Search

The clinical presentation of Parkinson’s disease and atypical Parkinsonian syndromes is often heterogeneous. Additional diagnostic procedures including brain imaging and biomarker analyses can help to appreciate the various syndromes, but a precise clinical evaluation and differentiation is always necessary. To better assess the relevance of distinct clinical symptoms that arose within 1 year of disease manifestation and evaluate their indicative potential for an atypical Parkinsonian syndrome, we conducted a modified Delphi panel with seven movement disorder specialists. Five different topics with several clinical symptom items were discussed and consensus criteria were tested. This resulted in distinct symptom patterns for each atypical Parkinsonian syndrome showing the multitude of clinical involvement in each neurodegenerative disease. Strongly discriminating clinical signs were few and levels of indication were variable. A prospective validation of the assessments made is needed. This demonstrates that both clinical evaluation and elaborate additional diagnostic procedures are needed to achieve a high diagnostic standard.

Introduction The MDS-PSP criteria expand the phenotypic spectrum of PSP by adding to Richardson's syndrome (PSP-RS) other presentations such as PSP-parkinsonism (PSP–P), PSP-pure-gait-freezing (PSP-PGF), PSP-speech-language (PSP-SL), PSP-frontal (PSP–F), PSP-postural-instability (PSP-PI) and PSP-corticobasal-syndrome (PSP-CBS). Evidence about the prognostic differences between PSP phenotypes is scarce and focused on PSP-RS vs. non-PSP-RS. Using a brain-bank cohort we assessed PSP survival not only in PSP-RS vs. non-PSP-RS, but also in PSP-RS + cortical vs. subcortical phenotypes. Besides, we assessed sensitivity and specificity of the MDS-PSP criteria in of PSP and other degenerative parkinsonisms. Methods We retrospectively applied the MDS-PSP diagnostic criteria to 32 definite PSP cases and 30 cases with other degenerative parkinsonian syndromes (Parkinson's disease [PD; n = 11], multiple system atrophy [MSA; n = 11], corticobasal degeneration [CBD; n = 8]). We conducted survival statistics in neuropathologically confirmed PSP cases considering PSP-RS vs. non-PSP-RS and PSP-RS + PSP-cortical (PSP–F + PSP-SL + PSP-CBS) vs. PSP-subcortical (PSP–P + PSP-PGF) phenotypes. We also adjusted survival analyses for PSP tau scores. Results Diagnostic sensitivity was 100% and specificity ranged from 47% to 87% when excluding cases that met the “suggestive of PSP” definition early in their disease course but with other clinical features better matching with a non-PSP pathological diagnosis. Survival was significantly shorter in PSP-RS vs. non-PSP-RS cases, but it was more markedly shorter in PSP-RS + PSP-cortical vs. PSP-subcortical, independently of PSP tau scores, which were not associated with survival. Conclusions PSP-subcortical phenotypes appear to have longer survival than PSP-RS and cortical phenotypes. This might be of prognostic relevance when informing patients upon clinical diagnosis.

ZusammenfassungDie vorliegende Arbeit gibt einen Überblick über die verschiedenen nuklearmedizinischen Verfahren in der Diagnostik bei neurodegenerativen Parkinson-Syndromen sowie ihre Evidenzlage und soll praxistaugliche Entscheidungshilfen in der Anwendung und Interpretation der Methoden und Befunde ermöglichen. Die Wertigkeit der Verfahren unterscheidet sich erheblich in Bezug auf die beiden relevanten diagnostischen Fragestellungen. Dies ist zum einen die Frage, ob überhaupt ein neurodegeneratives Parkinson-Syndrom vorliegt, zum anderen die Frage, welches. Während zur Beantwortung der ersten Frage das DAT-SPECT unter Berücksichtigung gewisser Parameter in der Praxis unbestritten die Methode der Wahl ist, eignet sich dieses Verfahren nicht zur Beantwortung der zweiten Fragestellung. Zur Unterscheidung der Parkinson-Syndrome in idiopathisch oder atypisch werden im klinischen Alltag mit der MIBG-Szintigraphie und dem FDG-PET verschiedene Verfahren angewendet. Wir legen dar, warum das FDG-PET von diesen Methoden nicht nur die geeignetste ist, um ein idiopathisches Parkinson-Syndrom von einem atypischen Parkinson-Syndrom abzugrenzen, sondern auch ausreichend valide ermöglicht, die verschiedenen atypischen neurodegenerativen Parkinson-Syndrome (d. h. MSA, PSP und CBD) voneinander zu unterscheiden, und deshalb in den Leistungskatalog der GKV aufgenommen werden sollte.

