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Purpose of Review: GBA1 mutations, which result in the lysosomal disorder Gaucher disease, are the most common known genetic risk factor for Parkinson disease and Dementia with Lewy Bodies (DLB). The pathogenesis of this association is not fully understood, but further elucidation of this link could lead to new therapeutic options., Recent Findings: The characteristic clinical phenotype of GBA1-PD resembles sporadic Parkinson disease, but with an earlier onset and more severe course. Many different GBA1 mutations increase the risk of Parkinson disease, some primarily detected in specific populations. Glucocerebrosidase deficiency appears to be associated with increased α-synuclein aggregation and accumulation, mitochondrial dysfunction because of impaired autophagy, and increased endoplasmic reticulum stress., Summary: As our understanding of GBA1-associated Parkinson disease increases, new treatment opportunities emerge. MicroRNA profiles are providing examples of both up-regulated and down-regulated proteins related to GBA1 and may provide new therapeutic targets. Chaperone therapy, directed at either misfolded glucocerebrosidase or α-synuclein aggregation, is currently under development and there are several early clinical trials ongoing. Substrate reduction therapy, aimed at lowering the accumulation of metabolic by-products, especially glucosylsphingosine, is also being explored. Basic science insights from the rare disorder Gaucher disease are serving to catapult drug discovery for parkinsonism.

Purpose of Review: Positron emission tomography (PET) and single-photon emission computed tomography (SPECT) are now available for routine clinical applications in neurology. This article discusses their diagnostic use in dementia, brain tumors, epilepsy, parkinsonism, cerebrovascular disease, and traumatic brain injury., Recent Findings: Neuromolecular imaging, also known as nuclear neurology, involves clinical imaging of both basal regional physiology (perfusion, metabolism, and transport mechanisms) and specific neurochemical physiology (currently, only the dopamine transporter). This article serves as an introduction to neuromolecular imaging, reviewing the literature supplemented by the author's experience., Summary: Neurologic PET and SPECT are no longer restricted to the research realm. These modalities have high diagnostic accuracy.

Purpose of Review: The different parkinsonian conditions can be challenging to separate clinically. This review highlights the important clinical features that guide the diagnosis of Parkinson disease (PD), progressive supranuclear palsy (PSP), multiple system atrophy (MSA), and corticobasal degeneration (CBD). Strategies for treatment and disease management are also discussed., Recent Findings: Over the past decade there has been an increasing recognition of the broad clinical presentations of the neurodegenerative forms of parkinsonism. Nonmotor symptoms in these diseases, including psychiatric, cognitive, autonomic, and gastrointestinal dysfunction, appear to have a major impact on quality of life and disability. PSP and CBD are now considered pathologic diagnoses, with several different and varied clinical phenotypes, that overlap and share features with PD and frontotemporal dementia syndromes. PD is distinguished by its excellent response to dopaminergic medications that is maintained over many years, in contrast to the response seen in patients with MSA and PSP. New diagnostic criteria have been proposed for CBD. No new therapeutic interventions have emerged for PSP, MSA, or CBD. Infusional therapies and deep brain stimulation surgery are established therapies for advanced PD., Summary: The "parkinsonian syndromes" encompass a number of nosologic entities that are grouped together on the basis of their shared clinical features but are separated on the basis of their different pathologies. Overall, the consideration of clinical signs, mode of disease onset, and nature of disease progression are all important to make a timely and definitive diagnosis.

Background: To date, only a few cases of improvement of Parkinsonism in depressed patients treated with electroconvulsive therapy (ECT) have been reported. However, no functional imaging data are available to support this finding., Objective: To describe the first observation of increase in dopamine transporter uptake after ECT., Methods: Iodine-123 fluoropropyl-carbomethoxy-3-β-(4-iodophenyltropane) single-photon emission computed tomographic imaging was conducted in a 77-year-old depressed patient displaying symptoms of Parkinson disease (PD) before and after a series of 12 bilateral ECTs., Results: The patient displayed improvement in PD symptoms and increase in dopamine transporter uptake after ECT., Conclusions: Our observation suggests that the PD symptoms and decrease in striatal uptake appearing in the context of a depressive episode might warrant further attention, as they might be reversible.

Purpose of Review: Atypical parkinsonian disorders (APDs) comprise a heterogenous group of disorders including multiple system atrophy (MSA), dementia with Lewy bodies (DLB), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Based on literature published in 2010, we here review recent advances in the APD field., Recent Findings: Genome-wide association studies have provided robust evidence of increased disease risk conferred by synuclein and tau gene variants in MSA and PSP. Furthermore, advanced imaging tools have been established in the differential diagnosis and as surrogate markers of disease activity in patients with APDs. Finally, although therapeutic options are still disappointing, translational research into disease-modifying strategies has accelerated with the increasing availability of transgenic animal models, particularly for MSA., Summary: Remarkable progress has been achieved in the field of APDs, and advances in the genetics, molecular biology and neuroimaging of these disorders will continue to facilitate intensified clinical trial activity.

