David C. Reutens

Apoptotic Mechanisms After Cerebral Ischemia

BACKGROUND AND PURPOSE Traditionally, cell death after cerebral ischemia was considered to be exclusively necrotic in nature, but research over the past decade has revealed that after a stroke, many neurons in the ischemic penumbra will undergo apoptosis. SUMMARY OF REVIEW This brief review provides a general overview and update of various signaling pathways in the development of apoptosis in ischemic lesions. Cerebral ischemia triggers two general pathways of apoptosis: the intrinsic pathway, originating from mitochondrial release of cytochrome c and associated stimulation of caspase-3; and the extrinsic pathway, originating from the activation of cell surface death receptors, resulting in the stimulation of caspase-8. Although many of the key apoptotic proteins have been identified, our understanding of the complex underlying mechanisms remains poor and hence treatment of stroke patients by manipulating apoptotic pathways remains a daunting task. However, recent advances in the field have helped broaden our knowledge of apoptosis after cerebral ischemia. Further to the simplistic concept that stroke-induced apoptosis occurs predominantly in neurons and is caspase-dependent, accumulating evidence now indicates that apoptosis is prevalent in nonneuronal cells and that caspase-independent mechanisms also play a key role. CONCLUSIONS Although the ischemic penumbra is under threat of infarction, it is potentially salvageable and thus represents an opportunity for therapeutic intervention.

PK11195 binding to the peripheral benzodiazepine receptor as a marker of microglia activation in multiple sclerosis and experimental autoimmune encephalomyelitis

Activated glial cells are implicated in regulating and effecting the immune response that occurs within the CNS as part of multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). The peripheral benzodiazepine receptor (PBR) is expressed in glial cells. We examined the utility of using in vitro and in vivo ligand binding to the PBR as a measure of lesion activity in autoimmune CNS demyelinating diseases. Applying a combined autoradiography and immunohistochemical approach to spinal cord and brain tissues from mice with EAE, we found a correlation at sites of inflammatory lesions between [3H]‐PK11195 binding and immunoreactivity for the activated microglial/macrophage marker Mac‐1/CD11b. In MS tissues, [3H]‐PK11195 binding correlated with sites of immunoreactivity for the microglial/macrophage marker CD68, at the edges of chronic active plaques. Positron emission tomography (PET) imaging with [11C]‐PK11195 showed ligand uptake only at sites of active MS lesions defined by magnetic resonance imaging criteria. Our results indicate the potential to develop markers suitable for both in vitro and in vivo use, which will serve to help correlate phenotypic and functional properties of cells which participate in disease or injury responses within the CNS. J. Neurosci. Res. 50:345–353, 1997.

Entorhinal cortex in temporal lobe epilepsy: A quantitative MRI study

Background: The entorhinal cortex (EC) is a distinct anatomic and functional region of the anterior parahippocampal gyrus, which plays a role in seizure generation and propagation in temporal lobe epilepsy (TLE). In tissue resected from TLE patients, cell loss in the EC has been described. Objectives: To develop a standardized protocol for identifying the anatomic boundaries of the EC using high-resolution MRI and to examine morphologic changes of the EC in TLE. Methods: We performed T1-weighted MRIs in 20 patients (7 males) with TLE (mean age 34 years) and 18 normal controls (mean age 26 years). Eleven patients had a left and 9 a right epileptic focus as defined by history, video-EEG, and surgical outcome. The volumes of the EC, the hippocampus, and the amygdala were measured using a standardized MRI protocol. Analysis of variance (ANOVA) was used to examine the effect of seizure focus lateralization and hemisphere on these volumes. An asymmetry ratio [A (%) = 100 × (R−L)/(R+L)/2] was also compared between groups using ANOVA. Results: In normal controls the volume of the right EC was 1,247 ± 127 mm3 (mean ± standard deviation), and that of the left EC was 1,215 ± 135 mm3 (p > 0.05). We found a bilateral reduction in the volume of the EC in TLE patients compared with controls (p < 0.05). Examination of the asymmetry ratios showed that the reduction in volume of the EC was greater ipsilateral to the epileptic focus (p < 0.05). The volumes of the hippocampus and the amygdala were smaller on the side of the focus in TLE patients compared with controls (p < 0.05). Conclusions: With a standardized protocol for the quantitative assessment of the EC, patients with unilateral TLE show bilateral reduction in the volume of the EC. However, this reduction is more severe ipsilateral to the epileptic focus.

