Carsten Wikkelsö

Human neuroblasts migrate to the olfactory bulb via a lateral ventricular extension

The rostral migratory stream (RMS) is the main pathway by which newly born subventricular zone cells reach the olfactory bulb (OB) in rodents. However, the RMS in the adult human brain has been elusive. We demonstrate the presence of a human RMS, which is unexpectedly organized around a lateral ventricular extension reaching the OB, and illustrate the neuroblasts in it. The RMS ensheathing the lateral olfactory ventricular extension, as seen by magnetic resonance imaging, cell-specific markers, and electron microscopy, contains progenitor cells with migratory characteristics and cells that incorporate 5-bromo-2′-deoxyuridine and become mature neurons in the OB.

Early Intrathecal Production of Interleukin-6 Predicts the Size of Brain Lesion in Stroke

BACKGROUND AND PURPOSE We have previously demonstrated that stroke influences systemic immune responses. The aim of the present study was to investigate patterns of local inflammatory response as a consequence of acute stroke. METHODS Thirty stroke patients were studied prospectively on days 0 to 3, 7 to 9, 21 to 26, and after day 90 with clinical evaluations, radiological assessments, and analysis of serum and cerebrospinal fluid cytokine levels. RESULTS Significantly increased levels of interleukin-6 (IL-6) in cerebrospinal fluid (P < .001) were observed in virtually all patients studied compared with healthy control subjects. This increase was observed during the whole observation period but was significantly more pronounced within the first days after stroke onset, with a peak level on days 2 and 3. This initial increase was significantly correlated (r = .65, P = .002) with the volume of infarct measured by MRI 2 to 3 months later. Serum levels of IL-6 in stroke patients were significantly lower than cerebrospinal fluid levels of IL-6 (P = .013) and did not display any significant correlation to the size of the brain lesion. Also, increase in intrathecal but not systemic production of IL-1 beta was observed early during the stroke. Only minor increases of cerebrospinal fluid interferon-gamma levels were observed in two patients. CONCLUSIONS Our study demonstrates an intrathecal production of IL-6 and IL-1 beta in patients with stroke, supporting the notion of localized inflammatory response to acute brain lesion. In addition, the significant correlation between early intrathecal production of IL-6 and the subsequent size of the brain lesion can be used as a prognostic tool, predicting the size of the brain damage before it is possible to accurately visualize it with radiological methods.

Patients with amyotrophic lateral sclerosis and other neurodegenerative diseases have increased levels of neurofilament protein in CSF.

Abstract: In the present study we describe an ELISA to quantify the light subunit of the neurofilament triplet protein (NFL) in CSF. The method was validated by measuring CSF NFL concentrations in healthy individuals and in two well‐characterized groups of patients with amyotrophic lateral sclerosis (ALS) and Alzheimers disease (AD). The levels were increased in ALS (1,743 ± 1,661 ng/L; mean ± SD) and AD (346 ± 176 ng/L) compared with controls (138 ± 31 ng/L; p < 0.0001 for both). Within the ALS group, patients with lower motor neuron signs only had lower NFL levels (360 ± 237 ng/L) than those with signs of upper motor neuron disease (2,435 ± 1,633 ng/L) (p < 0.05). In a second study patients with miscellaneous neurodegenerative diseases were investigated (vascular dementia, olivopontocerebellar atrophy, normal pressure hydrocephalus, cerebral infarctions, and multiple sclerosis), and the CSF NFL level was found to be increased (665 ± 385 ng/L; p < 0.0001). NFL is a main structural protein of axons, and we suggest that CSF NFL can be used to monitor neurodegeneration in general, but particularly in ALS with involvement of the pyramidal tract.

