Klaus L. Leenders

Blood-brain barrier dysfunction in parkinsonian midbrain in vivo

Parkinsons disease (PD) is associated with a loss of neurons from the midbrain. The cause of PD is unknown, but it is established that certain neurotoxins can cause similar syndromes. The brain is normally protected from these noxious blood‐borne chemicals by the blood–brain barrier which includes specialized proteins on the inside of blood vessels in the brain. These act as molecular efflux pumps and P‐glycoprotein (P‐gp) is an abundant representative. Vulnerability to PD appears codetermined by the genotype for the P‐gp gene. We hypothesized that PD patients have reduced P‐gp function in the blood–brain barrier. We used positron emission tomography to measure brain uptake of [11C]‐verapamil, which is normally extruded from the brain by P‐gp. Here, we show significantly elevated uptake of [11C]‐verapamil (18%) in the midbrain of PD patients relative to controls. This is the first evidence supporting a dysfunctional blood–brain barrier as a causative mechanism in PD. Ann Neurol 2005;57:176–179

Typical cerebral metabolic patterns in neurodegenerative brain diseases

The differential diagnosis of neurodegenerative brain diseases on clinical grounds is difficult, especially at an early disease stage. Several studies have found specific regional differences of brain metabolism applying [18F]‐fluoro‐deoxyglucose positron emission tomography (FDG‐PET), suggesting that this method can assist in early differential diagnosis of neurodegenerative brain diseases.

Mesiobasal versus lateral temporal lobe epilepsy Metabolic differences in the temporal lobe shown by interictal 18F‐FDG positron emission tomography

Metabolic abnormalities in the temporal lobe (TL) of 25 patients suffering from temporal lobe epilepsy of mesiobasal or lateral TL origin have been investigated using interictal [18F]-fluorodeoxyglucose (FDG) positron emission tomography (PET). The epileptogenic area was determined by ictal EEG recordings using foramen ovale and scalp electrodes in 20 patients, and by the use of stereo-electroencephalography in one patient. Four patients with structural lesions on their MRIs had noninvasive ictal surface EEG recordings. Sixteen patients had a clear-cut mesiobasal seizure onset, and in five patients the seizures originated from the lateral temporal neocortex. Twenty-four patients underwent selective surgery. Patients with temporal limbic seizures associated with mesial gliosis (n = 15) had the lowest FDG uptake in the entire TL, followed by patients with lateral temporal seizure origin (n = 5). Patients with tumors located in the mesiobasal TL (n = 5) showed, in general, only a slight decrease of glucose metabolism in all TL structures. There was no clear-cut correlation between the degree of hypometabolism and the location of EEG-defined epileptogenic focus. The metabolic pattern, however, differed between the patient groups and allowed a discrimination between patients of mesial temporal and lateral temporal seizure onset.

Dystonia in neurodegeneration with brain iron accumulation: outcome of bilateral pallidal stimulation.

Neurodegeneration with brain iron accumulation encompasses a heterogeneous group of rare neurodegenerative disorders that are characterized by iron accumulation in the brain. Severe generalized dystonia is frequently a prominent symptom and can be very disabling, causing gait impairment, difficulty with speech and swallowing, pain and respiratory distress. Several case reports and one case series have been published concerning therapeutic outcome of pallidal deep brain stimulation in dystonia caused by neurodegeneration with brain iron degeneration, reporting mostly favourable outcomes. However, with case studies, there may be a reporting bias towards favourable outcome. Thus, we undertook this multi-centre retrospective study to gather worldwide experiences with bilateral pallidal deep brain stimulation in patients with neurodegeneration with brain iron accumulation. A total of 16 centres contributed 23 patients with confirmed neurodegeneration with brain iron accumulation and bilateral pallidal deep brain stimulation. Patient details including gender, age at onset, age at operation, genetic status, magnetic resonance imaging status, history and clinical findings were requested. Data on severity of dystonia (Burke Fahn Marsden Dystonia Rating Scale—Motor Scale, Barry Albright Dystonia Scale), disability (Burke Fahn Marsden Dystonia Rating Scale—Disability Scale), quality of life (subjective global rating from 1 to 10 obtained retrospectively from patient and caregiver) as well as data on supportive therapy, concurrent pharmacotherapy, stimulation settings, adverse events and side effects were collected. Data were collected once preoperatively and at 2–6 and 9–15 months postoperatively. The primary outcome measure was change in severity of dystonia. The mean improvement in severity of dystonia was 28.5% at 2–6 months and 25.7% at 9–15 months. At 9–15 months postoperatively, 66.7% of patients showed an improvement of 20% or more in severity of dystonia, and 31.3% showed an improvement of 20% or more in disability. Global quality of life ratings showed a median improvement of 83.3% at 9–15 months. Severity of dystonia preoperatively and disease duration predicted improvement in severity of dystonia at 2–6 months; this failed to reach significance at 9–15 months. The study confirms that dystonia in neurodegeneration with brain iron accumulation improves with bilateral pallidal deep brain stimulation, although this improvement is not as great as the benefit reported in patients with primary generalized dystonias or some other secondary dystonias. The patients with more severe dystonia seem to benefit more. A well-controlled, multi-centre prospective study is necessary to enable evidence-based therapeutic decisions and better predict therapeutic outcomes.

