Neurodegenerative Parkinsonian Disorders Research Articles

Neuropathological findings and in vivo imaging correlates of the red nucleus compared to those of the substantia nigra pars compacta in parkinsonisms

IntroductionThe substantia nigra pars compacta (SNc) is the key pathologic locus in neurodegenerative parkinsonian disorders. Recently, in vivo susceptibility MRI metrics were associated with postmortem glial cell density and tau burden in the SNc of parkinsonism subjects. This study investigated the red nucleus (RN), another iron-rich region adjacent to the SNc and a potential site of higher functionality in parkinsonisms. MethodsIn vivo MRI and postmortem data were obtained from 34 parkinsonism subjects and 3 controls. Neuron density, glial cell density, and percentages of area occupied by α-synuclein and tau were quantified using digitized midbrain slides. R2* and quantitative susceptibility mapping (QSM) metrics in the RN and SNc were derived from multi-gradient echo images. Histopathology data were compared between the RN and SNc using paired t-tests. MRI-histology associations were analyzed using partial Pearson correlations. ResultsThe RN had greater neuron (t23 = 3.169, P = 0.004) and glial cell densities (t23 = 2.407, P = 0.025) than the SNc, whereas the SNc had greater α-synuclein (t28 = 4.614, P < 0.0001) and tau burden (t24 = 4.513, P = 0.0001). In both the RN (R2*: r = 0.47, P = 0.043; QSM: r = 0.52, P = 0.024) and SNc (R2*: r = 0.57, P = 0.01; QSM: r = 0.58, P = 0.009), MRI values were associated with glial cell density but not neuron density or α-synuclein (Ps > 0.092). QSM associated with tau burden (r = 0.49, P = 0.038) in the SNc, but not the RN. ConclusionsThe RN is resilient to parkinsonian-related pathological processes compared to the SNc, and susceptibility MRI captured glial cell density in both regions. These findings help to further our understanding of the underlying pathophysiological processes in parkinsonisms.

Effects of medication on dopamine transporter imaging using [123I]I-FP-CIT SPECT in routine practice.

Dopamine transporter (DAT) imaging is used to support the diagnosis of neurodegenerative parkinsonian disorders. Specific medications have been reported to confound the interpretation of[123I]I-FP-CIT SPECT scans, but there is limited data. The aim of the current study is to identify potential medication effects on the interpretation of[123I]I-FP-CIT SPECT scans in routine practice. Consecutive patients undergoing a[123I]I-FP-CIT SPECT/CT scan on a 360° CZT camera between September 2019 and December 2022 were included. An exhaustive review of patient medications (antidepressants, antipsychotics, anti-epileptics, anti-parkinsonians, benzodiazepines, lithium, opioids, and stimulants) was performed. Two experienced nuclear physicians, blinded to the medication reports, interpreted the[123I]I-FP-CIT SPECT scans visually and a semi-quantitative analysis was performed using a local normal database. The study included 305 patients (71.0 ± 10.4, 135 women) and 145 (47.5%) visually interpreted normal scans. In normal scans, the striatum/occiput radioligand uptake ratio was decreased by noradrenergic and specific serotonergic antidepressants (NASSAs) (n = 15, z-score of - 0.93) and opioid medication (tramadol, n = 6, z-score of - 0.85) and was associated with a younger age in the multivariate analysis. In the overall population, the striatum/occiput ratio was influenced by NASSAs and associated with consensual visual analysis, age, sex, and anti-parkinsonian medications related to the status of the disease. Our study confirms the potential impact of antidepressant (NASSA) and opioid (tramadol) medications on the semi-quantitative analysis of[123I]I-FP-CIT SPECT scans. However, when performing a visual analysis, only NASSAs significantly impacted the interpretation of[123I]I-FP-CIT SPECT scans.

Metabolic network alterations as a supportive biomarker in dementia with Lewy bodies with preserved dopamine transmission.

