Neurological update: non-motor symptoms in atypical parkinsonian syndromes.

Among people with Parkinson's disease (PD), non-motor symptoms (NMS) are a well-recognised cause of significant morbidity and poor quality of life. Yet, it is only more recently that NMS have been recognised to affect the lives of patients with atypical parkinsonian syndromes in a similar fashion. The aim of this article is to highlight and compare the relative prevalence of NMS among patients with atypical parkinsonian syndromes in the published literature, which largely remain underreported and unaddressed in routine clinical practice. All NMS that are recognised to occur in PD are also found to commonly occur in atypical parkinsonian syndromes. In particular, excessive daytime sleepiness is more prevalent among atypical parkinsonian syndromes (94.3%) compared to PD (33.9%) or normal controls (10.5%) (p < 0.001). Urinary dysfunction (not limited to urinary incontinence) is not only found to occur in MSA (79.7%) and PD (79.9%), but has also been reported in nearly half of the patients with PSP (49.3%), DLB (42%) and CBD (53.8%) (p < 0.001). Apathy is significantly more common among the atypical parkinsonian syndromes [PSP (56%), MSA (48%), DLB (44%), CBD (43%)] compared to PD (35%) (p = 0.029). Early recognition and addressing of NMS among atypical parkinsonian syndromes may help improve the holistic patient care provided and may encompass a range of conservative and pharmacotherapeutic treatments to address these symptoms.

Thalamic and cerebellar hypoperfusion in single photon emission computed tomography may differentiate multiple system atrophy and progressive supranuclear palsy.

Neuroimaging in the context of examining atypical parkinsonian tauopathies is an evolving matter. Positron emission tomography and single photon emission computed tomography (SPECT) bring tools, which may be reasonable in supplementary examination, however, cannot be interpreted as a criterion standard for correct diagnosis. The aim of this observational study was to assess the differentiating potential of perfusion SPECT in 3 types of atypical parkinsonisms: multiple system atrophy parkinsonian type (MSA-P), corticobasal syndrome (CBS), and progressive supranuclear palsy (PSP). The study was carried out using the comparison of standard deviations of perfusion in patients from these 3 groups. Data obtained from 10 patients with clinical diagnosis MSA-P, 14 patients with CBS and 21 patients with PSP, which were analyzed using Tukey honest significant difference post-hoc test, revealed significant differences of perfusion P < .05 between MSA-P and PSP within the cerebellum and thalamus. No significant differences between CBS and PSP were observed.

In vivo evidence for decreased scyllo-inositol levels in the supplementary motor area of patients with Progressive Supranuclear Palsy: A proton MR spectroscopy study.

INTRODUCTION: Several structural and functional neuroimaging studies have shown that the Supplementary Motor Area (SMA) is affected by tau pathology in patients with Progressive Supranuclear Palsy (PSP). The aim of the study was to investigate the biochemical profile of SMA in PSP patients, using proton magnetic resonance spectroscopy (1H-MRS). METHODS: Sixteen PSP patients and 18 healthy controls participated in this study. 1H-MRS was performed by using a Point RESolving Spectroscopy (PRESS) single-voxel sequence implemented on a 3-T scanner. A voxel of 25 × 25 × 15 mm involving the right and left SMA was acquired in all subjects. Peak areas of N-acetyl-aspartate + N-acetyl-aspartyl-glutamate (NAA), creatine with phosphocreatine (Cr), glycerophosphocholine + phosphocholine (Cho), glutamate + glutamine (Glx), glutathione (GSH), myo-Inositol (mI) and Scyllo-Inositol (Scyllo) were calculated using a version 6.3-1K of the fitting program LCModel. Comparative analysis was performed on both absolute concentrations and ratio values relative to Cr. RESULTS: PSP patients showed a significant decrease in Scyllo concentration and Scyllo/Cr ratio values in SMA, compared to controls, whereas no difference between groups was found for the other ratio values. Of note, the attention and working memory functions were positively related to Scyllo and Scyllo/Cr values in PSP patients. CONCLUSIONS: Our study demonstrates that Scyllo and Scyllo/Cr were significantly reduced in the SMA of PSP patients. Because Scyllo seems to be able to protect against formation of toxic fibrils of amyloid-beta fragments and tau oligomers deposition, these preliminary findings may open new perspectives to investigate Scyllo as a new potential disease-modifying therapy for PSP.

