Atypical Parkinsonian Disorders Research Articles

MRI biomarkers of motor and non-motor symptoms in Parkinson's disease

Parkinson's disease is a heterogeneous disorder with both motor and non-motor symptoms that contribute to functional impairment. To develop effective, disease modifying treatments for these symptoms, biomarkers are necessary to detect neuropathological changes early in the disease course and monitor changes over time. Advances in MRI scan sequences and analytical techniques present numerous promising metrics to detect changes within the nigrostriatal system, implicated in the cardinal motor symptoms of the disease, and detect broader dysfunction involved in the non-motor symptoms, such as cognitive impairment. There is emerging evidence that iron sensitive, neuromelanin sensitive, diffusion sensitive, and resting state functional magnetic imaging measures can capture changes within the nigrostriatal system. Iron, neuromelanin, and diffusion sensitive measures demonstrate high specificity and sensitivity in distinguishing Parkinson's disease relative to controls, with inconsistent results differentiating Parkinson's disease relative to atypical parkinsonian disorders. They may also serve as useful monitoring biomarkers, with each possibly detecting different aspects of the disease course (early nigrosome changes versus broader substantia nigra changes). Investigations of non-motor symptoms, such as cognitive impairment, require careful consideration of the nature of cognitive deficits to characterize regional and network specific impairment. While the early, executive dysfunction observed is consistent with nigrostriatal degeneration, the memory and visuospatial impairments, the harbingers of a dementia process reflect dopaminergic independent dysfunction involving broader regions of the brain.

Segregation and potential functional impact of a rare stop-gain PABPC4L variant in familial atypical Parkinsonism

Atypical parkinsonian disorders (APDs) comprise a group of neurodegenerative diseases with heterogeneous clinical and pathological features. Most APDs are sporadic, but rare familial forms have also been reported. Epidemiological and post-mortem studies associated APDs with oxidative stress and cellular protein aggregates. Identifying molecular mechanisms that translate stress into toxic protein aggregation and neurodegeneration in APDs is an active area of research. Recently, ribonucleic acid (RNA) stress granule (SG) pathways were discussed to be pathogenically relevant in several neurodegenerative disorders including APDs. Using whole genome sequencing, mRNA expression analysis, transfection assays and cell imaging, we investigated the genetic and molecular basis of a familial neurodegenerative atypical parkinsonian disorder. We investigated a family with six living members in two generations exhibiting clinical symptoms consistent with atypical parkinsonism. Two affected family members suffered from parkinsonism that was associated with ataxia. Magnetic resonance imaging (MRI) of these patients showed brainstem and cerebellar atrophy. Whole genome sequencing identified a heterozygous stop-gain variant (c.C811T; p.R271X) in the Poly(A) binding protein, cytoplasmic 4-like (PABPC4L) gene, which co-segregated with the disease in the family. In situ hybridization showed that the murine pabpc4l is expressed in several brain regions and in particular in the cerebellum and brainstem. To determine the functional impact of the stop-gain variant in the PABPC4L gene, we investigated the subcellular localization of PABPC4L in heterologous cells. Wild-type PABPC4L protein localized predominantly to the cell nucleus, in contrast to the truncated protein encoded by the stop-gain variant p.R271X, which was found homogeneously throughout the cell. Interestingly, the wild-type, but not the truncated protein localized to RasGAP SH3 domain Binding Protein (G3BP)-labeled cytoplasmic granules in response to oxidative stress induction. This suggests that the PABPC4L variant alters intracellular distribution and possibly the stress granule associated function of the protein, which may underlie APD in this family. In conclusion, we present genetic and molecular evidence supporting the role of a stop-gain PABPC4L variant in a rare familial APD. Our data shows that the variant results in cellular mislocalization and inability of the protein to associate with stress granules.

