Adhesion molecules are promising candidates to establish surrogate markers for natalizumab treatment.

BACKGROUND: Natalizumab is the first monoclonal antibody therapy approved for multiple sclerosis (MS). Its therapeutic mechanism is the blockade of the α4-integrin subunit of the adhesion molecule (AM) very late activation antigen-4 (VLA-4), which leads to an inhibition of immune cell extravasation into the central nervous system (CNS). METHODS: We investigated changes in the expression levels of unblocked α4-integrin and further AM (intercellular adhesion molecule-1, -2, -3 (cICAM-1, -2, -3), leukocyte function associated antigen-1 (LFA-1)) on peripheral blood mononuclear cells (PBMC) determined by flow cytometry from 25 patients with MS before the first natalizumab infusion and before the fourth infusion. In 15 MS patients AM expression was evaluated every 3 months over 1 year. RESULTS: We found a significant decrease (p < 0.0001) of unblocked α4-integrin cell surface expression on all investigated PBMC subsets (T cells -61.7%, B cells -69.1%, monocytes/macrophages -46.4%) in the blood of MS patients after 3 months of natalizumab treatment. Moreover, a continuous decrease (p < 0.05) of unblocked α4-integrin expression levels was seen after 3, 6, 9, and 12 months. As a secondary effect, expression levels of the other investigated AM were differentially affected. CONCLUSIONS: Results show a sustained decrease of unblocked α4-integrin expression not only in all patients but also in all investigated PBMC subsets. This probably results in a continuously decreasing transmigration of PBMC into the CNS and may explain the improved clinical efficacy in the second treatment year and also the increasing risk of progressive multifocal leukoencephalopathy during long-term natalizumab therapy. We conclude that AM expression profiles are promising candidates for the development of a biomarker system to determine both natalizumab treatment response and patients at risk for opportunistic CNS infections.

Cerebral perfusion (HMPAO-SPECT) in patients with depression with cognitive impairment versus those with mild cognitive impairment and dementia of Alzheimer's type: a semiquantitative and automated evaluation.

PURPOSE: Comparative evaluation of regional brain perfusion measured by HMPAO-SPECT of patients with mild cognitive impairment (MCI), dementia of Alzheimer's type (DAT) and depression with cognitive impairment (DCI). METHODS: A total of 736 patients were investigated because of suspected cognitive dysfunction. After exclusion of patients with other forms of dementia than DAT or relevant accompanying disorders, SPECT data from 149 MCI, 131 DAT and 127 DCI patients, and 123 controls without any cognitive impairment, were analysed. Relative cerebral blood flow of 34 anatomical regions was assessed with automated analysis software (BRASS). RESULTS: Calculation of global forebrain perfusion discriminated demented from nondemented patients. Compared to controls DCI patients showed hypoperfusion of the thalamus, lentiform nucleus and medial temporal cortex. MCI patients differed significantly from controls concerning perfusion in both hemispheric temporal and parietal areas, and in the (right hemispheric) posterior part of the cingulate gyrus. MCI and DCI patients differed in the parietal, temporal superior and right hemispheric cingulate gyrus posterior cortices. Global forebrain and regional perfusion was more extensively reduced in DAT patients and discriminated them from controls, and MCI and DCI patients. Frontal perfusion disturbance was only present in DAT patients. CONCLUSION: Automated analysis of HMPAO-SPECT data from MCI patients showed significant perfusion deficits in regions also involved in DAT patients, but ROC analysis demonstrated only moderate sensitivity and specificity for differentiating DAT patients from controls and DCI patients. Frontal hypoperfusion seems to correspond with conversion from MCI to DAT. Finally, the results in DCI patients again raise the question of depression as an early symptom of neurodegeneration.

HMPAO-SPECT Can Discriminate between Patients with Subjective Cognitive Complaints with and without Cognitive Deficits and those with Mild Cognitive Impairment.

