Neurofilament light levels predict clinical progression and death in multiple system atrophy.

Disease-modifying treatments are currently being trialled in multiple system atrophy. Approaches based solely on clinical measures are challenged by heterogeneity of phenotype and pathogenic complexity. Neurofilament light chain protein has been explored as a reliable biomarker in several neurodegenerative disorders but data on multiple system atrophy have been limited. Therefore, neurofilament light chain is not yet routinely used as an outcome measure in multiple system atrophy. We aimed to comprehensively investigate the role and dynamics of neurofilament light chain in multiple system atrophy combined with cross-sectional and longitudinal clinical and imaging scales and for subject trial selection. In this cohort study, we recruited cross-sectional and longitudinal cases in a multicentre European set-up. Plasma and CSF neurofilament light chain concentrations were measured at baseline from 212 multiple system atrophy cases, annually for a mean period of 2 years in 44 multiple system atrophy patients in conjunction with clinical, neuropsychological and MRI brain assessments. Baseline neurofilament light chain characteristics were compared between groups. Cox regression was used to assess survival; receiver operating characteristic analysis to assess the ability of neurofilament light chain to distinguish between multiple system atrophy patients and healthy controls. Multivariate linear mixed-effects models were used to analyse longitudinal neurofilament light chain changes and correlated with clinical and imaging parameters. Polynomial models were used to determine the differential trajectories of neurofilament light chain in multiple system atrophy. We estimated sample sizes for trials aiming to decrease neurofilament light chain levels. We show that in multiple system atrophy, baseline plasma neurofilament light chain levels were better predictors of clinical progression, survival and degree of brain atrophy than the neurofilament light chain rate of change. Comparative analysis of multiple system atrophy progression over the course of disease, using plasma neurofilament light chain and clinical rating scales, indicated that neurofilament light chain levels rise as the motor symptoms progress, followed by deceleration in advanced stages. Sample size prediction suggested that significantly lower trial participant numbers would be needed to demonstrate treatment effects when incorporating plasma neurofilament light chain values into multiple system atrophy clinical trials in comparison to clinical measures alone. In conclusion, neurofilament light chain correlates with clinical disease severity, progression and prognosis in multiple system atrophy. Combined with clinical and imaging analysis, neurofilament light chain can inform patient stratification and serve as a reliable biomarker of treatment response in future multiple system atrophy trials of putative disease-modifying agents.

The genetic and clinico-pathological profile of early-onset progressive supranuclear palsy.

BACKGROUND: Studies on early-onset presentations of progressive supranuclear palsy (PSP) have been limited to those where a rare monogenic cause has been identified. Here, we have defined early-onset PSP (EOPSP) and investigated its genetic and clinico-pathological profile in comparison with late-onset PSP (LOPSP) and Parkinson's disease (PD). METHODS: We included subjects from the Queen Square Brain Bank, PROSPECT-UK study, and Tracking Parkinson's study. Group comparisons of data were made using Welch's t-test and Kruskal-Wallis analysis of variance. EOPSP was defined as the youngest decile of motor age at onset (≤55 years) in the Queen Square Brain Bank PSP case series. RESULTS: We identified 33 EOPSP, 328 LOPSP, and 2000 PD subjects. The early clinical features of EOPSP usually involve limb parkinsonism and gait freezing, with 50% of cases initially misdiagnosed as having PD. We found that an initial clinical diagnosis of EOPSP had lower diagnostic sensitivity (33%) and positive predictive value (38%) in comparison with LOPSP (80% and 76%) using a postmortem diagnosis of PSP as the gold standard. 3/33 (9%) of the EOPSP group had an underlying monogenic cause. Using a PSP genetic risk score (GRS), we showed that the genetic risk burden in the EOPSP (mean z-score, 0.59) and LOPSP (mean z-score, 0.48) groups was significantly higher (P < 0.05) when compared with the PD group (mean z-score, -0.08). CONCLUSIONS: The initial clinical profile of EOPSP is often PD-like. At the group level, a PSP GRS was able to differentiate EOPSP from PD, and this may be helpful in future diagnostic algorithms. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Compulsive versifying after treatment of transient epileptic amnesia.

Compulsive production of verse is an unusual form of hypergraphia that has been reported mainly in patients with right temporal lobe seizures. We present a patient with transient epileptic amnesia and a left temporal seizure focus, who developed isolated compulsive versifying, producing multiple rhyming poems, following seizure cessation induced by lamotrigine. Functional neuroimaging studies in the healthy brain implicate left frontotemporal areas in generating novel verbal output and rhyme, while dysregulation of neocortical and limbic regions occurs in temporal lobe epilepsy. This case complements previous observations of emergence of altered behavior with reduced seizure frequency in patients with temporal lobe epilepsy. Such cases suggest that reduced seizure frequency has the potential not only to stabilize or improve memory function, but also to trigger complex, specific behavioral alterations.

Deep brain stimulation of the subthalamic nucleus: histological verification and 9.4-T MRI correlation.

BACKGROUND: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) using an MRI-guided and MRI-verified technique without microelectrode recording is an effective and safe surgical treatment for patients with Parkinson's disease (PD). OBJECTIVES: To assess the anatomical accuracy of lead placement after MRI-guided, MRI-verified STN DBS using post-mortem histology and high-field MRI at 9.4 T. METHODS: We conducted post-mortem analysis of a patient's brain who had had MRI-guided, MRI-verified STN DBS for PD, using 9.4-T MRI and histology. After death, the brain was retrieved and a block including the electrode tracks down to the mesencephalon was examined with high-field MRI at 9.4 T and histological analysis. RESULTS: High-field MRI images and corresponding histological examination showed that each electrode track ended within the intended target area, and that DBS did not cause significant neuroparenchymal tissue damage. CONCLUSIONS: This study supports the anatomical accuracy of the MRI-guided and MRI-verified method of STN DBS.

Improving Conversations about Parkinson's Dementia.

BACKGROUND: People with Parkinson's disease (PD) have an increased risk of dementia, yet patients and clinicians frequently avoid talking about it due to associated stigma, and the perception that "nothing can be done about it". However, open conversations about PD dementia may allow people with the condition to access treatment and support, and may increase participation in research aimed at understanding PD dementia. OBJECTIVES: To co-produce information resources for patients and healthcare professionals to improve conversations about PD dementia. METHODS: We worked with people with PD, engagement experts, artists, and a PD charity to open up these conversations. 34 participants (16 PD; 6 PD dementia; 1 Parkinsonism, 11 caregivers) attended creative workshops to examine fears about PD dementia and develop information resources. 25 PD experts contributed to the resources. RESULTS: While most people with PD (70%) and caregivers (81%) shared worries about cognitive changes prior to the workshops, only 38% and 30%, respectively, had raised these concerns with a healthcare professional. 91% of people with PD and 73% of caregivers agreed that PD clinicians should ask about cognitive changes routinely through direct questions and perform cognitive tests at clinic appointments. We used insights from the creative workshops, and input from a network of PD experts to co-develop two open-access resources: one for people with PD and their families, and one for healthcare professionals. CONCLUSION: Using artistic and creative workshops, co-learning and striving for diverse voices, we co-produced relevant resources for a wider audience to improve conversations about PD dementia.

Hypokinesia without decrement distinguishes progressive supranuclear palsy from Parkinson's disease.

Repetitive finger tapping is commonly used to assess bradykinesia in Parkinson's disease. The Queen Square Brain Bank diagnostic criterion of Parkinson's disease defines bradykinesia as 'slowness of initiation with progressive reduction in speed and amplitude of repetitive action'. Although progressive supranuclear palsy is considered an atypical parkinsonian syndrome, it is not known whether patients with progressive supranuclear palsy have criteria-defined bradykinesia. This study objectively assessed repetitive finger tap performance and handwriting in patients with Parkinson's disease (n = 15), progressive supranuclear palsy (n = 9) and healthy age- and gender-matched controls (n = 16). The motion of the hand and digits was recorded in 3D during 15-s repetitive index finger-to-thumb tapping trials. The main finding was hypokinesia without decrement in patients with progressive supranuclear palsy, which differed from the finger tap pattern in Parkinson's disease. Average finger separation amplitude in progressive supranuclear palsy was less than half of that in controls and Parkinson's disease (P < 0.001 in both cases). Change in tap amplitude over consecutive taps was computed by linear regression. The average amplitude slope in progressive supranuclear palsy was nearly zero (0.01°/cycle) indicating a lack of decrement, which differed from the negative slope in patients with Parkinson's disease OFF levodopa (-0.20°/cycle, P = 0.002). 'Hypokinesia', defined as <50% of control group's mean amplitude, combined with 'absence of decrement', defined as mean positive amplitude slope, were identified in 87% of finger tap trials in the progressive supranuclear palsy group and only 12% in the Parkinson's disease OFF levodopa group. In progressive supranuclear palsy, the mean amplitude was not correlated with disease duration or other clinimetric scores. In Parkinson's disease, finger tap pattern was compatible with criteria-defined bradykinesia, characterized by slowness with progressive reduction in amplitude and speed and increased variability in speed throughout the tap trial. In Parkinson's disease, smaller amplitude, slower speed and greater speed variability were all associated with a more severe Unified Parkinson's Disease Rating Scale motor score. Analyses of handwriting showed that micrographia, defined as smaller than 50% of the control group's mean script size, was present in 75% of patients with progressive supranuclear palsy and 15% of patients with Parkinson's disease (P = 0.022). Most scripts performed by patients with progressive supranuclear palsy did not exhibit decrements in script size. In conclusion, patients with progressive supranuclear palsy have a specific finger tap pattern of 'hypokinesia without decrement' and they do not have criteria-defined limb bradykinesia. Similarly, 'micrographia' and 'lack of decrement in script size' are also more common in progressive supranuclear palsy than in Parkinson's disease.

Conventional magnetic resonance imaging in confirmed progressive supranuclear palsy and multiple system atrophy.

Conventional magnetic resonance imaging (cMRI) is often used to aid the diagnosis of progressive supranuclear palsy (PSP) and multiple system atrophy (MSA), but its ability to predict the histopathological diagnosis has not been systematically studied. cMRI from 48 neuropathologically confirmed cases, including PSP (n = 22), MSA (n = 13), Parkinson's disease (PD) (n = 7), and corticobasal degeneration (n = 6), and controls (n = 9) were assessed blinded to clinical details and systematically rated for reported abnormalities. Clinical diagnosis and macroscopic postmortem findings were retrospectively assessed. Radiological assessment of MRI was correct in 16 of 22 (72.7%) PSP cases and 10 of 13 (76.9%) MSA cases with substantial interrater agreement (Cohen's kappa 0.708; P < .001); no PSP case was misclassified as MSA or vice versa. MRI was less sensitive but more specific than clinical diagnosis in PSP and both more sensitive and specific than clinical diagnosis in MSA. The "hummingbird" and "morning glory" signs were highly specific for PSP, and "the middle cerebellar peduncle sign" and "hot cross bun" for MSA, but sensitivity was lower (up to 68.4%) and characteristic findings may not be present even at autopsy. cMRI, clinical diagnosis, and macroscopic examination at postmortem have similar sensitivity and specificity in predicting a neuropathological diagnosis. We have validated specific radiological signs in pathologically confirmed PSP and MSA. However, the low sensitivity of these and macroscopic findings at autopsy suggest a need for imaging techniques sensitive to microstructural abnormalities without regional atrophy.

Targeting of the pedunculopontine nucleus by an MRI-guided approach: a cadaver study.

Laboratory evidence suggests that the pedunculopontine nucleus (PPN) plays a central role in the initiation and maintenance of gait. Translational research has led to reports on deep brain stimulation (DBS) of the rostral brainstem in parkinsonian patients. However, initial clinical results appear to be rather variable. Possible factors include patient selection and the wide variability in anatomical location of implanted electrodes. Clinical studies on PPN DBS efficacy would, therefore, benefit from an accurate and reproducible method of stereotactic localization of the nucleus. The present study evaluates the anatomical accuracy of a specific protocol for MRI-guided stereotactic targeting of the PPN in a human cadaver. Imaging at 1.5 and 9.4 T confirmed electrode location in the intended region as defined anatomically by the surrounding fiber tracts. The spatial relations of each electrode track to the nucleus were explored by subsequent histological examination. This confirmed that the neuropil surrounding each electrode track contained scattered large neurons morphologically consistent with those of the subnucleus dissipatus and compactus of the PPN. The results support the accuracy of the described specific MR imaging protocol.

Does corticobasal degeneration exist? A clinicopathological re-evaluation.

The pathological findings of corticobasal degeneration are associated with several distinct clinical syndromes, and the corticobasal syndrome has been linked with a number of diverse pathologies. We have reviewed all the archival cases in the Queen Square Brain Bank for Neurological Disorders over a 20-year period with either a clinical diagnosis of corticobasal syndrome or pathological diagnosis of corticobasal degeneration in an attempt to identify the main diagnostic pitfalls. Of 19 pathologically confirmed corticobasal degeneration cases, only five had been diagnosed correctly in life (sensitivity=26.3%) and four of these had received an alternative earlier diagnosis. All five of these had a unilateral presentation, clumsy useless limb, limb apraxia and myoclonus, four had cortical sensory impairment and focal limb dystonia and three had an alien limb. Eight cases of corticobasal degeneration had been clinically diagnosed as progressive supranuclear palsy, all of whom had vertical supranuclear palsy and seven had falls within the first 2 years. On the other hand, of 21 cases with a clinical diagnosis of corticobasal syndrome, only five had corticobasal degeneration pathology, giving a positive predictive value of 23.8%; six others had progressive supranuclear palsy pathology, five had Alzheimer's disease and the remaining five had other non-tau pathologies. Corticobasal degeneration can present very commonly with a clinical picture closely resembling classical progressive supranuclear palsy or Richardson's syndrome, and we propose the term corticobasal degeneration-Richardson's syndrome for this subgroup. Cases of corticobasal degeneration-Richardson's syndrome have delayed onset of vertical supranuclear gaze palsy (>3 years after onset of first symptom) and the infrequent occurrence of predominant downgaze abnormalities, both of which can be helpful pointers to their underlying corticobasal degeneration pathology. Fourty-two per cent of corticobasal degeneration cases presented clinically with a progressive supranuclear palsy phenotype and 29% of cases with corticobasal syndrome had underlying progressive supranuclear palsy pathology. In contrast, in the Queen Square Brain Bank archival collection, corticobasal syndrome is a rare clinical presentation of progressive supranuclear palsy occurring in only 6 of the 179 pathologically diagnosed progressive supranuclear palsy cases (3%). Despite these diagnostic difficulties we conclude that corticobasal degeneration is a discrete clinicopathological entity but with a broader clinical spectrum than was originally proposed.

Nonmotor symptoms as presenting complaints in Parkinson's disease: a clinicopathological study.

Nonmotor symptoms (NMS) are increasingly recognized as a significant cause of morbidity in later stages of Parkinson's disease (PD). Prodromal NMS are also a well recognized component of the clinical picture in some patients but the prevalence of NMS as presenting complaints, and their impact on clinical management, in pathologically-proven cases of PD is unknown. The presenting complaints of 433 cases of pathologically-proven PD archived at the Queen Square Brain Bank for Neurological Diseases were identified from the clinical case notes. 91/433 (21%) of patients with PD presented with NMS of which the most frequent were pain (15%), urinary dysfunction (3.9%), anxiety, or depression (2.5%). Presenting with NMS is associated with a delayed diagnosis of PD (Mann-Whitney U, P = 0.001). These patients were more likely to be misdiagnosed initially and were more likely to have been referred to orthopedic surgeons or rheumatologists than neurologists (nonmotor group 5.5% vs. motor group 44.2%, chi(2) P < 0.0001). NMS are commonly seen as presenting complaints in pathologically confirmed PD, and initial misdiagnosis may be associated with potentially inappropriate medical interventions. Presenting with NMS does not affect the motor response to medication, but is associated with shorter disease duration (chi(2) P = 0.016).

MM2 subtype of sporadic Creutzfeldt-Jakob disease may underlie the clinical presentation of progressive supranuclear palsy.