Mutation analysis of LRP10 in Japanese patients with familial Parkinson's disease, progressive supranuclear palsy, and frontotemporal dementia

Mutations of the gene encoding low-density lipoprotein receptor–related protein 10 (LRP10) were recently detected in patients (heterogeneous races) with autosomal dominant inheritance of familial Parkinson's disease. The patients with Parkinson's disease, Parkinson's disease with dementia, and dementia with Lewy bodies whose brain pathology indicated deposit of alpha-synuclein along with the co-occurrence of tau pathology and amyloid-beta plaques presented LRP10 mutations. LRP10 is localized in the vesicular structures and trans-Golgi network; its alteration leads to alpha-synuclein aggregation. Thus, we conducted the genetic screening of LRP10 among 187 patients with familial Parkinson's disease and 19 patients with atypical parkinsonian disorders, including frontotemporal dementia, progressive supranuclear palsy, and corticobasal syndrome. There were no putative pathogenic variants among patients with Parkinson's disease. We detected one rare variant, p.D198N, in a patient with frontotemporal dementia, without a cosegregation study. Overall, our findings showed that LRP10 variants are not causative for disease in our cohort.

Posturographic abnormalities in ambulatory atypical parkinsonian disorders: Differentiating characteristics

BackgroundPostural instability is a common complaint in patients with Parkinson's disease (PD), multiple system atrophy (MSA) and progressive supranuclear palsy (PSP). However, objective evaluation to identify posturographic characteristics to enable clinical differentiation is limited. MethodPostural sway abnormalities in 35 atypical parkinsonian patients (19 PSP, 16 MSA), 35 matched PD patients, and healthy subjects were assessed under static posturography with eyes-open (EO) and eyes-closed (EC). ResultsWith EO, MSA patients showed a significantly greater mean ML sway than PD patients (p = 0.03), but with EC even more parameters were significantly different, including mean sway in both ML (p = 0.02) and AP directions (p = 0.01), sway area (p = 0.001), and sway path length (p = 0.003). While differences between MSA and PD were seen in both ML and AP directions, significant differences between PD and PSP were limited to greater mean ML sway (p = 0.01) with EO, greater mean (p = 0.002) and maximal AP sway (p = 0.02) amongst PSP patient with EC. Moderate and significant correlation was demonstrated between HY stage and mean AP sway amongst APD patients (r = 0.56, p < 0.01) and in PSP patients (r = 0.62, p < 0.01). ConclusionOur study identifies a number of objective sway measures assessed with EC that are potentially useful for clinical differentiation between APDs and PD. In comparison to PD, MSA showed greater sway area and a mean sway distance in both AP and ML directions, while the difference was limited to AP in PSP. Significant correlation between HY stage and sway parameters further supports postural sway as a potential disease progression marker in APDs.

Cerebrospinal fluid neurofilament light and tau protein as mortality biomarkers in parkinsonism.

Mortality is increased in parkinsonian disorders, moderately in Parkinson's disease (PD) but markedly in atypical parkinsonian disorders (APD), including multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD). Still, there are no reliable quantitative biomarkers for mortality. The cerebrospinal fluid (CSF) neurodegeneration biomarkers such as neurofilament light chain (NF-L), total tau (t-tau), and the tau pathology marker phosphorylated tau (p-tau) are related to mortality in other neurological disorders (eg, amyotrophic lateral sclerosis, Alzheimer's disease), but have not been investigated in this respect in parkinsonian disorders. To investigate the CSF biomarkers' (NF-L, t-tau, and p-tau) relationship to mortality in parkinsonian disorders. Demographic, mortality, and CSF data were collected from 68 PD and 83 APD patients. Survival analysis was conducted using Cox regression, with age at lumbar puncture, gender, diagnosis, and levels of CSF biomarkers as predictors. NF-L in CSF was associated with increased mortality in synucleinopathies (PD, MSA; HR 3.698 [2.196-6.228, 95% confidence interval (CI)], P<0.001), in PSP (HR 2.767 [1.126-6.802 95% CI], P=0.027), and in the entire cohort (HR 1.661 [1.082-2.55, 95% CI], P=0.02). t-Tau in CSF was associated with increased mortality in PSP (HR 9.587 [1.143-80.418], P=0.037). p-Tau in CSF was associated with decreased mortality in synucleinopathies (HR 0.196 [0.041-0.929, 95% CI], P=0.040). Atypical parkinsonian disorders and tauopathies were associated with higher mortality (HR 8.798 [4.516-17.14, 95% CI] and HR 3.040 [1.904-4.854], respectively, P<0.001). NF-L and tau protein in CSF might be useful for mortality prognosis in patients with parkinsonian disorders and should be investigated in larger studies.

