Zygmunt Jamrozik

Tauopathies with parkinsonism: clinical spectrum, neuropathologic basis, biological markers, and treatment options

Tauopathies with parkinsonism represent a spectrum of disease entities unified by the pathologic accumulation of hyperphosphorylated tau protein fragments within the central nervous system. These pathologic characteristics suggest shared pathogenetic pathways and possible molecular targets for disease‐modifying therapeutic interventions. Natural history studies, for instance, in progressive supranuclear palsy, frontotemporal dementia with parkinsonism linked to chromosome 17, corticobasal degeneration, and Niemann‐Pick disease type C as well as in amyotrophic lateral sclerosis/Parkinson–dementia complex permit clinical characterization of the disease phenotypes and are crucial to the development and validation of biological markers for differential diagnostics and disease monitoring, for example, by use of neuroimaging or proteomic approaches. The wide pathologic and clinical spectrum of the tauopathies with parkinsonism is reviewed in this article, and perspectives on future advances in the understanding of the pathogenesis are given, together with potential therapeutic strategies.

Novel VCP mutations in inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia.

Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia (IBMPFD, OMIM 167320) has recently been attributed to eight missense mutations in valosin‐containing protein (VCP). We report novel VCP mutations N387H and L198W in six individuals from two families who presented with proximal muscle weakness at a mean age of diagnosis of 40 years, most losing the ability to walk within a few years of onset. Electromyographic studies in four individuals were suggestive of ‘myopathic’ changes, and neuropathic pattern was identified in one individual in family 1. Muscle biopsy in four individuals showed myopathic changes characterized by variable fiber size, two individuals showing rimmed vacuoles and IBM‐type cytoplasmic inclusions in muscle fibers, and electron microscopy in one individual revealing abundant intranuclear inclusions. Frontotemporal dementia associated with characteristic behavioral changes including short‐term memory loss, language difficulty, and antisocial behavior was observed in three individuals at a mean age of 47 years. Detailed brain pathology in one individual showed cortical degenerative changes, most severe in the temporal lobe and hippocampus. Abundant ubiquitin‐positive tau‐, α‐synuclein‐, polyglutamine repeat‐negative neuronal intranuclear inclusions and only rare intracytoplasmic VCP positive inclusions were seen. These new mutations may cause structural changes in VCP and provide some insight into the functional effects of pathogenic mutations.

A multi-centre clinico-genetic analysis of the VPS35 gene in Parkinson disease indicates reduced penetrance for disease-associated variants

Background Two recent studies identified a mutation (p.Asp620Asn) in the vacuolar protein sorting 35 gene as a cause for an autosomal dominant form of Parkinson disease . Although additional missense variants were described, their pathogenic role yet remains inconclusive. Methods and results We performed the largest multi-center study to ascertain the frequency and pathogenicity of the reported vacuolar protein sorting 35 gene variants in more than 15,000 individuals worldwide. p.Asp620Asn was detected in 5 familial and 2 sporadic PD cases and not in healthy controls, p.Leu774Met in 6 cases and 1 control, p.Gly51Ser in 3 cases and 2 controls. Overall analyses did not reveal any significant increased risk for p.Leu774Met and p.Gly51Ser in our cohort. Conclusions Our study apart from identifying the p.Asp620Asn variant in familial cases also identified it in idiopathic Parkinson disease cases, and thus provides genetic evidence for a role of p.Asp620Asn in Parkinson disease in different populations worldwide.

Anti-neural antibodies in serum and cerebrospinal fluid of amyotrophic lateral sclerosis (ALS) patients

Objectives ‐ An autoimmune basis has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). This hypothesis is supported by the presence of antibodies that interact with motoneuron antigens in serum of these patients. Against autoimmunity are the discrepances in the frequency of the antibodies appearance and also failure of immunosuppression. The aim of our study was to evaluate the titer of antibodies against GM1‐gangliosides, AGM1‐gangliosides and anti‐sulfatides in paired serum and cerebrospinal fluid samples in the ALS patients. Material and methods ‐ Serum of 103 and CSF of 79 patients with ALS was examined. The “disease controls” consisted of 22 cases of other motor neuron diseases and 50 healthy, age‐matched normals. CSF was drawn at the same time from 79 ALS patients, 6 cases of the “disease controls” and 50 normals. To study the titer of antibodies against GM1‐gangliosides, AGM1‐gangliosides and sulfatides the ELISA technique has been applied. Results ‐ An increased titer against GM1‐gangliosides, AGM1‐gangliosides and sulfatides in ALS appeared in serum in 18%, 32% and 11%, resp., in the “disease controls” the increased antibodies titer appeared in single cases. In CSF the appropriate values in ALS were 20%, 15%, 8%, resp. In the “disease controls” a high antibodies titer was a rare finding. Conclusions ‐ It is concluded that in some ALS cases and also in some patients with other motor neuron diseases an autoimmune mechanism may contribute to motor neuron injury.