Sensory tricks in cervical dystonia: Perceptual dysbalance of parietal cortex modulates frontal motor programming

Cervical dystonia is a disabling basal ganglia disorder characterized by an involuntary head deviation to one side. A typical but also mysterious feature is the impressive improvement of muscle spasms and involuntary head posture by application of a sensory facial stimulus (sensory trick). Here, we report the effect of a sensory trick on cortical activation patterns in 7 patients with cervical dystonia by using H215O positron emission tomography. The application of the sensory trick stimulus, resulting in a near‐neutral head position, led to an increased activation mainly of the superior and inferior parietal lobule (ipsilateral to the original head turn) and bilateral occipital cortex and to a decreased activity of the supplementary motor area and the primary sensorimotor cortex (contralateral to the head turn). We propose that a perceptual dysbalance induced by a sensory trick maneuver leads to a relative displacement of the egocentric midvertical reference to the opposite side and a decrease in motor cortex activity. This modulation of motor programming gives novel insights into the mechanisms involved in sensorimotor integration in movement disorders. Ann Neurol 2000;47:322–328

Disease progression continues in patients with advanced Parkinson's disease and effective subthalamic nucleus stimulation

Objectives: Glutamate mediated excitotoxicity of the hyperactive subthalamic nucleus (STN) has been reported to contribute to nigral degeneration in Parkinson’s disease (PD). Deep brain stimulation of the STN (STN DBS), in its role as a highly effective treatment of severe PD motor complications, has been thought to inhibit STN hyperactivity and therefore decrease progression of PD. Methods: In a prospective two centre study, disease progression was determined by means of serial 18F-fluorodopa (F-dopa) positron emission tomography (PET) in 30 patients with successful STN DBS over the first 16 (SD 6) months after surgery. Results: Depending on the method of PET data analysis used in the two centres, annual progression rates relative to baseline were 9.5–12.4% in the caudate and 10.7–12.9% in the putamen. Conclusions: This functional imaging study is the first to demonstrate a continuous decline of dopaminergic function in patients with advanced PD under clinically effective bilateral STN stimulation. The rates of progression in patients with STN DBS were within the range of previously reported data from longitudinal imaging studies in PD. Therefore this study could not confirm the neuroprotective properties of DBS in the STN target.

Blood-brain barrier P-glycoprotein function decreases in specific brain regions with aging: A possible role in progressive neurodegeneration

Cerebrovascular P-glycoprotein (P-gp) acts at the blood-brain barrier (BBB) as an active cell membrane efflux pump for several endogenous and exogenous compounds. Age-associated decline in P-gp function could facilitate the accumulation of toxic substances in the brain, thus increasing the risk of neurodegenerative pathology with aging. We hypothesised a regionally reduced BBB P-gp function in older healthy subjects. We studied cerebrovascular P-gp function using [(11)C]-verapamil positron emission tomography (PET) in seventeen healthy volunteers with age 18-86. Logan analysis was used to calculate the distribution volume (DV) of [(11)C]-verapamil in the brain. Statistical Parametric Mapping was used to study specific regional differences between the older compared with the younger adults. Older subjects showed significantly decreased P-gp function in internal capsule and corona radiata white matter and in orbitofrontal regions. Decreased BBB P-gp function in those regions could thus explain part of the vulnerability of the aging brain to white matter degeneration. Moreover, decreased BBB P-gp function with aging could be a mechanism by which age acts as the main risk factor for the development of neurodegenerative disease.

Chorein Detection for the Diagnosis of Chorea-Acanthocytosis

Chorea‐acanthocytosis (ChAc) is a severe, neurodegenerative disorder that shares clinical features with Huntingtons disease and McLeod syndrome. It is caused by mutations in VPS13A, which encodes a large protein called chorein. Using antichorein antisera, we found expression of chorein in all human cells analyzed. However, chorein expression was absent or noticeably reduced in ChAc patient cells, but not McLeod syndrome and Huntingtons disease cells. This suggests that loss of chorein expression is a diagnostic feature of ChAc. Ann Neurol 2004;56:299–302

Neuroinflammation in the pathophysiology of Parkinson's disease: evidence from animal models to human in vivo studies with [11C]-PK11195 PET.

Increasing evidence suggests that neuroinflammation is an active process in Parkinsons disease (PD) that contributes to ongoing neurodegeneration. PD brains and experimental PD models show elevated cytokine levels and up‐regulation of inflammatory‐associated factors as cyclo‐oxygenase‐2 and inducible nitric oxide oxidase. Antiinflammatory treatment reduced neuronal degeneration in experimental models. In this review, we summarize the place of neuroinflammation in the pathophysiology of PD. In vivo PET studies are discussed. These methods provide a means to monitor in vivo potential clinical relevance of antiinflammatory treatment strategies in PD.

Dexamethasone treatment of brain tumor patients: effects on regional cerebral blood flow, blood volume, and oxygen utilization.

Regional values for cerebral blood flow, blood volume, oxygen extraction fraction, and oxygen utilization were measured, using PET, in 10 brain tumor patients before and after treatment with dexamethasone. Dexamethasone treatment decreased cerebral blood flow and blood volume and increased the fractional extraction of oxygen throughout the brain without affecting oxygen utilization. Dexamethasone probably causes direct vasoconstriction of cerebral blood vessels.