•Defective clearance can be an initiating factor of age-related brain pathologies.•Blood-brain barrier transport and glymphatic clearance are complementary mechanisms.•Blood-brain barrier disruption ...and glymphatic dysfunction interact.•Imaging brain fluid dynamics might help in early detection of neurodegeneration.•Recent imaging advances focus on imaging fluid flow in the perivascular spaces.
Neurovascular pathology concurs with protein accumulation, as the brain vasculature is important for waste clearance. Interstitial solutes, such as amyloid-β, were previously thought to be primarily cleared from the brain by blood-brain barrier transport. Recently, the glymphatic system was discovered, in which cerebrospinal fluid is exchanged with interstitial fluid, facilitated by the aquaporin-4 water channels on the astroglial endfeet. Glymphatic flow can clear solutes from the interstitial space. Blood-brain barrier transport and glymphatic clearance likely serve complementary roles with partially overlapping mechanisms providing a well-conditioned neuronal environment. Disruption of these mechanisms can lead to protein accumulation and may initiate neurodegenerative disorders, for instance amyloid-β accumulation and Alzheimer’s disease. Although both mechanisms seem to have a similar purpose, their interaction has not been clearly discussed previously. This review focusses on this interaction in healthy and pathological conditions. Future health initiatives improving waste clearance might delay or even prevent onset of neurodegenerative disorders. Defining glymphatic flow kinetics using imaging may become an alternative way to identify those at risk of Alzheimer’s disease.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Abstract There is wide acknowledgement that apathy is an important behavioural syndrome in Alzheimer's disease and in various neuropsychiatric disorders. In light of recent research and the renewed ...interest in the correlates and impacts of apathy, and in its treatments, it is important to develop criteria for apathy that will be widely accepted, have clear operational steps, and that will be easily applied in practice and research settings. Meeting these needs is the focus of the task force work reported here. The task force includes members of the Association Française de Psychiatrie Biologique, the European Psychiatric Association, the European Alzheimer's Disease Consortium and experts from Europe, Australia and North America. An advanced draft was discussed at the consensus meeting (during the EPA conference in April 7th 2008) and a final agreement reached concerning operational definitions and hierarchy of the criteria. Apathy is defined as a disorder of motivation that persists over time and should meet the following requirements. Firstly, the core feature of apathy, diminished motivation, must be present for at least four weeks; secondly two of the three dimensions of apathy (reduced goal-directed behaviour, goal-directed cognitive activity, and emotions) must also be present; thirdly there should be identifiable functional impairments attributable to the apathy. Finally, exclusion criteria are specified to exclude symptoms and states that mimic apathy.
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GEOZS, IMTLJ, KILJ, NUK, OILJ, PNG, SBCE, SBJE, UL, UM, UPUK
The extent to which specific factors influence diagnostic delays in dementia is unclear. Therefore, the aim of the present study was to compare duration from symptom onset to diagnosis for ...young-onset dementia (YOD) and late-onset dementia (LOD) and to assess the effect of age at onset, type of dementia, gender, living situation, education and family history of dementia on this duration.
Data on 235 YOD and 167 LOD patients collected from caregivers from two prospective cohort studies were used. Multiple linear regression analysis was performed.
The duration between symptom onset and the diagnosis of YOD exceeded that of LOD by an average of 1.6 years (2.8 v. 4.4 years). Young age and being diagnosed with frontotemporal dementia were related to increases in the time to diagnosis. Subjects with vascular dementia experienced shorter time to diagnosis.
There is a need to raise special awareness of YOD to facilitate a timely diagnosis.
Background and Objectives
Obesity has been associated with increased risk of cognitive impairment or dementia, but recent findings are contradictory, possibly due to methodological differences. The ...present study tries to clarify these inconsistencies by following the cognitive trajectories of individuals with obesity over 12 years and studying the effect of obesity status (obesity at baseline versus incident obesity at follow-up), chronicity, definition, potential confounding (e.g. age, cardiovascular factors), and non-linear associations.
Design
Longitudinal study with 12 years follow-up.
Setting
Community based.
Participants
1,807 cognitively healthy individuals (aged 24-83) from the Maastricht Aging Study (1992-2004).
Measurements
Memory, executive function and processing speed were assessed at baseline and at 6- and 12-year follow-up. Obesity was defined as having a body mass index (BMI) of ≥ 30.0 kg/m
2
or waist circumference (WC) of > 102 cm for men and > 88 cm for women.
Results
At baseline, 545 persons were obese (BMI: 329 (18%); WC: 494 (27%); both: 278 (15%). They showed faster decline in memory, executive function, and processing speed. Chronic obese showed less widespread impairment than those who regained normal weight. Associations across cognitive domains were weaker for obesity defined by BMI than for WC. At follow-up, 190 developed obesity, and they performed worse on executive function at baseline, but showed less decline compared with participants with normal weight. Yet, age-stratification and post-hoc analyses showed that most of these associations were confounded by age.
Conclusions
This study shows that the association between obesity and cognitive decline was confounded by the effect of age on rate of decline. Future studies should take this into account.
This systematic review and collaborative recalculation was set up to recalculate schizophrenia incidence rates from previously published studies by age and sex.
PubMed, EMBASE and PsycINFO databases ...were searched (January 1950 to December 2009) for schizophrenia incidence studies. Numerator and population data were extracted by age, sex and, if possible, study period. Original data were requested from the authors to calculate age- and sex-specific incidence rates. Incidence rate ratios (IRRs) with their 95% confidence intervals (CIs) were computed by age and sex from negative binomial regression models.