Preclinical, phase I, and phase II investigational clinical trials for treatment of progressive supranuclear palsy.

INTRODUCTION: Our understanding of the pathological basis of progressive supranuclear palsy (PSP), as the most common atypical parkinsonian syndrome, has greatly increased in recent years and a number of disease-modifying therapies are under evaluation as a result of these advances. AREAS COVERED: In this review, we discuss disease-modifying therapeutic options which are currently under evaluation or have been evaluated in preclinical or clinical trials based on their targeted pathophysiologic process. The pathophysiologic mechanisms are broadly divided into three main categories: genetic mechanisms, abnormal post-translational modifications of tau protein, and transcellular tau spread. EXPERT OPINION: Once the best therapeutic approaches are identified, it is likely that some combination of interventions will need to be evaluated, but this will take time. It is critical to treat patients at early stages, and development of the Movement Disorder Society PSP diagnostic criteria is an important step in this direction. In addition, development of biological biomarkers such as tau PET and further refinement of tau ligands may help both diagnose early and measure disease progression. In the meantime, a comprehensive, personalized interdisciplinary approach to this disease is absolutely necessary.

Machine learning on brain MRI data for differential diagnosis of Parkinson's disease and Progressive Supranuclear Palsy.

BACKGROUND: Supervised machine learning has been proposed as a revolutionary approach for identifying sensitive medical image biomarkers (or combination of them) allowing for automatic diagnosis of individual subjects. The aim of this work was to assess the feasibility of a supervised machine learning algorithm for the assisted diagnosis of patients with clinically diagnosed Parkinson's disease (PD) and Progressive Supranuclear Palsy (PSP). METHOD: Morphological T1-weighted Magnetic Resonance Images (MRIs) of PD patients (28), PSP patients (28) and healthy control subjects (28) were used by a supervised machine learning algorithm based on the combination of Principal Components Analysis as feature extraction technique and on Support Vector Machines as classification algorithm. The algorithm was able to obtain voxel-based morphological biomarkers of PD and PSP. RESULTS: The algorithm allowed individual diagnosis of PD versus controls, PSP versus controls and PSP versus PD with an Accuracy, Specificity and Sensitivity>90%. Voxels influencing classification between PD and PSP patients involved midbrain, pons, corpus callosum and thalamus, four critical regions known to be strongly involved in the pathophysiological mechanisms of PSP. COMPARISON WITH EXISTING METHODS: Classification accuracy of individual PSP patients was consistent with previous manual morphological metrics and with other supervised machine learning application to MRI data, whereas accuracy in the detection of individual PD patients was significantly higher with our classification method. CONCLUSIONS: The algorithm provides excellent discrimination of PD patients from PSP patients at an individual level, thus encouraging the application of computer-based diagnosis in clinical practice.

PSP as distinguished from CBD, MSA-P and PD by clinical and imaging differences at an early stage.

OBJECTIVE: Because it is often difficult to precisely diagnose and distinguish progressive supranuclear palsy (PSP) from corticobasal degeneration (CBD), multiple system atrophy-parkinsonism (MSA-P) and Parkinson's disease (PD) at the onset of the disease, we compared the patients and clarified the features of these diseases. METHODS: We compared 77 PSP, 26 CBD, 26 MSA-P and 166 PD patients from clinical and imaging points of view including cerebral blood flow (CBF) in the frontal eye field. RESULTS: The clinical characteristics of PSP were supranuclear gaze disturbance, optokinetic nystagmus (OKN) impairment and falls at the first visit. On head MRI, midbrain tegmentum atrophy was much more frequently detected in PSP than in all of the other groups. Heart-to-mediastinum average count ratio (H/M) in iodine-123 meta-iodobenzyl guanidine ((123)I-MIBG) myocardial scintigraphy was not decreased in PSP, CBD, MSA-P and PD-Yahr 1 (-1), but patients of PD-2, 3, 4 and 5 showed a significant decrease compared with the PSP group. The CBF in the left frontal eye field of PD-3 group and that in right frontal eye field of PD-3 and PD-4 groups were lower than that of PSP group, although other groups showed a tendency without a significant decrease compared with PSP group. CONCLUSION: PSP is distinguishable from CBD, MSA-P and PD even at the early stage with extra-ocular movement (EOM) disturbance, falls, atrophy of the midbrain tegmentum, and H/M in (123)I-MIBG myocardial scintigraphy, and the reduction of CBF in area 8 could serve as a supplemental diagnostic method for distinguishing PSP from PD-3 or PD-4.

