Apolipoprotein E-dependent load of white matter hyperintensities in Alzheimer's disease: a voxel-based lesion mapping study.

INTRODUCTION: White matter (WM) magnetic resonance imaging (MRI) hyperintensities are common in Alzheimer's disease (AD), but their pathophysiological relevance and relationship to genetic factors are unclear. In the present study, we investigated potential apolipoprotein E (APOE)-dependent effects on the extent and cognitive impact of WM hyperintensities in patients with AD. METHODS: WM hyperintensity volume on fluid-attenuated inversion recovery images of 201 patients with AD (128 carriers and 73 non-carriers of the APOE ε4 risk allele) was determined globally as well as regionally with voxel-based lesion mapping. Clinical, neuropsychological and MRI data were collected from prospective multicenter trials conducted by the German Dementia Competence Network. RESULTS: WM hyperintensity volume was significantly greater in non-carriers of the APOE ε4 allele. Lesion distribution was similar among ε4 carriers and non-carriers. Only ε4 non-carriers showed a correlation between lesion volume and cognitive performance. CONCLUSION: The current findings indicate an increased prevalence of WM hyperintensities in non-carriers compared with carriers of the APOE ε4 allele among patients with AD. This is consistent with a possibly more pronounced contribution of heterogeneous vascular risk factors to WM damage and cognitive impairment in patients with AD without APOE ε4-mediated risk.

The metabolism hypothesis of Alzheimer's disease: from the concept of central insulin resistance and associated consequences to insulin therapy.

The concept of central insulin resistance and dysfunctional insulin signaling in Alzheimer's disease (AD) has been developed by Siegfried Hoyer in 1985-2000. It is widely recognized that a cerebrometabolic deficiency is one of the most relevant proximate characteristics of sporadic AD, including functional deficits in oxidative glucose breakdown, oxidative stress and amplifying the action of glucocorticoids in the brain. Insulin and insulin receptors are widely distributed in the brain and are impaired in the post-mortem Alzheimer brain. Functionally, altered insulin signaling may promote synaptic dysfunction and impaired connectivity, especially in highly connected and metabolically active regions of the brain, which in turn predisposes towards AD pathology. Thus, the hypothesis has been proposed that defects in the brain insulin signal transduction system and associated consequences, e.g., oxidative stress, are centrally involved in the etiopathogenesis of sporadic AD. Most importantly, in a research field still awaiting substantial progress in therapeutic options, the idea of AD as a brain type of diabetes mellitus is now being translated into clinical trials with promising early results.

Amygdala habituation: a reliable fMRI phenotype.

Amygdala function is of high interest for cognitive, social and psychiatric neuroscience, emphasizing the need for reliable assessments in humans. Previous work has indicated unsatisfactorily low within-subject reliability of amygdala activation fMRI measures. Based on basic science evidence for strong habituation of amygdala response to repeated stimuli, we investigated whether a quantification of habituation provides additional information beyond the usual estimate of the overall mean activity. We assessed the within-subject reliability of amygdala habituation measures during a facial emotion matching paradigm in 25 healthy subjects. We extracted the amygdala signal decrement across the course of the fMRI run for the two test-retest measurement sessions and compared reliability estimates with previous findings based on mean response amplitude. Retest-reliability of the session-wise amygdala habituation was significantly higher than the evoked amygdala mean amplitude (intraclass correlation coefficients (ICC)=0.53 vs. 0.16). To test the task-specificity of this finding, we compared the retest-reliability of amygdala habituation across two different tasks. Significant amygdala response decrement was also seen in a cognitive task (n-back working memory) that did not per se activate the amygdala, but was totally unreliable in that context (ICC~0.0), arguing for task-specificity. Together the results show that emotion-dependent amygdala habituation is a robust and considerably more reliable index than the mean amplitude, and provides a robust potential endpoint for within-subject designs including pharmaco-fMRI studies.

Genetic interaction of PICALM and APOE is associated with brain atrophy and cognitive impairment in Alzheimer's disease.