Metabolic network analysis of FDG-PET utilizes an index of inter-regional correlation of resting state glucose metabolism and has been proven to provide complementary information regarding the disease process in parkinsonian syndromes. The goals of this study were (i) to evaluate pattern similarities of glucose metabolism and network connectivity in dementia with Lewy bodies (DLB) subjects with subthreshold dopaminergic loss compared to advanced disease stages and to (ii) investigate metabolic network alterations of FDG-PET for discrimination of patients with early DLB from other neurodegenerative disorders (Alzheimer's disease, Parkinson's disease, multiple system atrophy) at individual patient level via principal component analysis (PCA). FDG-PETs of subjects with probable or possible DLB (n = 22) without significant dopamine deficiency (z-score < 2 in putamen binding loss on DaT-SPECT compared to healthy controls (HC)) were scaled by global-mean, prior to volume-of-interest-based analyses of relative glucose metabolism. Single region metabolic changes and network connectivity changes were compared against HC (n = 23) and against DLB subjects with significant dopamine deficiency (n = 86). PCA was applied to test discrimination of patients with DLB from disease controls (n = 101) at individual patient level. Similar patterns of hypo- (parietal- and occipital cortex) and hypermetabolism (basal ganglia, limbic system, motor cortices) were observed in DLB patients with and without significant dopamine deficiency when compared to HC. Metabolic connectivity alterations correlated between DLB patients with and without significant dopamine deficiency (R2 = 0.597, p < 0.01). A PCA trained by DLB patients with dopamine deficiency and HC discriminated DLB patients without significant dopaminergic loss from other neurodegenerative parkinsonian disorders at individual patient level (area-under-the-curve (AUC): 0.912). Disease-specific patterns of altered glucose metabolism and altered metabolic networks are present in DLB subjects without significant dopaminergic loss. Metabolic network alterations in FDG-PET can act as a supporting biomarker in the subgroup of DLB patients without significant dopaminergic loss at symptoms onset.

Cross species systems biology discovers glial DDR2, STOM, and KANK2 as therapeutic targets in progressive supranuclear palsy

Progressive supranuclear palsy (PSP) is a neurodegenerative parkinsonian disorder characterized by cell-type-specific tau lesions in neurons and glia. Prior work uncovered transcriptome changes in human PSP brains, although their cell-specificity is unknown. Further, systematic data integration and experimental validation platforms to prioritize brain transcriptional perturbations as therapeutic targets in PSP are currently lacking. In this study, we combine bulk tissue (n = 408) and single nucleus RNAseq (n = 34) data from PSP and control brains with transcriptome data from a mouse tauopathy and experimental validations in Drosophila tau models for systematic discovery of high-confidence expression changes in PSP with therapeutic potential. We discover, replicate, and annotate thousands of differentially expressed genes in PSP, many of which reside in glia-enriched co-expression modules and cells. We prioritize DDR2, STOM, and KANK2 as promising therapeutic targets in PSP with striking cross-species validations. We share our findings and data via our interactive application tool PSP RNAseq Atlas (https://rtools.mayo.edu/PSP_RNAseq_Atlas/). Our findings reveal robust glial transcriptome changes in PSP, provide a cross-species systems biology approach, and a tool for therapeutic target discoveries in PSP with potential application in other neurodegenerative diseases.

FDG PET in the differential diagnosis of degenerative parkinsonian disorders: usefulness of voxel-based analysis in clinical practice

BackgroundThe early differential diagnosis among neurodegenerative parkinsonian disorders becomes essential to set up the correct clinical-therapeutic approach. The increased utilization of [18F] fluoro-deoxy-glucose positron emission tomography (FDG PET) and the pressure for cost-effectiveness request a systematic evaluation and a validation of its utility in clinical practice. This retrospective study aims to consider the contribution, in terms of increasing accuracy and increasing diagnostic confidence, of voxel-based FDG PET analyses in the differential diagnosis of these disorders, including Parkinson’s disease, multiple system atrophy, progressive supranuclear palsy, and cortico-basal syndrome.MethodEighty-three subjects with a clinically confirmed diagnosis of degenerative parkinsonian disorders who underwent FDG brain PET/CT were selected. A voxel-based analysis was set up using statistical parametric mapping (SPM) on MATLAB to produce maps of brain hypometabolism and relative hypermetabolism. Four nuclear physicians (two expert and two not expert), blinded to the patients’ symptoms, other physicians’ evaluations, and final clinical diagnosis, independently evaluated all data by visual assessment and by adopting metabolic maps.ResultsIn not-expert evaluators, the support of both hypometabolism and hypermetabolism maps results in a significant increase in diagnostic accuracy as well as clinical confidence. In expert evaluators, the increase in accuracy and in diagnostic confidence is mainly supported by hypometabolism maps alone.ConclusionsIn this study, we demonstrated the additional value of combining voxel-based analyses with qualitative assessment of brain PET images. Moreover, maps of relative hypermetabolism can also make their contribution in clinical practice, particularly for less experienced evaluators.

