Evaluation of cerebrospinal fluid alpha-synuclein seed amplification assay in PSP and CBS.

Background: Seed amplification assay (SAA) testing has become an important biomarker in the diagnosis of alpha-synuclein related neurodegenerative disorders. Objectives: To assess the rate of alpha-synuclein SAA positivity in progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS), and analyse the clinical and pathological features of SAA positive and negative cases. Methods: 106 CSF samples from clinically diagnosed PSP (n=59), CBS (n=37) and indeterminate parkinsonism cases (n=10) were analysed using alpha-synuclein SAA. Results: Three cases (1 PSP, 2 CBS) were Multiple System Atrophy (MSA)-type SAA positive. 5/59 (8.5%) PSP cases were Parkinson's disease (PD)-type SAA positive, and these cases were older and had a shorter disease duration compared with SAA negative cases. In contrast, 9/35 (25.7%) CBS cases were PD-type SAA positive. Conclusions: Our results suggest that PD-type seeds can be detected in PSP and CBS using a CSF alpha-synuclein SAA, and in PSP this may impact on clinical course.

Novel clinicopathological characteristics differentiate dementia with Lewy bodies from Parkinson's disease dementia.

Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) known as Lewy body dementias have overlapping clinical and neuropathological features. Neuropathology in both includes combination of Lewy body and Alzheimer's disease (AD) pathology. Cerebral amyloid angiopathy (CAA), often seen in AD, is increasingly recognized for its association with dementia. AIMS: This study investigated clinical and neuropathological differences between DLB and PDD. METHODS: 52 PDD and 16 DLB cases from the Queen Square Brain Bank (QSBB) for Neurological disorders were included. Comprehensive clinical data of motor and cognitive features were obtained from medical records. Neuropathological assessment included examination of CAA, Lewy body and AD pathology. RESULTS: CAA was more common in DLB than in PDD (P = 0.003). The severity of CAA was greater in DLB than in PDD (P = 0.009), with significantly higher CAA scores in the parietal lobe (P = 0.043), and the occipital lobe (P = 0.008), in DLB than in PDD. The highest CAA scores were observed in cases with APOE ε4/4 and ε2/4. Survival analysis showed worse prognosis in DLB, as DLB reached each clinical milestone sooner than PDD. Absence of dyskinesia in DLB is linked to the significantly lower lifetime cumulative dose of levodopa in comparison with PDD. CONCLUSIONS: This is the first study which identified prominent concurrent CAA pathology as a pathological substrate of DLB. More prominent CAA and rapid disease progression as measured by clinical milestones distinguish DLB from PDD.

Review: Clinical, neuropathological and genetic features of Lewy body dementias.

Lewy body dementias are the second most common neurodegenerative dementias after Alzheimer's disease and include dementia with Lewy bodies and Parkinson's disease dementia. They share similar clinical and neuropathological features but differ in the time of dementia and parkinsonism onset. Although Lewy bodies are their main pathological hallmark, several studies have shown the emerging importance of Alzheimer's disease pathology. Clinical amyloid-ß imaging using Pittsburgh Compound B (PiB) supports neuropathological studies which found that amyloid-ß pathology is more common in dementia with Lewy bodies than in Parkinson's disease dementia. Nevertheless, other co-occurring pathologies, such as cerebral amyloid angiopathy, TDP-43 pathology and synaptic pathology may also influence the development of neurodegeneration and dementia. Recent genetic studies demonstrated an important role of APOE genotype and other genes such as GBA and SNCA which seem to be involved in the pathophysiology of Lewy body dementias. The aim of this article is to review the main clinical, neuropathological and genetic aspects of dementia with Lewy bodies and Parkinson's disease dementia. This is particularly relevant as future management for these two conditions may differ.

Identification of candidate cerebrospinal fluid biomarkers in parkinsonism using quantitative proteomics.