Novel A18T and pA29S substitutions in α-synuclein may be associated with sporadic Parkinson's disease.

OBJECTIVE Mutations in the α-synuclein-encoding gene SNCA are considered as a rare cause of Parkinsons disease (PD). Our objective was to examine the frequency of the SNCA point mutations among PD patients of Polish origin. METHODS Detection of the known SNCA point mutations A30P (c.88G>C), E46K (c.136G>A) and A53T (c.157A>T) was performed either using the Sequenom MassArray iPLEX platform or by direct sequencing of the SNCA exons 2 and 3. As the two novel substitutions A18T (c.52G>A) and A29S (c.85G>T) were identified, their frequency in a control population of Polish origin was assessed and in silico analysis performed to investigate the potential impact on protein structure and function. RESULTS We did not observe the previously reported point mutations in the SNCA gene in our 629 PD patients; however, two novel potentially pathogenic substitutions A18T and A29S were identified. Each variant was observed in a single patient presenting with a typical late-onset sporadic PD phenotype. Although neither variant was observed in control subjects and in silico protein analysis predicts a damaging effect for A18T and pA29S substitutions, the lack of family history brings into question the true pathogenicity of these rare variants. CONCLUSIONS Larger population based studies are needed to determine the pathogenicity of the A18T and A29S substitutions. Our findings highlight the possible role of rare variants contributing to disease risk and may support further screening of the SNCA gene in sporadic PD patients from different populations.

Are electrophysiological autonomic tests useful in the assessment of dysautonomia in Parkinson's disease?

To assess the autonomic system in Parkinsons disease (PD), the sympathetic skin response (SSR) and the R-R interval variation (RRIV) tests were studied in 26 PD patients and in 24 healthy controls. The aim of the study was to evaluate the sympathetic and parasympathetic system function in PD, to define the pattern of autonomic abnormalities found in SSR and RRIV in parkinsonian patients as well as to analyze the usefulness of both tests in paraclinical assessment of the dysautonomia, compared with clinical symptoms and signs of the autonomic nervous system involvement. The corrrelations between both autonomic tests results were also studied. In PD patients SSR test was abnormal in about 35% and RRIV was abnormal in about 54% of patients. SSR and RRIV were both abnormal in about 27% of PD patients whereas at least one of electrophysiological autonomic tests was abnormal in about 62% of PD patients. Clinical and paraclinical signs of dysautonomia occurred in a similar proportion of patients (i.e. in about 62%). A weak correlation was found between the latency of SSR from upper limbs and the value of RRIV during deep breathing (p=0.063). Our results show that SSR and RRIV are non-invasive paraclinical electrophysiological tests that confirm clinical dysautonomia in PD and can supplement the clinical differentiation of Parkinsonian syndromes.

Glucocerebrosidase mutations p.L444P and p.N370S are not associated with multisystem atrophy, progressive supranuclear palsy and corticobasal degeneration in Polish patients

Recently, mutations in the GBA gene coding for lysosomal beta-glucocerebrosidase have been found as a risk factor for Parkinson’s disease (PD) and Dementia with Lewy Bodies (DLB) [1–3]. These mutations seem to participate in the formation of Lewy bodies. PD and DLB have been classified as synucleinopathies; the third most common synucleinopathy are multisystem atrophies (MSA), which may share with PD and DLB at least part of the molecular pathogenesis. The incidence of mutations in the GBA gene in PD patients is variable and related to different populations studied, methods of DNA testing (sequencing versus looking for the most common mutations only), and different control groups. Lewy bodies were also found in some patients with tauopathies like Progressive Supranuclear Palsy (PSP) and corticobasal degeneration (CBD) [4–6]. Thus lysosomal dysfunction caused by GBA mutations may alter or disrupt the processing of the alphaor beta-synuclein [4]. To identify mutations in the GBA gene, genomic DNA was extracted from the white blood cells by standard techniques. A screening for mutations, p.L444P and p.N370S was performed in a group of 66 MSA patients (MSA-P = 34) and (MSA-C = 31), 34 PSP patients and in five cases of CBD. The patients were diagnosed at two movement disordered centers according to clinical criteria and the level of diagnosis (possible and probable) is shown in Table 1. PCR-RFLP methods were used as described earlier. Our results were compared to incidence of GBA mutations in other European populations and in PD/DLB patients [1–3]. None of the examined mutations in the GBA gene has been found in our cohort of patients with MSA, PSP and CBD. Although a limited number of our patients, and a less sensitive technique than direct sequencing [7], cannot completely rule out the possibility of increased frequency of p.L444P and p.N370S mutations in the beta-glucocerebrosidase gene (GBA), it seems rather unlikely that the incidence of these particular GBA mutations in MSA and PSP are compatible to their frequency in PD (about 4%) and DLB (from 4 to 23%), as reported in the literature [2, 8]. As yet, a total number of the published patients with MSA tested for GBA mutations are below the level of sensitivity because the incidence of the heterozygote state for the above mutations in European populations, excluding Scandinavia, is about 0.3%. Our results are also in agreement with those of neuropathologically confirmed MSA patients, published recently [9]. These results may indicate that PD and (DLB) have another pathway in formation of Lewy bodies than has MSA [10]. We also didn’t see differences between parkinsonian and cerebellar type of MSA. Moreover, we didn’t identify any GBA mutations in PSP and CBD patients. Z. Jamrozik (&) H. Kwiecinski Department of Neurology, Medical University of Warsaw, Warsaw, Poland e-mail: zjamrozik@amwaw.edu.pl

Late onset GM2 gangliosidosis mimicking spinal muscular atrophy.

