Differentiating idiopathic Parkinson9s disease from atypical parkinsonian syndromes is challenging, especially in the early stages. We assessed whether the Revised Addenbrooke9s Cognitive Examination (ACE-R) could differentiate between parkinsonian syndromes and reflect longitudinal changes in cognition in these disorders.
Methods
The ACE-R was administered at baseline and after approximately 18 months to 135 patients with parkinsonian disorders: 86 with idiopathic Parkinson9s disease (PD), 30 with progressive supranuclear palsy (PSP), 19 with corticobasal degeneration (CBD). We assessed differences between groups for ACE-R, ACE-R subscores and Mini Mental State Examination (MMSE) scores at baseline (analyses of variance, receiver operating characteristics curves), and the interaction between diagnosis and change in ACE-R scores between visits (analyses of variance).
Results
The ACE-R verbal fluency subscore distinguished between PSP and PD with a high sensitivity (0.92) and specificity (0.87); total ACE-R score and the visuospatial subscore were less specific (0.87 and 0.84 respectively) and sensitive (0.70 and 0.73). Significant group level differences were found between PD and PSP for MMSE and ACE-R (total score and subscores for attention and concentration, fluency, language, and visuospatial function), and between PD and CBD for the ACE-R visuospatial subscore. Performance worsened between visits for ACE-R score in PD (p=0.001) and CBD (p=0.001); visuospatial subscore in PD (p=0.003), PSP (p=0.022) and CBD (p=0.0002); and MMSE in CBD (p=0.004).
Conclusions
We propose the ACE-R, particularly the verbal fluency subscore, as a valuable contributor to the differential diagnosis of parkinsonian syndromes in the correct clinical context. The ACE-R may reflect disease progression in PD and CBD.
Conventional 3-Tesla MRI shows volume loss in the motor cortex (M1) up to 15 years before motor onset. Post-mortem data, typically at the end stage of Huntington9s disease, suggests selective pyramidal cell loss of layers 3 and 5 in M1. However, the extent and patterns of cortical layer specific M1 pathology in the premanifest stage are unknown.
Aims
Here we present a preliminary data from the CLEAR-HD study. We demonstrate quantitative measurements of M1 cortical layers at 600μm resolution using MRI contrasts, R1, which is sensitive to myelin and R2*, which is sensitive to both myelin and iron.
Methods
7-Tesla MRI was used to acquire multi-parametric maps at 600μm resolution in 11 premanifest HD individuals and 14 healthy controls. The HCP-MMP 1.0 atlas was used to parcellate the motor cortex and R1 and R2* values were sampled across 8 equi-volume cortical layers, generated using Nighres.
Results
Both r1 and r2* profiles in m1 were similar between prehd and healthy controls. R1 values were lowest in the superficial layers and rose with increasing depth (figure 1(a), (b)). The preHD group had lower R2* values than controls in the superficial and deep layers of M1 (figure 1(b)).
Conclusion
This preliminary analysis demonstrates the first in-vivo quantitative measures across cortical layers in premanifest HD. The CLEAR-HD study is ongoing and we hope to present the complete dataset in the near future.
Introduction Visual dysfunction predicts Parkinson’s dementia but whether this translates to structural change is not known. We aimed to identify longitudinal white matter changes in Parkinson’s with low visual function and those who developed mild cognitive impairment(MCI). Methods We used fixel-based analysis to examine longitudinal white matter change in Parkinson’s. Diffusion MRI and clinical assessments were performed in 77 patients (22 low/55 high visual performers; and 13 MCI/51 normal cognition) and 25 controls at baseline and after 18 months. We compared micro-structural changes in fibre density, macro-structural changes in fibre cross-section and combined fibre density and cross-section across white matter, adjusting for age, gender and intracranial volume. Results Parkinson’s with low visual performance showed worse cognition at follow-up (r=-0.386, p-0.024) and were more likely to develop MCI than those with normal vision (p=0.008). Parkinson’s with poor visual function showed diffuse micro-structural and macro-structural changes at baseline, whereas those with MCI showed fewer baseline changes. At follow-up, Parkinson’s with low visual function showed wide- spread macrostructural changes with up to 22% further reductions in fibre cross-section, involving the fronto-occipital fasciculi, external capsules, and middle cerebellar peduncles bilaterally. No longitudinal change was seen in baseline MCI or in MCI converters, even when combining the two groups. Conclusions Parkinson’s with poor visual function show increased white matter damage over time, providing further evidence for visual function as a marker of imminent cognitive decline. a.zarkali@ucl.ac.uk
A 43 year–old right–handed Nigerian man initially presented with weight loss of 20 kg over a 3–month period in March 2011. Over the following year he became progressively more drowsy and confused and developed urinary and erectile dysfunction. Since May 2012 he has suffered recurrent episodes of transient neurological disturbance characterised by slurred speech with right arm and leg weakness lasting 30 minutes. More recently he has developed hearing difficulties and painless paraesthesia. General examination was unremarkable. He had horizontal gaze evoked nystagmus and a brisk jaw jerk, increased tone in the lower limbs, brisk reflexes in the upper and lower limbs and bilateral heel–shin ataxia. Magnetic resonance imaging (MRI) of brain and spine showed extensive leptomeningeal enhancement without any signal change within the parenchyma. Cerebrospinal fluid (CSF) analysis showed a raised CSF protein of 6.4 g/dl. His nerve conduction studies confirmed both a mild large fibre and severe small fibre neuropathy. Autonomic testing showed asymptomatic autonomic neuropathy. Echocardiogram and cardiac MRI suggested cardiac amyloidosis. Meningeal and brain biopsy confirmed widespread amyloid angiopathy involving dura matter, leptomeninges and neocortical blood vessels. After discussion with all relevant specialists it was agreed that the patient was not a suitable candidate for liver transplantation. During his admission he fluctuated from being drowsy but orientated to being very confused with episodes of agitation, paranoia and hallucinations. No ictal changes were captured on electroencephalography (EEG) but he was nevertheless started on Levetiracetam. Arterial blood gas measurement showed evidence of type 2 respiratory failure and overnight oximetry revealed cyclical episodes of oxygen desaturation. Non–invasive ventilation was poorly tolerated. He also developed acute renal failure secondary to clot retention from haematuria, possibly secondary to widespread amyloid angiopathy, however this was treated and he improved. He remains in this fluctuant state.