INTRODUCTION: Neurodegenerative parkinsonian syndromes have significant clinical and pathological overlap, making early diagnosis difficult. Cerebrospinal fluid (CSF) biomarkers may aid the differentiation of these disorders, but other than α-synuclein and neurofilament light chain protein, which have limited diagnostic power, specific protein biomarkers remain elusive. OBJECTIVES: To study disease mechanisms and identify possible CSF diagnostic biomarkers through discovery proteomics, which discriminate parkinsonian syndromes from healthy controls. METHODS: CSF was collected consecutively from 134 participants; Parkinson's disease (n = 26), atypical parkinsonian syndromes (n = 78, including progressive supranuclear palsy (n = 36), multiple system atrophy (n = 28), corticobasal syndrome (n = 14)), and elderly healthy controls (n = 30). Participants were divided into a discovery and a validation set for analysis. The samples were subjected to tryptic digestion, followed by liquid chromatography-mass spectrometry analysis for identification and relative quantification by isobaric labelling. Candidate protein biomarkers were identified based on the relative abundances of the identified tryptic peptides. Their predictive performance was evaluated by analysis of the validation set. RESULTS: 79 tryptic peptides, derived from 26 proteins were found to differ significantly between atypical parkinsonism patients and controls. They included acute phase/inflammatory markers and neuronal/synaptic markers, which were respectively increased or decreased in atypical parkinsonism, while their levels in PD subjects were intermediate between controls and atypical parkinsonism. CONCLUSION: Using an unbiased proteomic approach, proteins were identified that were able to differentiate atypical parkinsonian syndrome patients from healthy controls. Our study indicates that markers that may reflect neuronal function and/or plasticity, such as the amyloid precursor protein, and inflammatory markers may hold future promise as candidate biomarkers in parkinsonism.

A panel of nine cerebrospinal fluid biomarkers may identify patients with atypical parkinsonian syndromes.

BACKGROUND: Patients presenting with parkinsonian syndromes share many clinical features, which can make diagnosis difficult. This is important as atypical parkinsonian syndromes (APSs) such as progressive supranuclear palsy (PSP), multiple system atrophy (MSA) and corticobasal syndrome (CBS) carry a poor prognosis, compared with patients with Parkinson's disease (PD). In addition, there is overlap between APS and dementia diseases, such as Alzheimer's disease (AD) and frontotemporal dementia (FTD). OBJECTIVE: To use a panel of cerebrospinal fluid (CSF) biomarkers to differentiate patients with APS from PD and dementia. METHODS: A prospective cohort of 160 patients and 30 control participants were recruited from a single specialist centre. Patients were clinically diagnosed according to current consensus criteria. CSF samples were obtained from patients with clinical diagnoses of PD (n=31), PSP (n=33), CBS (n=14), MSA (n=31), AD (n=26) and FTD (n=16). Healthy, elderly participants (n=30) were included as controls. Total τ (t-τ), phosphorylated τ (p-τ), ß-amyloid 1-42 (Aß42), neurofilament light chain (NFL), α-synuclein (α-syn), amyloid precursor protein soluble metabolites α and ß (soluble amyloid precursor protein (sAPP)α, sAPPß) and two neuroinflammatory markers (monocyte chemoattractant protein-1 and YKL-40) were measured in CSF. A reverse stepwise regression analysis and the false discovery rate procedure were used. RESULTS: CSF NFL (p<0.001), sAPPα (p<0.001) and a-syn (p=0.003) independently predicted diagnosis of PD versus APS. Together, these nine biomarkers could differentiate patients with PD from APS with an area under the curve of 0.95 and subtypes of APS from one another. There was good discriminatory power between parkinsonian groups, dementia disorders and healthy controls. CONCLUSIONS: A panel of nine CSF biomarkers was able to differentiate APS from patients with PD and dementia. This may have important clinical utility in improving diagnostic accuracy, allowing better prognostication and earlier access to potential disease-modifying therapies.

The role of torsinA in dystonia.

DYT1 dystonia is an autosomal-dominant movement disorder, characterised by early onset of involuntary sustained muscle contractions. It is caused by a 3-bp deletion in the DYT1 gene, which results in the deletion of a single glutamate residue in the C-terminus of the protein torsinA. TorsinA is a member of the AAA-ATPase family of; chaperones with multiple functions in the cell. There is no evidence of neurodegeneration in DYT1 dystonia, which suggests that mutant torsinA leads to functional neuronal abnormalities leading to dystonic movements. In the recent years, different functional roles have been attributed to torsinA, including being a component of the cytoskeleton and the nuclear envelope, and involvement in the secretory pathway and synaptic vesicle machinery. The aim of this review is to summarise these findings and the different models proposed, which have contributed to our current understanding of the function of torsinA.

