Magnetic resonance imaging in “typical” and “late onset” Friedreich''s disease and early onset cerebellar ataxia with retained tendon reflexes

MRI makes it possible to study the in vivo brain and spinal cord morphology of patients with hereditary ataxia. We performed T1-and T2-weighted studies in eleven patients with Friedreich's disease (FD), five with late onset FD and ten with early onset cerebellar ataxia with retained tendon reflexes (EOCA). Cervical cord atrophy was constant in FD and late onset FD and often associated with atrophy of the cerebellum and of the brainstem; T2-weighted studies showed posterior column degeneration in the cervical cord. The most frequent finding in EOCA was cerebellar atrophy, pure or associated with cervical cord or brainstem atrophy; the cerebellar atrophy was marked in a few cases and was related to disease duration.This study was partially supported by the CNR (Grant 91.04180) and the Ministry of Health.     

Progressive myoclonus ataxia: Time for a new definition?

Background: The clinical demarcation of the syndrome progressive myoclonus ataxia is unclear, leading to a lack of recognition and difficult differentiation from other neurological syndromes. Objectives: The objective of this study was to apply a refined definition of progressive myoclonus ataxia and describe the clinical characteristics in patients with progressive myoclonus ataxia and with isolated cortical myoclonus. Methods: A retro‐ and prospective analysis was performed in our tertiary referral center between 1994 and 2014. Inclusion criteria for progressive myoclonus ataxia patients were the presence of myoclonus and ataxia with or without infrequent (all types, treatment responsive) epileptic seizures. Inclusion criteria for isolated cortical myoclonus was the presence of isolated cortical myoclonus. Clinical and electrophysiological characteristics data were systematically scored. Results: A total of 14 progressive myoclonus ataxia patients (males, 7; females, 7), median age 14.5 years, and 8 isolated cortical myoclonus patients (males, 2; females, 6), median age 23.5 years, were identified. In 93% of the progressive myoclonus ataxia patients, ataxia started first (median 2 years) followed by myoclonus (4 years) and finally infrequent epilepsy (9.3 years), with a progressive course in 93%. In 64% of the progressive myoclonus ataxia patients, a genetic underlying etiology was identified, including 3 not earlier reported causative progressive myoclonus ataxia genes. In isolated cortical myoclonus patients, myoclonus started at (median) 12 years with progression over time in 63% and a single epileptic seizure in 1 patient. No genetic causes were identified. Conclusion: Using a refined definition, we could create a rather homogenous progressive myoclonus ataxia group. Patients with isolated cortical myoclonus have a different course and do not appear to evolve in progressive myoclonus ataxia. The refined progressive myoclonus ataxia definition is a successful first step toward creating a separate syndrome for both clinical practice and future genetic research. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.     

Acetyl-dl-leucine in cerebellar ataxia ([18F]-FDG-PET study): how does a cerebellar disorder influence cortical sensorimotor networks?

Journal of Neurology - The aim of the study was to deepen our insights into central compensatory processes of brain networks in patients with cerebellar ataxia (CA) before and with treatment with...     

Is late onset depression a prodrome to dementia?

BACKGROUND: Recent research suggests there are clinical and biological differences between late onset depression (LOD) and early-onset depression (EOD). OBJECTIVES: In this paper we review clinical, epidemiological, structural neuroimaging and genetic investigations of late life depression that have been performed over the past two decades and offer evidence that LOD is often a prodromal disorder for dementia. RESULTS: LOD patients are more likely to have cognitive impairment and to have more deep white matter lesions (DWMLs). Evidence concerning cortical and temporal lobe atrophy is conflicting, while the ApoE 4 allele is not associated with LOD. CONCLUSIONS: It is likely that LOD is not a prodrome for a particular type of dementia, but the majority of patients who do develop dementia will acquire Alzheimer's disease (AD) or a vascular dementia, as these are by far the most common causes of dementia. This issue requires further clarification with follow-up of patients over the long term.     

How is disease progress in Friedreich's ataxia best measured? A study of four rating scales

Background

Friedreich''s ataxia (FRDA), the most common genetic cause of ataxia, is characterised by progressive neurodegeneration and cardiomyopathy. Initial treatments are likely to slow progression rather than reverse morbidity. An appropriate and sensitive scale to measure disease progress is critical to detect the benefit of treatments.