BACKGROUND: Growing evidence suggests that pathological processes leading to Alzheimer's disease occurs gradually and begins to develop decades before the earliest clinical symptoms occur. The use of biomarkers has been proposed to detect evidence of preclinical Alzheimer's pathologic change in asymptomatic subjects. Subjective cognitive complaints (SCC) i.e. self-reported cognitive decline with normal cognition have been reported as an indicator of future cognitive decline, however, this condition is unspecific. OBJECTIVE: In the present study we used the regional brain perfusion measured by HMPAO-SPECT as Biomarker of neurodegeneration to compare the regional brain perfusion of patient with subjective cognitive complaints with and without minimal cognitive dysfunction (SCC+ and SCC- respectively) in respect to patients with mild cognitive impairment (MCI). METHODS: We retrospectively examined 736 Patients who referred to our Memory Clinic because of suspected cognitive dysfunction. After exclusion of patients with overt dementia, automated, quantitatively assessed relative cerebral blood flow of 10 forebrain regions (thalamus, parietotemporal, medial temporal, posterior temporal, posterior cingulate gyrus, each region left hemispheric and right hemispheric) and neuropsychological assessment of 64 SCC (32 SCC+; 32 SCC-) and 28 MCI subjects were analysed. RESULTS: .The most relevant differences between groups in cognitive performance concerned verbal memory. Left hemispheric medial temporal region could significantly discriminate between all three groups, with a progressive decrease n perfusion from SCC towards MCI. Area under the curve of left medial temporal region showed a sensitivity of 0,61 and a specificity of 0,78 for discriminating MCI from SCC. CONCLUSION: Automated analysis of HMPAO-SPECT data of MCI and SCC+ patients showed significant perfusion differences in medial temporal region and impaired verbal memory, both of which are known features of Alzheimer's disease. Perfusion patterns and verbal memory performance in SCC+ are more similar to MCI than SCC-. Thus, SPECT analysis could distinguish those subjects whose perfusion pattern resembles that of an MCI from those who do not. In our opinion, this could identify two populations with a different risk of progression to AD, with SCC+ subjects needing further diagnostic examination and repeated follow-up.

Imaging the basilar artery by contrast-enhanced color-coded ultrasound.

Conventional transcranial color-coded real-time sonography of the vertebrobasilar system is limited by imaging problems of the distal segment of the basilar artery. Lung-stable contrast-enhancing agents may overcome this problem by enhancing the quality of Doppler signals by as much as 20%. Fourty-two patients underwent sonographic evaluation of the vertebrobasilar system before and after receiving intravenously administered galactose-based contrast-enhancing agent Levovist by transforaminal and transtemporal routes. Imaging quality was classified into five categories depending on the length of visible color-flow by transforaminal approach: 1--no signal, 2--1-9.9 mm, 3--10-19.9 mm, 4--20-29.9 mm, 5--> or = 30 mm. For transtemporal insonation, imaging quality was classified either as no color flow or sufficient color flow of the basilar tip. By unenhanced investigation, average signal length of color flow was 16 +/- 8 mm for transforaminal investigation; application of Levovist improved this value to 26.6 +/- 6 mm. For unenhanced transforminal approach, 4.8% were assigned to category 1, 11.9% to category 2, 54.8% to category 3, 23.8% to category 4 and 4.8% to category 5. After signal enhancement with Levovist, category 1 covered 0%, category 2 2.4%, category 3 7.14%, category 4 59.5% and category 5 30.9% (p < 0.001). Unenhanced transtemporal approach allowed identification of the basilar tip in 78.6% with an average length of 6.3 +/- 2 mm; contrast enhancement improved this values to 92.9% and 8.3 +/- 3.3 mm respectively (p < 0.05). The application of transpulmonary contrast-enhancing agents improves the reliability of transcranial color-coded duplex sonography of the basilar artery.

Clinical and diagnostic findings in a patient with Creutzfeldt-Jakob disease (type Heidenhain).

A 61-year-old woman had Creutzfeldt-Jakob disease, type Heidenhain, that progressed for 4 months until death, 3 of which she spent in a hospital. The diagnosis was verified by autopsy. Consecutive brain computed tomography, magnetic resonance imaging, blood flow measurements, electroencephalography (EEG), and routine laboratory tests were performed. All imaging techniques showed nonspecific pathological changes, whereas EEG revealed alterations indicative for Creutzfeldt-Jakob disease.

Brief report: melatonin facilitates sleep in individuals with mental retardation and insomnia.