Disrupted thalamocortical connectivity in PSP: a resting-state fMRI, DTI, and VBM study.

Progressive supranuclear palsy (PSP) is associated with pathological changes along the dentatorubrothalamic tract and in premotor cortex. We aimed to assess whether functional neural connectivity is disrupted along this pathway in PSP, and to determine how functional changes relate to changes in structure and diffusion. Eighteen probable PSP subjects and 18 controls had resting-state (task-free) fMRI, diffusion tensor imaging and structural MRI. Functional connectivity was assessed between thalamus and the rest of the brain, and within the basal ganglia, salience and default mode networks (DMN). Patterns of atrophy were assessed using voxel-based morphometry, and patterns of white matter tract degeneration were assessed using tract-based spatial statistics. Reduced in-phase functional connectivity was observed between the thalamus and premotor cortex including supplemental motor area (SMA), striatum, thalamus and cerebellum in PSP. Reduced connectivity in premotor cortex, striatum and thalamus were observed in the basal ganglia network and DMN, with subcortical salience network reductions. Tract degeneration was observed between cerebellum and thalamus and in superior longitudinal fasciculus, with grey matter loss in frontal lobe, premotor cortex, SMA and caudate nucleus. SMA functional connectivity correlated with SMA volume and measures of cognitive and motor dysfunction, while thalamic connectivity correlated with degeneration of superior cerebellar peduncles. PSP is therefore associated with disrupted thalamocortical connectivity that is associated with degeneration of the dentatorubrothalamic tract and the presence of cortical atrophy.

[Somatoform disorder or neurological syndrome? Complex mental and movement disorder and autonomic dysfunction in a 65-year-old patient - Case 1/2011]. / Somatoforme Störung oder neurologisches Syndrom? Komplexe psychische, vegetative und motorische Störungen bei einer 65-jährigen Patientin - Fall 1/2011.

HISTORY AND ADMISSION FINDINGS: A 65-year-old female patient presented with increasing vertigo, tendency to fall, dry cough and, in addition, numerous psychic and somatic symptoms since 6 years. Former diagnostic attempts did not yield clarifying results. In part, the patient had not followed up on former recommendations for further diagnostic procedures. With a suspected somatization disorder the patient was admitted to the Department of Psychosomatic Medicine. INVESTIGATIONS: The neurological examination at admission revealed vertical oculomotor palsy and tendency to fall backwards indicating an affection of the brain stem. A magnetic resonance imaging of the head showed atrophy of the mesencephalon. DIAGNOSIS AND TREATMENT: In light of these findings the patient was diagnosed Steele-Richardson-Olszewksi syndrome. The therapy which comprises training measures and medication with a cholinesterase inhibitor aims to retain neuropsychological and motional abilities. Besides, psychotherapy is offered alongside to help the patient to cope with the disease. CONCLUSIONS: Treating patients with somatic and psychological symptoms calls for careful anamnestic exploration and clinical examination. Psychological alterations following neurological affection of the brain can imitate somatization disorder.

Magnetic resonance imaging in progressive supranuclear palsy.

Progressive supranuclear palsy (PSP) is a tauopathy, presenting clinically most often with a symmetrical akinetic-rigid syndrome, postural instability, supranuclear gaze palsy and frontal dementia. In the absence of reliably validated biomarkers, the diagnosis of PSP in vivo is presently based on clinical criteria, which to date do not include supporting imaging findings, as is accepted for other neurodegenerative diseases. However, data from conventional magnetic resonance imaging (MRI) and various advanced MRI techniques including magnetic resonance volumetry, voxel-based morphometry, diffusion-weighted and diffusion-tensor imaging, magnetization transfer imaging and proton resonance spectroscopy suggest that MRI can contribute valuable information for the differential diagnosis of PSP. We review here the presently published literature concerning MRI in PSP and discuss the potential role of MRI in differentiating PSP from other parkinsonian syndromes.

