B.N.M. van Berckel

Reduced GABAA benzodiazepine receptor binding in veterans with post-traumatic stress disorder.

γ-Aminobutyric acid (GABAA) receptors are thought to play an important role in modulating the central nervous system in response to stress. Animal data have shown alterations in the GABAA receptor complex by uncontrollable stressors. SPECT imaging with benzodiazepine ligands showed lower distribution volumes of the benzodiazepine-GABAA receptor in the prefrontal cortex of patients with post-traumatic stress disorder (PTSD) in one, but not in another study. The objective of the present study was to assess differences in the benzodiazepine-GABAA receptor complex in veterans with and without PTSD using [11C]flumazenil and positron emission tomography (PET). Nine drug naive male Dutch veterans with deployment related PTSD and seven male Dutch veterans without PTSD were recruited, and matched for age, region and year of deployment. Each subject received a [11C]flumazenil PET scan and a structural magnetic resonance imaging scan. Dynamic 3D PET scans with a total duration of 60 min were acquired, and binding in template based and manually defined regions of interest (ROI) was quantified using validated plasma input and reference tissue models. In addition, parametric binding potential images were compared on a voxel-by-voxel basis using statistical parametric mapping (SPM2). ROI analyses using both template based and manual ROIs showed significantly reduced [11C]flumazenil binding in PTSD subjects throughout the cortex, hippocampus and thalamus. SPM analysis confirmed these results. The observed global reduction of [11C]flumazenil binding in patients with PTSD provides circumstantial evidence for the role of the benzodiazepine-GABAA receptor in the pathophysiology of PTSD and is consistent with previous animal research and clinical psychopharmacological studies.

Cerebral blood flow measured with 3D pseudocontinuous arterial spin-labeling MR imaging in Alzheimer disease and mild cognitive impairment: a marker for disease severity.

PURPOSE To compare quantitative cerebral blood flow (CBF) values in patients with Alzheimer disease (AD), patients with mild cognitive impairment (MCI), and subjects with subjective complaints by using a whole-brain three-dimensional (3D) pseudocontinuous arterial spin-labeling (ASL) technique at 3.0 T. MATERIALS AND METHODS The local institutional review board approved the study. All subjects provided informed consent. Whole-brain 3D fast spin-echo pseudocontinuous ASL images were acquired at 3.0 T in 71 patients with AD (mean age, 65 years ± 7; 55% women), 35 patients with MCI (mean age, 65 years ± 8; 42% women), and 73 subjects with subjective complaints (mean age, 60 years ± 9; 39% women) who visited a memory clinic. Analyses were performed by using both uncorrected maps and maps corrected for partial volume effects. Regional CBF was compared by using analyses of variance; permutation tests were used for voxel-wise comparisons. Associations with cognition (Mini-Mental State Examination) were investigated by using linear regression analyses. All analyses were corrected for age and sex. RESULTS Uncorrected CBF was decreased in patients with AD compared with subjects with subjective complaints (27 mL/100 g/min ± 5 vs 33 mL/100 g/min ± 5; P < .001), with strongest reductions in the parietal lobes (22 mL/100 g/min ± 6 vs 30 mL/100 g/min ± 5; ie, decrease of 27%). Corrected cortical CBF showed similar results. In patients with MCI, CBF was decreased in the precuneus and the parietal and occipital lobes compared with subjects with subjective complaints. Voxel-wise comparisons confirmed the region of interest-based findings, showing the largest CBF differences in the precuneus and bilateral parietal cortex. Uncorrected and corrected cortical CBF were associated with cognition across diagnostic groups (β = 0.46 and β = 0.42, P < .001) and within the AD group (β = 0.41 and β = 0.42, P < .001). CONCLUSION CBF measured with 3D pseudocontinuous ASL MR imaging helps detect functional changes in the prodromal and more advanced stages of AD and is a marker for disease severity.

The effect of physical activity on cognitive function in patients with dementia: A meta-analysis of randomized control trials.

