Sebastian Köhler

Target risk factors for dementia prevention: a systematic review and Delphi consensus study on the evidence from observational studies

Dementia has a multifactorial etiology, but the importance of individual health and lifestyle related risk factors is often uncertain or based on few studies. The goal of this paper is to identify the major modifiable risk factors for dementia as a first step in developing an effective preventive strategy and promoting healthy late life cognitive functioning.

The pattern and course of cognitive impairment in late-life depression

BACKGROUND Cognitive deficits persist despite clinical recovery in subjects with late-life depression, but more needs to be known about their longer-term outcome and factors affecting their course. To investigate this, we followed the pattern of cognitive impairments over time and examined the effects of current mood, remission status, age of depression onset and antidepressant (AD) treatment on these deficits. METHOD Sixty-seven subjects aged > or = 60 years with DSM-IV major depressive disorder and 36 healthy comparison subjects underwent tests of global cognition, memory, executive functioning and processing speed at baseline, 6 and 18 months, with some subjects tested again after 4 years. z scores were compared between groups, with analyses of clinical factors that may have influenced cognitive performance in depressed subjects. RESULTS Half of the patients exhibited a generalized cognitive impairment (GCI) that persisted after 18 months. Patients performed worse across all cognitive domains at all time points, without substantial variability due to current mood, remission status or AD treatment. Late age of onset was associated significantly with decline in memory and executive functioning. Impaired processing speed may be a partial mediator of some deficits, but was insufficient to explain differences between patients and controls. Four-year follow-up data suggest impairments persist, but do not further decline. CONCLUSIONS Cognitive deficits in late-life depression persist up to 4 years, affect multiple domains and are related to trait rather than state effects. Differences in severity and course between early and late onset depression suggest different pathogenic processes.

White matter hyperintensities, cortisol levels, brain atrophy and continuing cognitive deficits in late-life depression.

BACKGROUND Cerebrovascular changes and glucocorticoid mediated hippocampal atrophy are considered relevant for depression-related cognitive deficits, forming putative treatment targets. AIMS This study examined the relative contribution of cortisol levels, brain atrophy and white matter hyperintensities to the persistence of cognitive deficits in older adults with depression. METHOD Thirty-five people aged > or =60 years with DSM-IV major depression and twenty-nine healthy comparison controls underwent magnetic resonance imaging (MRI) and were followed up for 18 months. We analysed the relationship between baseline salivary cortisol levels, whole brain, frontal lobe and hippocampal volumes, severity of white matter hyperintensities and follow-up cognitive function in both groups by testing the interaction between the groups and these biological measures on tests of memory, executive functions and processing speed in linear regression models. RESULTS Group differences in memory and executive function follow-up scores were associated with ratings of white matter hyperintensities, especially of the deep white matter and periventricular regions. Compared with healthy controls, participants with depression scoring within the third tertile of white matter hyperintensities dropped two and three standard deviations in executive function and memory scores respectively. No biological measure related to group differences in processing speed, and there were no significant interactions between group and cortisol levels, or volumetric MRI measures. CONCLUSIONS White matter hyperintensities, rather than cortisol levels or brain atrophy, are associated with continuing cognitive impairments in older adults with depression. The findings suggest that cerebrovascular disease rather than glucocorticoid-mediated brain damage are responsible for the persistence of cognitive deficits associated with depression in older age.

Neuropsychiatric outcomes of stroke

The most common neuropsychiatric outcomes of stroke are depression, anxiety, fatigue, and apathy, which each occur in at least 30% of patients and have substantial overlap of prevalence and symptoms. Emotional lability, personality changes, psychosis, and mania are less common but equally distressing symptoms that are also challenging to manage. The cause of these syndromes is not known, and there is no clear relation to location of brain lesion. There are important gaps in knowledge about how to manage these disorders, even for depression, which is the most studied syndrome. Further research is needed to identify causes and interventions to prevent and treat these disorders.

