Anna L. Bartels

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.

Parkinson's disease: The syndrome, the pathogenesis and pathophysiology

Parkinsons disease (PD) is characterised by a slowly expanding degeneration of neurons particularly in the mesencephalon. The causes are unknown although risk factors in the genetic and toxic domain are being discovered. An important pathophysiological feature in PD is the loss of part of the dopaminergic neurons in the substantia nigra (SN) resulting in a specific dysorganisation of the complicated basal ganglia (BG) circuits. The relay functions at the level of the striatum e.g., are out of balance leading to disturbed subcortico-cortical interactions. At a functional level this is shown by timing and scaling problems when performing movements and clinically this translates into initiation problems, bradykinesia and others. Dysarthria can of course be an important problem. However, how these basic disturbances of motor organisation can be copied into the cognitive domain (in terms of disturbed mental movements) is a topic under discussion. It remains to be seen whether the basic pathophysiology of PD has consequences for the specific language organisation by the brain or whether language problems are merely secondary to the overall mental motor slowing. Here an overview of the pathogenesis, basic pathophysiology and clinical problems of PD will be given.

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.

[11C]-PK11195 PET: Quantification of neuroinflammation and a monitor of anti-inflammatory treatment in Parkinson's disease?☆

UNLABELLEDn[(11)C]-PK11195 PET has been used for in vivo brain imaging of microglia activation in Parkinsons disease (PD) patients. COX-2 inhibition has been shown to reduce neuroinflammation and neurodegeneration in animal models of PD. This pilot study assessed the use of [(11)C]-PK11195 PET to quantify neuroinflammation and evaluate the ability of COX-2 inhibition to reduce neuroinflammation in PD patients.nnnMETHODSnFourteen PD patients and eight healthy, age matched controls underwent a [(11)C]-PK11195 PET and MRI scan. Five PD patients were scanned before and after one month of celecoxib treatment 200 mg/day. Arterial plasma sampling and metabolite analysis were performed to create plasma input curves. A 2-compartment model and Logan analysis were applied and parametric DV images were compared using t-test in SPM2. In addition a simplified reference region model (SRTM) was applied, with both the cerebellum and a reference region derived from cluster analysis.nnnRESULTSnUsing the cluster analysis, PD patients showed higher contralateral putamen BP and midbrain BP compared to controls, although considerable overlap was seen and differences were not statistically significant. Unexpectedly, BP and DV after celecoxib were slightly higher. Cerebellum as reference region resulted in lower BP values and k(3)/k(4) gave 10-fold higher BP values. Linearization of the data did not show differences between PD patients and controls.nnnCONCLUSIONSnIn current practice, [(11)C]-PK11195 seems an unsuitable tracer for accurate or reliable quantification of neuroinflammation. Refinement of [(11)C]-PK11195 uptake analysis and, more importantly, further development of better tracers is necessary to enable accurate measurement of neuroinflammation and effects of anti-inflammatory treatment in patients.

Brain imaging in patients with freezing of gait

Freezing of gait (FOG) is a disabling gait disturbance with unknown cerebral pathophysiology. In this review, we discuss the functional brain imaging studies that address gait physiology and pathophysiology of FOG. Radiotracer metabolic studies show basal ganglia‐cortical circuitry involvement in different aspects of gait control. FOG patients showed orbitofrontal and posterior parietal deficits and possibly predominant involvement of right‐sided circuitry. We suggest that FOG results from neuronal circuitry dysfunction in right‐sided parietal‐lateral premotor circuits. These circuits incorporate sensory information into the control of gait. Furthermore, abnormal function of frontostriatal loops, which probably sheer cognitive and attentional activities is also a main factor in FOG. Gait‐induced brain circuitry activation can not adequately be achieved when investigated subjects are in a supine rest position, as is the case in most present day imaging studies. Some radiotracer activation studies were performed after walking. Imagination of gait has been used in some radiotracer activation studies with positron emission tomography (PET) and in studies with functional magnetic resonance imaging (fMRI), showing cortical activation patterns involved in several aspects of gait control. For future investigation of FOG, it is suggested to design PET and fMRI studies which concentrate on activation of neuropsychological and sensory integration circuits.

Blood–brain barrier P-glycoprotein function is not impaired in early Parkinson's disease

The cause of Parkinsons disease (PD) is unknown. Genetic susceptibility and exposure to environmental toxins contribute to specific neuronal loss in PD. Decreased blood-brain barrier (BBB) P-glycoprotein (P-gp) efflux function has been proposed as a possible causative link between toxin exposure and PD neurodegeneration. In the present study BBB P-gp function was investigated in vivo in 10 early stage PD patients and 8 healthy control subjects using (R)-[(11)C]-verapamil and PET. Cerebral volume of distribution (V(d)) of verapamil was used as measure of P-gp function. Both region of interest (ROI) analysis and voxel analysis using statistical parametric mapping (SPM) were performed to assess regional brain P-gp function. In addition, MDR1 genetic polymorphism was assessed. In the present study, a larger variation in V(d) of (R)-[(11)C]-verapamil was seen in the PD group as compared to the control group. However, decreased BBB P-gp function in early stage PD patients could not be confirmed.

Handedness and dominant side of symptoms in Parkinson’s disease

The aim of this retrospective study was to assess the presence of a possible association between handedness and the side of symptom dominance in 963 patients with Parkinsons disease (PD). In only 287 patients the hand dominance was registered. Out of 254 right-handed patients, 158 (62%) had a right-side dominance of PD symptoms, while 96 patients (38%) had left-lateralized symptom dominance (p < 0.001). For the 33 left-handed subjects, 18 (55%) had left- and 15 (45%) had right-sided symptom dominance (p = 0.602). Right-handedness thus appeared to be associated with right-sided dominance of PD symptoms, while the group of left-handed patients was too small to draw conclusions from. Possible explanations are discussed.

11C-verapamil to Assess P-gp Function in Human Brain During Aging,Depression and Neurodegenerative Disease

P-glycoprotein (P-gp) at the blood-brain barrier (BBB) functions as an active efflux pump by extruding a wide range of substrates from the brain. This is important for maintaining loco-regional homeostasis and for protecting the brain against blood-borne toxic substances. Altered P-gp function seems to be involved in the pathophysiology of neurodegenerative disease and various neurological and psychiatric disorders. Positron emission tomography (PET) with the radiotracer (11)C-verapamil (VPM-PET) is a validated technique allowing measurement of P-gp function at the human BBB. In this review, we highlight changes of P-gp function, as measured with VPM-PET, in aging and in the pathogenesis and progression of neurodegenerative disease, as well as their role in depressive disorders.

Regional increase in P-glycoprotein function in the blood-brain-barrier of patients with chronic schizophrenia

a Department of Psychiatry, University Medical Center Groningen (UMCG), P.O. Box 30.001, 9700 RB Groningen, The Netherlands b Psychiatric Hospital GGZ Drenthe, P.O. Box 30007, 9400 RA Assen, The Netherlands c Department of Nuclear Medicine and Molecular Imaging, UMCG, Groningen, The Netherlands d Department of Neurology, UMCG, Groningen, The Netherlands e Department of Nuclear Medicine and PET Research, VU Medical Center, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands