Atypical Parkinsonian Syndromes

The cardinal characteristics of parkinsonism are represented in the mnemonic TRAP: tremor at rest, rigidity, akinesia and bradykinesia, and postural instability. The parkinsonian phenotype encompasses a broad range of clinical and pathologic disorders; the most common (about 55% of cases) is idiopathic (sporadic) Parkinson disease. Rapid disease progression, poor initial response to dopaminergic therapy, or the early presence of certain other signs may suggest an atypical parkinsonian syndrome, sometimes called parkinsonism-plus syndrome.

A Novel deep learning approach for the automated diagnosis of normal pressure hydrocephalus

Normal Pressure Hydrocephalus (NPH), an Atypical Parkinsonian syndrome, is a neurological syndrome that mainly affects elderly people. This syndrome shows the symptoms of Parkinson’s disease (PD), such as walking impairment, dementia, impaired bladder control, and mental impairment. The Magnetic Resonance Imaging (MRI) is the aptest modality for the detection of the abnormal build-up of cerebrospinal fluid in the brain’s cavities or ventricles, which is the major cause of NPH. This work aims to develop an automated biomarker for NPH segmentation and classification (NPH-SC) that efficiently detect hydrocephalus using a deep learning-based approach. Removal of non-cerebral tissues (skull, scalp, and dura) and noise from brain images by skull stripping, unsharp-mask based edge sharpening, segmentation by marker-based watershed algorithm, and labelling are performed to improve the accuracy of the CNN based classification system. The brain ventricles are extracted using the external and internal markers and then fed into the convolutional neural networks (CNN) for classification. This automated NPH-SC model achieved a sensitivity of 96%, a specificity of 100%, and a validation accuracy of 97%. The prediction system, with the help of a CNN classifier, is used for the calculation of test accuracy of the system and obtained promising 98% accuracy.

Current Symptomatic and Disease-Modifying Treatments in Multiple System Atrophy

Multiple system atrophy (MSA) is a rare, severe, and rapidly progressive neurodegenerative disorder categorized as an atypical parkinsonian syndrome. With a mean life expectancy of 6–9 years after diagnosis, MSA is clinically characterized by parkinsonism, cerebellar ataxia, autonomic failure, and poor l-Dopa responsiveness. Aside from limited symptomatic treatment, there is currently no disease-modifying therapy available. Consequently, distinct pharmacological targets have been explored and investigated in clinical studies based on MSA-related symptoms and pathomechanisms. Parkinsonism, cerebellar ataxia, and autonomic failure are the most important symptoms targeted by symptomatic treatments in current clinical trials. The most prominent pathological hallmark is oligodendroglial cytoplasmic inclusions containing alpha-synuclein, thus classifying MSA as synucleinopathy. Additionally, myelin and neuronal loss accompanied by micro- and astrogliosis are further distinctive features of MSA-related neuropathology present in numerous brain regions. Besides summarizing current symptomatic treatment strategies in MSA, this review critically reflects upon potential cellular targets and disease-modifying approaches for MSA such as (I) targeting α-syn pathology, (II) intervening neuroinflammation, and (III) neuronal loss. Although these single compound trials are aiming to interfere with distinct pathogenetic steps in MSA, a combined approach may be necessary to slow down the rapid progression of the oligodendroglial associated synucleinopathy.

277 Disentangling corticobasal syndrome from corticobasal degeneration

Mutations in the TANK-binding kinase (TBK1) gene have been shown to cause frontotemporal dementia (FTLD) and amyotrophic lateral sclerosis (ALS). The phenotype is highly variable and has been associated with behavioural variant FTD, primary progressive aphasia and pure amyotrophic lateral sclerosis. We describe the clinical, anatomical and pathological features of a patient with onset of a corticobasal syndrome (CBS)/primary progressive aphasia overlap aged 59. The patient presented with progressive speech difficulties and later developed an asymmetric akinetic-rigid syndrome. Neuroimaging showed asymmetrical frontal atrophy, predominantly affecting the right side. There was a strong family history of neurodegenerative disease with 4/7 siblings developing either dementia or ALS in their 50’s-60’s. Following death at age 71, post mortem examination revealed FTLD TDP-43 type A pathology. Genetic screening did not reveal a mutation in the progranulin, microtubule-associated protein tau or C9orf72 genes. However exome sequencing revealed a novel E703X mutation in the TBK1 gene. Although segregation data was not available, this loss of function mutation is highly likely to be pathogenic. In conclusion, we show that TBK1 can be a cause of an atypical parkinsonian syndrome and screening for TBK1 should be considered in CBS patients with a family history of dementia, ALS or CBS.