Understanding the transcriptional (dys)regulation in progressive supranuclear palsy

Progressive Supranuclear Palsy (PSP) is an incurable, neurodegenerative parkinsonian disorder characterized by tau proteinopathy in multiple brain cell types. We previously reported global gene expression changes associated with neuropathologic endophenotypes in PSP. In this study, we expanded this work to brain RNA sequence (RNAseq) transcriptome data from two independent cohorts and assessed both bulk and analytically deconvoluted transcriptome integrated with other omics data from humans and mice to discover dysregulated genes and networks in PSP. Transcriptome was measured in 408 temporal cortex samples from two independent cohorts of PSP and control brains, all of which had quantitative neuropathology scores. Differentially expressed genes (DEG) were identified using both bulk and analytically deconvoluted transcriptome for each brain cell type. Weighted Gene Co-expression Network Analysis (WGCNA) was used to construct modules, which were annotated for enrichment of Gene Ontology terms and cell type markers. We sought validations using a multitude of complementary datasets, including PSP GWAS, eQTL, proteome data and tau transgenic mouse models. There were 22,560 genes detected in both cohorts of which 1,709 were significantly differentially expressed. Among the DEGs, 721 genes also had nominal associations with one or more neuropathology endophenotypes. Additionally, 104 of the bulk DEGs were also differentially expressed in one of the brain cell types, i.e. were cell-intrinsic DEGs (CI-DEGs). There were 23 co-expression network modules, 10 of which were enriched for brain cell type markers; 8 of these also demonstrated enrichment of CI-DEGs of the corresponding cell-type. Importantly, 3 of these 8 modules also associated with PSP diagnosis. The most significant modules were enriched for oligodendrocyte and astrocyte genes and CI-DEGs. Most notably, we identified one module with enrichment of oligodendrocyte gene markers that are likewise downregulated in PSP. This module was also enriched with myelin gene expression changes identified in oligodendrocyte CI-DEGs. The expression profile of PSP brain changes in a cell-specific manner. Astrocyte and oligodendrocyte gene expression appears most impacted in PSP. Our findings implicate novel genes and pathways which underlie disease risk and neuropathology in PSP and may serve as novel therapeutic and biomarker targets.

Latent trait modeling of tau neuropathology in progressive supranuclear palsy

Progressive supranuclear palsy (PSP) is the second most common neurodegenerative Parkinsonian disorder after Parkinson’s disease, and is characterized as a primary tauopathy. Leveraging the considerable clinical and neuropathologic heterogeneity associated with PSP, we measured tau neuropathology as quantitative traits to perform a genome-wide association study (GWAS) within PSP to identify genes and biological pathways that underlie the PSP disease process. In 882 PSP cases, semi-quantitative scores for phosphorylated tau-immunoreactive coiled bodies (CBs), neurofibrillary tangles (NFTs), tufted astrocytes (TAs), and tau threads were documented from 18 brain regions, and converted to latent trait (LT) variables using the R ltm package. LT analysis utilizes a multivariate regression model that links categorical responses to unobserved covariates allowing for a reduction of dimensionality, generating a single, continuous variable to account for the multiple lesions and brain regions assessed. We first tested for association with PSP LTs and the top PSP GWAS susceptibility loci. Significant SNP/LT associations were identified at rs242557 (MAPT H1c sub-haplotype) with hindbrain CBs and rs1768208 (MOBP) with forebrain tau threads. Digital microscopy was employed to quantify phosphorylated tau burden in midbrain tectum and red nucleus in 795 PSP cases and tau burdens were used as quantitative phenotypes in GWAS. Top associations were identified at rs1768208 with midbrain tectum and red nucleus tau burden. Additionally, we performed a PSP LT GWAS on an initial cohort, a follow-up SNP panel (37 SNPs, P < 10–5) in an extended cohort, and a combined analysis. Top SNP/LT associations were identified at SNPs in or near SPTBN5/EHD4, SEC13/ATP2B2, EPHB1/PPP2R3A, TBC1D8, IFNGR1/OLIG3, ST6GAL1, HK1, CALB1, and SGCZ. Finally, testing for SNP/transcript associations using whole transcriptome and whole genome data identified significant expression quantitative trait loci at rs3088159/SPTBN5/EHD4 and rs154239/GHRL. Modeling tau neuropathology heterogeneity using LTs as quantitative phenotypes in a GWAS may provide substantial insight into biological pathways involved in PSP by affecting regional tau burden.