Four novel SPG3A/atlastin mutations identified in autosomal dominant hereditary spastic paraplegia kindreds with intra-familial variability in age of onset and complex phenotype.

Mutation of the atlastin gene (SPG3A) is responsible for approximately 10% of autosomal dominant hereditary spastic paraplegia (AD-HSP) cases. The goal of this study was to identify novel disease causing atlastin mutations. Atlastin nucleotide variations were detected by direct sequencing of all 14 exons in 70 autosomal dominant (AD), 16 single sibship and 14 sporadic spastic paraplegia patients. Six mis-sense mutations (four of which were novel) were identified in six unrelated AD-HSP kindreds in exons 4, 7 and 8 of the atlastin gene. One kindred with a novel mutation showed variability in clinical phenotype and age of onset. Mutations are predicted to decrease GTPase activity, cause morphological abnormalities of the endoplasmic reticulum and prevent maturation of the Golgi complex resulting in impaired vesicle trafficking. Our study significantly adds to the spectrum of mutations and clinical phenotype of SPG3A. We advocate that all spastin mutation negative AD-HSP kindreds should be screened for pathogenic atlastin mutations regardless of age of onset or phenotypic complexity.

CDIP-58 can measure the impact of botulinum toxin treatment in cervical dystonia.

We compared the responsiveness of the Cervical Dystonia Impact Profile (CDIP-58), Medical Outcome Study Short Form-Health Survey (SF-36), Functional Disability Questionnaire (FDQ), and Pain and Activities of Daily Living subscales of the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) in participants with cervical dystonia treated with botulinum toxin A. Subscales of CDIP-58 were more sensitive in detecting statistical and clinical change than comparable subscales of the SF-36, FDQ, and TWSTRS.

Increased rate of whole-brain atrophy over 6 months in early Huntington disease.

The authors measured the rate of whole-brain atrophy over 6 months in 13 patients with early Huntington disease (HD) and seven matched controls. Patients with early HD had significantly increased rates of whole-brain atrophy vs controls (mean [SD] HD, 1.10 [0.88]%/year; controls, 0.26 [0.54]%/year). The measurement of cerebral change over short time periods (e.g., 6 months) may be relevant for trials designed to assess effects on neurodegeneration or atrophy.

Capturing the true burden of dystonia on patients: the Cervical Dystonia Impact Profile (CDIP-58).

OBJECTIVES: To develop a new rating scale for measuring the health impact of cervical dystonia (CD) that includes patients' perceptions and complements existing observer dependent clinician rating scales. METHODS: Scale development was in three stages. In Stage 1, a large pool of items was generated from patient interviews (n = 25), expert opinion, and literature review. In Stage 2, these items were administered by postal survey to people with CD. The resulting data were analyzed using Rasch item analysis to construct, from the item pool, a rating scale that satisfied criteria for rigorous measurement. In Stage 3, the measurement properties of this rating scale were examined in an independent sample of people with CD. RESULTS: In Stage 1, 150 items concerning the health impact of CD were generated. In Stage 2, 556 people completed questionnaires (87% response rate) and a 58-item rating scale measuring the health impact of CD in eight areas was constructed (CD Impact Profile, CDIP-58). In Stage 3, CDIP-58 data from 391 people (87% response rate) were received. Analyses supported the measurement of eight unidimensional constructs (infit mean square range 0.62 to 1.50), item calibration (33.37 to 67.56), and patient separation statistics (2.59 to 3.38). Items demonstrated stable calibrations in subgroups of people with CD supporting the stability of the CDIP-58. CONCLUSIONS: The CDIP-58 is a reliable and valid patient-based rating scale measuring the health impact of CD in eight health dimensions.

SPG3A mutation screening in English families with early onset autosomal dominant hereditary spastic paraplegia.