Parkinson's disease (PD) may involve sudden unintended arrests in gait or failure to initiate gait, known as gait freezing. Deep brain stimulation of the pedunculopontine nucleus (PPN) has been found to be an effective therapy for this phenomenon. In this study, we characterized the connectivity of the PPN freezing of gait (FOG) patients, compared with non-FOG PD and healthy controls using diffusion tensor imaging techniques. Differences in PPN connectivity profiles of the study groups were shown in the cerebellum and pons. The PPN showed connectivity with the cerebellum in controls and non-FOG PD. FOG patients showed absence of cerebellar connectivity, and increased visibility of the decussation of corticopontine fibres in the anterior pons. The findings suggest that corticopontine projections, which cross at the pons are increased in gait freezing, highlighting the importance and role of corticopontine-cerebellar pathways in the pathophysiology of this phenomenon.

Purpose of Review: This timely update discusses novel diagnostic approaches, recently identified genes, and innovative experimental symptomatic treatments for these devastating disorders., Recent Findings: Differential patterns in the basal ganglia transcranial sonography, magnetic resonance diffusion-weighted imaging regional apparent diffusion coefficients in the brainstem, basal ganglia T2-weighted gradient echo sequences combined with fluid attenuated inversion recovery, or saccades error rates in single and mixed-task blocks could help differentiate the various parkinsonian disorders. In addition to the familial tauopathies (frontotemporal dementia associated with chromosome 17) presenting with an atypical parkinsonian phenotype, 'TDP-43opathies' and 'tataboxbinding or ataxinopathies', depending on the protein deposited in the brain, widen the scope of the familial atypical parkinsonian disorders. Recent identification of novel deep brain stimulation targets such as the pedunculopontine nucleus may help treat the balance and gait disorder in atypical parkinsonian disorders in the near future., Summary: These new findings are important for diagnosis, help better understanding of the nosology of these disorders, and will likely in the near future impact our clinical practice.

The present report describes for the first time, the stability of recombinant adeno-associated virus serotype 2 (AAV2) human aromatic L-amino acid decarboxylase (hAADC) gene transfer after 3-year survival time in a non-human primate model of Parkinson's disease. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned monkeys were treated with six injections of 30 microl/site of AAV2-hAADC at a concentration of 2 x 10(12) vg/ml into the caudate and putamen. Stereological analysis revealed a 46.6% increase in the total number of AAV2-hAADC-transduced cells in the striatum between 8 weeks and 3 years after gene transfer survival time. In the 8-week animals, the distribution of the AADC+ cells was dispersed and heterogeneous, whereas in the 3-year animals it was widespread and homogenous. Confocal analysis demonstrated that approximately 85% of the AADC+ cells were neuronal nuclei immunoreactive.

Unlabelled: The evaluation of Parkinson disease relies on the use of clinical scales, mainly the UPDRS. However, especially for those candidates for functional surgery, other objective methods are also considered, including the use of timed tests., Methods: The authors studied the motor performance of 33 patients with advanced Parkinson disease (PD) who were candidates for subthalamic nucleus (STN) stimulation. Presurgical motor evaluation included UPDRS and the 4 timed tests of the CAPIT protocol, including pronation-supination (PS), finger dexterity (FD), movement between 2 points (MTP), and the walking test (WT). A clinical evaluation was performed during patients' OFF condition and during their best ON state. Fifteen patients were implanted with STN stimulation and were evaluated at 6 months with the same protocol described for the presurgical evaluation., Results: At baseline, all 4 timed tests significantly correlated with total and motor UPDRS scores, in the OFF and ON states, especially MTP. All timed tests, save WT, significantly improved after surgery in the OFF state (especially MTP; P = 0.002). After surgery, all timed tests, save FD, significantly correlated with total and motor UPDRS scores in the OFF state. Timed tests, especially MTP, maintained an excellent correlation with UPDRS in both OFF and ON states before and after surgery.

We have studied the effects of stimulating the pedunculopontine nuclei through a fully implanted macroelectrode with a s.c. implantable pulse generator whose parameters can be programmed telemetrically, in a macaque before and after inducing Parkinsonian akinesia with MPTP. Our results show that in the normal monkey high frequency stimulation of the pedunculopontine nuclei reduces motor activity while low frequency stimulation increases it significantly over baseline. After making the monkey Parkinsonian with MPTP, unilateral low frequency stimulation of the pedunculopontine nuclei led to significant increases in activity. These results suggest that pedunculopontine nuclei stimulation could be clinically effective in treating advanced Parkinson's disease and other akinetic disorders.