Objective

To compare the Friedreich Ataxia Rating Scale (FARS) with other scales proposed as outcome measures for FRDA.

Methods

76 participants were assessed with the FARS and the International Cooperative Ataxia Rating Scale (ICARS) and 72 of these participants were also assessed with the Functional Independence Measure and the Modified Barthel Index. 43 participants had repeat measures at an interval of 12 months. Sensitivity and responsiveness were assessed using the effect size for each measure and the sample size required for a placebo‐controlled clinical trial.

Results

The FARS showed a high correlation with the other three measures. A significant change in the score over 12 months was detected by the FARS, the International Cooperative Ataxia Rating Scale and the Functional Independence Measure. The FARS had the greatest effect size and requires fewer patients for an equivalently powered study.

Conclusions

Of the scales assessed, the FARS is the best to use in clinical trials of FRDA. This is based on effect size, and power calculations that show that fewer participants are required to demonstrate the same effect of an intervention. Further work is required to develop more sensitive and responsive instruments.Friedreich''s ataxia (FRDA) is characterised by progressive neurological symptoms and cardiac dysfunction. It results in a reduced life span.^1,2 As the pathogenesis of FRDA has become better understood, several potential treatments have arisen. Initial beneficial treatments will probably slow progression rather than reverse morbidity. An appropriate and responsive scale for FRDA is critical if the benefits of potential treatments are to be identified. As there is no gold standard to examine disease progress in FRDA, the evaluation of measurement scales is essential to ensure that trials are efficient and their conclusions are accurate.³The Friedreich Ataxia Rating Scale (FARS) comprises a measure of ataxia, an activities of daily living (ADL) subscale and a neurological subscale. Face and content validity and inter‐rater reliability are good.⁴ Other aspects of validity have not been examined. The International Cooperative Ataxia Rating Scale (ICARS) was developed to assess pharmacotherapies in ataxia,⁵ and has good inter‐rater reliability.⁶ The Functional Independence Measure (FIM)⁷ and the Modified Barthel Index (MBI)⁸ examine the assistance required to complete ADLs. They are validated instruments used widely for neurological disease.We aimed to examine these ordinal scales proposed as outcome measures for FRDA to establish concurrent criterion validity and compare the change in score over time to determine the sensitivity of the scales and confirm which measure is most appropriate for use in clinical trials.     

Neurodegeneration in ataxia telangiectasia: what is new? What is evident?

This article summarizes evident and recent findings on the characteristics of the neurological phenotype in ataxia telangiectasia (AT), reviews neuropathological and neuroradiological findings, and outlines therapeutic treatment options. In addition, this review offers an overview of current hypotheses on mechanisms of neurodegeneration in AT and discusses their relevance in clinical neurology. The obvious features of neurodegeneration in AT-cerebellar ataxia and dysarthia-are accompanied by a variety of further disabling disease symptoms. Review of the literature outlines a complex pattern of central nervous degeneration in AT that might have been underestimated so far. Neurodegeneration in AT is closely related to the absence or partial lack of the ataxia telangiectasia-mutated (ATM) kinase. ATM is a central player in maintaining cellular homeostasis. Systemic review of the literature reveals a subset of cellular targets hypothesized to count responsible for degeneration in ATM-deficient neurons. Further systematic cliniconeurological, pathoanatomical, and neuroradiological studies are required to understand the structural basis of this neurodegenerative disease. This better understanding has implications for the treatment of AT patients. Second, biochemical and molecular biological studies aimed at deciphering the pathomechanisms of this progressive disorder are necessary for the development of promising future therapies.     

A case of neuro-Beh?et's disease presenting as chronic progressive cerebellar ataxia]