Hippocampal volume and 2-year outcome in depression

Although the hippocampus has been found to be smaller in people with depression, the clinical relevance of this is unclear. We investigated hippocampal volume (using high-resolution magnetic resonance imaging) and 2-year outcome in 57 patients with major depression. The left and right hippocampal volumes of patients with a depression relapse were significantly smaller than those of healthy controls. Our results support the hypothesis that the hippocampus is crucial in the outcome of depression.

Effects of Type 2 Diabetes on 12-Year Cognitive Change: Results from the Maastricht Aging Study

OBJECTIVE To examine the effects of baseline and incident diabetes on change in cognitive function over 12 years. RESEARCH DESIGN AND METHODS A sample of 1,290 individuals aged ≥40 years at baseline, participating in the Maastricht Aging Study, were cognitively tested at baseline, after 6 years, and after 12 years. Of these, 68 participants had type 2 diabetes at baseline, and 54 and 57 had incident diabetes at the 6- and 12-year follow-up, respectively. Changes in performance on tests of information-processing speed, executive function, and verbal memory from baseline to 6- and 12-year follow-up were compared between groups using linear mixed models. Effects of diabetes on cognitive decline were adjusted for demographic variables, history of smoking, alcohol intake, and comorbid conditions, including hypertension, cardiovascular disease, BMI, and depression. RESULTS Participants with baseline diabetes showed larger decline in information-processing speed (estimate −7.64; P < 0.01), executive function (21.82; P < 0.01), and delayed word recall (−1.35; P < 0.05) over the 12-year follow-up compared with control subjects. No significant difference in decline was observed for immediate word recall. Compared with control subjects, participants with incident diabetes showed subtle early decline in information-processing speed only. Interestingly, they did not show larger decline in any other cognitive domain. CONCLUSIONS Individuals with baseline type 2 diabetes show accelerated cognitive decline, particularly in information-processing speed and executive function, compared with individuals without diabetes. In incident diabetes, decline in speed becomes detectable first, and cognitive decline seems to increase with increasing exposure time.

Systematic review and collaborative recalculation of 133,693 incident cases of schizophrenia

BACKGROUND This systematic review and collaborative recalculation was set up to recalculate schizophrenia incidence rates from previously published studies by age and sex. METHOD 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. RESULTS 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. CONCLUSIONS 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.

Temporal Evolution of Cognitive Changes in Incident Hypertension Prospective Cohort Study Across the Adult Age Span

Midlife hypertension is a risk factor for dementia, but little is known about the cognitive trajectories of individuals with incident hypertension. This study follows the cognitive functioning in prevalent and incident hypertension for 12 years and in relation to age and treatment status. Cognitively intact adults aged 25 to 84 years (n=1805) were serially assessed at baseline, 6 years, and 12 years. Hypertension was defined by sphygmomanometry or antihypertensive medication use, and its association with cognitive decline was tested in random-effects models. At baseline, 638 (35.3%) participants had hypertension. They showed faster decline in memory (&khgr;2 test for homogeneity=35.75; df=2; P<0.001), executive functions (&khgr;2=21.68; df=2; P<0.001), and information processing speed (&khgr;2=81.96; df= 2; P<0.001) than baseline normotensive participants. At follow-up, 352 individuals (30.2%) developed incident hypertension. They showed faster decline in memory (&khgr;2=7.88; df=2; P=0.019) and information processing speed (&khgr;2= 18.06; df=2; P<0.001), especially from 6- to 12-year follow-up. Effects were most pronounced and widespread in midlife for both prevalent and incident hypertension and in those with untreated and uncontrolled hypertension. This study shows that incident hypertension predicts cognitive decline in middle-aged individuals, and those with poorly controlled blood pressure are most at risk. In newly diagnosed individuals, decline evolves gradually, possibly opening a window for early intervention.Midlife hypertension is a risk factor for dementia, but little is known about the cognitive trajectories of individuals with incident hypertension. This study follows the cognitive functioning in prevalent and incident hypertension for 12 years and in relation to age and treatment status. Cognitively intact adults aged 25 to 84 years (n=1805) were serially assessed at baseline, 6 years, and 12 years. Hypertension was defined by sphygmomanometry or antihypertensive medication use, and its association with cognitive decline was tested in random-effects models. At baseline, 638 (35.3%) participants had hypertension. They showed faster decline in memory (χ2 test for homogeneity=35.75; df =2; P <0.001), executive functions (χ2=21.68; df =2; P <0.001), and information processing speed (χ2=81.96; df = 2; P <0.001) than baseline normotensive participants. At follow-up, 352 individuals (30.2%) developed incident hypertension. They showed faster decline in memory (χ2=7.88; df =2; P =0.019) and information processing speed (χ2= 18.06; df =2; P <0.001), especially from 6- to 12-year follow-up. Effects were most pronounced and widespread in midlife for both prevalent and incident hypertension and in those with untreated and uncontrolled hypertension. This study shows that incident hypertension predicts cognitive decline in middle-aged individuals, and those with poorly controlled blood pressure are most at risk. In newly diagnosed individuals, decline evolves gradually, possibly opening a window for early intervention. # Novelty and Significance {#article-title-38}

