Anna L. Bartels

This chapter summarizes the contribution of imaging to the current understanding of the mechanisms underlying surgical interventions for PD. Structural imaging studies using MRI techniques have served to improve the accuracy of stereotaxic targeting. That said, functional imaging with positron emission tomography (PET), single photon emission tomography (SPECT), and fMRI have provided an in vivo method to assess changes in brain function in the vicinity of the surgical target and in remote, interconnected brain regions within a spatially distributed neural network. This chapter provides an overview of functional/anatomical models of basal ganglia circuitry, followed by a discussion of the changes mediated by surgery at both the regional and network levels. Specific attention is dedicated to the effects of deep brain stimulation (DBS) on network organization and on disease progression.

Protection of the brain is strengthened by active transport and ABC transporters. P-glycoprotein (P-gp) at the blood-brain barrier (BBB) functions as an active efflux pump by extruding a substrate from the brain, which is important for maintaining loco-regional homeostasis in the brain and protection against toxic compounds. Importantly, dysfunctional BBB P-gp transport is postulated as an important factor contributing to accumulation of aggregated protein in neurodegenerative disorders such as Alzheimers disease (AD) and Parkinsons disease (PD). Furthermore, P-gp is a major factor in mediating resistance to brain entry of numerous exogenous compounds, including toxins that can be involved in PD pathogenesis. This review highlights the role of altered P-gp function in the pathogenesis and progression of neurodegenerative disease. Also the implications of alterations in P-gp function for the treatment of these diseases are discussed.

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 11C-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.

Cyclooxygenase (COX) expression in the brain is associated with pro-inflammatory activities, which are instrumental in neurodegenerative processes such as Parkinsons disease (PD). It is discussed that drugs with the capacity to rescue dopaminergic neurons from microglia toxicity and neuroinflammatory processes may result in an amelioration of parkinsonian symptoms by delaying the onset or slowing progression. This article reviews the involvement of COX in neuroinflammation, specifically focussing at the role of selective COX-2 inhibition in neuroinflammation and neurodegeneration in Parkinsons disease.

Fluorodeoxyglucose positron emission tomography scanning has an established role in the diagnostic work-up of many malignant diseases and also in the evaluation of cancer treatment response. Fluorodeoxyglucose positron emission tomography may, however be non-specific as infectious processes are depicted as well. We present a patient with longstanding leg pain and weakness due to plexopathy developed a few years after treatment for prostate cancer. Prostate-specific antigen was raised and magnetic resonance imaging showed contrast uptake in thickened sacral nerves, suspicious for metastasis. While fluorodeoxyglucose positron emission tomography showed increased uptake in the plexus region, (11)C-Choline- positron emission tomography did not show any uptake. It was concluded that the FDG uptake reflected plexus neuritis and no tumor. Treatment for pain relief was started. (11)C-Choline- positron emission tomography can be used to detect metastasis in patients with plexopathy suspicious for malignancy, while fluorodeoxyglucose positron emission tomography is more sensitive to inflammatory processes.

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. © 2008 Movement Disorder Society

Decreased blood–brain barrier (BBB) efflux function of the P-glycoprotein (P-gp) transport system could facilitate the accumulation of toxic compounds in the brain, increasing the risk of neurodegenerative pathology such as Parkinson’s disease (PD). This study investigated in vivo BBB P-gp function in patients with parkinsonian neurodegenerative syndromes, using [¹¹C]-verapamil PET in PD, PSP and MSA patients. Regional differences in distribution volume were studied using SPM with higher uptake interpreted as reduced P-gp function. Advanced PD patients and PSP patients had increased [¹¹C]-verapamil uptake in frontal white matter regions compared to controls; while de novo PD patients showed lower uptake in midbrain and frontal regions. PSP and MSA patients had increased uptake in the basal ganglia. Decreased BBB P-gp function seems a late event in neurodegenerative disorders, and could enhance continuous neurodegeneration. Lower [¹¹C]-verapamil uptake in midbrain and frontal regions of de novo PD patients could indicate a regional up-regulation of P-gp function.