Dystonia, clinical lateralization, and regional blood flow changes in temporal lobe seizures

We analyzed the lateralizing value of ictal dystonia and head-turning in temporal lobe epilepsy, and sought the biologic basis of these clinical signs by studying the regional changes in perfusion with ictal single-photon emission computed tomography (SPECT). We identified unilateral temporal lobe epilepsy in 40 of 42 patients undergoing evaluation for temporal lobe surgery, and with ictal SPECT all 40 showed striking hyperperfusion of the epileptogenic temporal lobe. Twenty-five of the 40 patients showed unilateral or predominantly unilateral upper limb dystonia, which was opposite the epileptic temporal lobe in all cases. Analysis of regional count ratios in cases with ictal dystonia, compared with those without, showed significant changes only in the basal ganglia. Specifically, we found that ictal dystonia was associated with a relative increase in perfusion of the basal ganglia opposite the dystonic limb. Although we found 26 cases with head-turning, the sign was of no lateralizing value, even when only those with major or “tonic” versions (n = 11) were analyzed. Slight increases in cortical blood flow on the side opposite the direction of version were associated with head-turning, irrespective of the side of seizure focus. In clinical practice, ictal SPECT is a highly accurate aid in the lateralization of temporal lobe foci, in addition to providing a new method to investigate the pathophysiology of clinical signs in focal seizures.

Cerebral White Matter Lesions, Gait, and the Risk of Incident Falls A Prospective Population-Based Study

Background and Purpose— The association between cerebral white matter lesions (WMLs) and the risk of falls in older people is uncertain, with no supporting prospective evidence. We aimed to determine the risk of incident falls associated with WML volume, and the interactions between WML volume, gait, and other sensorimotor factors leading to falls. Methods— We conducted a prospective, population-based study (n=294, mean age 72.3 years, independently mobile). Volumetric MRI, computerized gait measures, and sensorimotor measures of falls risk were obtained at baseline. Incident falls were recorded prospectively over a 12-month period. Using regression modeling, we estimated the risk of incident falls associated with baseline WML volume. Results— Increasing baseline WML volume was independently associated with any incident fall (P=0.01) and multiple incident falls (P=0.02). The risk of incident falls was doubled in people with lesion volumes in the highest quintile of its distribution compared with the lowest (adjusted relative risk, 2.32; 95% CI, 1.28–4.14). Greater lesion volume was also associated with poorer gait and greater gait variability (both P<0.001). The effect of WML volume on the risk of falls was magnified in people with poorer quadriceps muscle strength (P=0.03) and greater gait variability (P=0.001). Conclusions— These data provide the first prospective evidence to our knowledge demonstrating that WMLs are strong risk factors for falls in the general older population. WMLs present potential therapeutic targets for interventional trials in falls prevention.

Cerebral [15O]Water Clearance in Humans Determined by PET: I. Theory and Normal Values

When used to measure blood flow in the brain, water leaves a residue in the vascular bed that influences the estimation of blood flow by current methods. To assess the magnitude of this influence, we developed a two-compartment model of blood flow with separate parameters for transport and vascular distribution of brain water. Maps of the water clearance, K1 into brain tissue, separated from the circulation by a measurably resistant blood–brain barrier (BBB), were generated by time-weighted integration. Depending on the validity of the assumptions underlying the two-compartment model presented here, the maps revealed a significant overestimation of the clearance of water when the vascular residue was ignored. Maps of Vo the estimate of the apparent vascular distribution volume of tracer H215O, clearly revealed major cerebral arteries. Thus, we claim that the accumulation of radioactive water in brain tissue also reflects the volume of the arterial vascular bed of the brain.

Ischemic Thresholds for Gray and White Matter. A Diffusion and Perfusion Magnetic Resonance Study