Fifty-five years have passed from the first description of PSP, but it is in the last decade that there has been a revolutionary change in understanding both clinical and pathophysiological aspects of this disease. Ten years ago, our knowledge about the clinical spectrum and pathophysiology of the disease was quite limited, and there was no credible clinical study on any drug treatment for this devastating disease. Today, we have discovered the wide clinical spectrum of PSP, and this led to the development of new diagnostic criteria in 2017, aiming to diagnose the disease earlier and include more phenotypes into clinical studies. Moreover, just over the past 10 years, numerous large, double-blind, clinical trials with disease-modifying agents have been conducted that provided important novel insights into disease biomarkers and progression. These studies were possible because of gained novel insights into pathophysiological processes of the disease and pave the way for the near future. In the next decade, we dare to predict the discovery of biomarkers for PSP, improvements in diagnosis using the new criteria in combination with these biomarkers, and ultimately the development of a neuroprotective therapy that could be applied to patients in a prodromal stage and spare them from this devastating disorder. © 2019 International Parkinson and Movement Disorder Society.

Alzheimer disease (AD) is a neurodegenerative disease characterized by deposition of pathologically aggregated amyloid-β in the extracellular space and pathologically aggregated tau protein in the intracellular space. Mainly affected brain areas are the temporal and the parietal lobe, which cause the classical AD phenotype consisting of increasing forgetfulness and difficulties to orientate. However, AD pathology is not restricted to these brain areas and spreads through the brain as the disease progresses, which can lead to a number of additional symptoms and to atypical presentations. Motor symptoms in AD are the topic of this chapter. Even though motor symptoms are usually not severe and seldomly treated, motor symptoms are quite frequent and can be observed in the majority of AD cases. Motor symptoms are especially frequent in cases with early onset and long disease duration, for example in Apolipoprotein E e4 carriers and in familial early onset AD. In severe cases treatment with pharmacological approaches might be considered. However, treatment strategies largely rely on expert opinions. Due to potential positive impact on prognosis non-pharmacological treatment and exercise might be considered in less advanced cases.

Dementia with Lewy bodies is characterized histopathologically by the deposition of α-synuclein in inclusion bodies. Clinical diagnosis is based on progressive cognitive deficits, cognitive fluctuations, early visual hallucinations, REM sleep disorders and symptoms of Parkinsonism. On the basis of the new criteria published in 2017, better differentiation from other neurodegenerative diseases with dementia should be possible. Therapy concepts include treatment of loss of motor and cognitive performance as well as psychological and behavioral symptoms. At present, only a few studies are available on this clinical picture so that evidence-based therapy approaches are only possible to a limited extent.Die Demenz mit Lewy-Körpern ist histopathologisch durch die Ablagerung von α-Synuclein in Einschlusskörpern gekennzeichnet. Für die klinische Diagnose wird eine fortschreitende Demenz sowie das Auftreten von Fluktuationen der Kognition, früh im Krankheitsverlauf auftretende visuelle Halluzinationen, REM-Schlafverhaltensstörungen sowie die Symptome eines Parkinson-Syndroms zugrunde gelegt. Anhand der 2017 erschienenen neuen Kriterien soll eine bessere Trennung von anderen neurodegenerativen Erkrankungen mit Demenz möglich sein. Therapiekonzepte beinhalten die Behandlung der motorischen sowie der kognitiven Leistungseinbuße sowie die psychologischen und Verhaltenssymptome. Gegenwärtig stehen nur wenige Studien für dieses Krankheitsbild zur Verfügung, so dass Evidenz-basierte Therapieansätze nur bedingt möglich sind.

In distinction to idiopathic Parkinson's disease (PD), the diagnosis of atypical Parkinson syndromes comprises dementia with Lewy bodies (DLB), multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD). We set out to write a state-of-the-art guideline as to which investigations and examinations help to differentiate PD vs. atypical Parkinson syndromes in clinical routine.

Autopsy is the diagnostic gold standard for progressive supranuclear palsy (PSP). The National Institute of Neurological Disorders and Stroke and Society for Progressive Supranuclear Palsy (NINDS-SPSP) criteria for the clinical diagnosis of probable PSP are thought to possess high specificity and low sensitivity. The NINDS-SPSP criteria for possible PSP are considered to increase sensitivity at the expense of specificity. The Neuroprotection and Natural History in Parkinson Plus Syndromes (NNIPPS) criteria are intended to improve sensitivity while maintaining high specificity. The aim of this study was to conduct a clinicopathological evaluation of the NINDS-SPSP and NNIPPS criteria in tertiary neurological centers. Defined clinical features and their year of onset were recorded by chart review in neuropathologically diagnosed patients with PSP, Parkinsons's disease (PD), MSA parkinsonism and corticobasal degeneration from four European brain banks. Fulfilment of the clinical diagnostic criteria was verified for each year after disease onset and for the final antemortem record. We analyzed 98 PSP patients and 46 disease controls. The NINDS-SPSP probable criteria yielded shorter time to diagnosis, slightly higher specificity and positive predictive value (PPV), and similar sensitivity, compared with the NNIPPS criteria. Unexpectedly, the NINDS-SPSP possible criteria yielded the lowest sensitivity, specificity, and PPV. A combination of NINDS-SPSP possible and probable criteria yielded the highest sensitivity. We suggest that the NINDS-SPSP probable criteria might be preferred for recruitment of patients for clinical trials, where an early and specific diagnosis is important. For routine clinical care, where high sensitivity is crucial, a combination of NINDS possible and probable criteria might be preferred. (c) 2013 Movement Disorder Society

