvement correlated with changes in hippocampal perfusion and hippocampal head volume. Perfusion tended to increase in younger, but to decrease in older individuals. The changes in fitness, hippocampal perfusion and volume were positively related to changes in recognition memory and early recall for complex spatial objects. Path analyses indicated that fitness-related changes in complex object recognition were modulated by hippocampal perfusion. These findings indicate a preserved capacity of the aging human hippocampus for functionally relevant vascular plasticity, which decreases with progressing age.
To determine the occurrence of neuropsychiatric symptomatology and the relation to future development of Alzheimer disease (AD) in persons with and without mild cognitive impairment (MCI).
We ...followed 185 persons with no cognitive impairment and 47 with MCI (amnestic and multidomain), ages 75 to 95, from the population-based Kungsholmen Project, Stockholm, Sweden, for 3 years. Three types of neuropsychiatric symptoms were assessed at baseline: mood-related depressive symptoms, motivation-related depressive symptoms, and anxiety-related symptomatology. AD at 3-year follow-up was diagnosed according to Diagnostic and Statistical Manual for Mental Disorders-III-R criteria.
Psychiatric symptoms occurred more frequently in persons with MCI (36.2% mood, 36.2% motivation, and 46.8% anxiety symptoms) than in cognitively intact elderly individuals (18.4% mood, 13.0% motivation, and 24.9% anxiety). Of persons with both MCI and anxiety symptoms, 83.3% developed AD over follow-up vs 6.1% of cognitively intact persons and 40.9% persons who had MCI without anxiety. Among persons with MCI, the 3-year risk of progressing to AD almost doubled with each anxiety symptom (relative risk RR = 1.8 1.2 to 2.7 per symptom). Conversely, among cognitively intact subjects, only symptoms of depressive mood were related to AD development (RR = 1.9 1.0 to 3.6 per symptom).
The predictive validity of mild cognitive impairment (MCI) for identifying future Alzheimer disease (AD) cases is improved in the presence of anxiety symptoms. Mood-related depressive symptoms (dysphoria, suicidal ideation, etc.) in preclinical AD might be related to the neuropathologic mechanism, as they appear preclinically in persons both with and without MCI.
Psychosocial stress has been related to changes in the nervous system, with both adaptive and maladaptive consequences. The aim of this study was to examine the relationship of negative events ...experienced throughout the entire lifespan and hippocampal and amygdala volumes in older adults.
In 466 non-demented old adults (age range 60-96 years, 58% female), hippocampal and amygdala volumes were segmented using Freesurfer. Negative life events and the age at which these events occurred were assessed by means of a structured questionnaire. Using generalized linear models, hippocampal and amygdala volumes were estimated with life events as independent variables. The statistical analyses were adjusted for age, gender, intracranial volume, lifestyle factors, cardiovascular risk factors, depressive symptoms, and cognitive functioning.
Total number of negative life events and of late-life events, but not of early-life, early-adulthood, or middle-adulthood events, was related to larger amygdala volume. There were interactions of early-life events with age and gender. Participants who reported two or more early-life events had significantly smaller amygdala and hippocampal volumes with increasing age. Furthermore, smaller hippocampal volume was found in men who reported two or more early-life events, but not in women.
These results suggest that the effect of negative life events on the brain depends on the time when the events occurred, with the strongest effects observed during the critical time periods of early and late life.
Abstract Cognitive decline is a characteristic feature of normal human aging. Previous work has demonstrated marked interindividual variability in onset and rate of decline. Such variability has been ...linked to factors such as maintenance of functional and structural brain integrity, genetics, and lifestyle. Still, few, if any, studies have combined a longitudinal design with repeated multimodal imaging and a comprehensive assessment of cognition as well as genetic and lifestyle factors. The present paper introduces the Cognition, Brain, and Aging (COBRA) study, in which cognitive performance and brain structure and function are measured in a cohort of 181 older adults aged 64 to 68 years at baseline. Participants will be followed longitudinally over a 10-year period, resulting in a total of three equally spaced measurement occasions. The measurement protocol at each occasion comprises a comprehensive set of behavioral and imaging measures. Cognitive performance is evaluated via computerized testing of working memory, episodic memory, perceptual speed, motor speed, implicit sequence learning, and vocabulary. Brain imaging is performed using positron emission tomography with 11 C-raclopride to assess dopamine D2/D3 receptor availability. Structural magnetic resonance imaging (MRI) is used for assessment of white and gray-matter integrity and cerebrovascular perfusion, and functional MRI maps brain activation during rest and active task conditions. Lifestyle descriptives are collected, and blood samples are obtained and stored for future evaluation. Here, we present selected results from the baseline assessment along with a discussion of sample characteristics and methodological considerations that determined the design of the study. This article is part of a Special Issue entitled SI: Memory & Aging.
This multicenter, 1:1‐randomized, parallel‐group, noninferiority study compared the efficacy and safety of twice‐daily tacrolimus (Tacrolimus BID; Prograf) and once‐daily tacrolimus prolonged release ...(Tacrolimus QD; Advagraf), combined with steroids and low‐dose mycophenolate mofetil without antibody induction, in 667 de novo kidney transplant recipients. A double‐blind, double‐dummy 24‐week period was followed by an open extension of up to 12 months posttransplant. Biopsy‐proven acute rejection rate at 24 weeks (primary endpoint, per‐protocol analysis) was 15.8% for Tacrolimus BID versus 20.4% for Tacrolimus QD (p = 0.182; treatment difference 4.5%, 95% confidence interval—1.8%, 10.9%, just outside the prespecified 10% noninferiority margin). Kaplan–Meier 12‐month patient and graft survival rates were 97.5% and 92.8% for Tacrolimus BID and 96.9% and 91.5% for QD. Both treatment groups showed equally well‐maintained renal function at 12 months (mean creatinine clearance approximately 67 mL/min) and similar adverse event profiles. Overall results obtained with either Tacrolimus QD or BID, without antibody induction, were good, supporting use of the once‐daily formulation as an effective alternative to the established twice‐daily formulation.
