Nikolaus R. McFarland

The Place of the Thalamus in Frontal Cortical-Basal Ganglia Circuits

The thalamus has long been thought to convey subcortical information to the cortex. Indeed, models of basal ganglia function attribute the primary role for the thalamus to a simple relay of information processed in the basal ganglia to the cortex. The thalamic nuclear groups that are associated primarily with this function are the ventral anterior and ventral lateral nuclei and the mediodorsal thalamic nucleus. However, recent studies have shown that the corticothalamic projection is important for the dynamics of the thalamo-cortical processing. Furthermore, the relay nuclei that carry basal ganglia output to the cortex have recently been shown to project back to the basal ganglia directly. These two recent developments indicate a more dynamic role for the thalamus in basal ganglia information processing than a passive relay.

α-Synuclein S129 Phosphorylation Mutants Do Not Alter Nigrostriatal Toxicity in a Rat Model of Parkinson Disease

Lewy bodies are found in Parkinson disease and related disorders and are extensively phosphorylated at Ser-129 (S129), but whether S129 phosphorylation mediates &agr;-synuclein aggregation and neurotoxicity has been controversial. We used recombinant adeno-associated virus to overexpress &agr;-synuclein in the rat nigrostriatal system. Rats were injected with recombinant adeno-associated virus 2/8 expressing either human wild-type (wt) or mutant &agr;-synuclein with S129 replaced by alanine (S129A) or aspartate (S129D). Contralateral substantia nigra injections containing empty vector served as controls. Both wt and S129 mutants resulted in significant dopaminergic cell loss in the recipients by 6 weeks, but there were only small decreases in nigrostriatal terminal density and tyrosine hydroxylase expression. There were no significant differences in dopaminergic cell loss, nigrostriatal terminal density, or tyrosine hydroxylase expression among the wt and S129 mutants. Furthermore, we did not observe any differences in &agr;-synuclein aggregate formation or distribution among wt and either S129 mutant. These findings contrast with those from previous studies and suggest that injections of both S129 phosphorylation mutants result in dopaminergic neurotoxicity similar to wt injections. Further study is needed to clarify the effects of these S129 mutants and &agr;-synuclein phosphorylation in mammalian systems.

Comparison of transduction efficiency of recombinant AAV serotypes 1, 2, 5, and 8 in the rat nigrostriatal system

J. Neurochem. (2009) 109, 838–845.

Free-water imaging in Parkinson’s disease and atypical parkinsonism

Conventional single tensor diffusion analysis models have provided mixed findings in the substantia nigra of Parkinsons disease, but recent work using a bi-tensor analysis model has shown more promising results. Using a bi-tensor model, free-water values were found to be increased in the posterior substantia nigra of Parkinsons disease compared with controls at a single site and in a multi-site cohort. Further, free-water increased longitudinally over 1 year in the posterior substantia nigra of Parkinsons disease. Here, we test the hypothesis that other parkinsonian disorders such as multiple system atrophy and progressive supranuclear palsy have elevated free-water in the substantia nigra. Equally important, however, is whether the bi-tensor diffusion model is able to detect alterations in other brain regions beyond the substantia nigra in Parkinsons disease, multiple system atrophy, and progressive supranuclear palsy and to accurately distinguish between these diseases. Free-water and free-water-corrected fractional anisotropy maps were compared across 72 individuals in the basal ganglia, midbrain, thalamus, dentate nucleus, cerebellar peduncles, cerebellar vermis and lobules V and VI, and corpus callosum. Compared with controls, free-water was increased in the anterior and posterior substantia nigra of Parkinsons disease, multiple system atrophy, and progressive supranuclear palsy. Despite no other changes in Parkinsons disease, we observed elevated free-water in all regions except the dentate nucleus, subthalamic nucleus, and corpus callosum of multiple system atrophy, and in all regions examined for progressive supranuclear palsy. Compared with controls, free-water-corrected fractional anisotropy values were increased for multiple system atrophy in the putamen and caudate, and increased for progressive supranuclear palsy in the putamen, caudate, thalamus, and vermis, and decreased in the superior cerebellar peduncle and corpus callosum. For all disease group comparisons, the support vector machine 10-fold cross-validation area under the curve was between 0.93-1.00 and there was high sensitivity and specificity. The regions and diffusion measures selected by the model varied across comparisons and are consistent with pathological studies. In conclusion, the current study used a novel bi-tensor diffusion analysis model to indicate that all forms of parkinsonism had elevated free-water in the substantia nigra. Beyond the substantia nigra, both multiple system atrophy and progressive supranuclear palsy, but not Parkinsons disease, showed a broad network of elevated free-water and altered free-water corrected fractional anisotropy that included the basal ganglia, thalamus, and cerebellum. These findings may be helpful in the differential diagnosis of parkinsonian disorders, and thereby facilitate the development and assessment of targeted therapies.