Mutations in the SPG3A gene encoding the novel GTPase atlastin have recently been implicated in causing autosomal dominant hereditary spastic paraplegia (ADHSP) in six unrelated families. The phenotype of affected individuals in all cases has been of an early onset uncomplicated form of the disease. One particular missense mutation, R239C, in exon 7 of SPG3A has been identified in three of these families. We performed mutation screening by direct sequencing of all 14 exons and flanking sequences of the SPG3A gene in affected individuals from 12 unrelated English families, all with an early onset uncomplicated ADHSP in whom spastin mutations had previously been excluded. The R239C mutation was found to co-segregate with the disease in one English ADHSP family confirming a widespread prevalence for this commonly occurring mutation. No additional SPG3A mutations were identified in the remaining 11 families suggesting that even within this specific sub-set of early onset uncomplicated ADHSP patients atlastin mutations are relatively rare.

A clinical and genetic study of SPG5A linked autosomal recessive hereditary spastic paraplegia.

The authors performed a clinical and genetic study of a large consanguineous English family with uncomplicated autosomal recessive hereditary spastic paraplegia (ARHSP). Linkage to the previously described SPG5A locus was established with maximum multipoint lod score of 4.84. The locus was refined to a 23.6 cM interval between markers D8S1833 and D8S285. No evidence of oxidative phosphorylation defects was found in muscle biopsies from two affected individuals.

Screening of patients with hereditary spastic paraplegia reveals seven novel mutations in the SPG4 (Spastin) gene.

Hereditary spastic paraplegia (HSP) is a heterogeneous condition characterised in its pure form by progressive lower limb spasticity. Mutations in SPG4 (encoding spastin) may be responsible for up to 40% of autosomal dominant (AD) cases. A cohort of 41 mostly pure HSP patients from Britain and Austria, 30 of whom displayed AD inheritance, was screened for mutations in SPG4 by single strand conformation polymorphism (SSCP) analysis followed by sequencing of samples with mobility shifts. We identified eight SPG4 mutations in pure AD HSP patients, seven of which were novel: one missense mutation within the AAA cassette (1633G>T), two splice site mutations (1130-1G>T, 1853+2T>A) and four frameshift mutations (190_208dup19, 1259_1260delGT, 1702_1705delGAAG, 1845delG). A novel duplication in intron 11 (1538+42_45dupTATA) was also detected. We report the HUGO-approved nomenclature of these mutations as well. Furthermore, we detected a silent change (1004G>A; P293P), previously reported as a mutation, which was also present in controls. The frequency of SPG4 mutations detected in pure AD HSP was 33.3%, suggesting that screening of such patients for SPG4 mutations is worthwhile. Most patients will have unique mutations. Screening of SPG4 in apparently isolated cases of HSP may be of less value.

A polymorphism in the dopamine receptor DRD5 is associated with blepharospasm.

Abnormalities in dopamine neurotransmission are thought to underlie the generation of dystonic movements. The authors performed a case-control allelic association study in patients with the focal dystonia blepharospasm, using polymorphisms in the dopamine receptor and transporter genes. Allele 2 of a DRD5 dinucleotide repeat was significantly associated with blepharospasm. This may indicate a pathogenic role for this receptor.

A large family with hereditary spastic paraparesis due to a frame shift mutation of the spastin (SPG4) gene: association with multiple sclerosis in two affected siblings and epilepsy in other affected family members.

Hereditary spastic paraparesis (HSP) is a clinically and genetically heterogeneous neurodegenerative disorder characterised by progressive lower limb spasticity and weakness. Some forms have been associated with white matter lesions and complex phenotypes. This study was prompted by the diagnosis of multiple sclerosis (MS) in two sisters from a large pedigree with hereditary spastic paraparesis. Twelve affected members of the extended family were examined (MRI and EEG were carried out and evoked potentials measured in five), and historical information was obtained from six affected deceased persons. The inherited disease phenotype was confirmed as autosomal dominant hereditary spastic paraparesis associated with epilepsy in four affected persons. None of the extended family had evidence of MS. Genetic analysis of the family has shown linkage to chromosome 2p and sequencing of the spastin gene has identified a 1406delT frameshift mutation in exon 10. This kindred demonstrates the clinical heterogeneity of HSP associated with spastin mutations. The possible relevance of the concurrence of HSP and MS in the sib pair is discussed.