BACKGROUND: Evidence has emerged indicating that the ε4 allele of APOE and PICALM interact in conferring risk of Alzheimer's disease (AD). The biologic basis of this interaction is unclear, but it is likely to have phenotypic relevance and contribute to the structural and clinical heterogeneity of AD. METHODS: The aim of this study was to investigate interaction effects of the APOE ε4 allele and the alleles at the single-nucleotide polymorphism rs3851179 located in the PICALM locus. We analyzed brain volumes and cognitive phenotypes of 165 patients with early AD dementia. RESULTS: There was a synergistic adverse effect of homozygosity for the PICALM risk allele G in rs3851179 and APOE ε4 on volume in prefrontal and performance on the Trail Making Test A, which is sensitive to processing speed and working memory function. CONCLUSIONS: The data suggest a neural mechanism for APOE-PICALM interactions in patients with manifest AD and indicate that the PICALM genotype modulates both brain atrophy and cognitive performance in APOE ε4 carriers.

CNVs conferring risk of autism or schizophrenia affect cognition in controls.

In a small fraction of patients with schizophrenia or autism, alleles of copy-number variants (CNVs) in their genomes are probably the strongest factors contributing to the pathogenesis of the disease. These CNVs may provide an entry point for investigations into the mechanisms of brain function and dysfunction alike. They are not fully penetrant and offer an opportunity to study their effects separate from that of manifest disease. Here we show in an Icelandic sample that a few of the CNVs clearly alter fecundity (measured as the number of children by age 45). Furthermore, we use various tests of cognitive function to demonstrate that control subjects carrying the CNVs perform at a level that is between that of schizophrenia patients and population controls. The CNVs do not all affect the same cognitive domains, hence the cognitive deficits that drive or accompany the pathogenesis vary from one CNV to another. Controls carrying the chromosome 15q11.2 deletion between breakpoints 1 and 2 (15q11.2(BP1-BP2) deletion) have a history of dyslexia and dyscalculia, even after adjusting for IQ in the analysis, and the CNV only confers modest effects on other cognitive traits. The 15q11.2(BP1-BP2) deletion affects brain structure in a pattern consistent with both that observed during first-episode psychosis in schizophrenia and that of structural correlates in dyslexia.

Risks and benefits of bupropion treatment in schizophrenia: a systematic review of the current literature.

BACKGROUND: Bupropion inhibits the reuptake of norepinephrine and dopamine, which are involved in the pathogenesis of affective, cognitive, and psychomotor impairment in schizophrenia. Because of reports on bupropion-associated psychoses, it is reluctantly used in schizophrenic patients. Risks and benefits, however, have never been comprehensively reviewed. OBJECTIVE: The objectives of this study were to evaluate the efficacy of bupropion on depression, negative symptoms, cognition, and smoking habits in schizophrenia and to appraise safety aspects. METHODS: MEDLINE OVID/PubMed, scholar.google.com and the Cochrane Database were screened for the keywords ("bupropion"/"wellbutrin"/"elontril"/"zyban") and ("psychosis"/"schizophrenia"/"psychotic disorder"). STUDY SELECTION: A total of 13 randomized controlled trials (28 publications), 3 open prospective evaluations, 5 multiple case reports, 22 single case reports, and 6 review articles were incorporated in the final analysis. DATA EXTRACTION: Information on patient population, age, diagnosis, bupropion dose and formulation, antipsychotic and concomitant medication, adverse events and treatment outcomes regarding psychosis, affective and negative symptoms, cognition, and smoking habits were collected from the published reports. RESULTS: A total of 30 cases of bupropion-induced psychoses have been published, 17 (57%) of which were associated with the immediate-release drug formulation and 28 (93%) of which occurred without concomitant antipsychotic medication. In comparison, 229 schizophrenic patients on stable antipsychotic regimens were successfully treated with bupropion and experienced marked clinical improvement without developing psychosis. Pharmacokinetic interactions with antipsychotics were rare, whereas electroencephalographic abnormalities occurred frequently. CONCLUSIONS: In schizophrenic patients treated with bupropion in addition to antipsychotics, the risk for bupropion-induced psychoses seems negligible. The efficacy of a combined dopamine and norepinephrine agonist in schizophrenia is biologically plausible. Further trials involving bupropion should integrate neurobiological methods and focus on negative symptoms and cognitive deficits in schizophrenia.