This international, multicenter, randomized, double‐blind, double‐dummy, phase III study finds that once‐daily, prolonged‐release tacrolimus has therapeutic equivalence and a comparable safety profile to twice‐daily tacrolimus in renal transplant recipients. See editorial by Srinivas et al on page 2571.
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The First Key Symposium was held in Stockholm, Sweden, 2–5 September 2003. The aim of the symposium was to integrate clinical and epidemiological perspectives on the topic of Mild Cognitive ...Impairment (MCI). A multidisciplinary, international group of experts discussed the current status and future directions of MCI, with regard to clinical presentation, cognitive and functional assessment, and the role of neuroimaging, biomarkers and genetics. Agreement on new perspectives, as well as recommendations for management and future research were discussed by the international working group. The specific recommendations for the general MCI criteria include the following: (i) the person is neither normal nor demented; (ii) there is evidence of cognitive deterioration shown by either objectively measured decline over time and/or subjective report of decline by self and/or informant in conjunction with objective cognitive deficits; and (iii) activities of daily living are preserved and complex instrumental functions are either intact or minimally impaired.
To investigate whether vitamin-B density in the diet 2-8 years before diagnosis is associated with olfactory function at the time of diagnosis.
This prospective nested case-control study included ...patients with Parkinson's disease (PD), multiple system atrophy and progressive supranuclear paralysis identified between 2004 and 2009 in the county of Västerbotten in northern Sweden. The case database (NYPUM study; Newly Diagnosed Parkinson in Umeå; n=147) was cross-linked to the Northern Sweden Health and Disease Study (NSHDS). Identified patients (n=96) and controls (n=375) were matched for sex, age, year of health survey, sub-cohort and geographical area. Dietary intake was assessed by a food frequency questionnaire, and the brief smell identification test (B-SIT) was used to measure olfactory function at the time of diagnosis.
There was no difference in vitamin-B or any other macro- or micro-nutrient densities, energy intake or body mass index (kg/m
; BMI) between patients and controls at baseline at the time of the healthcare survey. A lower thiamin and folate density, amount per 1 megajoule, was reported in patients who scored below median on B-SIT (<7) when compared with that in patients who scored ⩾7 at the time of diagnosis. After adjusting for age, sex and BMI using linear and logistic regressions, an even stronger association was found between thiamin density and olfactory function.
A low thiamin and folate density in the reported diet, 2-8 years before PD diagnosis, was significantly associated with olfactory dysfunction at the time of PD diagnosis.
To determine incidence rates of non-dementia cognitive impairment, to examine the impact of attrition due to death on the observed incidence estimates, and to compare the observed and corrected ...estimates of non-dementia cognitive impairment with dementia incidence rates.
A total of 1,435 persons without dementia aged 75+ from the Kungsholmen Project were evaluated for occurrence of dementia over 9 years. A total of 1,070 cognitively unimpaired subjects were also followed using amnestic mild cognitive impairment (aMCI) and other cognitive impairment, no dementia (OCIND) definitions. To correct the observed incidence rates for attrition due to death, cognitive status for subjects lost due to death was imputed using information on previous cognitive and health status. Observed and corrected incidence rates (IR) and 95% CIs were calculated with the person-years method, using Poisson distribution.
Incidence rates per 1,000 person-years were as follows: dementia IR = 70.4 (64.0 to 77.4); aMCI observed IR = 11.4 (8.6 to 15.1), corrected IR = 13.7 (10.3 to 18.2); OCIND observed IR = 33.8 (28.7 to 39.8), corrected IR = 42.1 (36.5 to 48.6). Both aMCI and OCIND incidence increased with advancing age. Observed incidence of aMCI and OCIND together was similar to that of dementia at age 75 to 79 but lower at more advanced ages. However, the cognitive impairment incidence after age 79 increased substantially when the estimates were corrected for attrition due to death during follow-up.
Non-dementia cognitive impairment is common and often underestimated in population studies that do not adjust for attrition.
•Higher iron load was linked to lower D1-like receptor availability across the adult lifespan.•The interplay between high iron, low D1DR and older age explained lower task-related brain ...response.•Lower brain response was related to deficient task performance.•The iron-DA coupling can help progress the understanding of the mechanisms behind DA-related neurodegeneration.
Brain iron overload and decreased integrity of the dopaminergic system have been independently reported as brain substrates of cognitive decline in aging. Dopamine (DA), and iron are co-localized in high concentrations in the striatum and prefrontal cortex (PFC), but follow opposing age-related trajectories across the lifespan. DA contributes to cellular iron homeostasis and the activation of D1-like DA receptors (D1DR) alleviates oxidative stress-induced inflammatory responses, suggesting a mutual interaction between these two fundamental components. Still, a direct in-vivo study testing the iron-D1DR relationship and their interactions on brain function and cognition across the lifespan is rare. Using PET and MRI data from the DyNAMiC study (n=180, age=20-79, %50 female), we showed that elevated iron content was related to lower D1DRs in DLPFC, but not in striatum, suggesting that dopamine-rich regions are less susceptible to elevated iron. Critically, older individuals with elevated iron and lower D1DR exhibited less frontoparietal activations during the most demanding task, which in turn was related to poorer working-memory performance. Together, our findings suggest that the combination of elevated iron load and reduced D1DR contribute to disturbed PFC-related circuits in older age, and thus may be targeted as two modifiable factors for future intervention.
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