Contains fulltext : 167923.pdf (Publisher’s version ) (Open Access) Autosomal-recessive early-onset parkinsonism is clinically and genetically heterogeneous. The genetic causes of approximately 50% of autosomal-recessive early-onset forms of Parkinson disease (PD) remain to be elucidated. Homozygozity mapping and exome sequencing in 62 isolated individuals with early-onset parkinsonism and confirmed consanguinity followed by data mining in the exomes of 1,348 PD-affected individuals identified, in three isolated subjects, homozygous or compound heterozygous truncating mutations in vacuolar protein sorting 13C (VPS13C). VPS13C mutations are associated with a distinct form of early-onset parkinsonism characterized by rapid and severe disease progression and early cognitive decline; the pathological features were striking and reminiscent of diffuse Lewy body disease. In cell models, VPS13C partly localized to the outer membrane of mitochondria. Silencing of VPS13C was associated with lower mitochondrial membrane potential, mitochondrial fragmentation, increased respiration rates, exacerbated PINK1/Parkin-dependent mitophagy, and transcriptional upregulation of PARK2 in response to mitochondrial damage. This work suggests that loss of function of VPS13C is a cause of autosomal-recessive early-onset parkinsonism with a distinctive phenotype of rapid and severe progression.

Background: Aside from idiopathic Parkinson syndrome (Parkinson's disease), there are a number of other, so-called atypical parkinsonian syndromes: dementia with Lewy bodies (DLB), multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD). DLB is a common disease, with a prevalence of 0.4% (400 cases per 100 000 persons) in the elderly;MSA and PSP both have a prevalence of 5 to 10 per 100 000 persons, while the prevalence of CBD is about 1 per 100 000. Methods: This review is based on pertinent publications retrieved by a selective literature search. Results: The atypical parkinsonian syndromes are synucleinopathies and tauopathies, i.e., disorders characterized by the abnormal deposition of the proteins a-synuclein and tau. The site of deposition is correlated with the clinical features. In DLB, synuclein is mainly deposited in neocortical neurons, with some brain stem involvement as well. The main clinical features are dementia and, later on, parkinsonism. In MSA, synuclein is deposited in oligodendrocytes, mainly in the cerebellum but also in the brain stem;the main clinical feature is autonomic dysfunction combined with parkinsonism or cerebellar ataxia. Synucleinopathies often impair REM (rapid eye movement) sleep. PSP and CBD, on the other hand, are primary tauopathies. PSP usually causes predominantly supranuclear vertical gaze palsy and early postural instability with falls, less commonly parkinsonism (PSP-P) or frontotemporal dementia (PSP-FTD) as its most prominent feature. CBD typically manifests itself as markedly asymmetrical parkinsonism with apraxia or cortical sensory disturbance. At present, there is no accepted causal treatment for any of these disorders;the available symptomatic treatments are of limited efficacy and are supported only by low-level evidence. Conclusion: Causal treatments for neurodegenerative diseases are now being developed and tested, and thus a molecular diagnosis is desirable. This will require the cooperation of primary care physicians with specialized centers.

Background: Mild parkinsonian signs (MPS) are common in the elderly population, and have been associated with vascular diseases, mild cognitive impairment and dementia; however their relation to Parkinson’s disease (PD) is unclear. Hypothesizing that individuals with MPS may reflect a pre-stage of PD, i.e. a stage in which the nigrostriatal system is already affected although to a milder degree than at the time of PD diagnosis, aim of this study was to evaluate the similarities between MPS and PD. Methods: The TREND study is a prospective cross-sectional cohort study in individuals .50 years with biennial assessments designed to identify markers for an earlier diagnosis of Parkinson’s and Alzheimer’s disease. For this substudy 992 individuals were included for analyses (892 controls, 73 MPS individuals, 27 PD patients). Parameters defining risk of PD (sex, age, positive family history), prodromal markers (hyposmia, REM sleep behavior disorder, depression and autonomic failure) as well as quantitative fine motor, axial motor and cognitive parameters were compared between the three cohorts. Results: As expected, PD patients differed from controls with regard to 12 of 15 of the assessed parameters. MPS individuals differed significantly from controls in 12 of the PD-associated parameters, but differed from PD only in 5 parameters. Conclusion: This study shows that individuals with MPS share many prodromal and clinical markers of PD with PD patients, implying that either a common dynamic process or similar constitutional factors occur in MPS individuals and PD patients.

