F.R.J. Verhey

The cerebrospinal fluid amyloid beta42/40 ratio in the differentiation of Alzheimer's disease from non-Alzheimer's dementia.

BACKGROUNDnAmyloid beta(40) (Abeta(40)) is the most abundant Abeta peptide in the brain. The cerebrospinal fluid (CSF) level of Abeta(40) might therefore be considered to most closely reflect the total Abeta load in the brain. Both in Alzheimers disease (AD) and in normal aging the Abeta load in the brain has a large inter-individual variability. Relating Abeta(42) to Abeta(40) levels might consequently provide a more valid measure for reflecting the change in Abeta metabolism in dementia patients than the CSF Abeta(42) concentrations alone. This measure may also improve differential diagnosis between AD and other dementia syndromes, such as vascular dementia (VaD), dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD).nnnOBJECTIVEnTo investigate the diagnostic value of the CSF Abeta(42)/Abeta(40) ratio in differentiating AD from controls, VaD, DLB and FTD.nnnMETHODSnWe analysed the CSF Abeta(42)/Abeta(40) ratio, phosphorylated tau(181) and total tau in 69 patients with AD, 26 patients with VaD, 16 patients with DLB, 27 patients with FTD, and 47 controls.nnnRESULTSnMean Abeta(40) levels were 2850 pg/ml in VaD and 2830 pg/ml in DLB patients, both significantly lower than in AD patients (3698 pg/ml; p<0.01). Abeta(40) levels in AD patients were not significantly different from those in controls (4035 pg/ml; p=0.384). The Abeta(42)/Abeta(40) ratio was significantly lower in AD patients than in all other groups (p <0.001, ANCOVA). Differentiating AD from VaD, DLB and non-AD dementia improved when the Abeta(42)/Abeta(40) ratio was used instead of Abeta(42) concentrations alone (p<0.01) The Abeta(42)/Abeta(40) ratio performed equally well as the combination of Abeta(42), phosphorylated tau(181) and total tau in differentiating AD from FTD and non-AD dementia. The diagnostic performance of the latter combination was not improved when the Abeta(42)/Abeta(40) ratio was used instead of Abeta(42) alone.nnnCONCLUSIONnThe CSF Abeta42/Abeta40 ratio improves differentiation of AD patients from VaD, DLB and non-AD dementia patients, when compared to Abeta42 alone, and is a more easily interpretable alternative to the combination of Abeta42, p-tau and t-tau when differentiating AD from either FTD or non-AD dementia.

Association between white matter microstructure, executive functions, and processing speed in older adults: The impact of vascular health

Cerebral white matter damage is not only a commonly reported consequence of healthy aging, but is also associated with cognitive decline and dementia. The aetiology of this damage is unclear; however, individuals with hypertension have a greater burden of white matter signal abnormalities (WMSA) on MR imaging than those without hypertension. It is therefore possible that elevated blood pressure (BP) impacts white matter tissue structure which in turn has a negative impact on cognition. However, little information exists about whether vascular health indexed by BP mediates the relationship between cognition and white matter tissue structure. We used diffusion tensor imaging to examine the impact of vascular health on regional associations between white matter integrity and cognition in healthy older adults spanning the normotensive to moderate–severe hypertensive BP range (43–87 years; N = 128). We examined how white matter structure was associated with performance on tests of two cognitive domains, executive functioning (EF) and processing speed (PS), and how patterns of regional associations were modified by BP and WMSA. Multiple linear regression and structural equation models demonstrated associations between tissue structure, EF and PS in frontal, temporal, parietal, and occipital white matter regions. Radial diffusivity was more prominently associated with performance than axial diffusivity. BP only minimally influenced the relationship between white matter integrity, EF and PS. However, WMSA volume had a major impact on neurocognitive associations. This suggests that, although BP and WMSA are causally related, these differential metrics of vascular health may act via independent pathways to influence brain structure, EF and PS. Hum Brain Mapp, 2013.

Combination of serum markers related to several mechanisms in Alzheimer’s disease

Alzheimers disease (AD) probably involves several pathobiochemical mechanisms and this may be reflected by changes in different serum components. The present study investigated whether the combined analysis of serum molecules related to different mechanisms improves the discrimination of AD patients from healthy controls. Serum of patients with AD was analyzed for a broad spectrum of marker molecules, including 11 inflammatory proteins, 12 sterol intermediates and phytosterols, 2 brain-specific proteins and 4 constituents involved in homocysteine homeostasis. The serum molecule concentrations were combined in a logistic regression model, using a forward stepwise inclusion mode. The results showed that the combination of interleukin-6 (IL-6) receptor, protein alpha1 fraction, cysteine and cholesterol concentrations improved the discrimination between AD patients and healthy controls compared to the single markers. In conclusion, the results of this study have shown that the complex pathology in AD is reflected in a pattern of altered serum concentrations of several marker molecules related to several pathobiochemical mechanisms.