Clinical parameters in 74 consecutive patients shunt operated for normal pressure hydrocephalus

ABSTRACT Seventy four consecutive patients diagnosed as normal pressure hydrocephalus (NPH) and operated with a ventriculo‐peritoneal shunt were followed prospectively for an average of 2.1 years. The mean age was 64 years. The effect of the operation was estimated by calculating 6 indices expression social functioning, neurological signs, gait ability, continence, psychometric performance and psychiatric condition. Ninety‐six % had mental symptoms, 95% gait disturbances and 75% incontinence. Improvement was observed in 78% after shunt surgery, while 22% deteriorated. Psychiatric improvement was seen in 80% and 76% improved in gait ability. Improvement was highest in the group caused by subarachnoid hemorrhage (98%) while 73% with idiopathic NPH improved. Old age was not correlated to poorer response, while long‐standing pre‐operative symptoms yielded worse results. No single symptom or sign could predict a positive outcome of the operation. Eleven % of the patients could leave long‐term care institutions and there was a 36% reduction of aid in daily living. Complications to shunt surgery were observed in 50% of the patients and shunt related mortality was 1%. Shunt malfunction was the most frequent complication (31%) followed by infection (19%). Epilepsy developed in 9% after surgery. All shunt complication except one appeared within the first year after surgery.

Intrathecal release of pro- and anti-inflammatory cytokines during stroke.

A growing body of evidence points out the potential role of inflammatory mechanisms in the pathophysiology of ischaemic brain damage. We have recently demonstrated that stroke patients display an intrathecal production of proinflammatory cytokines, such as IL‐1β and IL‐6 already within the first 24 h after the beginning of symptoms (Tarkowski et al., 1995). The aim of the present study was to investigate patterns of local inflammatory responses as a consequence of acute stroke. Thirty stroke patients were studied prospectively on days 0–3, 7–9, 21–26 and after day 90 with clinical evaluations, radiological assessments and analysis of cerebrospinal fluid (CSF) cytokine levels. In addition, 15 healthy control CSF samples were used. Significantly increased CSF levels of IL‐8, granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) and IL‐10 were observed early during the stroke with a peak on day 2 for the proinflammatory cytokines IL‐8 and GM‐CSF, and on day 3 for the immunoregulatory cytokine IL‐10. Patients with a brain infarct predominantly located in the white matter showed significantly higher levels of IL‐8 in CSF than patients with an infarct mainly located in the grey matter. Also, high levels of intrathecal tumour necrosis factor‐alpha (TNF‐α) were associated with the presence of white matter disease. Our study demonstrates an intrathecal production of proinflammatory and immunoregulatory cytokines in patients with stroke, supporting the notion of localized immune response to the acute brain lesion. A better understanding of the inflammatory response in stroke may lead to new treatment strategies.

The clinical effect of lumbar puncture in normal pressure hydrocephalus.

Owing to all the difficulties involved in selecting patients with normal pressure hydrocephalus for shunt-operation, a cerebrospinal fluid-tap-test (CSF-TT) is introduced. Psychometric and motor capacities of the patients are measured before and after lumbar puncture and removal of 40-50 ml CSF. Patients fulfilling criteria for normal pressure hydrocephalus were compared to patients with dementia and atrophy shown by computed tomography. Normal pressure hydrocephalus patients showed temporary improvement after lumbar puncture. The extent of the temporary improvement appeared to be well correlated with the improvement after shunt operation. Accordingly, the CSF-TT seems to be of value when selecting those patients who will probably benefit from a shunt operation.

Normal pressure hydrocephalus: predictive value of the cerebrospinal fluid tap-test

Twenty-seven patients with normal pressure hydrocephalus were operated upon by a ventriculo-peritoneal shunt. Selection for shunt surgery was based on typical symptoms (gait disturbancy, mental deterioration and urgency incontinence) and characteristic changes at cranial computed tomography and/or radionuclide cisternography. Prior to operation a cerebrospinal fluid tap-test (CSF-TT) was performed with measurements of psychometric functions and gait pattern before and after a lumbar puncture of 50 cc CSF. Nineteen patients improved and 5 were unchanged after shunt operation. Three patients could not be evaluated. Improvement in the psychometric functions and gait pattern after lumbar puncture correlated to improvement after the shunt operation (r = 0.64, p less than 0.01: r = 0.96, p less than 0.001, respectively). Improvement in 2 or more of the 4 tests used (3 psychometric and 1 gait test) at CSF-TT implied in all cases successful result of the shunt operation. It was concluded that CSF-TT could predict which NPH patient will improve by a shunt operation, and albeit to envisage the degree of improvement.