Purpose of review This update discusses novel aspects on genetics, diagnosis, and treatments of atypical parkinsonism published over the past 2 years. Recent findings A genome-wide association study identified new genetic risk factors for progressive supranuclear palsy and new genetic conditions presenting with atypical parkinsonism have been described. The clinical criteria for diagnosis of corticobasal degeneration have been revised, and for progressive supranuclear palsy are under revision. Novel molecular techniques to identify possible biomarkers, as in other neurodegenerative disorders, have started being studied on atypical parkinsonian conditions, and although preliminary results seem promising, further studies are urgently warranted. Therapeutic trials based on disease-specific targets have shown no clinical improvement. Summary The knowledge obtained recently on atypical parkinsonian conditions points out the major deficits in this field. With the expanding phenotypical spectrum of atypical parkinsonian conditions, the early identification of patients has become difficult. The inability of conventional methods to identify these disorders earlier and better than clinicians, and the recent failure of promising therapeutic compounds, highlight the fact that the lack of biomarkers is probably the greatest limitation for developing treatments for these disorders. Thus, current and future research in this direction will be crucial.

Objectives Degeneration of dopaminergic neurons in the substantia nigra (SN) pars compacta is the primary cause of idiopathic Parkinson's disease (iPD). In early stages of disease in particular, presentation of symptoms is non-specific leading to difficulties in differentiating between iPD and atypical parkinsonian syndromes (aPS). The aim of this study was to evaluate the feasibility of three-dimensional magnetic resonance spectroscopic imaging (MRSI) of the SN region for differentiation between iPD and aPS. Methods 20 patients with iPD, 10 with aPS and 22 controls were examined on a 3 T MR scanner using three-dimensional MRSI with a voxel size of 0.252 ml and an echo time of 30 ms. Excitation volume was positioned in such a way that in each hemisphere 1 voxel defines the rostral and 1 voxel the caudal SN region. Using a fully automatic spectra evaluation, the metabolite ratios of N-acetyl aspartate/creatine (NAA/Cr) were calculated. Results In all cases spectra with good quality were obtained. Differences in rostral to caudal NAA/Cr ratios were significant between controls and iPD patients, as well as between iPD and aPS patients (p

Progressive supranuclear palsy (PSP) is the most common atypical parkinsonian syndrome comprising two main clinical subtypes: Richardson's syndrome (RS), characterized by prominent postural instability, supranuclear vertical gaze palsy and frontal dysfunction ; and PSP-parkinsonism (PSP-P) which is characterized by an asymmetric onset, tremor and moderate initial therapeutic response to levodopa. The early clinical features of PSP-P are often difficult to discern from idiopathic Parkinson's disease (PD), and other atypical parkinsonian disorders, including multiple system atrophy (MSA) and corticobasal syndrome (CBS). In addition, rare PSP subtypes may be overlooked or misdiagnosed if there are atypical features present. The differentiation between atypical parkinsonian disorders and PD is important because the prognoses are different, and there are different responses to therapy. Structural and functional imaging, although currently of limited diagnostic value for individual use in early disease, may contribute valuable information in the differential diagnosis of PSP. A growing body of evidence shows the importance of CSF biomarkers in distinguishing between atypical parkinsonian disorders particularly early in their course when disease-modifying therapies are becoming available. However, specific diagnostic CSF biomarkers have yet to be identified. In the absence of reliable disease-specific markers, we provide an update of the recent literature on the assessment of clinical symptoms, pathology, neuroimaging and biofluid markers that might help to distinguish between these overlapping conditions early in the course of the disease.

We reviewed eight studies on transcranial sonography (TCS) as a tool for differentiating idiopathic Parkinson's disease (IPD) from atypical parkinsonian syndromes (APS) and included some first data on TCS findings in the subforms of PSP. Changes of specific structures on TCS like the substantia nigra (SN), lenticular nucleus (LN), and the third ventricle are discussed as well as how they can contribute to differentiate between IPD, multiple system atrophy (MSA), progressive supranuclear palsy (PSP), Lewy body disease (LBD), and corticobasal degeneration (CBD). We finish with an algorithm that may be used to employ TCS as a diagnostic instrument delineating IPD from the APS and discerning among the APS themselves. As TCS is at present the most promising tool for this particular diagnostic problem, this algorithm might be a suitable hypothesis to study in future research.