Predictive value of Mild Cognitive Impairment for dementia: the influence of case definition and age.

Background/Aims: In population studies, different mild cognitive impairment (MCI) definitions have been used to predict dementia at a later stage. This study compared predictive values of different MCI definitions for dementia, and the effect of age on the predictive values was investigated. Methods: This study was conducted as part of an ongoing longitudinal study into the determinants of cognitive aging, the Maastricht Aging Study. Results: MCI best predicted dementia when multiple cognitive domains were considered and subjective complaints were not (sensitivity: 0.66, specificity: 0.78). Age had a strong influence on the sensitivity of MCI for dementia (age 60–70 years: sensitivity = 0.56; age 70–85 years: sensitivity = 0.70). Conclusion: The inclusion of multiple cognitive domains and participants aged 70 years and older leads to the best prediction of dementia, regardless of subjective complaints.

Functional integration of parietal lobe activity in early Alzheimer disease.

Objectives: Parietal lobe dysfunction is an important characteristic of early Alzheimer disease (AD). Functional studies have shown conflicting parietal activation patterns indicative of either compensatory or dysfunctional mechanisms. This study aimed at examining activation differences in early AD using a visuospatial task. We focused on functional characteristics of the parietal lobe and examined compensation or disconnection mechanisms by combining a fMRI task with effective connectivity measures from Granger causality mapping (GCM). Methods: Eighteen male patients with amnestic mild cognitive impairment (aMCI) and 18 male cognitively healthy older individuals were given a mental rotation task with different rotation angles. Results: There were no behavioral group differences on the fMRI task. Separate measurements at each angle revealed widespread activation group differences. More temporal and parietal activation in the higher angle condition was observed in patients with aMCI. The parametric modulation, which identifies regions associated with increasing angle, confirmed these results. The GCM showed increased connectivity within the parietal lobe and between parietal and temporal regions in patients with aMCI. Decreased connectivity was found between the inferior parietal lobule and posterior cingulate gyrus. Connectivity patterns correlated with memory performance scores in patients with aMCI. Conclusions: Our results demonstrate increased effective temporoparietal connectivity in patients with aMCI, while maintaining intact behavioral performance. This might be a compensational mechanism to counteract a parietal-posterior cingulate gyrus disconnection. These findings highlight the importance of connectivity changes in the pathophysiology of AD. In addition, effective connectivity may be a promising method for evaluating interventions aimed at the promotion of compensatory mechanisms.

A study into the psychosocial determinants of perceived forgetfulness: implications for future interventions.

Many healthy individuals perceive themselves as forgetful and are interested in interventions to decrease their worries and increase their memory functioning. Educational interventions can be more effective when determinants are targeted that are known to predict perceived forgetfulness. In the present study, first, a broad range of determinants was selected from the literature and from experiences in clinical settings and, second, the most important determinants among the selected ones were identified with multivariate regression analyses. The study had a cross-sectional design. A sample of 300 healthy participants aged over 54 years filled in a self-report questionnaire. Findings indicated that low memory self-efficacy, high memory-related anxiety, negative attitude and high subjective norm (e.g. anticipating negative evaluations by important others) were the most important correlates of perceived forgetfulness. It is argued that future interventions should focus on the specified determinants to improve programme effectiveness in reducing subjective memory complaints.

Subjective forgetfulness is associated with lower quality of life in middle-aged and young-old individuals: a 9-year follow-up in older participants from the Maastricht Aging Study

Objectives: Many people regard themselves as being forgetful. They may be hindered by or worried about this subjective forgetfulness in daily life. The first aim of the present study was to determine whether perceived forgetfulness in healthy older adults is related to a lower quality of life. The second objective was to assess whether the association between perceived forgetfulness and quality of life changes over a 9-year follow-up period. Method: A group of 412 participants in the longitudinal Maastricht Aging Study, aged 54 years or older, were interviewed and tested at baseline, 3, 6, and 9 years. Four proxy measures of quality of life were studied; satisfaction with life, mental well-being, and symptoms of anxiety and depression. Results: Results showed that subjective forgetfulness was associated with a lower quality of life. In addition, in individuals considering themselves forgetful, a significant increase was found in symptoms of anxiety, compared to those who had no perceived forgetfulness. The relation between perceived forgetfulness and decreased satisfaction with life was stronger in younger (54–69 years) than in older participants (70–91 years). Conclusion: The observation that perceived forgetfulness and reduced quality of life are related and that this relation persists over time demonstrates the relevance of subjective forgetfulness for daily life functioning, particularly in relatively young subjects.