Obsessive-compulsive behavior as a symptom of dementia in progressive supranuclear palsy.

AIMS: To describe obsessive-compulsive symptoms (OCS) as under-recognized behavioral and psychological symptoms of dementia of progressive supranuclear palsy (PSP) and to discuss possible mechanisms based on MRI and SPECT findings. METHODS: We studied 74 PSP patients. OCS are defined as persistent and unreasonable, but non-delusional/hallucinatory, ideas and behaviors. Demography, cognition, the widths of middle cerebellar peduncles (MCP) and the inter-caudate distances (ICD), both corrected by the intracranial size (MCP and ICD ratios), and changes on voxel-based SPECT were compared between the subgroups with and without OCS. Finally, the predicative power of various factors to OCS was investigated. RESULTS: We observed OCS in 18 patients (24%). They were obsessed with daily trifles and physical symptoms among other things. OCS was not associated with demography or cognitive levels. OCS-positive patients had significantly smaller MCP and ICD ratios and showed marked uptake decreases in the orbitofrontal cortex, caudate and thalamus. Relative uptake increases in the cerebellum, specifically the tonsils, were milder in OCS-positive than -negative patients. A smaller right MCP, a smaller ICD ratio and lower uptake increases in the right cerebellar were the significant predictors of OCS. CONCLUSIONS: OCS are frequent but under-recognized behavioral and psychological symptoms of dementia in PSP. Dysfunction of the fronto-caudate-thalamus-cerebellum circuit may be involved.

Weber's syndrome with vertical gaze palsy.

Weber's syndrome with vertical gaze palsy is rarely reported in literature. We present a case of a 47-year-old female who developed sudden onset of left exotropia, right sided hemiplegia and vertical gaze palsy. Magnetic resonance imaging (MRI) showed multiple infarcts involving both thalami and extending caudally into the midbrain. This case presents the diverse clinical picture following midbrain infarcts.

Development of a sensitive ELISA for quantification of three- and four-repeat tau isoforms in tauopathies.

Tau protein plays an important role in stabilising and assembling neuronal microtubules. Pathological changes in expression and aggregation of tau isoforms containing three (3R-tau) and four (4R-tau) microtubule-binding repeat domains are associated with several tauopathies. This paper describes novel sandwich ELISAs for quantification of 3R- and 4R-tau in brain. The assays are constructed using well-characterised isoform-specific antibodies (RD3 and RD4) as capture antibodies and an affinity-purified HRP-anti-tau peptide antibody and biotin-tyramide amplification for detection. For 3R-tau, we achieved a minimal detection limit in buffer of 460 pg mL(-1) and a recovery of 81.0% using 500 pg mL(-1) recombinant 3R-tau spiked in diluted brain homogenate. Mean intra- and inter-assay variation of the 3R-tau ELISA was 8.8 and 10.5%, respectively. For 4R-tau, the detection limit was 780 pg mL(-1) and the recovery of 5 ng mL(-1) spiked recombinant 4R-tau was 86.0% and the mean intra- and inter-assay variation was 10.4 and 15.6%, respectively. With these assays, we showed that in progressive supranuclear palsy (PSP) brains, 4R-tau is significantly increased in frontal cortex and caudate, the two regions that are usually associated with 4R-tau-dominant pathology. This increase was not observed in occipital lobe, a region that is spared of tau inclusions. No differences in 3R-tau levels were found between PSP and control brains in all regions tested. With this, we have for the first time developed ELISAs for quantification of 3R- and 4R-tau isoforms in pathological samples. These could prove useful in the pathological investigation and differential diagnosis of tauopathies.

Differentiation of PA from early PSP with different patterns of symptoms and CBF reduction.