A novel diagnostic marker for progressive supranuclear palsy targeting atrophy of the subthalamic nucleus

IntroductionDespite great progress in radiological diagnostic tools for neurodegenerative disorders, their diagnostic accuracy has been unsatisfactory. One of the pathological hallmarks of progressive supranuclear palsy (PSP) is atrophy of the subthalamic nucleus, which has not attracted much attention for imaging analysis. MethodsThe clinical data of patients with PSP, multiple system atrophy (MSA), Parkinson's disease (PD), and corticobasal syndrome (CBS) who underwent brain magnetic resonance imaging at our department between June 2019 and March 2020 were retrospectively reviewed. The volumes of the subthalamic nucleus and of the whole cerebrum were then analyzed and compared among the disorders. ResultsFourteen PSP-Richardson syndrome (RS), 14 MSA, 14 PD, and 8 CBS patients were assessed. The mean volume of the bilateral subthalamic nuclei was smaller in PSP patients (0.148 ± 0.012 cm3) than in MSA (0.183 ± 0.026 cm3; p < 0.001), PD (0.209 ± 0.031 cm3; p < 0.001), and CBS (0.180 ± 0.056 cm3; p < 0.001) patients. The volume of the whole cerebrum was not significantly different among the disorders. Using an STN volume cut-off of 0.01925, the sensitivity and specificity for differential diagnosis between PSP and the other disorders were 0.846 and 0.972, respectively. ConclusionSubthalamic nucleus volume may be a useful diagnostic marker for PSP; it may easily differentiate it from other neurodegenerative parkinsonian disorders.

End of life planning in parkinsonian diseases

IntroductionThe utilization of advance directives in individuals with Parkinson's disease (PD) and atypical parkinsonian disorders (APD) and their caregivers requires further investigation. This study determined the utilization rates of four forms of advance directives: living will, durable power of attorney, durable power of attorney for healthcare, and medical orders in these individuals. We hypothesized that having a neurodegenerative parkinsonian disorder or exposure to these disorders would increase the likelihood of having advance directives. Methods50 PD participants, 49 APD participants, 50 caregivers and 50 non-caregiver controls were surveyed regarding advance directives. ResultsThe median number of advance directives was 1 in controls, 2 in caregivers and PD participants and 3 in APD participants. Patients with PD were 4.08 times more likely to have durable power of attorney (p < 0.001) and 2.08 times more likely to have durable power of attorney for healthcare (p = 0.011) than controls. Patients with APD were 1.66 times more likely to have a living will (p = 0.006), 4.81 times more likely to have a durable power of attorney (p < 0.001) and 2.47 times more likely to have a durable power of attorney for healthcare (p = 0.003) than controls. Caregivers were1.58 times more likely to have a living will (p = 0.012) and 2.21 times more likely to have a durable power of attorney for healthcare than controls. ConclusionHaving or being exposed to parkinsonian disorders significantly increases the likelihood of utilizing advance directives. Additionally, exposure to a parkinsonian disorder as a caregiver increases advance directive use.

Exploring bedside clinical features of parkinsonism: A focus on differential diagnosis

The proper diagnosis of parkinsonian disorders usually involves three steps: identifying core features of parkinsonism; excluding other causes; and collating supportive evidence based on clinical signs or investigations. While the recognition of cardinal parkinsonian features is usually straightforward, the appreciation of clinical features suggestive of specific parkinsonian disorders can be challenging, and often requires greater experience and skills. In this review, we outline the clinical features that are relevant to the differential diagnosis of common neurodegenerative parkinsonian disorders, including Parkinson's disease, multiple system atrophy, progressive supranuclear palsy, and corticobasal degeneration. We aim to make this process relatable to clinicians-in-practice, therefore, have categorised the list of clinical features into groups according to the typical sequence on how clinicians would elicit them during the examination, starting with observation of facial expression and clinical signs of the face, spotting eye movement abnormalities, examination of tremors and jerky limb movements, and finally, examination of posture and gait dysfunction. This review is not intended to be comprehensive. Rather, we have focused on the most common clinical signs that are potentially key to making the correct diagnosis and those that do not require special skills or training for interpretation. Evidence is also provided, where available, such as diagnostic criteria, consensus statements, clinicopathological studies or large multi-centre registries. Pitfalls are also discussed when relevant to the diagnosis. While no clinical signs are pathognomonic for certain parkinsonian disorders, certain clinical clues may assist in narrowing a differential diagnosis and tailoring focused investigations for the individual patient.

