Molecular Imaging of Extrapyramidal Movement Disorders

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Extrapyramidal movement disorders including Parkinson disease, multiple systems atrophy, progressive supranuclear palsy, and corticobasal degeneration are neurodegenerative syndromes with distinct neuropathological changes, indicating differing underlying etiologies. Clinical features that may distinguish among these conditions are often absent, particularly early after the onset of symptoms. Therapy is presently limited, and there are no established disease-modifying or neuroprotective interventions. Advances in therapeutics will depend on the early and accurate diagnostic classification of patients. Existing molecular imaging approaches demonstrate ability to separate several of these syndromes, but are clinically underutilized or are available only in research settings. The development of additional, specific imaging approaches targeting the misfolded protein deposits that characterize these neurodegenerative pathologies promises to advance not only the sensitive and specific endophenotyping of patients, but may also serve to measure directly potential therapeutic responses in the initial evaluations of new treatments.

Introduction

Movement disorders are a collection of neurologic syndromes characterized by deficits in the execution of voluntary movement, but in the absence of significant muscle weakness or paralysis, loss of sensation or proprioception, or of spinal cord or peripheral nerve lesions. Most movement disorders involve dysfunction of subcortical neural structures involved in sequencing and controlling movements—especially the basal ganglia and cerebellum and their connections. The most common human movement disorders are age-related in their symptomatic onset and are of idiopathic etiology. Essential tremor is the most frequently encountered movement disorder, and is characterized clinically by a high-frequency, (usually) low-amplitude, distal limb or vocal tremor or both, expressed during actively maintained posture and superimposed on movement. In typical presentations of essential tremor, it is absent at rest. The second most frequent type of human movement disorder is classified as extrapyramidal in its characteristics, emphasizing that the corticospinal motor pathways (pyramidal projections) are not the primary site(s) of dysfunction. The most common extrapyramidal movement disorder is idiopathic Parkinson disease (PD), and aspects of its signs and symptoms, including rigidity, bradykinesia, and rest tremor (termed parkinsonism) are variably expressed across the majority of extrapyramidal movement disorders. In the following sections, the molecular imaging aspects of the most frequent extrapyramidal movement disorders will be reviewed and summarized with regard to new and emerging opportunities for their diagnosis, classification, and ultimately treatment advances.

Section snippets

Clinical Features of Extrapyramidal Movement Disorders

Extrapyramidal movement disorders, including PD, progressive supranuclear palsy (PSP), multiple system atrophy (MSA), and corticobasal degeneration (CBD) share aspects of parkinsonism, particularly bradykinesia and rigidity. All have clinical aspects that can serve to distinguish them. However, many individual patients lack expression of the differentiating features, particularly, early in symptomatic presentation.1, 2, 3 These disorders are progressive neurodegenerations, and none have an

Glucose Metabolic Imaging

Many investigators have applied 18F-FDG imaging with PET to distinguish among patient groups with extrapyramidal neurodegenerative movement disorders. Initial studies employed univariate image analysis approaches to separate patient groups, and in many instances, demonstrated relative success. The metabolic appearance of PD is typified by increased FDG activity in the striatum, particularly in the putamen, relative to the cerebral cortex in early presentation before use of DA replacement

Imaging Dopaminergic Synapses in Extrapyramidal Disorders

As noted previously, the nigrostriatal dopaminergic projection is central to the pathology of PD, but is also affected in the non-PD parkinsonian neurodegenerations. The mammalian nervous system contains relatively few DA neurons, and all have a relatively discrete distribution.53 Most dopaminergic neurons reside in the ventral midbrain, including the SNc and the adjacent ventral tegmental area. Projections from the SNc proceed through the medial forebrain bundle, terminating predominantly

Nondopaminergic Synaptic Markers in PD

Although there is extensive clinico-pathological correlation underlying emphasis on nigrostriatal DA projections in the “typical” motor symptomatology in PD, it has been appreciated for some time that midbrain DA neurons are not the only sites of frequent PD pathology.83 Neuropathological investigations of PD have been advanced significantly by the identification of specific proteins contained in the “hallmark” neuronal PD lesion, the Lewy body (LB). The LB seen typically in the somata of

Imaging Nondopaminergic Presynaptic Markers in PD

An important caveat to the (above) neuropathological PD progression schemes is the lack of direct functional salience of the αSyn inclusions used to accomplish the staging. Although permitting the rapid and sensitive screening of multiple brain samples, there is no reason to expect that the intensity of αSyn pathology need correspond to the severity of neuronal and synaptic dysfunction or losses. For example, the development of SNc LB pathology corresponds to Braak stage 3, while in the

Cognitive Impairment in Synucleinopathies

An important consideration in the clinical and pathologic characterization of PD is the development of dementia. Cognitive impairment is common in PD, and the risk of developing dementia in the setting of PD is 2-to-6-fold higher than in the general population, corresponding to lifetime risk estimates of 30%-80%.116, 117, 118 PD with dementia (PDD) is related closely to an increasingly recognized syndrome, dementia with LBs (DLB). DLB is in fact the second most common neurodegenerative

Neuropathologies in PDD and DLB

Common to both PDD and DLB (together, termed LB dementias: LBD) are accumulations of αSyn aggregates affecting nigrostriatal DA neurons and limbic, and neocortical neurites. Virtually all pathological series investigating PDD or DLB find evidence of SNc and cortical αSyn pathology equivalent to Braak stages 5 or 690 (stages III and IV of the proposed Unified LB Staging System.92) No cases with dementia lack significant midbrain αSyn in the series of 417 cases resulting in the unified staging

Molecular Imaging of LBD

Distinction of LBD from other neurodegenerative dementia syndromes is important both for prognostic and symptomatic therapeutic perspectives.120 As was discussed previously (above), functional neuroimaging with FDG-PET may identify subjects with LBD as distinct from those with typical Alzheimer disease (AD) or with frontotemporal dementia (FTD).40, 144, 145 Patients with DLB or with PDD may demonstrate FDG hypometabolism involving the primary visual cortices in addition to the temporoparietal

Future Directions

As discussed above, there are clear neuropathological distinctions among the neurodegenerative extrapyramidal movement disorders. Progress in development of effective therapy, including the possibility of neuroprotective approaches, will require the ability to make accurate diagnostic classifications in life, and especially early at symptomatic onset. Although there are some phenotypic distinctions among PD, MSAp, PSP, and CBD, more sensitive and accurate distinctions on the basis of molecular

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