Metabolic pattern analysis of 18F-FDG PET as a marker for Parkinson's disease: a systematic review and meta-analysis.

A large number of articles have assessed the diagnostic accuracy of the metabolic pattern analysis of [18F]fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) in Parkinson's disease (PD); however, different studies involved small samples with various controls and methods, leading to discrepant conclusions. This study aims to consolidate the available observational studies and provide a comprehensive evaluation of the clinical utility of 18F-FDG PET for PD. The methods included a systematic literature search and a hierarchical summary receiver operating characteristic approach. Sensitivity analyses according to different pattern analysis methods (statistical parametric mapping versus scaled subprofile modeling/principal component analysis) and control population [healthy controls (HCs) versus atypical parkinsonian disorder (APD) patients] were performed to verify the consistency of the main results. Additional analyses for multiple system atrophy (MSA) and progressive supranuclear palsy (PSP) were conducted. Fifteen studies comprising 1446 subjects (660 PD patients, 499 APD patients, and 287 HCs) were included. The overall diagnostic accuracy of 18F-FDG in differentiating PD from APDs and HCs was quite high, with a pooled sensitivity of 0.88 [95% confidence interval (95% CI), 0.85-0.91] and a pooled specificity of 0.92 (95% CI, 0.89-0.94), with sensitivity analyses indicating statistically consistent results. Additional analyses showed an overall sensitivity and specificity of 0.87 (95% CI, 0.76-0.94) and 0.93 (95% CI, 0.89-0.96) for MSA and 0.91 (95% CI, 0.78-0.95) and 0.96 (95% CI, 0.92-0.98) for PSP. Our study suggests that the metabolic pattern analysis of 18F-FDG PET has high diagnostic accuracy in the differential diagnosis of parkinsonian disorders.

Grand Total EEG Score Can Differentiate Parkinson's Disease From Parkinson-Related Disorders.

Background: Semi-quantitative electroencephalogram (EEG) analysis is easy to perform and has been used to differentiate dementias, as well as idiopathic and vascular Parkinson's disease.Purpose: To study whether a semi-quantitative EEG analysis can aid in distinguishing idiopathic Parkinson's disease (IPD) from atypical parkinsonian disorders (APDs), and furthermore, whether it can help to distinguish between APDs.Materials and Methods: A comprehensive retrospective review of charts was performed to include patients with parkinsonian disorders who had at least one EEG recording available. A modified grand total EEG (GTE) score evaluating the posterior background activity, and diffuse and focal slow wave activities was used in further analyses.Results: We analyzed data from 76 patients with a final diagnosis of either IPD, probable corticobasal degeneration (CBD), multiple system atrophy (MSA), or progressive supra-nuclear palsy (PSP). IPD patients had the lowest mean GTE score, followed those with CBD or MSA, while PSP patients scored the highest. However, none of these differences were statistically significant. A GTE score of ≤9 distinguished IPD patients from those with APD (p < 0.01) with a sensitivity of 100% and a specificity of 33.3%.Conclusion: The modified GTE score can distinguish patients with IPD from those with CBD, PSP or MSA at a cut-off score of 9 with excellent sensitivity but poor specificity. However, this score is not able to distinguish a particular form of APD from other forms of the disorder.