Non-pharmacological therapies, such as physical activity interventions, are an appealing alternative or add-on to current pharmacological treatment of cognitive symptoms in patients with dementia. In this meta-analysis, we investigated the effect of physical activity interventions on cognitive function in dementia patients, by synthesizing data from 802 patients included in 18 randomized control trials that applied a physical activity intervention with cognitive function as an outcome measure. Post-intervention standardized mean difference (SMD) scores were computed for each study, and combined into pooled effect sizes using random effects meta-analysis. The primary analysis yielded a positive overall effect of physical activity interventions on cognitive function (SMD[95% confidence interval]=0.42[0.23;0.62], p<.01). Secondary analyses revealed that physical activity interventions were equally beneficial in patients with Alzheimers disease (AD, SMD=0.38[0.09;0.66], p<.01) and in patients with AD or a non-AD dementia diagnosis (SMD=0.47[0.14;0.80], p<.01). Combined (i.e. aerobic and non-aerobic) exercise interventions (SMD=0.59[0.32;0.86], p<.01) and aerobic-only exercise interventions (SMD=0.41[0.05;0.76], p<.05) had a positive effect on cognition, while this association was absent for non-aerobic exercise interventions (SMD=-0.10[-0.38;0.19], p=.51). Finally, we found that interventions offered at both high frequency (SMD=0.33[0.03;0.63], p<.05) and at low frequency (SMD=0.64[0.39;0.89], p<.01) had a positive effect on cognitive function. This meta-analysis suggests that physical activity interventions positively influence cognitive function in patients with dementia. This beneficial effect was independent of the clinical diagnosis and the frequency of the intervention, and was driven by interventions that included aerobic exercise.

Amyloid burden and metabolic function in early-onset Alzheimer's disease: parietal lobe involvement

Alzheimers disease with early onset often presents with a distinct cognitive profile, potentially reflecting a different distribution of underlying neuropathology. The purpose of this study was to examine the relationships between age and both in vivo fibrillary amyloid deposition and glucose metabolism in patients with Alzheimers disease. Dynamic [(11)C]Pittsburgh compound-B (90 min) and static [(18)F]fluorodeoxyglucose (15 min) scans were obtained in 100 patients with Alzheimers disease and 20 healthy controls. Parametric non-displaceable binding potential images of [(11)C]Pittsburgh compound-B and standardized uptake value ratio images of [(18)F]fluorodeoxyglucose were generated using cerebellar grey matter as reference tissue. Nine [(11)C]Pittsburgh compound-B-negative patients were excluded. The remaining patients were categorized into younger (n=45, age: 56 ± 4 years) and older (n=46, age: 69 ± 5 years) groups, based on the median age (62 years) at time of diagnosis. Younger patients showed more severe impairment on visuo-spatial function, attention and executive function composite scores (P<0.05), while we found a trend towards poorer memory performance for older patients (P=0.11). Differences between groups were assessed using a general linear model with repeated measures (gender adjusted) with age as between subjects factor, region (frontal, temporal, parietal and occipital and posterior cingulate cortices) as within subjects factor and [(11)C]Pittsburgh compound-B binding/[(18)F]fluorodeoxyglucose uptake as dependent variables. There was no main effect of age for [(11)C]Pittsburgh compound-B or [(18)F]fluorodeoxyglucose, suggesting that overall, the extent of amyloid deposition or glucose hypometabolism did not differ between groups. Regional distributions of [(11)C]Pittsburgh compound-B binding and [(18)F]fluorodeoxyglucose uptake (both P for interaction <0.05) differed between groups, however, largely due to increased [(11)C]Pittsburgh compound-B binding and decreased [(18)F]fluorodeoxyglucose uptake in the parietal cortex of younger patients (both P<0.05). Linear regression analyses showed negative associations between visuo-spatial functioning and parietal [(11)C]Pittsburgh compound-B binding for younger patients (standardized β: -0.37) and between visuo-spatial functioning and occipital binding for older patients (standardized β: -0.39). For [(18)F]fluorodeoxyglucose, associations were found between parietal uptake with visuo-spatial (standardized β: 0.55), attention (standardized β: 0.39) and executive functioning (standardized β: 0.37) in younger patients, and between posterior cingulate uptake and memory in older patients (standardized β: 0.41, all P<0.05). These in vivo findings suggest that clinical differences between younger and older patients with Alzheimers disease are not restricted to topographical differentiation in downstream processes but may originate from distinctive distributions of early upstream events. As such, increased amyloid burden, together with metabolic dysfunction, in the parietal lobe of younger patients with Alzheimers disease may contribute to the distinct cognitive profile in these patients.

The sensitivity of pharmacodynamic tests for the central nervous system effects of drugs on the effects of sleep deprivation