Discussion
Hereditary leptomeningeal amyloidosis is a rare manifestation of transthyretin (TTR) amyloidosis, characterised by amyloid deposition in the meninges of the brain and spinal cord with occasional ocular involvement. Patients present with a wide variety of neurological problems including epilepsy, sub–arachnoid haemorrhage, hearing or visual loss and headache. We described the first case of the TTR Leu12Pro mutation in 1999. To date it has been only described in a total of 3 patients, all European. Here we describe the first report of the TTR Leu12Pro variant in an African patient.
Acute cerebellar ataxia is a rare manifestation of Epstein–Barr virus (EBV) infection. We present a case of a 17-year-old male who presented with acute cerebellar ataxia occurring before the onset of tonsillitis and lymphadenopathy. Serological testing confirmed acute EBV infection.
A 17-year-old male college student complained of feeling ‘drunk’ and unsteady when walking. This progressed over a few days so that he could only crawl. By this time he had developed a sore throat and persistent nausea and vomiting. His general practitioner prescribed penicillin, without effect. On day 6, he presented to hospital bed-bound due to severe loss of balance with severe nausea and vomiting.
He was afebrile (37.2°C) but cardiovascular and respiratory examinations were normal. He had bilateral cervical lymphadenopathy and tonsillar enlargement, and there was no hepatosplenomegaly. He was dysarthric with truncal ataxia and dysmetria in all four limbs. He had no nystagmus.
His serum C reactive protein was raised at 24 mg/l (<10). Serum urea and electrolytes, full blood count and liver function tests were normal. Lymphocytosis developed on day 8, with reactive lymphocytes on a blood film. C reactive protein rose steadily and peaked at 88 mg/l on day 10, and then gradually returned …
Visual hallucinations are common in Parkinson's disease and are associated with poorer prognosis. Imaging studies show white matter loss and functional connectivity changes with Parkinson's visual hallucinations, but the biological factors underlying selective vulnerability of affected parts of the brain network are unknown. Recent models for Parkinson's disease hallucinations suggest they arise due to a shift in the relative effects of different networks. Understanding how structural connectivity affects the interplay between networks will provide important mechanistic insights. To address this, we investigated the structural connectivity changes that accompany visual hallucinations in Parkinson's disease and the organizational and gene expression characteristics of the preferentially affected areas of the network. We performed diffusion-weighted imaging in 100 patients with Parkinson's disease (81 without hallucinations, 19 with visual hallucinations) and 34 healthy age-matched controls. We used network-based statistics to identify changes in structural connectivity in Parkinson's disease patients with hallucinations and performed an analysis of controllability, an emerging technique that allows quantification of the influence a brain region has across the rest of the network. Using these techniques, we identified a subnetwork of reduced connectivity in Parkinson's disease hallucinations. We then used the Allen Institute for Brain Sciences human transcriptome atlas to identify regional gene expression patterns associated with affected areas of the network. Within this network, Parkinson's disease patients with hallucinations showed reduced controllability (less influence over other brain regions), than Parkinson's disease patients without hallucinations and controls. This subnetwork appears to be critical for overall brain integration, as even in controls, nodes with high controllability were more likely to be within the subnetwork. Gene expression analysis of gene modules related to the affected subnetwork revealed that down-weighted genes were most significantly enriched in genes related to mRNA and chromosome metabolic processes (with enrichment in oligodendrocytes) and upweighted genes to protein localization (with enrichment in neuronal cells). Our findings provide insights into how hallucinations are generated, with breakdown of a key structural subnetwork that exerts control across distributed brain regions. Expression of genes related to mRNA metabolism and membrane localization may be implicated, providing potential therapeutic targets.
We lack a mechanistic explanation for the stereotyped pattern of white matter loss seen in Huntington's disease (HD). While the earliest white matter changes are seen around the striatum, within the corpus callosum, and in the posterior white matter tracts, the order in which these changes occur and why these white matter connections are specifically vulnerable is unclear. Here, we use diffusion tractography in a longitudinal cohort of individuals yet to develop clinical symptoms of HD to identify a hierarchy of vulnerability, where the topological length of white matter connections between a brain area and its neighbors predicts the rate of atrophy over 24 months. This demonstrates a new principle underlying neurodegeneration in HD, whereby brain connections with the greatest topological length are the first to suffer damage that can account for the stereotyped pattern of white matter loss observed in premanifest HD.
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