Neuroimaging biomarkers for clinical trials in atypical parkinsonian disorders: Proposal for a Neuroimaging Biomarker Utility System

IntroductionTherapeutic strategies targeting protein aggregations are ready for clinical trials in atypical parkinsonian disorders. Therefore, there is an urgent need for neuroimaging biomarkers to help with the early detection of neurodegenerative processes, the early differentiation of the underlying pathology, and the objective assessment of disease progression. However, there currently is not yet a consensus in the field on how to describe utility of biomarkers for clinical trials in atypical parkinsonian disorders. MethodsTo promote standardized use of neuroimaging biomarkers for clinical trials, we aimed to develop a conceptual framework to characterize in more detail the kind of neuroimaging biomarkers needed in atypical parkinsonian disorders, identify the current challenges in ascribing utility of these biomarkers, and propose criteria for a system that may guide future studies. ResultsAs a consensus outcome, we describe the main challenges in ascribing utility of neuroimaging biomarkers in atypical parkinsonian disorders, and we propose a conceptual framework that includes a graded system for the description of utility of a specific neuroimaging measure. We included separate categories for the ability to accurately identify an intention-to-treat patient population early in the disease (Early), to accurately detect a specific underlying pathology (Specific), and the ability to monitor disease progression (Progression). DiscussionWe suggest that the advancement of standardized neuroimaging in the field of atypical parkinsonian disorders will be furthered by a well-defined reference frame for the utility of biomarkers. The proposed utility system allows a detailed and graded description of the respective strengths of neuroimaging biomarkers in the currently most relevant areas of application in clinical trials.

Improved language production with transcranial direct current stimulation in progressive supranuclear palsy

Progressive supranuclear palsy (PSP) is an atypical parkinsonian disorder that can present with language production deficits in addition to the characteristic progressive parkinsonian motor symptoms. Although typical parkinsonism treatments such as pharmacotherapy are not effective in PSP, non-invasive brain stimulation techniques such as transcranial direct current stimulation (tDCS) have shown promise for treating cognitive deficits relating to this disorder. We report the case of KN, who presented with reduced verbal fluency and connected speech production in the context of PSP. KN completed a set of language tasks, followed by an alternate version of the tasks in conjunction with either sham or active tDCS over the left dorsolateral prefrontal cortex (DLPFC) across four sessions. Results showed improved performance with active stimulation compared to sham stimulation for phonemic fluency and action naming, as well as mixed results suggesting possible benefits for connected speech production. There were no benefits of active stimulation for control tasks, indicating that tDCS can produce specific benefits for phonemic fluency, action naming, and connected speech production in PSP. These promising, preliminary findings warrant further investigation into whether these benefits of tDCS can be a useful therapeutic tool for PSP patients to maintain language.

Serum NFL discriminates Parkinson disease from atypical parkinsonisms.

To investigate the diagnostic value of serum neurofilament light chain (NFL) in patients with clear signs of parkinsonism but whose specific diagnosis was yet uncertain. Serum samples were collected from patients with clear signs of parkinsonism but with uncertain diagnosis at the inclusion. Clinical diagnoses of Parkinson disease (PD) and atypical parkinsonism disorders (APDs) were established after 3 years of follow-up and updated again after a maximum of 12 years in case longer follow-up data were available. Serum NFL was quantified by single molecule array in patients with PD (n = 55) and APD (n = 29, multiple system atrophy = 22, progressive supranuclear palsy = 7) and 53 nonneurologic controls. Serum NFL levels were elevated and differentiated the APD group (mean 23.8 ± 10.3 ng/L) from PD (mean 10.4 ± 4.9 ng/L) and controls (mean 11.5 ± 6.5 ng/L, p < 0.0001) with accuracy levels up to 91% (sensitivity = 86% and specificity = 85%). Serum NFL strongly correlated with CSF NFL levels (r = 0.72, p < 0.0001) in all groups and with age in PD (r = 0.78, p < 0.0001) and controls (r = 0.66, p < 0.0001). In our cohort, the probability of having APD was 76% (positive predictive value) and of having PD 92% (negative predictive value). Serum NFL levels are markedly elevated in APD compared to PD and discriminate APDs from PD with high accuracy. Serum NFL may be a useful clinical biomarker to identify APD, even at stages when clinical symptoms are not yet conclusive. This study provides Class II evidence that serum NFL levels accurately discriminate APDs from PD.

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.

The Diagnostic Scope of Sensor-Based Gait Analysis in Atypical Parkinsonism: Further Observations.