APOE-dependent phenotypes in subjects with mild cognitive impairment converting to Alzheimer's disease.

BACKGROUND: The E4 isoform of the APOE genotype is the most significant genetic risk factor for sporadic Alzheimer's disease (AD) and has recently been found to modulate disease expression in patients with AD. OBJECTIVE: To investigate APOE-dependent cognitive and structural phenotypes in subjects with mild cognitive impairment who converted to AD within the following three years. METHODS: Subjects converting to AD (n = 63) were compared to a control group with stable mild cognitive impairment (n = 131). Clinical, neuropsychological, and MRI data were obtained by the German Dementia Competence Network. Subgroups of converting and stable APOE E4 carriers and non-carriers were investigated longitudinally with MRI to examine structural correlates of conversion. Voxel-based morphometry was applied to investigate gray matter distribution. RESULTS: At baseline, executive performance correlated with global and bilateral prefrontal gray matter volume and predicted conversion only among non-carriers. Converting carriers and non-carriers presented distinct patterns of brain atrophy on longitudinal analysis, in line with a dissociation between more pronounced occipital atrophy in carriers and more frontoparietal volume loss in non-carriers at follow-up. CONCLUSIONS: The current findings suggest that in APOE E4 non-carriers with AD, executive dysfunction is closely linked to frontal gray matter atrophy and predictive of progression to dementia. The results are consistent with APOE genotype-dependent profiles of structural damage and cognitive decline in patients with imminent conversion to AD.

Test-retest reliability of evoked BOLD signals from a cognitive-emotive fMRI test battery.

Even more than in cognitive research applications, moving fMRI to the clinic and the drug development process requires the generation of stable and reliable signal changes. The performance characteristics of the fMRI paradigm constrain experimental power and may require different study designs (e.g., crossover vs. parallel groups), yet fMRI reliability characteristics can be strongly dependent on the nature of the fMRI task. The present study investigated both within-subject and group-level reliability of a combined three-task fMRI battery targeting three systems of wide applicability in clinical and cognitive neuroscience: an emotional (face matching), a motivational (monetary reward anticipation) and a cognitive (n-back working memory) task. A group of 25 young, healthy volunteers were scanned twice on a 3T MRI scanner with a mean test-retest interval of 14.6 days. FMRI reliability was quantified using the intraclass correlation coefficient (ICC) applied at three different levels ranging from a global to a localized and fine spatial scale: (1) reliability of group-level activation maps over the whole brain and within targeted regions of interest (ROIs); (2) within-subject reliability of ROI-mean amplitudes and (3) within-subject reliability of individual voxels in the target ROIs. Results showed robust evoked activation of all three tasks in their respective target regions (emotional task=amygdala; motivational task=ventral striatum; cognitive task=right dorsolateral prefrontal cortex and parietal cortices) with high effect sizes (ES) of ROI-mean summary values (ES=1.11-1.44 for the faces task, 0.96-1.43 for the reward task, 0.83-2.58 for the n-back task). Reliability of group level activation was excellent for all three tasks with ICCs of 0.89-0.98 at the whole brain level and 0.66-0.97 within target ROIs. Within-subject reliability of ROI-mean amplitudes across sessions was fair to good for the reward task (ICCs=0.56-0.62) and, dependent on the particular ROI, also fair-to-good for the n-back task (ICCs=0.44-0.57) but lower for the faces task (ICC=-0.02-0.16). In conclusion, all three tasks are well suited to between-subject designs, including imaging genetics. When specific recommendations are followed, the n-back and reward task are also suited for within-subject designs, including pharmaco-fMRI. The present study provides task-specific fMRI reliability performance measures that will inform the optimal use, powering and design of fMRI studies using comparable tasks.

Investigation of mindfulness meditation practitioners with voxel-based morphometry.

