Cerebral microbleeds: a review.

Cerebral microbleeds (CMBs) are frequent findings in MRI scans of elderly subjects. Depending on the MRI protocols applied 4.7% to 24.4% of community-based subjects show incidental CMBs. The rates reported for various types of ischemic strokes and intracerebral hemorrhages vary between 19.4% and 68.5%. Most studies also demonstrated CMBs in approximately one third of Alzheimer cases. A lobar distribution of CMBs is considered to relate to cerebral amyloid angiopathy, while CMBs located in the basal ganglia or in infratentorial brain regions are thought to relate to hypertensive vasculopathy. Besides age, hypertension, diabetes mellitus, and low serum cholesterol have so far been identified as risk factors for CMBs. Presence of an APOE ε4 allele is the only genetic factor that was consistently shown to increase the risk for CMB development. There are only few longitudinal studies on the predictive value of CMBs. For incident ischemic strokes and intracerebral hemorrhages hazard ratios of 4.48 and 50.2 have been reported. CMBs also doubled the risk for conversion to dementia in MCI patients, and there are indications for CMBs being possible predictors of increased mortality. Given the small number of longitudinal investigations with often small sample sizes the role of CMBs as predictors of disease needs to be further elucidated. CMBs were significantly more common in warfarin-treated stroke patients who developed intracerebral hemorrhages (ICH). These data are cross-sectional. They do not provide enough evidence to consider CMBs as a contraindication for antithrombotic agents in primary and secondary stroke prevention. CMBs are likely to unfavourably affect cognitive functioning. It remains to be determined if direct lesion-related effects are responsible for this finding or if CMBs are sole markers of more extensive tissue damage in the wake of cerebral small vessel disease leading to widespread visible but also non-visible tissue destruction with a high likelihood for cognitive consequences.

Determinants of brain iron in multiple sclerosis: a quantitative 3T MRI study.

OBJECTIVES: Abnormal high cerebral iron deposition may be implicated in chronic neurologic disorders, including multiple sclerosis (MS). R2* relaxometry has been recently validated in a postmortem study to indicate brain iron accumulation in a quantitative manner. We used this technique to assess brain iron levels in different stages of MS and healthy controls (HC) and determined their relation with demographic, clinical, neuropsychological, and other imaging variables. METHODS: We studied 113 consecutive patients (35 clinically isolated syndrome [CIS], 78 MS) and 35 HC with 3 T MRI and clinical and neuropsychological examination. Iron deposition in subcortical gray matter structures was assessed by automated, regional calculation of R2* rates. RESULTS: Basal ganglia (BG) R2* levels were significantly increased in MS compared to CIS (p < 0.001) and HC (p < 0.005). They were correlated with age (r = 0.5, p < 0.001), disease duration (r = 0.5, p < 0.001), Expanded Disability Status Scale (r = 0.3, p < 0.005), and the z values of mental processing speed (r = -0.3, p < 0.01). Stepwise linear regression analysis revealed gray matter atrophy as the strongest independent predictor of BG R2* levels (p < 0.001), followed by age (p < 0.001) and T2 lesion load (p < 0.005). CONCLUSION: BG iron accumulation in MS occurs with advancing disease and is related to the extent of morphologic brain damage, which argues for iron deposition as an epiphenomenon. The absence of increased iron levels in patients with CIS indicates that iron accumulation does not precede the development of MS.

The functional correlates of face perception and recognition of emotional facial expressions as evidenced by fMRI.

Recognition and processing of emotional facial expression are crucial for social behavior and employ higher-order cognitive and visual working processes. In neuropsychiatric disorders, impaired emotion recognition most frequently concerned three specific emotions, i.e., anger, fear, and disgust. As incorrect processing of (neutral) facial stimuli per se might also underlie deficits in the recognition of emotional facial expressions, we aimed to assess all these aspects in one experiment. We therefore report here a functional magnetic resonance imaging (fMRI) paradigm for parallel assessment of the neural correlates of both the recognition of neutral faces and the three clinically most relevant emotions for future use in patients with neuropsychiatric disorders. FMRI analyses were expanded through comparisons of the emotional conditions with each other. The differential insights resulting from these two analyses strategies are compared and discussed. 30 healthy participants (21 F/9 M; age 36.3 ± 14.3, 17-66 years) underwent fMRI and behavioral testing for non-emotional and emotional face recognition. Recognition of neutral faces elicited activation in the fusiform gyri. Processing angry faces led to activation in left middle and superior frontal gyri and the anterior cingulate cortex. There was considerable heterogeneity regarding the fear versus neutral contrast, resulting in null effects for this contrast. Upon recognition of disgust, activation was noted in bilateral occipital, in the fronto-orbital cortex and in the insula. Analyzing contrasts between emotional conditions showed similar results (to those of contrasting with reference conditions) for separated emotional network patterns. We demonstrate here that our paradigm reproduces single aspects of separate previous studies across a cohort of healthy subjects, irrespective of age. Our approach might prove useful in future studies of patients with neurologic disorders with potential effect on emotion recognition.