Mentally retarded people typically exhibit poor sleep efficiency and reduced nocturnal plasma melatonin levels. The daytime administration of oral melatonin to those people, in doses that raise their plasma melatonin levels to the nocturnal range, can accelerate sleep onset. We examined the ability of similar, physiological doses to restore nighttime melatonin levels and sleep efficiency in mentally retarded subjects with sleep deficits. In a double-blind, placebo-controlled study, mentally retarded subjects (n = 20) received, in randomized order, a placebo and two melatonin doses (0.1, and 3.0 mg) orally 30 minutes before bedtime for a week. Treatments were separated by 1-week washout periods. Sleep data were obtained by polysomnography on the last three nights of each treatment period. The physiologic melatonin dose (0.3 mg) restored sleep efficiency (p < 0.0001), acting principally in the midthird of the night; it also elevated plasma melatonin levels (p < 0.0008) to normal. The lowest dose (0.1 mg) also improved sleep.

SPET investigations in extrapyramidal diseases using specific ligands.

Single photon emission tomographic investigations of the extrapyramidal system have become easier to perform since the development of the ligands [123I]-beta-CIT and [123I]-IBZM. Thirty-three patients were investigated with [123I]-IBZM. The images were evaluated visually and semi-quantitatively (ratio of the striatum to front cortex). Ten controls showed a mean (+/- S.D.) ratio of 1.513 +/- 0.06; nine patients with Parkinson's disease had a smaller ratio of 1.425 +/- 0.095; six patients with Huntington's disease had a significantly lower ratio (1.147 +/- 0.105). Eight patients were not classified, because of different nosologic entities. Twenty-three patients were investigated with [123I]-beta-CIT. They were evaluated using standard techniques and the ratio of the striatum to cerebellum. Six controls had a mean ratio of 5.128 +/- 0.787. In 11 Parkinson patients, the ratio was significantly less (3.359 +/- 0.769). Patients with focal dystonia showed normal values. One patient with Huntington's disease had a significantly lower ratio. Receptor studies of the extrapyramidal system may help with diagnoses and could be of relevance therapeutically.

[123I] beta-CIT binding and SPET compared with clinical diagnosis in parkinsonism.

The largest group of neurodegenerative disorders are extrapyramidal diseases, especially parkinsonism. The development of the cocaine derivative [123I] beta-CIT and single photon emission tomography (SPET) may help in the diagnosis of these patients. The aim of this study was to demonstrate the diagnostic value of this method and its relationship with clinical data. Ninety-eight individuals were investigated: 11 healthy volunteers, 58 patients with idiopathic Parkinson's disease (IPD) and 29 patients with symptomatic parkinsonism (SPD). All patients with parkinsonism were staged according to the clinical classification of Hoehn and Yahr. [123I] beta-CIT was injected intravenously and a triple-headed camera was used to obtain images 20 h later. The images were evaluated visually and semi-quantitatively to obtain comparable values (ratio: specific to non-displaceable binding). The ratios differed significantly between controls and IPD patients. A significant correlation also existed between the ratios and clinical stages. In 11 hemiparkinsonian patients, a significantly diminished ratio was demonstrated not only contralateral to the affected side, but also in the clinically silent striatum. A clinical threshold at a reduction of 34% [123I] beta-CIT binding was calculated in this group. The ratios of all SPD patients in our study did not differ significantly from those of the healthy volunteers. According to the clinical degree of symptoms, the more severe subgroup showed a diminished mean ratio of 22% and therefore could not be clearly differentiated from mild IPD. In contrast, ratios were significantly different when comparing groups of the same clinical severity. We conclude that this method is not only a powerful diagnostic tool in IPD patients, but it is also possible to differentiate between IPD and SPD patients, if clinical aspects are also included.

Clinical relevance of 201Tl-chloride SPET in the differential diagnosis of brain tumours.

Magnetic resonance imaging (MRI) and computed tomography (CT) may not be reliable in the differential diagnosis of tumour necrosis, scar and recurrent tumour. We compared 201Tl-chloride SPET with CT and MRI for the differential diagnosis of these cerebral lesions. Brain SPET was performed in 40 patients after the intravenous injection of 201Tl-chloride. All 40 patients also had a CT or MRI scan, and a histological diagnosis was available for 27 of the patients. For each patient, the ratio of counts in the lesion region of interest (ROI) to counts in the contralateral ROI was calculated and found to be between 0.58 and 9.60. The ratios for high-grade gliomas, metastases and meningiomas were high (> 2.7), especially in tumours with good vascularization. A low ratio (< 1.7) was noted in patients with low-grade astrocytoma, necrosis or ischaemic lesions. There were two exceptional cases of ischaemic lesions in the luxury perfusion stage (ratios of 3.61 and 3.87), as verified by HMPAO-SPET. We found that 201Tl-chloride SPET helps to differentiate between malignant tumours, poorly vascularized benign lesions and necrosis. Differentiation between low-grade astrocytoma and non-malignant lesions was not possible, but there was a trend towards differentiating between low-grade astrocytoma and ischaemic infarction. The timing of the investigation is important to avoid false-positive results in hyperperfused ischaemic tissue.