Mindfulness meditators practice the non-judgmental observation of the ongoing stream of internal experiences as they arise. Using voxel-based morphometry, this study investigated MRI brain images of 20 mindfulness (Vipassana) meditators (mean practice 8.6 years; 2 h daily) and compared the regional gray matter concentration to that of non-meditators matched for sex, age, education and handedness. Meditators were predicted to show greater gray matter concentration in regions that are typically activated during meditation. Results confirmed greater gray matter concentration for meditators in the right anterior insula, which is involved in interoceptive awareness. This group difference presumably reflects the training of bodily awareness during mindfulness meditation. Furthermore, meditators had greater gray matter concentration in the left inferior temporal gyrus and right hippocampus. Both regions have previously been found to be involved in meditation. The mean value of gray matter concentration in the left inferior temporal gyrus was predictable by the amount of meditation training, corroborating the assumption of a causal impact of meditation training on gray matter concentration in this region. Results suggest that meditation practice is associated with structural differences in regions that are typically activated during meditation and in regions that are relevant for the task of meditation.

Synchronized measurement of simultaneous EEG-fMRI: a simulation study.

OBJECTIVE: The quality of averaged gradient artifact subtraction from EEG recorded during fMRI is highly dependent on the accuracy of gradient artifact sampling. Even small sampling shifts (e.g. a single datapoint at 5kHz) increase the variance of the sampled gradient artifacts because of very steep slopes in the signal time course. Hence, although principally gradient artifacts are invariant signals because of their technical origin, variance attributed to sampling errors attenuates the effect of artifact removal. Recently, it has been shown that synchronizing the EEG-amplifier clock to the MR-scanner control-device clock improves artifact reduction by subtraction. METHODS: In order to investigate the synchronized measurement of combined EEG-fMRI, we used simulated EEG by measuring function generator signals in the MR-scanner. Only the usage of known signals allows an assessment of the improvement in accuracy of artifact recording by synchronized compared to non-synchronized measurement, since the signal is identical in both conditions. RESULTS: After averaged gradient artifact subtraction synchronized recorded signals were apparently less distorted than non-synchronized recorded signals. Spectral analyses revealed that especially artifact frequencies above 50Hz had less power in restored synchronized compared to restored non-synchronized recorded signals. Computed total signal variances were not always less in restored synchronized compared to restored non-synchronized recorded signals. CONCLUSIONS: Taken together, synchronizing simultaneous EEG-fMRI measurement is a useful enhancement for averaged gradient artifact subtraction although post-correction filtering is still necessary. SIGNIFICANCE: Our results support the recent finding that synchronization improves the quality of averaged gradient artifact subtraction. However, quantitatively we could not verify a systematic benefit of recording electrical signals during fMRI synchronously rather than non-synchronously to the MR-scanner control-device clock.

Distinct mechanisms of altered brain activation in patients with multiple sclerosis.

Cerebral reorganization may limit the effects of central nervous system tissue damage on cognition in patients with multiple sclerosis (MS). This study investigated fMRI activation patterns in patients with relapsing-remitting MS and healthy control subjects during performance of a delayed recognition task. As intended, fMRI task performance was similar in the MS and the control group, whereas neuropsychological testing revealed reduced performance in the patient group on the Paced Serial Addition Test, a reference task for the assessment of cognitive function in MS. Patients overall showed more activation in left posterior parietal cortex than healthy control subjects. Global gray matter atrophy in the patient group was associated with low PASAT scores. In a multiple regression analysis including white matter lesion load and gray matter atrophy as covariates, PASAT performance correlated with activation in left posterior parietal cortex and right anterior midfrontal gyrus, indicating a reallocation of neuronal resources to help preserve function. Global gray matter atrophy correlated with activation in bilateral prefrontal cortex, dorsal ACC and left posterior parietal cortex and, furthermore, was associated with a low degree of deactivation in rostral ACC, suggesting neural inefficiency and consistent with a reduced capacity to modulate between frontoparietal task-associated activation and 'default network' activity. The current study provides evidence that altered brain activation in MS patients has two distinct components, one related to compensatory processes and one to neural inefficiency associated with tissue damage.