Background and Purpose— Although gray matter (GM) and white matter (WM) have differing neurochemical responses to ischemia in animal models, it is unclear whether this translates into differing thresholds for infarction. We studied this issue in ischemic stroke patients using magnetic resonance (MR) techniques. Methods— MR studies were performed in patients with acute hemispheric ischemic stroke occurring within 24 hours and at 3 months. Cerebral blood flow (CBF), cerebral blood volume (CBV), mean transit time (MTT), and apparent diffusion coefficient (ADC) were calculated. After segmentation based on a probabilistic map of GM and WM, tissue-specific diffusion and perfusion thresholds for infarction were established. Results— Twenty-one patients were studied. Infarction thresholds for CBF were significantly higher in GM (median 34.6 mL/100 g per minute, interquartile range 26.0 to 38.8) than in WM (20.8 mL/100 g per minute; interquartile range 18.0 to 25.9; P<0.0001). Thresholds were also significantly higher in GM than WM for CBV (GM: 1.67 mL/100 g; interquartile range 1.39 to 2.17; WM: 1.19 mL/100 g; interquartile range 0.94 to 1.53; P<0.0001), ADC (GM: 918×10−6 mm2/s; 868 to 975×10−6; WM: 805×10−6; 747 to 870×10−6; P<0.001), and there was a trend toward a shorter MTT in GM (GM 4.94 s, 4.44 to 5.38; WM 5.15, 4.11 to 5.68; P=0.11). Conclusions— GM has a higher infarction threshold for CBF, CBV, and ADC than WM in patients within 24 hours of ischemic stroke onset. Hence, when assessing patients for potential therapies, tissue-specific rather than whole-brain thresholds may be a more precise measure of predicting the likelihood of infarction.

Early but not late-blindness leads to enhanced auditory perception

The notion that blindness leads to superior non-visual abilities has been postulated for centuries. Compared to sighted individuals, blind individuals show different patterns of brain activation when performing auditory tasks. To date, no study has controlled for musical experience, which is known to influence auditory skills. The present study tested 33 blind (11 congenital, 11 early-blind, 11 late-blind) participants and 33 matched sighted controls. We showed that the performance of blind participants was better than that of sighted participants on a range of auditory perception tasks, even when musical experience was controlled for. This advantage was observed only for individuals who became blind early in life, and was even more pronounced for individuals who were blind from birth. Years of blindness did not predict task performance. Here, we provide compelling evidence that superior auditory abilities in blind individuals are not explained by musical experience alone. These results have implications for the development of sensory substitution devices, particularly for late-blind individuals.

Validation of a questionnaire for clinical seizure diagnosis

Summary: A detailed questionnaire has been devised for diagnosis of seizure type. It is suitable for administration by trained interviewers, either directly or by telephone. A comparison of physician‐based and questionnaire‐based diagnoses showed almost perfect agreement in classification of patients into those with seizures of either generalized or focal origin. Substantial to almost‐perfect agreement was reached in diagnosis of patients with most individual seizure types. Disagreement in differentiation between simple and complex partial seizures (CPS) probably reflects the limitations of the clinical method rather than of the questionnaire itself. The questionnaire should be of value in large‐scaled clinical and epidemiologic studies.

T2 relaxometry can lateralize mesial temporal lobe epilepsy in patients with normal MRI.

In unselected patients with intractable temporal lobe epilepsy (TLE), approximately 15% do not have detectable hippocampal atrophy on MRI. The purpose of this study was to evaluate whether T2 relaxometry can identify hippocampal pathology and lateralize the epileptic focus in patients with intractable TLE, who do not demonstrate hippocampal atrophy on volumetric MRI (MRIV). We selected 14 patients with unilateral TLE who had unilateral atrophy and 11 patients with unilateral TLE who had no evidence of atrophy on MRIV. Images were acquired on a 1.5 T MR scan using a dual echo sequence with 23 contiguous oblique coronal slices in all patients and in 14 healthy subjects. Fitting a single exponential decay equation to the imaging data generated T2 maps. Averages of six slices containing the head, body, and tail of the hippocampus were used to calculate hippocampal T2 relaxation times (HT2). The epileptic focus was defined by history, video-EEG, and surgical response. All TLE patients with hippocampal atrophy and 9/11 (82%) patients with normal MRI had abnormally high HT2 ipsilateral to the epileptic focus. Bilateral abnormal HT2 were found in 6/14 (43%) of patients with unilateral hippocampal atrophy and 2/11 (18%) of patients with normal MRI. However, this increase was always greater ipsilateral to the epileptic focus. Qualitative hippocampal pathology showed gliosis and neuronal loss in 10/14 operated patients with hippocampal atrophy on MRIV and in 5/7 operated patients with normal MRI. In conclusion, hippocampal T2 mapping provides evidence of hippocampal damage in the majority of patients with intractable TLE who have no evidence of atrophy on MRI and can correctly lateralize the epileptic focus in most patients.