A case of late onset GM2 gangliosidodis with spinal muscular atrophy phenotype followed by cerebellar and extrapyramidal symptoms is presented. Genetic analysis revealed compound heterozygous mutation in exon 10 of the HEXA gene. Patient has normal intelligence and emotional reactivity. Neuroimaging tests of the brain showed only cerebellar atrophy consistent with MR spectroscopy (MRS) abnormalities. (18)F-fluorodeoxyglucose positron emission tomography (18)F-FDG PET/CT of the brain revealed glucose hypometabolism in cerebellum and in temporal and occipital lobes bilaterally.

The role of neuroimaging in the diagnosis of the atypical parkinsonian syndromes in clinical practice.

Atypical parkinsonian disorders (APD) are a heterogenous group of neurodegenerative diseases such as: progressive supranuclear palsy (PSP), multiple system atrophy (MSA), cortico-basal degeneration (CBD) and dementia with Lewy bodies (DLB). In all of them core symptoms of parkinsonian syndrome are accompanied by many additional clinical features not typical for idiopathic Parkinsons disease (PD) like rapid progression, gaze palsy, apraxia, ataxia, early cognitive decline, dysautonomia and usually poor response to levodopa therapy. In the absence of reliably validated biomarkers the diagnosis is still challenging and mainly based on clinical criteria. However, robust data emerging from routine magnetic resonance imaging (MRI) as well as from many advanced MRI techniques such as: diffusion weighted imaging (DWI) and diffusion tensor imaging (DTI), magnetic resonance spectroscopy (MRS), voxel-based morphometry (VBM), susceptibility-weighted imaging (SWI) may help in differential diagnosis. The main aim of this review is to summarize briefly the most important and acknowledged radiological findings of conventional MRI due to its availability in standard clinical settings. Nevertheless, we present shortly other methods of structural (like TCS - transcranial sonography) and functional imaging (like SPECT - single photon emission computed tomography or PET - positron emission tomography) as well as some selected advanced MRI techniques and their potential future applications in supportive role in distinguishing APD.

Immunochemical quantification of glycoconjugates in serum and cerebrospinal fluid of amyotrophic lateral sclerosis patients.

Glycoconjugates in the serum of 73 patients with amyotrophic lateral sclerosis (ALS), 21 cases of other motor neuron diseases and 20 healthy controls were determined. Cerebrospinal fluid (CSF) was studied in 64, 7 and 10 of these subjects. respectively. The level of sialic acid containing glycoconjugates, detected by Maakia amurensis agglutinin (M.AA), was decreased in the serum of 61.6% of the ALS patients, while in the CSF it was decreased, on average, in 75% of these cases. Only in single ALS cases was the concentration of these glycoconjugates increased. There was no correlation between the content of MAA‐labelled glycoconjugates both in serum and CSF and the titre of sialic acid containing antiGMI gangliosides. The glycoconjugates, detected by peanut agglutinin (PNA) which recognizes the disaccharide galactose β(1‐3)N‐acetylgalactosamine (GGN), were decreased in the serum of 78.1% of ALS patients, while in CSF they were increased in 54.7% of these cases. There was no correlation between the concentration of PNA‐labelled glycoconjugates both in serum and CSF as well as the titre of antibodies against GGN‐containing anti‐GM1 and anti‐AGM1 gangliosides. Changes in the level of the MAA‐ and PNA‐labelled glycoconjugates, as well as the titre of anti‐GM1 and anti‐AGM1 gangliosides antibodies were not specific for ALS. They were also observed in some cases of other motor neuron diseases. The low level of the lectin‐labelled glycoconjugates in serum and party in CSF of the majority of ALS patients is possibly the consequence of their accelerated clearance and/or specific inactivation by the formation of immune complexes or epitope binding. Degeneration of neurons and muscle cells could also be responsible. The relatively low incidence of high anti‐glycolipids antibodies titre may be, at least partly, connected with the low concentration of the appropriate antigens. The increased content of PNA‐labelled glycoconjugates in the CSF of the majority of ALS patients, together with the low incidence of high titre of antibodies against the appropriate glycolipids, could indicate that in CSF this lectin binds to the GGN epitope of glycoproteins rather than to the GGN epitope of glycolipids.