Relationship between regional hemodynamic activity and simultaneously recorded EEG-theta associated with mental arithmetic-induced workload.

Theta increases with workload and is associated with numerous processes including working memory, problem solving, encoding, or self monitoring. These processes, in turn, involve numerous structures of the brain. However, the relationship between regional brain activity and the occurrence of theta remains unclear. In the present study, simultaneous EEG-fMRI recordings were used to investigate the functional topography of theta. EEG-theta was enhanced by mental arithmetic-induced workload. For the EEG-constrained fMRI analysis, theta-reference time-series were extracted from the EEG, reflecting the strength of theta occurrence during the time course of the experiment. Theta occurrence was mainly associated with activation of the insular cortex, hippocampus, superior temporal areas, cingulate cortex, superior parietal, and frontal areas. Though observation of temporal and insular activation is in accord with the theory that theta specifically reflects encoding processes, the involvement of several other brain regions implies that surface-recorded theta represents comprehensive functional brain states rather than specific processes in the brain. The results provide further evidence for the concept that emergent theta band oscillations represent dynamic functional binding of widely distributed cortical assemblies, essential for cognitive processing. This binding process may form the source of surface-recorded EEG theta.

Evidence for a direct association between cortical atrophy and cognitive impairment in relapsing-remitting MS.

Cognitive deficits affecting memory, attention and speed of information processing are common in multiple sclerosis (MS). The mechanisms of cognitive impairment remain unclear. Here, we examined the association between neuropsychological test performance and brain atrophy in a group of mildly disabled patients with relapsing-remitting MS. We applied voxel-based morphometry (SPM2) to investigate the distribution of brain atrophy in relation to cognitive performance. Patients had lower scores than control subjects on tests of memory and executive function, including the PASAT, Digit Span Backward and a test of short-term verbal memory (Memo). Among patients, but not healthy controls, performance on the PASAT, a comprehensive measure of cognitive function and reference task for the cognitive evaluation of MS-patients, correlated with global grey matter volume as well as with grey matter volume in regions associated with working memory and executive function, including bilateral prefrontal cortex, precentral gyrus and superior parietal cortex as well as right cerebellum. Compared to healthy subjects, patients showed a volume reduction in left temporal and prefrontal cortex, recently identified as areas predominantly affected by diffuse brain atrophy in MS. A comparison of low performers in the patient group with their matched control subjects showed more extensive and bilateral temporal and frontal volume reductions as well as bilateral parietal volume loss, compatible with the progression of atrophy found in more advanced MS-patients. These findings indicate that MS-related deficits in cognition are closely associated with cortical atrophy.

Central nervous system disease in primary Sjogrens syndrome: the role of magnetic resonance imaging.

OBJECTIVES: To examine the frequency of central nervous system (CNS) disease in primary Sjogrens syndrome (pSS) and indicate ways in which cerebral magnetic resonance imaging (MRI) may help determine the significance of CNS involvement. METHODS: The current review was based on a Medline (Pubmed) literature search through May 2003, focused on Sjogrens syndrome, other vasculitides, multiple sclerosis (MS), specific MRI techniques, and MRI findings with regard to the above-mentioned diseases. Additional literature was identified in the reference sections of articles listed in Medline. RESULTS: Severe CNS manifestations reminiscent of MS have been described in pSS patients. Moreover, the prevalence of nonfocal neuropsychological abnormalities has been found to be elevated in some pSS patient populations. MRI studies suggest discrete cerebral tissue damage even in neurologically asymptomatic patients. However, small white matter lesions are nonspecific and may be related to age or cerebrovascular risk factors such as hypertension. A large controlled study, complementing established T2-weighted MRI with fluid-attenuated inversion recovery (FLAIR) to achieve high sensitivity in lesion detection, could indicate the disease specificity of white matter lesions in pSS. Newer MR techniques, such as spectroscopy and magnetization transfer imaging, applied, for example, in MS and systemic lupus erythematosus (SLE) to evaluate CNS tissue injury, could help determine the extent and mechanisms of macroscopic and microscopic CNS lesions in pSS. CONCLUSIONS: Future controlled studies will be necessary to more precisely estimate the prevalence of CNS lesions in pSS, specifically of discrete white matter abnormalities. Newer MRI techniques have the potential to provide information on the severity and pathophysiological mechanisms of CNS tissue damage.