OBJECTIVE: To clarify the features of pure akinesia (PA) and progressive supranuclear palsy (PSP) in the early stage of disease. METHODS: We investigated 15 PA and 41 PSP patients' clinical and radiologic features including head MRI, ethyl cysteinate dimmer-single photon emission-computed tomography (ECD-SPECT) and iodine-123 meta-iodobenzyl guanidine (123I-MIBG) myocardial scintigraphy. In ECD-SPECT study, cerebral blood flow (CBF) reduction was quantitatively expressed as Z-score, and that in the frontal lobe was evaluated. RESULTS: Many PSP patients claimed falls as the initial symptom but no PA patients did. Eye movement, as well as optokinetic nystagmus elicitation, was more frequently disturbed in PSP. Dementia, dysarthria and rigidity were also more frequent in PSP than in PA. Midbrain tegmentum atrophy in head MRI was more frequently observed in PSP. CBF in the frontal lobe, especially in the frontal eye field, was significantly lower in PSP than in PA. MIBG myocardial scintigraphy showed no difference between two groups. DISCUSSION: PA and PSP show distinct symptoms from the early stage, indicating that they are distinct disorders. The occurrence of falls and eye movement disturbance, as well as CBF reduction at the frontal eye field, is very important for distinguishing these disorders.

Clinical diagnosis of MM2-type sporadic Creutzfeldt-Jakob disease.

BACKGROUND: No method for the clinical diagnosis of MM2-type sporadic Creutzfeldt-Jakob disease (sCJD) has been established except for pathologic examination. OBJECTIVE: To identify a reliable marker for the clinical diagnosis of MM2-type sCJD. METHODS: CSF, EEG, and neuroimaging studies were performed in eight patients with MM2-type sCJD confirmed by neuropathologic, genetic, and western blot analyses. RESULTS: The eight cases were pathologically classified into the cortical (n = 2), thalamic (n = 5), and combined (corticothalamic) (n = 1) forms. The cortical form was characterized by late-onset, slowly progressive dementia, cortical hyperintensity signals on diffusion-weighted imaging (DWI) of brain, and elevated levels of CSF 14-3-3 protein. The thalamic form showed various neurologic manifestations including dementia, ataxia, and pyramidal and extrapyramidal signs with onset at various ages and relatively long disease duration. Characteristic EEG and MRI abnormalities were almost absent. However, all four patients examined with cerebral blood flow (CBF) study using SPECT showed reduction of the CBF in the thalamus as well as the cerebral cortex. The combined form had features of both the cortical and the thalamic forms, showing cortical hyperintensity signals on DWI and hypometabolism of the thalamus on [18F]2-fluoro-2-deoxy-d-glucose PET. CONCLUSION: For the clinical diagnosis of MM2-type sporadic Creutzfeldt-Jakob disease, cortical hyperintensity signals on diffusion-weighted MRI are useful for the cortical form and thalamic hypoperfusion or hypometabolism on cerebral blood flow SPECT or [18F]2-fluoro-2-deoxy-d-glucose PET for the thalamic form.

Sonographic discrimination of corticobasal degeneration vs progressive supranuclear palsy.

OBJECTIVE: To study the use of brain parenchyma sonography (BPS) in discriminating between patients with corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP). METHODS: Thirteen patients with PSP and eight with CBD were studied with BPS according to a standardized protocol. RESULTS: Seven (88%) of the eight CBD patients showed marked hyperechogenicity of the substantia nigra (SN) but none of eleven PSP patients (Mann-Whitney U test, p < 0.001). This finding indicated CBD with a positive predictive value of 100%. Marked dilatation of the third ventricle (width > 10 mm) was found in 10 (83%) of 12 PSP patients, but in none of the CBD patients (p < 0.005). BPS measurements of ventricle widths closely matched MRI measurements (Pearson correlation, r = 0.90, p < 0.001). The presence of at least one of the BPS findings 1) marked SN hyperechogenicity and 2) third-ventricle width < 10 mm indicated CBD with a sensitivity of 100%, a specificity of 83%, and a positive predictive value of 80%. Other BPS findings such as echogenicity of lentiform and caudate nuclei and widths of the frontal horns did not discriminate between CBD and PSP. One PSP patient could not be assessed because of insufficient acoustic temporal bone windows. CONCLUSIONS: Substantia nigra hyperechogenicity, reported earlier as characteristic brain parenchyma sonography finding in idiopathic Parkinson disease, is also typical for corticobasal degeneration.