Divergent brain gene expression patterns associate with distinct cell-specific tau neuropathology traits in progressive supranuclear palsy

Progressive supranuclear palsy (PSP) is a neurodegenerative parkinsonian disorder characterized by tau pathology in neurons and glial cells. Transcriptional regulation has been implicated as a potential mechanism in conferring disease risk and neuropathology for some PSP genetic risk variants. However, the role of transcriptional changes as potential drivers of distinct cell-specific tau lesions has not been explored. In this study, we integrated brain gene expression measurements, quantitative neuropathology traits and genome-wide genotypes from 268 autopsy-confirmed PSP patients to identify transcriptional associations with unique cell-specific tau pathologies. We provide individual transcript and transcriptional network associations for quantitative oligodendroglial (coiled bodies = CB), neuronal (neurofibrillary tangles = NFT), astrocytic (tufted astrocytes = TA) tau pathology, and tau threads and genomic annotations of these findings. We identified divergent patterns of transcriptional associations for the distinct tau lesions, with the neuronal and astrocytic neuropathologies being the most different. We determined that NFT are positively associated with a brain co-expression network enriched for synaptic and PSP candidate risk genes, whereas TA are positively associated with a microglial gene-enriched immune network. In contrast, TA is negatively associated with synaptic and NFT with immune system transcripts. Our findings have implications for the diverse molecular mechanisms that underlie cell-specific vulnerability and disease risk in PSP.

MR planimetry in neurodegenerative parkinsonism yields high diagnostic accuracy for PSP

IntroductionSeveral previous studies examined different brainstem-derived MR planimetric measures with regards to their diagnostic accuracy in separating patients with neurodegenerative parkinsonian disorders and reported conflicting results. The current study aimed to compare their performance in a well-characterized sample of patients with neurodegenerative parkinsonian disorders. MethodsMR planimetric measurements were assessed in a large retrospective cohort of 55 progressive supranuclear palsy (PSP), 194 Parkinson's disease (PD) and 63 multiple system atrophy (MSA) patients. This cohort served as a training set used to build C4.5 decision tree models to discriminate PSP, PD and MSA. The models were validated in two independent test sets. The first test set comprised 84 patients with early, clinically unclassifiable parkinsonism (CUP). A prospective cohort of patients with PSP (n = 23), PD (n = 40) and MSA (n = 22) was exploited as a second test-set. ResultsThe pons-to-midbrain diameter ratio, the midbrain diameter, the middle cerebellar peduncle width and the pons area were identified as the most predictive parameters to separate PSP, MSA and PD in C4.5 decision tree models derived from the training set. Using these decision models, AUCs in discriminating PSP, MSA and PD were 0.90, 0.57 and 0.73 in the CUP-cohort and 0.95, 0.61 and 0.87 in the prospective cohort, respectively. ConclusionWe were able to demonstrate that brainstem-derived MR planimetric measures yield high diagnostic accuracy for the discrimination of PSP from related disorders when decision tree algorithms are applied, even at early, clinically uncertain stages. However, their diagnostic accuracy in discriminating PD and MSA was suboptimal.

State of the art neuroimaging in neurodegenerative Parkinsonian disorders: The role of structural MRI

State of the art neuroimaging in neurodegenerative Parkinsonian disorders: The role of structural MRI