Background: Differentiating idiopathic Parkinson's disease (IPD) from atypical Parkinsonian disorders (APD) is challenging, especially in early disease stages. Postural instability and gait difficulty (PIGD) are substantial motor impairments of IPD and APD. Clinical evidence implies that patients with APD have larger PIGD impairment than IPD patients. Sensor-based gait analysis as instrumented bedside test revealed more gait deficits in APD compared to IPD. However, the diagnostic value of instrumented bedside tests compared to clinical assessments in differentiating APD from IPD patients have not been evaluated so far.Objective: The objectives were (a) to evaluate whether sensor-based gait parameters provide additional information to validated clinical scores in differentiating APD from matched IPD patients, and (b) to investigate if objective, instrumented gait assessments have comparable discriminative power to clinical scores.Methods: In a previous study we have recorded instrumented gait parameters in patients with APD (Multiple System Atrophy and Progressive Supranuclear Palsy). Here, we compared gait parameters to those of retrospectively pairwise disease duration-, age-, and gender-matched IPD patients in order to address this new research questions. To this aim, the PIGD score was calculated as sum of the MDS-UPDRS-3-items “gait,” “postural stability,” “arising from chair,” and “posture.” Gait characteristics were evaluated in standardized gait tests using an instrumented, sensor-based gait analysis system. Machine learning algorithms were used to extract spatio-temporal gait parameters. Receiver Operating Characteristic analysis was performed in order to detect the discriminative power of the instrumented vs. the clinical bedside tests in differentiating IPD from APD.Results: Sensor-based stride length, gait velocity, toe off angle, and parameters representing gait variability significantly differed between IPD and APD groups. ROC analysis revealed a high Area Under the Curve (AUC) for PIGD score (0.919), and UPDRS-3 (0.848). Particularly, the objective parameters stance time variability (0.841), swing time variability (0.834), stride time variability (0.821), and stride length variability (0.804) reached high AUC's as well.Conclusions: PIGD symptoms showed high discriminative power in differentiating IPD from APD supporting gait disorders as substantial diagnostic target. Sensor-based gait variability parameters provide metric, objective added value, and serve as complementary outcomes supporting clinical diagnostics and long-term home-monitoring concepts.

Review: Clinical, genetic and neuroimaging features of frontotemporal dementia.

Frontotemporal dementia (FTD) is a heterogeneous group of disorders causing neurodegeneration within a network of areas centred on the frontal and temporal lobes. Clinically, patients present with behavioural symptoms (behavioural variant FTD) or language disturbance (primary progressive aphasia), although there is an overlap with motor neurone disease and atypical parkinsonian disorders. Whilst neuroimaging commonly reveals abnormalities in the frontal and temporal lobes, a closer review identifies a more complex picture with variable asymmetry of neuronal loss, widespread subcortical involvement and in many cases more posterior cortical atrophy. An autosomal-dominant genetic disorder is found in around a third of people with mutations in progranulin, C9orf72 and the microtubule-associated protein tau being the commonest causes. In the other two-thirds, the disorder is sporadic, although recent genome-wide association studies have started to identify genetic risk factors within this group. Much of this knowledge has been understood only in the past 10years and so this review will discuss the current knowledge about the clinical, genetic and neuroimaging features of FTD.

Genetic mimics of the non-genetic atypical parkinsonian disorders - the 'atypical' atypical.

With the advent in genetics, many genetic parkinsonian conditions have been described that, in some cases, share features that resemble the widely recognized Richardson's syndrome (the commonest described phenotype of progressive supranuclear palsy pathology), corticobasal syndrome and multiple system atrophy syndromes. A positive family history, an earlier age at onset, and clinical features that are unusual for or characteristic of a certain condition, may help in the differential diagnosis. The recognition of these syndromes is quite important as, in contrast to the non-genetic atypical parkinsonian syndromes, a definite diagnosis can be made, there are implications for other generations and there may be an opportunity to participate in clinical trials with genetic treatments that are well under way.

Review: Fluid biomarkers for frontotemporal dementias.