Attention and cognition in bradykinetic-rigid syndromes: an event-related potential study.

Bradykinetic-rigid syndromes are often accompanied by cognitive impairment. Because prominent motor involvement in these disorders may interfere with neuropsychological testing, we used event-related potentials (ERPs) for the assessment of cognition and attention in 41 patients with various bradykinetic-rigid syndromes of less than 5 years duration: idiopathic Parkinson's disease corticobasal degeneration, Steele-Richardson-Olszewski syndrome (SRO), and multiple system atrophy. Patients were compared with matched normals. ERP abnormalities in the auditory "oddball" paradigm were found only in corticobasal degeneration and SRO. ERP abnormalities in selective attention tasks were present in all patient groups, changes in SRO being the most prevalent. Abnormalities in corticobasal degeneration were present under "less-attention-demanding" conditions and suggested involvement of posterior parts of the brain. Multiple system atrophy and idiopathic Parkinson's disease patient groups had minimal ERP abnormalities. However, reaction times in MSA were longer in all paradigms. The results of the study support the view that bradykinetic-rigid syndromes involve some attentional deficits, but also have distinct reaction time and ERP characteristics, which may be helpful in differential diagnosis.

The auditory startle reaction in parkinsonian disorders.

The auditory startle reaction to an unexpected loud stimulus is regarded as a brainstem reflex originating in the nucleus reticularis pontis caudalis and being distributed up the brainstem and down the spinal cord along slowly conducting pathways. Auditory startle responses (ASR) have been reported absent or reduced in progressive supranuclear palsy (PSP), and delayed in Parkinson's disease (PD), but normal in multiple-system atrophy (MSA). For the first time we studied ASR in patients fulfilling the clinical criteria of dementia with Lewy bodies (DLB) (n = 8), a neurodegenerative disorder characterized by cortical and subcortical depositions of Lewy bodies resulting in parkinsonism and progressive cognitive decline. For comparison, we also investigated patients with PD (n = 10), MSA (n = 7), PSP (n = 10), and age-matched healthy controls (n = 10). ASR were elicited by binaural high-intensity auditory stimuli. Surface electromyographic activity was simultaneously recorded from facial, upper, and lower extremity muscles. For each muscle, we assessed response probability and measured latency, amplitude, duration, and habituation rate. Patients with DLB had fewer and abnormally delayed ASR of low amplitude and short duration in extremity muscles compared to healthy controls. Furthermore, we confirm and extend previous findings of abnormal ASR in PSP and PD, and also demonstrate exaggerated ASR in extremity muscles of MSA patients. The different patterns of ASR abnormalities may reflect distinct types of brainstem dysfunction in DLB.

Parálisis supranuclear progresiva / Progressive supranuclear palsy

La parálisis supranuclear progresiva (PSP), también llamada síndrome de Steele-Richardson-Olszewski, es uno de los síndromes parkinsionanos atípicos más frecuentes. Es una afección degenerativa de causa desconocida caracterizada por atrofia del tegmentum protuberancial y mesencéfalo, decoloración de la sustancia nigra y relativo respeto de la corteza cerebral. Existe un consenso sobre la dificultad para llegar al diagnóstico de certeza tanto clínico como patológico. Ha habido casos de PSP clínica cuyas autopsias no confirmaron el diagnóstico, y autopsias con hallazgos diagnósticos de PSP que fueron interpretados clínicamente como otros padecimientos o síndromes degenerativos. En Latinoamérica no existen estadísticas epidemiológicas sobre esta entidad nosológica y en Chile no se ha publicado ningún caso hasta la fecha. El objetivo del presente reporte es la presentación de seis casos que cumplen con los criterios diagnósticos establecidos por el National Institute of Neurological Disorders and Stroke and The Society for PSP (NINDS-SPSP) en 1996. Se concluye, a partir del presente trabajo que la PSP no es excepcional en nuestro medio y que debe considerarse entre los diagnósticos diferenciales de los síndromes parkinsonianos