Clinical and EEG findings in complex partial status epilepticus with tiagabine.

A case of complex partial status epilepticus (CPSE) with high dose treatment of tiagabine (TGB) is reported. Seizure aggravation and CPSE developed after stepwise increase of TGB to a dose of 60 mg per day as add-on treatment to carbamazepine (CBZ) 1200 mg/day and vigabatrine (VGB) 1000 mg/day. The EEG during CPSE showed bilateral rhythmic slow activity. Clinical symptoms of CPSE and the EEG normalized after i.v. treatment with clonazepam. The literature and the possible mechanism of this paradoxical phenomenon are discussed.

Features in families and family relationships.

Standardized assessment of family features is not used routinely, although these factors may play an important role in the course of children's psychological disorders. The present study investigated the association among relationships within the families of 115 healthy children (M=8.2 yr., SD=2.13; 70 boys, 45 girls). 115 mothers and fathers were asked to complete a standardized questionnaire assessing the family features (Familienklima-Testsystem by Schneewind, et al.) and another asking for their estimation of emotional relationships of the members of the family (Subjektives Familianbild-Test System by Mattejat). Analysis showed that the parents' ratings indicated significantly more empathic fathers as well as significantly more autonomous mothers in well-organized, conflict-free families. Our results indicate an association between families' organization and measured scores for fathers' empathy and mothers' autonomy. Sufficient intrafamilial communication is associated with roles of the parents within the family. Psychotherapeutic interventions might focus on the families' organization.

Family coherence and ADHD.

A lack of perseverance, poor attention, and poorly modulated behaviour are important criteria of Attention Deficit Hyperactivity Disorder (ADHD). Instructions often must be repeated, sometimes even by different family members, before a child with ADHD attends and complies. The hyperkinetic child might cause less disruption in families with high coherence. Families of 15 boys (aged 6 to 12 years) diagnosed with ADHD using the Mannheim Parent's Interview and the teacher's form of the Conners scale were compared with a matched healthy control group of 15 boys. Parents completed a form assessing the family's cooperation and childrearing practices. Intrafamilial coherence seems to have little positive association with the family's characteristics, especially for boys with Attention Deficit Hyperactivity Disorder. Low coherence among family members may reduce ADHD symptoms and may have protective effects on children with ADHD.

Brain perfusion SPECT in patients with mild cognitive impairment and Alzheimer's disease: comparison of a semiquantitative and a visual evaluation.

Due to the increasing importance of early recognition and differential diagnosis of dementias, cerebral perfusion scans using "single photon emission computed tomography" (SPECT) are increasingly integrated into the examination routine. The goal of this study was to check the diagnostic validity of SPECT scans of MCI- and DAT-patients, two subgroups out of 369 persons with etiologically unclear cognitive dysfunction, which underwent an assessment program for probable dementia including cognitive testing, cranial computed tomography, ultrasound, routine laboratory testing including vascular risk factors. After exclusion of patients with no or other forms of dementia we analyzed SPECT data of patients with mild cognitive impairment (MCI; n = 85) and dementia of the Alzheimer type (DAT; n = 78) in comparison with a healthy control group (n = 34).Visual assessment as well as a manual "regions of interest" (ROI) regionalization of the cortex were performed, whereby a ROI/cerebellum ratio was calculated as a semi-quantitative value. Association cortex areas were assessed regarding frontal, temporal, and parietal lobes of both hemispheres. When comparing the ratios of patients with DAT and controls, we found a statistically significant reduction of the cerebral perfusion in all measured cortex areas (p < 0.001). The comparison of patients with MCI with the selected control group also established a statistically significant difference in the cerebral perfusion for the evaluated cortex areas with the exception of the left hemispheric frontal and parietal cortex.A considerable number of the MCI patients showed an MMSE-score within the normal range, but with regard to the perfusion in the right hemispheric association cortex these patients also could be distinguished unambiguously from controls. Sensitivity levels found by visual assessment were at least as high as those found by the ROI method (pathological assessment: visual 49.4% vs. ROI 47.1% for MCI; visual 75.6% vs. ROI 73.1% for DAT). High experienced visual assessment of cerebral perfusion scans using SPECT provides an useful additional tool in diagnosis of cognitive impairment. The used semiquantitative ROI-method is nearly equivalent and does not depend on the experience of the investigator.