Forty-three independent samples met inclusion criteria, yielding 133 693 incident cases of schizophrenia for analysis. Men had a 1.15-fold (95% CI 1.00-1.31) greater risk of schizophrenia than women. In men, incidence peaked at age 20-29 years (median rate 4.15/10,000 person-years, IRR 2.61, 95% CI 1.74-3.92). In women, incidence peaked at age 20-29 (median rate 1.71/10,000 person-years, IRR 2.34, 95% CI 1.66-3.28) and 30-39 years (median rate 1.24/10,000 person-years, IRR 2.25, 95% CI 1.55-3.28). This peak was followed by an age-incidence decline up to age 60 years that was stronger in men than in women (χ² = 57.90, p < 0.001). The relative risk of schizophrenia was greater in men up to age 39 years and this reversed to a greater relative risk in women over the age groups 50-70 years. No evidence for a second incidence peak in middle-aged women was found.
Robust sex differences exist in the distribution of schizophrenia risk across the age span, suggesting differential susceptibility to schizophrenia for men and women at different stages of life.
Anxiety, apathy and depression are common in subjects with mild cognitive impairment (MCI) and may herald Alzheimer's disease (AD). We investigated whether these symptoms correlated with ...cerebrospinal fluid (CSF) markers for AD in subjects with MCI. Method Subjects with MCI (n=268) were selected from the 'Development of screening guidelines and criteria for pre-dementia Alzheimer's disease' (DESCRIPA) and Alzheimer's Disease Neuroimaging Initiative (ADNI) studies. We measured amyloid β(1-42) protein (Aβ42) and total tau (t-tau) in CSF. Neuropsychiatric symptoms were measured with the Neuropsychiatric Inventory.
Depressive symptoms were reported by 55 subjects (21%), anxiety by 35 subjects (13%) and apathy by 49 subjects (18%). The presence of anxiety was associated with abnormal CSF Aβ42 odds ratio (OR) 2.3, 95% confidence interval (CI) 1.6-3.3 and t-tau (OR 2.6, 95% CI 1.9-3.6) concentrations and with the combination of abnormal concentrations of both Aβ42 and t-tau (OR 3.1, 95% CI 2.0-4.7). The presence of agitation and irritability was associated with abnormal concentrations of Aβ42 (agitation: OR 1.6, 95% CI 1.1-2.3; irritability: OR 2.2, 95% CI 1.5-3.3). Symptoms of depression and apathy were not related to any of the CSF markers.
In subjects with MCI, symptoms of anxiety, agitation and irritability may reflect underlying AD pathology, whereas symptoms of depression and apathy do not.
The main aim of the present study was to compare volume differences in the hippocampus and parahippocampal gyrus as biomarkers of Alzheimer’s disease (AD). Based on the previous findings, we ...hypothesized that there would be significant volume differences between cases of healthy aging, amnestic mild cognitive impairment (aMCI), and mild AD. Furthermore, we hypothesized that there would be larger volume differences in the parahippocampal gyrus than in the hippocampus. In addition, we investigated differences between the anterior, middle, and posterior parts of both structures. We studied three groups of participants: 18 healthy participants without memory decline, 18 patients with aMCI, and 18 patients with mild AD. 3 T T1-weighted MRI scans were acquired and gray matter volumes of the anterior, middle, and posterior parts of both the hippocampus and parahippocampal gyrus were measured using a manual tracing approach. Volumes of both the hippocampus and parahippocampal gyrus were significantly different between the groups in the following order: healthy > aMCI > AD. Volume differences between the groups were relatively larger in the parahippocampal gyrus than in the hippocampus, in particular, when we compared healthy with aMCI. No substantial differences were found between the anterior, middle, and posterior parts of both structures. Our results suggest that parahippocampal volume discriminates better than hippocampal volume between cases of healthy aging, aMCI, and mild AD, in particular, in the early phase of the disease. The present results stress the importance of parahippocampal atrophy as an early biomarker of AD.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Context:
Advanced glycation end-products (AGEs) are thought to be involved in the pathogenesis of Alzheimer's disease. AGEs are products resulting from nonenzymatic chemical reactions between reduced ...sugars and proteins, which accumulate during natural aging, and their accumulation is accelerated in hyperglycemic conditions such as type 2 diabetes mellitus.
Objective:
The objective of the study was to examine associations between AGEs and cognitive functions.
Design, Setting, and Participants:
This study was performed as part of the Maastricht Study, a population-based cohort study in which, by design, 215 participants (28.1%) had type 2 diabetes mellitus.
Main Outcome Measures:
We examined associations of skin autofluorescence (SAF) (n = 764), an overall estimate of skin AGEs, and specific plasma protein-bound AGEs (n = 781) with performance on tests for global cognitive functioning, information processing speed, verbal memory (immediate and delayed word recall), and response inhibition.
Results:
After adjustment for demographics, diabetes, smoking, alcohol, waist circumference, total cholesterol/high-density lipoprotein cholesterol ratio, triglycerides, and lipid-lowering medication use, higher SAF was significantly associated with worse delayed word recall (regression coefficient, b = −0.44; P = .04), and response inhibition (b = 0.03; P = .04). After further adjustment for systolic blood pressure, cardiovascular disease, estimated glomerular filtration rate, and depression, associations were attenuated (delayed word recall, b = −0.38, P = .07; response inhibition, b = 0.02, P = .07). Higher pentosidine levels were associated with worse global cognitive functioning (b = −0.61; P = .04) after full adjustment, but other plasma AGEs were not. Associations did not differ between individuals with and without diabetes.
Conclusion:
We found inverse associations of SAF (a noninvasive marker for tissue AGEs) with cognitive performance, which were attenuated after adjustment for vascular risk factors and depression.
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