A case of neuro-Beh?et's disease manifested as chronic progressive cerebellar ataxia is reported. A 56-year-old woman had suffered from recurrent oral aphthous ulcers, genital ulcers and polyarthritis since her late twenties. At age 53, she noticed small stepped-gait; at age 55, she developed scanning speech, a wide-based gait and memory disturbance. On admission she had oral aphthous ulcers, scarring of genital ulcers and polyarthralgia. A neurological examination revealed memory disturbance, saccadic eye movement, scanning speech, a slow tongue wiggle, moderate limb and truncal ataxia and moderate hyperreflexia in four limbs without pathological reflexes. Relevant laboratory examination data showed a positive HLA-B51. The cerebrospinal fluid (CSF) had a mild elevation of the cell counts and the amounts of protein. Brain magnetic resonance imaging showed mild atrophy of the cerebellum and brainstem. Fluoro-2-deoxyglucose-positron emission tomography showed a decreased glucose metabolism in the cerebellum and brainstem. Methylprednisolone pulse therapy (1 g x 3 days) followed by oral corticosteroids (50 mg/day) with gradual tapering markedly alleviated the cerebellar ataxia. The presence of oral and genital ulcers and CSF pleocytosis as well as effectiveness of corticosteroids in relieving the neurologic symptoms suggested neuro-Beh?et's disease. We propose the existence of a new subtype of neuro-Beh?et's disease characterized by chronic progressive cerebellar involvement possibly due to microvasculitis for which corticosteroids may be effective.     

Predictors of onset of psychosis in patients with Parkinson's disease: Who gets it early?

IntroductionPsychosis is one of the common non-motor symptoms of PD, which substantially worsens the quality of life. Hence, it is important to identify factors that are associated with early onset of psychosis in PD. In order to identify those factors, the current study aims to compare various demographic and clinical features of PD patients with early and late onset psychosis.MethodologyIn this prospective case-control study, 51 consecutive patients with PD having psychosis (PDP) were recruited. Median of the latency of onset of psychotic symptoms from the onset of motor symptoms was calculated (5.5 years) and after doing a median split, the cohort of PDP was divided into early onset PDP (EOP, n = 25) and late onset PDP (LOP, n = 26). Both the groups were compared for several demographic and clinical characteristics.ResultsCompared to those with LOP, patients with EOP had poor scores on frontal assessment battery (13.8 ± 2.0 vs 15.3 ± 1.8, p = 0.007), more frequently had Rapid Eye movement sleep Behavior Disorder (RBD) (80% vs 46.2%, p = 0.02), Postural Instability with Gait Difficulty (PIGD) phenotype (72% vs 26.9%, p = 0.002), and excessive daytime sleepiness (Epworth Sleepiness Scale: 8.04 ± 3.7 vs 3.9 ± 3.1). Patients with LOP were older (63.4 ± 7.0 years vs 56.5 ± 8.1 years, p = 0.002) and had higher Levodopa equivalent dose/day (LEDD: 819.1 ± 365.8 vs 608.5 ± 356.3, p = 0.04) compared to those with EOP.ConclusionPresence of RBD, excessive daytime sleepiness, frontal lobe dysfunction, and PIGD phenotype of PD may be associated with early onset of psychosis in PD. Higher LEDD may not trigger early occurrence of psychosis in PD.     

Working memory and FDG–PET dissociate early and late onset Alzheimer disease patients

The aims of this study were to determine the influence of the onset of Alzheimers disease (AD) on 1) memory and cerebral glucose metabolism, 2) the relationships between cognitive performance and cerebral glucose metabolism. Brain metabolism was measured by ¹⁸FDG–PET in 12 early onset AD patients (age < 65 years) and 26 late onset ones (> 65), with comparable mean MMSE scores. Working memory, semantic memory and episodic memory were assessed. Cognitivo–metabolic correlations (CMC) and complementary interregional correlations were performed in order to identify specific neurocognitive processes within each group. Both AD groups performed poorly on all tasks, except digit span in the late onset group. The early onset group performed more poorly than the late onset one on both the digit span and Brown–Peterson Paradigm (BPP) tasks. Temporo–parietal hypometabolism was found in both groups, the left hemisphere being more affected than the right, especially in the early onset patients, who also showed specific left frontal hypometabolism. For the BPP task, the CMC principally involved left frontal areas in the early onset group, and the cerebellum in the late onset one. For the digit span task, they involved cerebellar and occipital regions in the latter. Regarding the digit span, the occipital and cerebellar involvement may have reflected an effective compensatory mechanism in the late onset patients, while high left supramarginal gyrus hypometabolism in the early onset patients may have explained their failure in this task. In the BPP task, the lower performance of the early onset group may have been due to a frontal lobe dysfunction, as suggested by 1) the hypometabolism of this region, 2) the CMC results, 3) the interregional correlations, which indicated greater disruption of the antero– posterior loop.     