Interferon-γ induces progressive nigrostriatal degeneration and basal ganglia calcification

We found that CNS-directed expression of interferon-γ (IFN-γ) resulted in basal ganglia calcification, reminiscent of human idiopathic basal ganglia calcification (IBGC), and nigrostriatal degeneration. Our results indicate that IFN-γ mediates age-progressive nigrostriatal degeneration in the absence of exogenous stressors. Further study of this model may provide insight into selective nigrostriatal degeneration in human IBGC and other Parkinson syndromes.

Direct detection of alpha synuclein oligomers in vivo

BackgroundRat models of Parkinson’s disease are widely used to elucidate the mechanisms underlying disease etiology or to investigate therapeutic approaches. Models were developed using toxins such as MPTP or 6-OHDA to specifically target dopaminergic neurons resulting in acute neuronal loss in the substantia nigra or by using viral vectors to induce the specific and gradual expression of alpha synuclein in the substantia nigra. The detection of alpha- synuclein oligomers, the presumed toxic species, in these models and others has been possible using only indirect biochemical approaches to date. Here we coinjected AAVs encoding alpha-synuclein fused to the N- or C-terminal half of VenusYFP in rat substantia nigra pars compacta and describe for the first time a novel viral vector rodent model with the unique ability to directly detect and track alpha synuclein oligomers ex vivo and in vivo.ResultsViral coinjection resulted in widespread VenusYFP signal within the nigrostriatal pathway, including cell bodies in the substantia nigra and synaptic accumulation in striatal terminals, suggestive of in vivo alpha-synuclein oligomers formation. Transduced rats showed alpha-synuclein induced dopaminergic neuron loss in the substantia nigra, the appearance of dystrophic neurites, and gliosis in the striatum. Moreover, we have applied in vivo imaging techniques in the living mouse to directly image alpha-synuclein oligomers in the cortex.ConclusionWe have developed a unique animal model that provides a tool for the Parkinson’s disease research community with which to directly detect alpha- synuclein oligomers in vivo and screen therapeutic approaches targeting alpha-synuclein oligomers.

Distinct functional and macrostructural brain changes in Parkinson's disease and multiple system atrophy.

Parkinsons disease (PD) and the parkinsonian variant of multiple system atrophy (MSAp) are neurodegenerative disorders that can be difficult to differentiate clinically. This study provides the first characterization of the patterns of task‐related functional magnetic resonance imaging (fMRI) changes across the whole brain in MSAp. We used fMRI during a precision grip force task and also performed voxel‐based morphometry (VBM) on T1‐weighted images in MSAp patients, PD patients, and healthy controls. All groups were matched on age, and the patient groups had comparable motor symptom durations and severities. There were three main findings. First, MSAp and PD had reduced fMRI activation in motor control areas, including the basal ganglia, thalamus, insula, primary sensorimotor and prefrontal cortices, and cerebellum compared with controls. Second, there were no activation differences among the disease groups in the basal ganglia, thalamus, insula, or primary sensorimotor cortices, but PD had more extensive activation deficits throughout the cerebrum compared with MSAp and controls. Third, VBM revealed reduced volume in the basal ganglia, middle and inferior cerebellar peduncles, pons, and throughout the cerebrum in MSAp compared with controls and PD, and additionally throughout the cerebellar cortex and vermis in MSAp compared with controls. Collectively, these results provide the first evidence that fMRI activation is abnormal in the basal ganglia, cerebellum, and cerebrum in MSAp, and that a key distinguishing feature between MSAp and PD is the extensive and widespread volume loss throughout the brain in MSAp. Hum Brain Mapp 36:1165–1179, 2015.