The classical presentation of sporadic Creutzfeldt-Jakob disease (sCJD) is rapid progressive dementia often associated with myoclonus and ataxia followed by death in less than a year from diagnosis. The few patients in the literature who presented with parkinsonism and who were suspected to have progressive supranuclear palsy (PSP) all ran a malignant course and most of them died within 3 years of diagnosis. We screened the Queen Square Brain Bank database and, among 213 patients with a clinical diagnosis of PSP, we found ten patients with 3 years or less disease duration, including one patient with CJD pathology. We report this patient and review other similar cases from the literature. Ten additional cases with similar presentation were identified in the literature. The mean disease duration was 24.2 months. The classical clinical, radiological and laboratory findings for sCJD were absent in the majority of these cases. Clinical presentation of these patients consists of: early falls, prominent dementia, early vertical supranuclear gaze palsy and symmetric akinetic syndrome. In the patients who were subtyped at post-mortem, all four represented the MM2 subtype of sCJD. A rapidly progressive course of PSP with early falls, cognitive impairments and vertical supranuclear gaze palsy should raise suspicion of underlying sCJD pathology regardless of absence of supportive findings on ancillary tests. This case and the literature support the notion that biochemical properties of the prion protein can influence the clinical presentation of sCJD.

The midbrain to pons ratio: a simple and specific MRI sign of progressive supranuclear palsy.

OBJECTIVES: MRI-based measurements used to diagnose progressive supranuclear palsy (PSP) typically lack pathologic verification and are not easy to use routinely. We aimed to develop in histologically proven disease a simple measure of the midbrain and pons on sagittal MRI to identify PSP. METHODS: Measurements of the midbrain and pontine base on midsagittal T1-weighted MRI were performed in confirmed PSP (n = 12), Parkinson disease (n = 2), and multiple system atrophy (MSA) (n = 7), and in controls (n = 8). Using receiver operating characteristic curve analysis, cutoff values were applied to a clinically diagnosed cohort of 62 subjects that included PSP (n = 21), Parkinson disease (n = 10), MSA (n = 10), and controls (n = 21). RESULTS: The mean midbrain measurement of 8.1 mm was reduced in PSP (p < 0.001) with reduction in the midbrain to pons ratio (PSP smaller than MSA; p < 0.001). In controls, the mean midbrain ratio was approximately two-thirds of the pontine base, in PSP it was <52%, and in MSA the ratio was greater than two-thirds. A midbrain measurement of <9.35 mm and ratio of 0.52 had 100% specificity for PSP. In the clinically defined group, 19 of 21 PSP cases (90.5%) had a midbrain measurement of <9.35 mm. CONCLUSIONS: We have developed a simple and reliable measurement in pathologically confirmed disease based on the topography of atrophy in PSP with high sensitivity and specificity that may be a useful tool in the clinic.

Parkinson's disease with Onuf's nucleus involvement mimicking multiple system atrophy.

Urinary frequency, urgency and nocturia are common complaints in Parkinson's disease (PD). The hypothesis most widely proposed to explain neurogenic bladder symptoms in PD is that cell loss in the substantia nigra may cause detrusor hyperactivity due to a loss in the D1 receptor-mediated tonic inhibition of the micturition reflex, although other causes including anti-parkinsonian medication cortical effects have been considered.1 We present the clinical and pathological findings of a patient with parkinsonism who presented with prominent dysautonomia and a poor response to dopaminergic medications and was considered to have possible multiple system atrophy parkinsonism (MSA-P). Pathological examination revealed that the patient had PD with α-synuclein pathology in the Onuf's nucleus (ON).

Concomitant progressive supranuclear palsy and multiple system atrophy: more than a simple twist of fate?

Progressive supranuclear palsy (PSP) and multiple system atrophy (MSA) are both rare neurodegenerative diseases. In the Queen Square Brain Bank, from 2001 to 2008, we received 120 cases of pathologically confirmed PSP and 36 of MSA, and one had concomitant PSP and MSA pathology. The clinical symptoms in this case were compatible with PSP and did not predict the dual pathology. The growing number of collective case reports, including the one reported here, might suggest an increased prevalence of concomitant PSP and MSA than what would be expected by chance.