CONVERGENT ANALYSIS OF ENDOPHENOTYPES IN PROGRESSIVE SUPRANUCLEAR PALSY

Progressive Supranuclear palsy (PSP) is a neurodegenerative parkinsonian disorder pathologically characterized by the presence of neurofibrillary tangles (NFT) and tau-positive glial lesions: tufted astrocytes (TA) and oligodendroglial coiled bodies (CB). Transcriptional regulation has been implicated as a likely disease mechanism at some of the disease risk loci identified by a genome-wide association study (GWAS). Genome-wide expression quantitative trait locus (eQTL) studies in the brains of PSP subjects, when combined with additional endophenotypes, may identify novel disease genes with an implied mechanism of action, important for future therapeutic targeting. Gene expression profiles were collected from temporal cortex for 2 cohorts of PSP samples (N: Cohort A =175, Cohort B = 106), using the Illumina Whole-Genome DASL assay (WG-DASL). All subjects had available GWAS genotypes from one of two platforms (Illumina Human Hap300 or Illumina Human 660W-Quad). Probes that were detected in > 50% of the subjects were assessed. Cis-eQTL (gene +/-100kb) analysis was implemented in PLINK using linear regression, including appropriate covariates. Meta-analysis was performed using METAL. 43 subjects from expression cohort A also have DNA methylation measures collected using reduced representation bisulfite sequencing (RRBS). Neuropathological measures for the following four lesions: NFT, CB, TA and tau neuropil threads (TAUTH) are available for 251 of the subjects with expression measures. The two expression cohorts had a total of 424,102 SNP-probe pairs in common (177,685 SNPs in-cis (+/-100kb) with 11,705 genes targeted using 14,880 probes). Meta-analysis identified 1,433 SNP probe pairs (341 unique genes) with a p-value < 1E-08. Gene Ontology enrichment analysis determined a significant enrichment of these genes within glutathione metabolism pathways (Bonferonni-adjusted p-value < 0.05). Additionally the PSP candidate gene MOBP, nominated by disease GWAS, has multiple cis-SNPs with a p<1E-08. We are pursuing the eQTL identified in this study for association with DNA methylation measures, neuropathological traits and linking these results to those of the PSP risk GWAS to identify significant eQTL enriched for PSP relevant variants. These studies will nominate regulatory genetic changes as the potential culprit for some of the PSP risk loci and can uncover novel biological pathways implicated in PSP.

Quetiapine for Psychosis in Parkinson Disease and Neurodegenerative Parkinsonian Disorders: A Systematic Review.

We performed a systematic review of randomized controlled trials to assess the high-level evidence regarding the role of quetiapine in the treatment of psychosis in patients with neurodegenerative parkinsonian disorders. Studies were included in the qualitative review if they (1) enrolled participants with diagnosis of Parkinson disease, Lewy body dementia, or any other neurodegenerative parkinsonian disorders; (2) assessed the efficacy of quetiapine; and (3) evaluated psychotic and motor outcomes using validated tools. Of the 341 manuscripts identified, 7 studies fulfilled our inclusion criteria. The studies' risk of bias was considered low. A total of 241 participants enrolled in these trials. Heterogeneity was high due to inclusion criteria, user definitions, assessment tools, and study design. Although not causing any motor deterioration, quetiapine failed to significantly reduce psychotic symptoms compared to placebo when objectively assessed on the Brief Psychotic Rating Scale, the most frequently reported scale in these studies. High loss to follow-up and dropout rates as well as significant improvement in psychotic symptoms in the placebo groups may have affected measurements of possible positive medication effects.

Imaging Striatal Microglial Activation in Patients with Parkinson's Disease.

This study investigated whether the second-generation translocator protein 18kDa (TSPO) radioligand, [18F]-FEPPA, could be used in neurodegenerative parkinsonian disorders as a biomarker for detecting neuroinflammation in the striatum. Neuroinflammation has been implicated as a potential mechanism for the progression of Parkinson’s disease (PD). Positron Emission Tomography (PET) radioligand targeting for TSPO allows for the quantification of neuroinflammation in vivo. Based on genotype of the rs6791 polymorphism in the TSPO gene, 16 mixed-affinity binders (MABs) (8 PD and age-matched 8 healthy controls (HCs)), 16 high-affinity binders (HABs) (8 PD and age-matched 8 HCs) and 4 low-affinity binders (LABs) (3 PD and 1 HCs) were identified. Total distribution volume (VT) values in the striatum were derived from a two-tissue compartment model with arterial plasma as an input function. There was a significant main effect of genotype on [18F]-FEPPA VT values in the caudate nucleus (p = 0.001) and putamen (p < 0.001), but no main effect of disease or disease x genotype interaction in either ROI. In the HAB group, the percentage difference between PD and HC was 16% in both caudate nucleus and putamen; in the MAB group, it was -8% and 3%, respectively. While this PET study showed no evidence of increased striatal TSPO expression in PD patients, the current findings provide some insights on the possible interactions between rs6791 polymorphism and neuroinflammation in PD.