Training-dependent plasticity in patients with multiple sclerosis.

Cortical reorganization has been demonstrated in the motor network that mediates performance of a motor task in patients with multiple sclerosis. How this network responds to motor training is not known. This study examined functional MRI (fMRI) activation patterns associated with performance of a motor task, consisting of repetition of directionally specific voluntary thumb movements, before and after motor training in a group of multiple sclerosis patients with mild motor impairment of the right upper extremity. Patients and healthy subjects were scanned in one session before, during and after a 30 min training period. fMRI data obtained during rest, thumb flexion (trained movement) and thumb extension (untrained movement) were analysed using random effects analysis (SPM99). Motor kinematics of training motions and EMG from the resting hand were monitored with an accelerometer and surface EMG electrodes. Kinematics of thumb movements before, during and after training were comparable in the absence of mirror EMG activity in the resting hand. Before training, thumb movements elicited more prominent activation of the contralateral dorsal premotor cortex [PMd, Brodmann area (BA) 6] in multiple sclerosis patients than in controls. After training, unlike the control group, multiple sclerosis patients did not exhibit task-specific reductions in activation in the contralateral primary somatosensory (S1), motor (M1) and adjacent parietal association (BA 40) cortices. These results indicate that patients engage the contralateral PMd more than controls in order to perform directionally specific movements before training. The absence of training-dependent reductions in activation in S1, M1 and BA 40 is consistent with a decreased capacity to optimize recruitment of the motor network with practice.

Interferon-beta 1b leads to a short-term increase of soluble but long-term stabilisation of cell surface bound adhesion molecules in multiple sclerosis.

Adhesion molecules (AMs) are believed to regulate the transmigration of blood leukocytes across the blood-brain barrier (BBB), which is an essential step in the pathogenesis of multiple sclerosis (MS). Previous studies have investigated changes of the soluble forms of AM during interferon-beta1b (IFN-beta1b) treatment in MS patients. In this study, we analysed the influence of IFN-beta1b treatment on the cell surface bound forms of the AMs cICAM-1 and cICAM-3 on blood mononuclear cells (MNC). Sixty-eight patients with relapsing-remitting MS were enrolled in this open study; thirty of them were treated with IFN-beta1b. Blood samples were collected every three months over a period of 18 months. The expression levels of cell surface bound forms of AM on blood MNC were measured by two colour flow cytometry analysis. sVCAM-1, sICAM-1 and sICAM-3 were determined by ELISA. We found a short-term induction effect on the serum concentrations of sICAM-1 and sVCAM-1 after three months of IFN-beta1b treatment. The expression levels of cell surface bound AMs on blood MNC remained stable during treatment. Untreated MS patients, however, showed a continuous decrease in the expression of cell surface bound AM expression over 18 months. Stabilisation of the expression of cell surface bound AMs on blood MNC may indicate the beneficial effects of IFN-beta1b therapy in MS patients.

Kinematic specificity of cortical reorganization associated with motor training.

Motor training consisting of repetition of directionally specific voluntary thumb movements elicits a short-term memory trace that encodes the kinematic details of the practiced motions in the primary motor cortex. Here, we studied activation patterns associated with this form of training using functional magnetic resonance imaging under careful monitoring of motor training kinematics and electromyography. We identified task-specific reductions in activation in contralateral motor cortex, a region that controls executive motor output, as well as somatosensory cortex and inferior parietal lobule, regions in charge of monitoring motor training kinematics. Our findings are consistent with the hypothesis that a short training period consisting of repetition of finger motions leads to cortical reorganization characterized by a smaller and more efficient network that is specific for the trained movement direction.