Altered Cortico-Limbic Network Connectivity in Parkinsonian Depression: The Effect of Antidepressants.

BACKGROUND: Depression is a common comorbidity of Parkinson's disease (PD); however, the impact of antidepressant status on cortical function in parkinsonian depression is not fully understood. While studies of resting state functional MRI in major depression have shown that antidepressant treatment affects cortical connectivity, data on connectivity and antidepressant status in PD is sparse. OBJECTIVE: We tested the hypothesis that cortico-limbic network (CLN) resting state connectivity is abnormal in antidepressant-treated parkinsonian depression. METHODS: Thirteen antidepressant-treated depressed PD and 47 non-depressed PD participants from the Parkinson's Progression Markers Initiative (PPMI) database were included. Data was collected using 3T Siemens TIM Trio MR scanners and analyzed using SPM and CONN functional connectivity toolbox. Volumetric analysis was also performed using BrainSuite. RESULTS: We found decreased connectivity in the antidepressant-treated depressed PD group when compared to non-depressed PD between the left frontal operculum and bilateral insula, and also reduced connectivity between right orbitofrontal cortex and left temporal fusiform structures. Increased depression scores were associated with decreased insular-frontal opercular connectivity. No ROI volumetric differences were found between groups. CONCLUSION: Given the relationship between depression scores and cortico-limbic connectivity in PD, the abnormal insular-frontal opercular hypoconnectivity in this cohort may be associated with persistent depressive symptoms or antidepressant effects.

Longer Duration of MAO-B Inhibitor Exposure is Associated with Less Clinical Decline in Parkinson's Disease: An Analysis of NET-PD LS1.

BACKGROUND: Monoamine oxidase type B (MAO-B) inhibitors exhibit neuroprotective effects in preclinical models of PD but clinical trials have failed to convincingly demonstrate disease modifying benefits in PD patients. OBJECTIVE: To perform a secondary analysis of NET-PD LS1 to determine if longer duration of MAO-B inhibitor exposure was associated with less clinical decline. METHODS: The primary outcome measure was the Global Outcome (GO), comprised of 5 measures: change from baseline in the Schwab and England (ADL) scale, the 39-item Parkinson's Disease Questionnaire (PDQ-39), the UPDRS Ambulatory Capacity Scale, the Symbol Digit Modalities Test, and the most recent Modified Rankin Scale. A linear mixed model was used to explore the association between the cumulative duration of MAO-B inhibitor exposure and the GO, adjusting for necessary factors and confounders. Associations between MAO-B inhibitor exposure and each of the five GO components were then studied individually. RESULTS: 1616 participants comprised the analytic sample. Mean observation was 4.1 (SD = 1.4) years, and 784 (48.5%) participants received an MAO-B inhibitor. The regression coefficient of cumulative duration of MAO-B inhibitor exposure (in years) on the GO was - 0.0064 (SE = 0.002, p = 0.001). Significant associations between duration of MAO-B inhibitor exposure and less progression were observed for ADL (p < 0.001), Ambulatory Capacity (p < 0.001), and the Rankin (p = 0.002). CONCLUSIONS: Our analysis identified a significant association between longer duration of MAO-B inhibitor exposure and less clinical decline. These findings support the possibility that MAO-B inhibitors slow clinical disease progression and suggest that a definitive prospective trial should be considered.

Alpha-synuclein targets the plasma membrane via the secretory pathway and induces toxicity in yeast.

A pathological feature of Parkinson's disease is the presence of Lewy bodies within selectively vulnerable neurons. These are ubiquitinated cytoplasmic inclusions containing alpha-synuclein, an abundant protein normally associated with presynaptic terminals. Point mutations in the alpha-synuclein gene (A30P and A53T), as well as triplication of the wild-type (WT) locus, have been linked to autosomal dominant Parkinson's. How these alterations might contribute to disease progression is unclear. Using the genetically tractable yeast Saccharomyces cerevisiae as a model system, we find that both the WT and the A53T isoforms of alpha-synuclein initially localize to the plasma membrane, to which they are delivered via the classical secretory pathway. In contrast, the A30P mutant protein disperses within the cytoplasm and does not associate with the plasma membrane, and its intracellular distribution is unaffected by mutations in the secretory pathway. When their expression is elevated, WT and A53T, but not A30P, are toxic to cells. At moderate levels of expression, WT and A53T induce the cellular stress (heat-shock) response and are toxic to cells bearing mutations in the 20S proteasome. Our results reveal a link between plasma membrane targeting of alpha-synuclein and its toxicity in yeast and suggest a role for the quality control (QC) system in the cell's effort to deal with this natively unfolded protein.

Cognitive and Psychiatric Disturbances in Parkinsonian Syndromes.

Parkinsonian syndromes share clinical signs including akinesia/bradykinesia and rigidity, which are consequences of pathology involving dopaminergic substantia nigra neurons. Yet cognitive and psychiatric disturbances are common, even early in the course of disease. Executive dysfunction is often measurable in newly diagnosed Parkinson's disease. Treatment with dopaminergic medications, particularly dopamine agonists, has been associated with hallucinations and impulse control disorder. Older age, presence of APOE-4 gene, and/or other factors result in amyloid plaque deposition that, in turn, accelerates cortical Lewy body plus tau pathology, linking Dementia with Lewy Bodies and Parkinson's disease with early dementia with Alzheimer's disease. Treatments available for cognitive deficits, depression, and psychotic symptoms are discussed.