Diagnostic impact of [18F]flutemetamol PET in early-onset dementia

BackgroundEarly-onset dementia patients often present with atypical clinical symptoms, hampering an accurate clinical diagnosis. The purpose of the present study was to assess the diagnostic impact of the amyloid-positron emission tomography (PET) imaging agent [18F]flutemetamol in early-onset dementia patients, in terms of change in (confidence in) diagnosis and patient management plan.MethodsThis prospective bi-center study included 211 patients suspected of early-onset dementia who visited a tertiary memory clinic. Patients were eligible with Mini Mental State Examinationu2009≥u200918 and age at diagnosisu2009≤u200970xa0years and in whom the diagnostic confidence was <90% after routine diagnostic work-up. All patients underwent [18F]flutemetamol PET, which was interpreted as amyloid-negative or amyloid-positive based on visual rating. Before and after disclosing the PET results, we assessed the diagnostic confidence (using a visual analog scale of 0–100%) and clinical diagnosis. The impact of [18F]flutemetamol PET on the patient management plan was also evaluated.Results[18F]flutemetamol PET scans were positive in 133 out of 211 (63%) patients, of whom 110 out of 144 (76%) patients had a pre-PET Alzheimer’s disease (AD) diagnosis and 23 out of 67 (34%) patients had a non-AD diagnosis. After disclosure of PET results, 41/211 (19%) diagnoses changed. Overall, diagnostic confidence increased from 69 ± 12% to 88 ± 15% after disclosing PET results (Pu2009<u20090.001; in 87% of patients). In 79 (37%) patients, PET results led to a change in patient management and predominantly the initiation of AD medication when PET showed evidence for amyloid pathology.Conclusions[18F]flutemetamol PET changed clinical diagnosis, increased overall diagnostic confidence, and altered the patient management plan. Our results suggest that amyloid PET may have added value over the standardized diagnostic work-up in early-onset dementia patients with uncertain clinical diagnosis. This study provides evidence for the recommendations put forward in the appropriate use criteria for amyloid PET in clinical practice.Trial registrationNederlands Trial Register NTR3743. Registered 7 December 2012.

Homocysteine in relation to cognitive performance in pathological and non-pathological conditions.

Abstract Elevated serum homocysteine has been associated with increased risk of Alzheimers disease. Furthermore, elevated homocysteine levels are related to cognitive dysfunction in the elderly. The aim of the present study was to explore the disease specificity of the relation between serum total homocysteine levels and cognitive function. For this, we summarize data from several studies on homocysteine levels in both normal and pathological conditions performed in our laboratories and evaluate possible mechanisms of effects of elevated homocysteine levels in the central nervous system. Total homocysteine levels were measured in serum of: 1) healthy aging individuals; 2) patients with Alzheimers and Parkinsons disease and patients with other cognitive disorders; and 3) patients with multiple sclerosis. Increased serum homocysteine concentration was related to worse cognitive performance over a 6-year period in the normal aging population (r=−0.36 to −0.14, p<0.01 for the Word learning tests; r=0.76, p<0.05 for the Stroop Colored Word test). Homocysteine was only increased in patients with Parkinsons disease on L-Dopa therapy (18.9 vs. 16.5μmol/L in healthy controls), and not in dementia patients. Homocysteine was elevated in patients with progressive multiple sclerosis (15.0μmol/L, n=39, compared to 12.0 μmol/L in 45 controls) and correlated to both cognitive and motor function (r=−0.33 and −0.33, p<0.05, respectively). The relationship between homocysteine and cognitive function in non-pathological and pathological situations indicates that changes in its levels may play a role in cognitive functioning in a broad spectrum of conditions.

Psychometric properties and feasibility of instruments used to assess awareness of deficits after acquired brain injury: a systematic review.

Background:Unawareness of deficits after acquired brain injury (ABI) is often reported in the clinic. Several methods have been developed to measure a patients awareness of deficits after ABI; however, no criterion standard currently exists to measure this phenomenon. Objective:To review all instruments for measuring awareness of deficits and evaluate their psychometric and conceptual properties as well as their feasibility. Methods:Systematic literature search for available awareness measurement instruments used in experimental ABI studies. Instruments were divided into the following 4 assessment methods: clinician ratings, structured interviews, performance-based discrepancy, and self-other rating discrepancy methods. The quality of the instruments was evaluated. Results:The literature search identified 39 instruments and 8 of these were selected. The following 3 instruments stood out in terms of quality: Self-Awareness of Deficits Interview, Patient Competency Rating Scale, and Awareness Questionnaire. Conclusion:Although these quantitative instruments are useful tools in research, they have limited utility in the clinic because they only measure intellectual awareness. Therefore, in addition to these instruments, qualitative tools should also be used to gain a complete view of a patients awareness problem.