Dorsolateral nigral hyperintensity on 3.0T susceptibility-weighted imaging in neurodegenerative Parkinsonism.

Absence of a hyperintense, ovoid area within the dorsolateral border of the otherwise hypointense pars compacta of the substantia nigra (referred to as dorsolateral nigral hyperintensity) on iron-sensitive high-field magnetic resonance imaging sequences seems to be a typical finding for patients with Parkinson's disease (PD). This study was undertaken to evaluate the diagnostic value of the dorsolateral nigral hyperintensity in a cohort of patients with neurodegenerative parkinsonism including PD, multiple system atrophy (MSA), and progressive supranuclear palsy (PSP) as well as healthy controls using high-field susceptibility-weighted imaging (SWI) at 3.0 Tesla (T). Absence of dorsolateral nigral hyperintensity was assessed on visual inspection of anonymized 3.0T SWI scans in a case-control study including 148 patients with neurodegenerative parkinsonism (PD: n = 104; MSA: n = 22; PSP: n = 22) and 42 healthy controls. Dorsolateral nigral hyperintensity was absent unilaterally in all patients with MSA or PSP, in 83 of 90 patients with PD, but only in one of the healthy controls resulting in an overall correct classification of 95.2% in discriminating neurodegenerative parkinsonism from controls in the per-protocol analysis. Overall correct classification was 93.2% in the intent-to-diagnose analysis, including also SWI scans with poor quality (12.1% of all scans) for nigral evaluation. Visual assessment of dorsolateral nigral hyperintensity on high-field SWI scans may serve as a new simple diagnostic imaging marker for neurodegenerative parkinsonian disorders.

Imaging Dopamine Transporters in Parkinson‘s Disease

The dopamine transporter (DAT) is responsible for clearance of dopamine from the synaptic cleft after its release. Imaging DAT availability provides a measure of dopamine terminal function and a method for detecting striatal dopamine deficiency states present in idiopathic Parkinson's disease and atypical neurodegenerative Parkinsonian disorders such as multiple system atrophy and progressive supranuclear palsy. DAT imaging with PET or single photon emission computed tomography can be used to support a diagnosis of dopamine-deficient parkinsonism in cases where this is suspected and rationalize the use of dopaminergic agents as therapy. It can also detect subclinical dopaminergic dysfunction when present in subjects at risk of Parkinson's disease, such as relatives of patients, susceptibility gene mutation carriers, and subjects with late-onset hyposmia or sleep disorders. Finally, the presence of normal DAT availability on imaging can help exclude nondopamine-deficient syndromes, such as dystonic and severe essential tremors, drug-induced and psychogenic parkinsonism that, on occasion, mimic Parkinson's disease.

Potential of advanced MR imaging techniques in the differential diagnosis of parkinsonism

The clinical differentiation of parkinsonian syndromes remains challenging not only for neurologists but also for movement disorder specialists. Conventional magnetic resonance imaging (cMRI) with the visual assessment of T2- and T1-weighted imaging as well as different advanced MRI techniques offer objective measures, which may be a useful tool in the diagnostic work-up of Parkinson's disease and atypical parkinsonian disorders (APDs). In clinical practice, cMRI is a well-established method for the exclusion of symptomatic parkinsonism due to other pathologies. Over the past two decades, abnormalities in the basal ganglia and infratentorial structures have been shown especially in APDs not only by cMRI but also by different advanced MRI techniques, including methods to assess regional cerebral atrophy quantitatively such as magnetic resonance volumetry, proton magnetic resonance spectroscopy, diffusion-weighted imaging, and magnetization transfer imaging. This article aims to review recent research findings on the role of advanced MRI techniques in the differential diagnosis of neurodegenerative parkinsonian disorders.

A case of corticobasal degeneration presenting with alien limb syndrome

Alien limb syndrome (ALS) is a very rare condition where the affected persons are not able to recognise the affected limb as their own, and regard it as being foreign or alien to them. We present a patient with ALS secondary to corticobasal degeneration, which is a rare neurodegenerative parkinsonian disorder. We discuss the clinical features, neuropathology and management of corticobasal degeneration.