Redefinition of Atypical Parkinsonian Syndromes

The definition of atypical parkinsonian syndromes is undergoing a change. The umbrella concept of atypical parkinsonian syndromes includes diseases with different underlying pathologies. These are, on the one hand, multiple system atrophy (MSA) and dementia with Lewy bodies (DLB), both of which are characterized by intracellular aggregates of the protein alpha-synuclein, and on the other hand, corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP), which are characterized by aggregates of the protein tau. The current syndrome-based classification of these diseases no longer meets current requirements since 1) numerous clinico-pathological studies have shown that the clinical syndromes do not always coincide with the molecular-pathological diagnosis, 2) a clinical parkinsonian syndrome is sometimes not even present in patients with a pathological diagnosis of an atypical parkinsonian syndrome, and 3) current therapeutic trials that intervene in the molecular disease mechanisms require no symptom-oriented, but a pathogenetically oriented diagnosis. The early and correct prediction of the underlying molecular pathology as a prerequisite for a causative therapy therefore presents a challenge that the old disease concept is no longer capable of meeting.

Corticobasal syndrome: A diagnostic conundrum

ABSTRACT Corticobasal syndrome (CBS) is an atypical parkinsonian syndrome of great interest to movement disorder specialists and behavioral neurologists. Although originally considered a primary motor disorder, it is now also recognized as a cognitive disorder, usually presenting cognitive deficits before the onset of motor symptoms. The term CBS denotes the clinical phenotype and is associated with a heterogeneous spectrum of pathologies. Given that disease-modifying agents are targeting the pathologic process, new diagnostic methods and biomarkers are being developed to predict the underlying pathology. The heterogeneity of this syndrome in terms of clinical, radiological, neuropsychological and pathological aspects poses the main challenge for evaluation.

Brain MR Contribution to the Differential Diagnosis of Parkinsonian Syndromes: An Update

Brain magnetic resonance (MR) represents a useful and feasible tool for the differential diagnosis of Parkinson’s disease. Conventional MR may reveal secondary forms of parkinsonism and may show peculiar brain alterations of atypical parkinsonian syndromes. Furthermore, advanced MR techniques, such as morphometric-volumetric analyses, diffusion-weighted imaging, diffusion tensor imaging, tractography, proton MR spectroscopy, and iron-content sensitive imaging, have been used to obtain quantitative parameters useful to increase the diagnostic accuracy. Currently, many MR studies have provided both qualitative and quantitative findings, reflecting the underlying neuropathological pattern of the different degenerative parkinsonian syndromes. Although the variability in the methods and results across the studies limits the conclusion about which technique is the best, specific radiologic phenotypes may be identified. Qualitative/quantitative MR changes in the substantia nigra do not discriminate between different parkinsonisms. In the absence of extranigral abnormalities, the diagnosis of PD is more probable, whereas basal ganglia changes (mainly in the putamen) suggest the diagnosis of an atypical parkinsonian syndrome. In this context, changes in pons, middle cerebellar peduncles, and cerebellum suggest the diagnosis of MSA, in midbrain and superior cerebellar peduncles the diagnosis of PSP, and in whole cerebral hemispheres (mainly in frontoparietal cortex with asymmetric distribution) the diagnosis of Corticobasal Syndrome.

Serotonin Transporter Availability in Early Stage Parkinson’s Disease and Multiple System Atrophy

Background. Differentiating Parkinson’s disease (PD) from multiple system atrophy (MSA) can be challenging especially early in the course of the disease. Previous studies have shown that midbrain serotonin transporter (SERT) availability in patients with established MSA was significantly lower compared to PD. It is unknown if this is also true for early-stage patients. Methods. 77 early-stage, untreated PD patients were recruited between 1995 and 1998, underwent [123I]β-CIT SPECT imaging, and were followed for at least five years. 16 patients were lost to followup, and in 4 the diagnosis was changed to another atypical parkinsonian syndrome, but not in MSA. In 50 patients, the PD diagnosis was unchanged at followup. In seven patients, the diagnosis was changed to MSA at followup. We retrospectively assessed baseline midbrain SERT availability as well as midbrain SERT-to-striatal dopamine transporter (DAT) ratios. Results. No difference in baseline [123I]β-CIT SERT availability was found. The midbrain SERT-to-striatal DAT ratio for whole striatum was significantly lower in patients with PD compared to MSA (P=0.049). However, when adjusting for the disease duration at imaging this difference is not significant (P=0.070). Conclusion. Midbrain SERT availability is not different between early-stage PD and MSA. Therefore, SERT imaging is not useful to differentiate between early PD and MSA.