Neuropsychological correlates of apathy in mild cognitive impairment and Alzheimer's disease: the role of executive functioning

BACKGROUND Apathy is a common and important behavioral syndrome in various neuropsychiatric diseases, such as mild cognitive impairment (MCI) and Alzheimers disease (AD). So far, only few studies have compared the neuropsychological correlates of apathy in patients with MCI and dementia. The aim of the current study was to examine the association between apathy and neuropsychological functioning in patients with MCI and AD. METHODS Two-hundred-and-sixty AD patients and 178 MCI patients visiting the Memory Clinic of the Maastricht University Medical Centre participated in the study. Linear regression analysis, corrected for age, gender, level of education and depression, was performed to reveal cross-sectional associations between apathy and scores on neuropsychological tests of memory, attention, psychomotor speed and executive functioning. RESULTS In patients with MCI, apathy was characterized by decreased verbal fluency and psychomotor tracking. In AD, patients with apathy differed from non-apathetic patients only on a verbal fluency task. CONCLUSION Apathy is related to executive dysfunction in the early phases of cognitive decline. In particular, in the prodromal phase of AD, apathy seems to be characterized by poor initiating. In the more advanced stages of cognitive deterioration, associations between apathy and specific neuropsychological correlates may be obscured by the more severe neuropathology. Awareness of apathy in the early phase of cognitive impairment may help in early diagnosis of AD.

Awareness and Its Association With Affective Symptoms in Young-onset and Late-onset Alzheimer Disease: A Prospective Study

Background:It is unknown whether there are differences between young-onset dementia and late-onset dementia in awareness levels and whether awareness is differentially associated with affective symptoms in both groups. The present study assesses possible differences between young-onset (YO-AD) and late-onset Alzheimer disease (LO-AD) in awareness levels and the association between awareness and affective symptoms. Methods:This study included 142 YO-AD and 126 LO-AD patients and their caregivers from 2 prospective studies. The participants were assessed 3 times during 1 year. Awareness was assessed using the Guidelines for the Rating of Awareness Deficits, and affective symptoms were assessed using the anxiety and depression items of the Neuropsychiatric Inventory. Population-averaged logistic regressions were used to analyze awareness and its association with affective symptoms. Results:The odds for impaired awareness in LO-AD were more than double the odds in YO-AD. Intact awareness was associated with depressive symptoms but not with anxiety. This effect was more pronounced in YO-AD compared with LO-AD at baseline. High awareness at baseline did not predict incident affective symptoms. Conclusions:Caregivers and clinicians should be prepared for affective symptoms in YO-AD patients with high awareness. The higher awareness in the YO-AD group also has potential positive implications for this group.