Various methods are used to quantify sedative drug effects, but it is unknown how these surrogate measures relate to clinically relevant sleepiness. This study assessed the sensivity of different surrogates of sedation to clinically relevant sleepiness induced by sleep deprivation. Nine healthy volunteers completed a balanced three-way cross-over study with 1-week wash-out periods. Adaptive tracking, smooth-pursuit and saccadic eye movements, body sway, digit symbol substitution (DSST), visual analogue scales (VAS) and electroencephalograms (EEG) were evaluated on three occasions: (1) during the day after normal sleep, (2) during wakefulness at night; and (3) during the day after a night of sleep deprivation.VAS of alertness showed a gradual decline at night and a constant average reduction of 38 percent [95% Confidence intervals (CI), 28–47%] during the day after sleep deprivation. Average mood scores diminished by 14 percent (95%, CI 2–24%) during the day after sleep deprivation. Adaptive tracking, saccadic eye movements and body sway tended to deteriorate at night, but overall this was not statistically significant. After a night of sleep deprivation, adaptive tracking decreased by 21 percent (95% CI, 11–30%), saccadic eye movements decreased by 9–10 percent (95% CI, 5–13%/6–15%) and body sway increased by 37 percent (95% CI, 5–79%). In contrast, EEG b2-amplitudes declined significantly at night by 18 percent (95% CI, 6–29%), without changes during the day after sleep deprivation. Smooth pursuit, DSST and other EEG-amplitudes remained unchanged. These resultsemphasize that reductions in adaptive tracking, saccadic peak velocity and body sway caused by sedative drugs really reflect sedation. They also provide a level of clinical significance for these surrogates of sedation. EEG parameters and smooth pursuit were unaffected by sleep deprivation, so drug-induced changes in these measures may notreflect sedation in a stricter sense. The motivation and alertnessnecessary for DSST may overcome mild sedation.

Metabolic Networks Underlying Cognitive Reserve in Prodromal Alzheimer Disease: A European Alzheimer Disease Consortium Project

This project aimed to investigate the metabolic basis for resilience to neurodegeneration (cognitive reserve) in highly educated patients with prodromal Alzheimer disease (AD). Methods: Sixty-four patients with amnestic mild cognitive impairment who later converted to AD dementia during follow-up, and 90 controls, underwent brain 18F-FDG PET. Both groups were divided into a poorly educated subgroup (42 controls and 36 prodromal AD patients) and a highly educated subgroup (48 controls and 28 prodromal AD patients). Brain metabolism was first compared between education-matched groups of patients and controls. Then, metabolism was compared between highly and poorly educated prodromal AD patients in both directions to identify regions of high education-related metabolic depression and compensation. The clusters of significant depression and compensation were further used as volumetric regions of interest (ROIs) in a brain interregional correlation analysis in each prodromal AD subgroup to explore metabolic connectivity. All analyses were performed by means of SPM8 (P < 0.001 uncorrected at peak level, P < 0.05 false discovery rate–corrected at cluster level; age, sex, Mini-Mental State Examination score, and center as nuisance). Results: Highly educated prodromal AD patients showed more severe hypometabolism than poorly educated prodromal AD patients in the left inferior and middle temporal gyri and the left middle occipital gyrus (ROI depression). Conversely, they showed relative hypermetabolism in the right inferior, middle, and superior frontal gyri (ROI compensation). The sites of compensation, mainly corresponding to the right dorsolateral prefrontal cortex (DLFC), showed wide metabolic correlations with several cortical areas in both hemispheres (frontotemporal cortex, parahippocampal gyrus, and precuneus) in highly educated prodromal AD patients but not in poorly educated prodromal AD patients. To provide evidence on whether these metabolic correlations represent preservation of the physiologic networks of highly educated control subjects (neural reserve) or rather the recruitment of alternative networks (neural compensation), or a combination of the two, we performed metabolic connectivity analysis of the DLFC in highly educated controls as well. The correlation sites of right DLFC partly overlapped those of highly educated prodromal AD patients but were less extended. Conclusion: The present findings suggest that highly educated prodromal AD patients can cope better with the disease thanks to neural reserve but also to the recruitment of compensatory neural networks in which the right DLFC plays a key role.

D-Cycloserine Increases Positive Symptoms in Chronic Schizophrenic Patients When Administered in Addition to Antipsychotics: A Double-Blind, Parallel, Placebo-Controlled Study

A hypofunction of the glutamatergic system and NMDA receptors in schizophrenia has been hypothesized. Therefore, stimulation of these receptors could be of benefit to patients with schizophrenia. D-cycloserine has been used for this purpose. This study reports the effects of 100 mg D-cyclo-serine, when added to typical antipsychotics in chronic schizophrenic patients exhibiting prominent negative symptoms, using a placebo-controlled, double-blind, parallel, design. D-cycloserine slightly worsened psychotic symptoms and general psychopathology as compared to placebo. D-cycloserine failed to change negative symptoms and had no effect on extrapyramidal symptoms. The exacerbation of schizophrenic symptoms may be explained by the antagonistic effects of this dose of D-cycloserine at the glycine recognition site of the NMDA receptor due to competition with the endogenous agonist glycine. Another explanation for the increase in psychopathology may be an interaction with the effects of antipsychotics on NMDA mediated neurotransmission. Thus, D-cycloserine in this study did not ameliorate schizophrenic symptoms. However, the fact that they actually worsened suggests that NMDA systems may be involved in the pathogenesis of schizophrenia. Further placebo-controlled studies with lower dosages of D-cycloserine, preferably in drug-free patients, are necessary to evaluate if D-cycloserine is of use for the treatment of patients with schizophrenia.