Reorganization in cognitive networks with progression of multiple sclerosis: insights from fMRI.

OBJECTIVES: Cognitive dysfunction (CD) is frequent in multiple sclerosis (MS) and can occur at early stages. Whereas functional reorganization with disease progression has been described for the motor system in MS using fMRI, no such studies exist for cognition. We attempted to assess the concept of functional reorganization concerning cognition using a simple "Go/No-go" fMRI paradigm. METHODS: Patients with a clinically isolated syndrome (CIS, n = 10), relapsing-remitting MS (RRMS) (n = 10), or secondary progressive MS (SPMS) (n = 10), and 28 healthy controls (HC), underwent a comprehensive neuropsychological test battery, clinical examination, structural imaging, and an fMRI Go/No-go discrimination task at 3 T. RESULTS: Patients performed worse than HC regarding memory, sustained attention and concentration, and information processing. These differences were driven by patients with SPMS. The fMRI task elicited activation in a widespread network including bilateral mesial and dorsolateral frontal, parietal, insular, basal ganglia, and cerebellar regions. Task performance was similar between phenotypes, but deviation from the activation pattern observed in HC and patients with CIS increased with disease progression. Patients with RRMS showed increased brain activation in the precuneus, both superior parietal lobes, and the right fusiform gyrus, and recruited the hippocampus with increasing demands. Patients with SPMS demonstrated the most abnormal network function, including recruitment of pre-SMA, bilateral superior and inferior parietal, dorsolateral prefrontal, right precentral, bilateral postcentral, and right temporal brain areas. CONCLUSION: Using a cognitive fMRI paradigm, we were able to confirm adaptive changes of neuronal activation with progressing MS and to provide strong evidence for their compensatory nature, at least partially.

Cognitive impairment in relation to MRI metrics in patients with clinically isolated syndrome.

BACKGROUND: Cognitive deficits are frequent in multiple sclerosis (MS) and have been associated with morphologic brain changes. Less information exists on their extent and relation to MRI findings in clinically isolated syndrome (CIS). It is also unclear if structural changes as detected by magnetization transfer (MT) imaging may provide an additional explanation for cognitive dysfunction. OBJECTIVE: To analyse the extent of cognitive deficits and their relation to MRI metrics including MT imaging in CIS compared to relapsing-remitting MS (RRMS). METHODS: Forty-four CIS and 80 RRMS patients underwent the Brief Repeatable Battery of Neuropsychological Tests (BRB-N) and a 3 T MRI scan. RESULTS: BRB-N subtests revealed similar results in CIS and RRMS. Impaired mental processing speed was most prevalent in both groups (CIS 13.6%; RRMS 16.3%) and thus served for correlation with MRI metrics. Using stepwise linear regression analyses, the strongest predictor for decreased mental processing speed was normalized cortex volume (p < 0.001) followed by T2-lesion load (p < 0.05) in RRMS, whereas cortical MT ratio was the only MRI parameter associated with decreased mental processing speed in CIS (p < 0.005). CONCLUSION: Cognitive dysfunction occurs in CIS in a pattern similar to RRMS, with impaired mental processing speed being most prevalent. Cortical MT-ratio changes may be an early sign for tissue changes related to impaired mental processing speed in CIS while this association shifts to increased signs of cortical atrophy and lesion load in RRMS.

Lesion probability mapping to explain clinical deficits and cognitive performance in multiple sclerosis.

BACKGROUND: Lesion dissemination in time and space represents a key feature and diagnostic marker of multiple sclerosis (MS). The correlation between magnetic resonance imaging (MRI) lesion load and disability is only modest, however. Strategic lesion location might at least partially account for this 'clinico-radiologic paradox'. OBJECTIVES: Here we used a non-parametric permutation-based approach to map lesion location probability based on MS lesions identified on T2-weighted MRI. We studied 121 patients with clinically isolated syndrome, relapsing-remitting or secondary progressive MS and correlated these maps to assessments of neurologic and cognitive functions. RESULTS: The Expanded Disability Status Scale correlated with bilateral periventricular lesion location (LL), and sensory and coordination functional system deficits correlated with lesion accumulation in distinct anatomically plausible regions, i.e. thalamus and middle cerebellar peduncule. Regarding cognitive performance, decreased verbal fluency correlated with left parietal LL comprising the putative superior longitudinal fascicle. Delayed spatial recall correlated with _amygdalar, _left frontal and parietal LL. Delayed selective reminding correlated with bilateral frontal and temporal LL. However, only part of the spectrum of cognitive and neurological problems encountered in our cohort could be explained by specific lesion location. CONCLUSIONS: Lesion probability mapping supports the association of specific lesion locations with symptom development in MS, but only to limited extent.