Reduced frontotemporal perfusion in psychopathic personality

Several brain-imaging studies have found associations between aberrant functioning in the frontal and temporal lobes and violent offending. We have previously reported decreased frontotemporal perfusion unrelated to psychosis, substance abuse, or current medication in 21 violent offenders. In the present study, we compared the regional cerebral blood flow (rCBF) in a new group of 32 violent offenders to scores on the Psychopathy Checklist-Revised (PCL-R), which rates two aspects of psychopathy: disturbed interpersonal attitudes (Factor 1) and impulsive antisocial behavior (Factor 2). A recently proposed model has split Factor 1 into a new Factor 1 (deceitful interpersonal style), a new Factor 2 (affective unresponsiveness), and a Factor 3, which approximately corresponds to the old Factor 2. The rCBF was assessed by single-photon emission computed tomography (SPECT) with technetium-99m-d,l-hexamethylpropyleneamine oxime (HMPAO) in regions of interest (ROIs) placed in accordance with fusioned magnetic resonance images (MRI) and SPECT scans. Significant negative correlations were found between interpersonal features of psychopathy (the old and especially the new Factor 1) and the frontal and temporal perfusion. The two most clearly associated ROIs were the head of the caudate nuclei and the hippocampi. These findings in a group of violent offenders living under the same conditions, which reduced the number of state-related confounders, add to the evidence indicating that aberrant frontotemporal activity may be a factor in violent behavior.

White matter changes in normal pressure hydrocephalus and Binswanger disease: Specificity, predictive value and correlations to axonal degeneration and demyelination

Objectives– To analyse the diagnostic and prognostic value of periventricular hyperintensity (PVH) and deep white matter hyperintensity (DWMH) magnetic resonance imaging (MRI) changes and their relation to symptoms and cerebrospinal fluid (CSF) markers of demyelination (sulphatide) and axonal degeneration [neurofilament triplet protein (NFL)] in a large series of patients with normal pressure hydrocephalus (NPH) and Binswanger disease (BD). Materials and methods– PVH and DWMH were determined by a semi‐automatic segmentation method on T2‐weighted images in 29 patients with NPH and 17 patients with BD. CSF analyses, psychometric testing and quantification of balance, gait and continence were performed in all patients and also postoperatively in NPH patients. Results– No MRI variable could identify NPH or BD patients. Abundant PVH and DWMH preoperatively correlated with improvement in gait, balance and psychometric performance after shunt surgery (P < 0.05). CSF sulphatide correlated positively with the amount of DWMH (P < 0.05) while NFL was correlated to both PVH and DWMH (P < 0.05). Abundant PVH correlated with poor psychometric performance while DWMH correlated with gait disturbance (P < 0.05). Postoperative reduction in PVH correlated with improvement in gait, balance and psychometric performance. Conclusion– In spite of a refined quantification method, NPH and BD patients exhibited similar MRI changes. MRI had a predictive value in NPH patients. DWMH might relate to demyelination and PVH to neuronal axonal dysfunction. NPH and BD share the major part of symptoms and MRI changes, indicating a common pathophysiological pattern, and we raise the question of how to treat BD patients.

Predictive value of the cerebrospinal fluid tap-test

ABSTRACT Twenty‐seven patients with normal pressure hydrocephalus were operated upon by a ventriculo‐peritoneal shunt. Selection for shunt surgery was based on typical symptoms (gait disturbancy, mental deterioration and urgency incontinence) and characteristic changes at cranial computed tomography and/or radionuclide cisternography. Prior to operation a cerebrospinal fluid tap‐test (CSF‐TT) was performed with measurements of psychometric functions and gait pattern before and after a lumbar puncture of 50 cc CSF. Nineteen patients improved and 5 were unchanged after shunt operation. Three patients could not be evaluated. Improvement in the psychometric functions and gait pattern after lumbar puncture correlated to improvement after the shunt operation (r = 0.64, p < 0.01: r = 0.96, p < 0.001, respectively). Improvement in 2 or more of the 4 tests used (3 psychometric and 1 gait test) at CSF‐TT implied in all cases successful result of the shunt operation. It was concluded that CSF‐TT could predict which NPH patient will improve by a shunt operation, and albeit to envisage the degree of improvement.