[The diagnostic value of nuclear magnetic resonance tomography, multimodal evoked potentials and cerebrospinal fluid examination in multiple sclerosis]. / Die diagnostische Wertigkeit der Kernspintomographie, der multimodal evozierten Potentiale und der Liquoruntersuchung bei multipler Sklerose.

Seventy patients with multiple sclerosis (according to Poser's criteria) were clinically assessed and examined with MRI, multimodal evoked potentials (VEP, AEP, SSEP) and CSF analysis (transformed lymphocytes, IgG-Index, oligoclonal banding). In relation to the clinical criteria of McAlpine 40 patients had possible, 16 patients probable and 14 patients definite MS. 81% of the patients (73% possible MS, 94% probable MS, 93% definite MS) had multiple white matter lesions detected by MRI, 79% (78% possible MS, 94% probable MS, 64% definite MS) had an abnormal CSF profile and 67% (60% possible MS, 75% probable MS, 79% definite MS) abnormal results in multimodal EP testing. Of the patients who experienced only one attack (n = 40) 78% had multiple lesions on MRI, 88% had abnormal CSF-findings and 60% had pathologic EPs. Patients with two or more attacks showed in 87% multiple lesions on MRI, in 77% abnormal EPs and in 70% abnormal CSF findings. The number of abnormal MRI and EPs increases with the duration of the disease. 13 patients with a normal MRI were discussed separately. MRI is the most sensitive method in detecting the spatial pattern of disseminated lesions. To monitor the dissemination over time a careful clinical follow-up is still mandatory.

Tianeptine: a novel strategy of psychopharmacological treatment of children with autistic disorder.

OBJECTIVES: Many autistic children have problems of eye contact and expressive language that limit the effectiveness of educational and behavioural interventions. Few controlled psychopharmacological trials have been conducted in autistic children to determine which agents may be effective for these associated features. METHODS: Twelve male children (7.3 +/- 3.3 years) with autistic disorder, diagnosed by ICD-10 criteria, completed a placebo-controlled, double-blind crossover trial of tianeptine, which lasted for 12 weeks. Subjects were included in the study if their eye contact and expressive language was inadaequate for their developmental level. Subjects had not tolerated or responded to other psychopharmacological treatments (neuroleptics, methylphenidate, clonidine or desipramine). RESULTS: Teacher ratings on the aberrant behaviour checklist irritability, stereotypy and inappropriate speech factors were lower during treatment with tianeptine than during treatment with placebo. Clinician ratings (children's psychiatric rating scale autism, anger and speech deviance factors; children's global assessment scale; clinical global impressions efficacy) of videotaped sessions were not significantly different between tianeptine and placebo. DISCUSSION: Tianeptine were modestly effective in the short-term treatment of irritability in some children with autistic disorder.

Inadequate management of cerebrovascular risk factors in participants of a public stroke prevention program in Austria.

The aim of our investigation was to identify frequencies and treatment quality of stroke risk factors in participants of a stroke prevention program in the province of Salzburg (Austria). A total of 9356 participants free of previous stroke were classified in three risk categories for suffering from ischemic stroke within the next 10 years and analyzed referring to history, therapy, and treatment quality of cerebrovascular risk factors. A total of 6519 (69.7%) participants were classified to be at low (<10%), 2232 (23.9%) at intermediate (10-20%) and 605 (6.5%) at high risk (>20%). Elevated blood pressure with the need for follow-up investigations was found in 5193 persons (55.5%); of 3713 (39.7%) persons with a history of hypertension, 3204 (86.3%) are under medical treatment, which is sufficient only in 765 patients (23.9%). Similar results were present for other well documented modifiable risk factors. In the investigated population there is high presence of stroke risk factors with inadequate treatment in most cases.