Detection of polyglutamine expansion in a new acidic protein: a candidate for childhood onset schizophrenia?

Polyglutamine expansion (PGE) encoded by a CAG repeat underlies eight inherited neurodegenerative diseases, among which is Huntington's disease. CAG expansion has also been reported in schizophrenia, suggesting a role for PGE. To investigate the potential role of PGE as a candidate for schizophrenia, we searched for PGE in nuclear families comprising a patient affected by childhood onset schizophrenia (COS, a rare and severe form of the disease) as a variation of the candidate gene approach for identifying susceptibility genes. We tested lymphoblastoid cell lines from COS patients (n = 32) by Western blot analysis with 1C2, a monoclonal antibody that specifically recognizes long polyglutamines. Eight of 11 unrelated black American COS patients showed a 60-kDa (approximately) band indicative of PGE. A strong 60-kDa band (suggestive of a large PGE) was detected in two of the eight positive patients. A weaker 60-kDa band (suggestive of a smaller and non pathogenic PGE) was detected in some unaffected parents or sibs of these two COS patients, and in six other black American COS patients. The strong and weak PGE signals were found to correspond to two different proteins. Unrelated black Americans unaffected by COS (n = 38) were negative for the strong 60-kDa PGE signal. Healthy white Americans (n = 53) were negative for both the strong and weak 60-kDa PGE signals. Two-dimensional gel analysis suggested that the strong PGE signal corresponds to an acidic (pI 4 approximately) protein and resulted in a more precise estimation (52-57 kDa) of its relative mass. This protein appeared to be not represented in Genbank, as suggested by the exclusion of several candidate CAG repeats. Our data suggest that this acidic protein might be a candidate for COS.     

Decrease in cerebellar blood flow in patients with Friedreich’s ataxia: A TC-HMPAO SPECT study of three cases

Abstract

Three cases of Friedreich’s ataxia were submitted to diverse neuroradiological procedures in order to determine the extent of atrophic processes in the central nervous system. All patients underwent computerized-tomography scan, Magnetic Resonance Imaging, and HMPA-single Photon emission computerized tomography studies, focusing in cerebellar lobes. A slight atrophy was observed in the vermis and the cerebellar lobes with CT scan and MRI. In contrast a significant decrease in cerebellar blood flow was shown by TC-HMPAE SPECT study. The significance of these findings in understanding physiopathological mechanisms in Friedreich’s ataxia is discussed. [Neurol Res 1994; 16: 342-344]     

Cognitive performance in relatives of patients with probable Alzheimer disease: An age at onset effect?

Abstract

Cognitive performance of 32 siblings and children of patients with probable Alzheimer disease was assessed longitudinally over an interval averaging 4 years. Mean scores were within normal limits for age on all measures at both test times. However, relatives of patients with early-onset dementia (≤ 67 years) were more likely to show a decline in performance from the first to second testing than relatives of patients with late-onset dementia. Additional follow-up will be needed to determine the reliability of performance trajectories and to assess whether mild cognitive changes are related to future dementia. However, findings suggest that it may be important to consider family history of dementia in studies of normal cognitive aging.     

Cardiovascular autonomic function in patients with relapsing remitting multiple sclerosis: a new surrogate marker of disease evolution?

Twenty patients with active relapsing remitting multiple sclerosis (MS) were examined annually for 2 years with a set of autonomic function tests (AFT) consisting of heart rate variability during deep breathing (IE), standing-up, and ratios of Valsalva manoeuvre (VR). Disease characteristics, including T2-weighted magnetic resonance imaging (MRI) of the brain and the expanded disability status scale (EDSS) score were documented each year within 1 week of the AFT. The EDSS score, MRI load lesion and VR did not change significantly over the follow-up period. The IE and initial heart-rate on standing during the first 30 s (DeltaHRMAX) showed significant worsening during follow-up. No relationship was found between deterioration of AFT and EDSS score, number of exacerbations, duration of disease, gender, age, size and number of lesions on MRI. We conclude that patients with active relapsing remitting MS show progression of autonomic dysfunction over a relatively short time. Therefore, in the absence of changes in clinical disability or brain MRI lesion load, AFT might be useful as a sensitive surrogate outcome measure for demonstrating subclinical change in MS.