Sex Differences in Clinical Features of Early, Treated Parkinson's Disease.

INTRODUCTION: To improve our understanding of sex differences in the clinical characteristics of Parkinson's Disease, we sought to examine differences in the clinical features and disease severity of men and women with early treated Parkinson's Disease (PD) enrolled in a large-scale clinical trial. METHODS: Analysis was performed of baseline data from the National Institutes of Health Exploratory Trials in Parkinson's Disease (NET-PD) Long-term Study-1, a randomized, multi-center, double-blind, placebo-controlled study of 10 grams of oral creatine/day in individuals with early, treated PD. We compared mean age at symptom onset, age at PD diagnosis, and age at randomization between men and women using t-test statistics. Sex differences in clinical features were evaluated, including: symptoms at diagnosis (motor) and symptoms at randomization (motor, non-motor, and daily functioning). RESULTS: 1,741 participants were enrolled (62.5% male). No differences were detected in mean age at PD onset, age at PD diagnosis, age at randomization, motor symptoms, or daily functioning between men and women. Differences in non-motor symptoms were observed, with women demonstrating better performance compared to men on SCOPA-COG (Z = 5.064, p<0.0001) and Symbol Digit Modality measures (Z = 5.221, p<0.0001). CONCLUSIONS: Overall, men and women did not demonstrate differences in clinical motor features early in the course of PD. However, the differences observed in non-motor cognitive symptoms suggests further assessment of the influence of sex on non-motor symptoms in later stages of PD is warranted.

Parkinson's disease severity and use of dopaminergic medications.

BACKGROUND: The effects of dopaminergic therapy in parkinson's disease (PD) can vary depending on the class of medication selected. OBJECTIVE: The aim of this post hoc study was to determine if the class of dopaminergic therapy correlated with disease severity in persons with early, treated PD. METHODS: A non-parametric global statistical test (GST) was used to assess the status of participants treated with dopamine agonist (DA) monotherapy, levodopa (LD) monotherapy or combined LD and DA therapy on multiple PD outcomes encompassing motor, cognitive, psychiatric and autonomic function, as well as disability and quality of life. RESULTS: The outcomes measured at the beginning of the study showed lower disease burden for participants on initial DA monotherapy compared to those taking combined LD and DA therapy after controlling for age, education, taking cog-meds and amantadine. CONCLUSION: This observation suggests that clinicians treating early PD patients favor combined LD and DA therapy in patients with more disabling features over DA monotherapy. As such, studies of PD progression in treated PD patients may be affected by the class of symptomatic dopaminergic therapy.

Transcriptome analysis of a tau overexpression model in rats implicates an early pro-inflammatory response.

Neurofibrillary tangles comprised of the microtubule-associated protein tau are pathological features of Alzheimer's disease and several other neurodegenerative diseases, such as progressive supranuclear palsy. We previously overexpressed tau in the substantia nigra of rats and mimicked some of the neurodegenerative sequelae that occur in humans such as tangle formation, loss of dopamine neurons, and microgliosis. To study molecular changes involved in the tau-induced disease state, we used DNA microarrays at an early stage of the disease process. A range of adeno-associated virus (AAV9) vector doses for tau were injected in groups of rats with a survival interval of 2 weeks. Specific decreases in messages for dopamine-related genes validated the technique with respect to the dopaminergic cell loss observed. Of the mRNAs upregulated, there was a dose-dependent effect on multiple genes involved in immune response such as chemokines, interferon-inducible genes and leukocyte markers, only in the tau vector groups and not in dose-matched controls of either transgene-less empty vector or control green fluorescent protein vector. Histological staining for dopamine neurons and microglia matched the loss of dopaminergic markers and upregulation of immune response mRNAs in the microarray data, respectively. RT-PCR for selected markers confirmed the microarray results, with similar changes found by either technique. The mRNA data correlate well with previous findings, and underscore microgliosis and immune response in the degenerative process following tau overexpression.

Efficient neuronal gene transfer with AAV8 leads to neurotoxic levels of tau or green fluorescent proteins.

Adeno-associated virus (AAV) serotype 8 appears to be the strongest of the natural serotypes reported to date for gene transfer in liver and muscle. In this study, we evaluated AAV8 in the brain by several methods, including biophotonic imaging of green fluorescent protein (GFP). In the adult rat hippocampus, levels of GFP expressed were clearly greater with AAV8 than with AAV2 or AAV5 by Western blot and biophotonic imaging and slightly but significantly greater than AAV1 by Western blot. In the substantia nigra, the GFP expression conferred by AAV8 was toxic to dopamine neurons, although toxicity could be avoided with dose titration. At the low dose at which there was no GFP toxicity from the GFP vector, another AAV8 vector for a disease-related (P301L) form of the microtubule-associated protein tau caused a 78% loss of dopamine neurons and significant amphetamine-stimulated rotational behavior. The AAV8 tau vector-induced cell loss was greater than that from AAV2 or AAV5 tau vectors, demonstrating that the increased gene transfer was functional. While the toxicity observed with GFP expression warrants great caution, the efficient AAV8 is promising for animal models of neurodegenerative diseases and potentially as well for gene therapy of brain diseases.