Frontotemporal dementias (FTDs) are clinically, genetically and pathologically heterogeneous neurodegenerative disorders that affect the frontal and anterior temporal lobes of the brain. They are relatively common causes of young-onset dementia and usually present with behavioural disturbance (behavioural variant FTD) or language impairment (primary progressive aphasia), but there is also overlap with motor neurone disease and the atypical parkinsonian disorders, corticobasal syndrome and progressive supranuclear palsy. At post mortem, neuronal inclusions containing tau, TDP-43 or infrequently FUS protein are seen in most cases. However, a poor correlation between clinical syndrome and underlying pathology means that it is difficult to diagnose the underlying molecular basis using clinical criteria. At this point, biomarkers for the underlying pathology come into play. This paper provides a brief update on fluid biomarkers for FTDs that may be useful to dissect the underlying molecular changes in patients presenting with signs of frontal and/or temporal lobe dysfunction. The hope is that such biomarkers, together with genetics and imaging, would be useful in clinical trials of novel drug candidates directed against specific pathologies and, in the long run, helpful in clinical practice to select the most appropriate treatment at the right dose for individual patients.

Multiparametric MR imaging of Parkinsonisms at 3 tesla: Its role in the differentiation of idiopathic Parkinson’s disease versus atypical Parkinsonian disorders

ObjectivesThe Nigrosome-1 and putaminal hypointensity depicted on susceptibility-weighted imaging (SWI), and midbrain atrophy assessed on T1-weighted are some of the most common radiological parameters to diagnose Parkinsonism at Magnetic Resonance (MR) imaging. Our aim is to assess the feasibility of these signs in the differentiation of Idiopathic Parkinson’s disease (IPD) patients versus disease (DC) and healthy controls (HC) and in the assessment of the Atypical Progressive Parkinsonisms (APPs). MethodsPresence or loss of the Nigrosome-1 was assessed retrospectively on multiple-echo SWI obtained on a 3 T scan by two neuroradiologists. Results were compared with the 123I-FP-CIT SPECT images. Morphologic diagnostic features suggestive of APPs such as midbrain atrophy and putaminal hypointensity were evaluated by qualitative scores. The midbrain and putaminal scores were summed (combined score) and then added to the Nigrosome-1 score (global score). ResultsThe study included 126 patients with IPD (n = 56), APPs patients (n = 30; 18 PSP, 3 MSA-C, 9 MSA-P), 16 DC and 24 HC. Sensitivity and specificity of the Nigrosome-1 in discriminating IPD from controls were 96,43% and 85.00%, APPs from controls were 100% and 85%, IPD from APPs were 96,43% and 0% respectively. Combined score for midbrain atrophy and putaminal hypointensity resulted in the most accurate for distinguishing APPs from IPD with a value of ≥ 2 (AUC = 0.98). ConclusionNigrosome-1 is a valid tool to differentiate IPD-APPs from controls. The combined score of midbrain atrophy and putaminal hypointensity represents a valid diagnostic pointer in the differential diagnosis of APPs from IPD.

Red flags phenotyping: A systematic review on clinical features in atypical parkinsonian disorders

To establish a clinical diagnosis of a parkinsonian disorder, physicians rely on their ability to identify relevant red flags, in addition to cardinal features, to support or refute their working diagnosis in an individual patient. The term ‘red flag’, was originally coined in 1989 to define the presence of non-cardinal features that may raise a suspicion of multiple system atrophy (MSA), or at least suggest alternative diagnosis to Parkinson's disease (PD). Since then, the term ‘red flag’, has been consistently used in the literature to denote the clinical history or signs that may signal to physicians the possibility of an atypical parkinsonian disorder (APD). While most red flags were originally based on expert opinion, many have gained acceptance and are now included in validated clinical diagnostic criteria of PD and APDs. The clinical appreciation of red flags, in conjunction with standard criteria, may result in a more accurate and earlier diagnosis compared to standard criteria alone. However, red flags can be clinical signs that are non-neurological, making the systematic assessment for them a real challenge in clinical practice. Here, we have conducted a systematic review to identify red flags and their clinical evidence in the differential diagnosis of common degenerative parkinsonism, including PD, MSA, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and dementia with Lewy body (DLB). Increasing awareness and appropriate use of red flags in clinical practice may benefit physicians in the diagnosis and management of their patients with parkinsonism.