Accuracy and precision of pseudo-continuous arterial spin labeling perfusion during baseline and hypercapnia: A head-to-head comparison with 15O H2O positron emission tomography

Measurements of the cerebral blood flow (CBF) and cerebrovascular reactivity (CVR) provide useful information about cerebrovascular condition and regional metabolism. Pseudo-continuous arterial spin labeling (pCASL) is a promising non-invasive MRI technique to quantitatively measure the CBF, whereas additional hypercapnic pCASL measurements are currently showing great promise to quantitatively assess the CVR. However, the introduction of pCASL at a larger scale awaits further evaluation of the exact accuracy and precision compared to the gold standard. (15)O H₂O positron emission tomography (PET) is currently regarded as the most accurate and precise method to quantitatively measure both CBF and CVR, though it is one of the more invasive methods as well. In this study we therefore assessed the accuracy and precision of quantitative pCASL-based CBF and CVR measurements by performing a head-to-head comparison with (15)O H₂O PET, based on quantitative CBF measurements during baseline and hypercapnia. We demonstrate that pCASL CBF imaging is accurate during both baseline and hypercapnia with respect to (15)O H₂O PET with a comparable precision. These results pave the way for quantitative usage of pCASL MRI in both clinical and research settings.

Differential effect of APOE genotype on amyloid load and glucose metabolism in AD dementia.

Objective: To examine the relationships between apolipoprotein E (APOE) ɛ4 dose and in vivo distributions of both fibrillary amyloid burden and glucose metabolism in the same Alzheimer disease dementia patients, selected for abnormal amyloid imaging. Methods: Twenty-two APOE ɛ4 negative, 40 heterozygous, and 22 homozygous Alzheimer disease dementia patients underwent dynamic (90 minutes) [11C]Pittsburgh compound B (PIB) and static [18F]fluorodeoxyglucose (FDG) PET scans. Parametric nondisplaceable binding potential images of [11C]PIB and standardized uptake value ratio images of [18F]FDG were generated using cerebellar gray matter as reference tissue. Frontal, parietal, temporal, posterior cingulate, and occipital cortices were selected as regions of interest. Results: Multivariate general linear models with adjustment for age, sex, and Mini-Mental State Examination showed main effects of APOE ɛ4 dose on distributions of both [11C]PIB (p for trend <0.05) and [18F]FDG (p for trend <0.01). More specifically, a univariate general linear model of individual regions showed increased [11C]PIB binding in frontal cortex of APOE ɛ4 noncarriers compared with APOE ɛ4 carriers (p < 0.05). In contrast, APOE ɛ4 carriers had reduced [18F]FDG uptake in occipital cortex (p < 0.05) and a borderline significant effect in posterior cingulate (p = 0.07) in a dose-dependent manner. Conclusion: We found a reversed APOE ɛ4 dose effect for amyloid deposition in the frontal lobe, whereas APOE ɛ4 carriership was associated with more profound metabolic impairment in posterior parts of the cortex. These findings suggest that APOE genotype has a differential effect on the distribution of amyloid plaques and glucose metabolism. This may have important implications for emerging therapies that aim to directly intervene in the disease process.

Longitudinal Amyloid Imaging Using 11C-PiB: Methodologic Considerations

Several methods are in use for analyzing 11C-Pittsburgh compound-B (11C-PiB) data. The objective of this study was to identify the method of choice for measuring longitudinal changes in specific 11C-PiB binding. Methods: Dynamic 90-min 11C-PiB baseline and follow-up scans (interval, 30 ± 5 mo) were obtained for 7 Alzheimer disease (AD) patients, 11 patients with mild cognitive impairment (MCI), and 11 healthy controls. Parametric images were generated using reference parametric mapping (RPM2), reference Logan values, and standardized uptake value volume ratios (SUVr), the latter for intervals between 60 and 90 (SUVr60–90) and 40 and 60 (SUVr40–60) minutes after injection. In all analyses, cerebellar gray matter was used as a reference region. A global cortical volume of interest was defined using a probability map–based template. Percentage change between baseline and follow-up was derived for all analytic methods. Results: SUVr60–90 and SUVr40–60 overestimated binding with 13% and 10%, respectively, compared with RPM2. Reference Logan values were on average 6% lower than RPM2. Both SUVr measures showed high intersubject variability. Over time, R1, the delivery of tracer to the cortex relative to that to the cerebellum, decreased in AD patients (P < 0.05) but not in MCI patients and controls. Simulations showed that SUVr, but not RPM2 and reference Logan values, was highly dependent on uptake period and that changes in SUVr over time were sensitive to changes in flow. Conclusion: To reliably assess amyloid binding over time—for example, in drug intervention studies—it is essential to use fully quantitative methods for data acquisition and analysis.