Are selective serotonin reuptake inhibitors associated with greater apathy in Parkinson's disease?

Apathy is a common neuropsychiatric feature of Parkinsons disease (PD), but little is known of relationships between apathy and specific medications in PD. Following a retrospective database and chart review of 181 Parkinsons patients, relationships between Apathy Scale scores and use of psychotropic and antiparkinsonian medications were examined with multiple regression. Controlling for age, sex, education, and depression, the use of selective serotonin reuptake inhibitors (SSRIs), but not other antidepressants, was associated with greater apathy. Use of monoamine oxidase B inhibitors was associated with less apathy. Longitudinal studies are needed to evaluate a potential SSRI-induced apathy syndrome in PD.

Distinct patterns of brain activity in progressive supranuclear palsy and Parkinson's disease

The basal ganglia‐thalamo‐cortical and cerebello‐thalamo‐cortical circuits are important for motor control. Whether their functioning is affected in a similar or different way by progressive supranuclear palsy (PSP) and Parkinsons disease (PD) is not clear. A functional magnetic resonance imaging (fMRI) force production paradigm and voxel‐based morphometry were used to assess differences in brain activity and macrostructural volumes between PSP, PD, and healthy age‐matched controls. We found that PSP and PD share reduced functional activity of the basal ganglia and cortical motor areas, but this is more pronounced in PSP than in PD. In PSP the frontal regions are underactive, whereas the posterior parietal and occipital regions are overactive as compared with controls and PD. Furthermore, lobules I through IV, V, and VI of the cerebellum are hypoactive in PSP and PD, whereas Crus I and lobule IX are hyperactive in PSP only. Reductions in gray and white matter volume are specific to PSP. Finally, the functional status of the caudate as well as the volume of the superior frontal gyrus predict clinical gait and posture measures in PSP. PSP and PD share hypoactivity of the basal ganglia, motor cortex, and anterior cerebellum. These patients also display a unique pattern, such that anterior regions of the cortex are hypoactive and posterior regions of the cortex and cerebellum are hyperactive. Together, these findings suggest that specific structures within the basal ganglia, cortex, and cerebellum are affected differently in PSP relative to PD.

An eight-year clinic experience with clozapine use in a Parkinson's disease clinic setting.

Background To examine our eight year clinic-based experience in a Parkinson’s disease expert clinical care center using clozapine as a treatment for refractory psychosis in Parkinsons disease (PD). Methods The study was a retrospective chart review which covered eight years of clozapine registry use. Statistical T-tests, chi-square, correlations and regression analysis were used to analyze treatment response for potential associations of age, disease duration, and Hoehn & Yahr (H&Y) score, and degree of response to clozapine therapy. Results There were 36 participants included in the analysis (32 PD, 4 parkinsonism-plus). The characteristics included 30.6% female, age 45–87 years (mean 68.3±10.15), disease duration of 17–240 months (mean 108.14±51.13) and H&Y score of 2 to 4 (mean 2.51±0.51). The overall retention rate on clozapine was 41% and the most common reasons for discontinuation were frequent blood testing (28%), nursing home (NH) placement (11%) and leucopenia (8%). Responses to clozapine across the cohort were: complete (33%), partial (33%), absent (16%), and unknown (16%). Age (r = −0.36, p<0.01) and H&Y score (r = −0.41, p<0.01) were shown to be related to response to clozapine therapy, but disease duration was not an associated factor (r = 0.21, p>0.05). Conclusions This single-center experience highlights the challenges associated with clozapine therapy in PD psychosis. Frequent blood testing remains a significant barrier for clozapine, even in patients with therapeutic benefit. Surprisingly, all patients admitted to a NH discontinued clozapine due to logistical issues of administration and monitoring within that setting. Consideration of the barriers to clozapine therapy will be important to its use and to its continued success in an outpatient setting.