Neuropsychiatric disturbances in atypical parkinsonian disorders.

Multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD) are the most common atypical parkinsonisms. These disorders are characterized by varying combinations of autonomic, cerebellar and pyramidal system, and cognitive dysfunctions. In this paper, we reviewed the evidence available on the presence and type of neuropsychiatric disturbances in MSA, PSP, and CBD. A MedLine, Excerpta Medica, PsycLit, PsycInfo, and Index Medicus search was performed to identify all articles published on this topic between 1965 and 2018. Neuropsychiatric disturbances including depression, anxiety, agitation, and behavioral abnormalities have been frequently described in these disorders, with depression as the most frequent disturbance. MSA patients show a higher frequency of depressive disorders when compared to healthy controls. An increased frequency of anxiety disorders has also been reported in some patients, and no studies have investigated apathy. PSP patients may have depression, apathy, disinhibition, and to a lesser extent, anxiety and agitation. In CBD, neuropsychiatric disorders are similar to those present in PSP. Hallucinations and delusions are rarely reported in these disorders. Neuropsychiatric symptoms in MSA, PSP, and CBD do not appear to be related to the severity of motor dysfunction and are one of the main factors that determine a low quality of life. The results suggest that neuropsychiatric disturbances should always be assessed in patients with atypical parkinsonisms.

Neuroimaging of Sleep Disturbances in Movement Disorders.

Sleep dysfunction is recognized as a distinct clinical manifestation in movement disorders, often reported early on in the disease course. Excessive daytime sleepiness, rapid eye movement sleep behavior disorder and restless leg syndrome, amidst several others, are common sleep disturbances that often result in significant morbidity. In this article, we review the spectrum of sleep abnormalities across atypical Parkinsonian disorders including multiple system atrophy (MSA), progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS), as well as Parkinson's disease (PD) and Huntington's disease (HD). We also explore the current concepts on the neurobiological underpinnings of sleep disorders, including the role of dopaminergic and non-dopaminergic pathways, by evaluating the molecular, structural and functional neuroimaging evidence based on several novel techniques including magnetic resonance imaging (MRI), functional magnetic resonance imaging (fMRI), diffusion tensor imaging (DTI), single-photon emission computed tomography (SPECT) and positron emission tomography (PET). Based on the current state of research, we suggest that neuroimaging is an invaluable tool for assessing structural and functional correlates of sleep disturbances, harboring the ability to shed light on the sleep problems attached to the limited treatment options available today. As our understanding of the pathophysiology of sleep and wake disruption heightens, novel therapeutic approaches are certain to transpire.

Cerebrospinal fluid concentrations of inflammatory markers in Parkinson\u2019s disease and atypical parkinsonian disorders

Inflammation has been implicated in the pathogenesis of Parkinson’s disease (PD). We here investigate levels of inflammatory biomarkers in cerebrospinal fluid (CSF) in PD and atypical parkinsonian disorders (APD) compared with neurologically healthy controls. We included 131 patients with PD and 27 PD with dementia (PDD), 24 with multiple system atrophy (MSA), 14 with progressive supranuclear palsy (PSP) and 50 controls, all part of the Swedish BioFINDER study. CSF was analyzed for CRP, SAA, IL-6, IL-8, YKL-40 and MCP-1 (CCL2) as well as α-synuclein (α-syn), tau, tau phosphorylated at Thr181 (P-tau), Aβ42 and NfL. In this exploratory study, we found higher levels of the inflammatory biomarker SAA in PDD and MSA compared with controls and PD and higher levels of CRP in PDD and MSA compared with PD. YKL-40 was lower in PD compared with controls. There were multiple positive correlations between the inflammatory markers, α-syn and markers of neuroaxonal injury (NfL and tau). In PD, higher levels of inflammatory biomarkers correlated with worse motor function and cognitive impairment. Thus, inflammatory biomarkers were increased in PDD and MSA. Furthermore, inflammatory biomarkers correlated with more severe disease regarding motor symptoms and cognitive impairment in PD, indicating an association between inflammation and more aggressive disease course. However, the results need confirmation in follow-up studies.