Binary reversals: a diagnostic sign in primary progressive aphasia.

BACKGROUND: Binary reversals (exemplified by 'yes'/'no' confusions) have been described in patients with primary progressive aphasia (PPA) but their diagnostic value and phenotypic correlates have not been defined. METHODS: We conducted a retrospective cohort study analysing demographic, clinical, neuropsychological, linguistic and behavioural data from patients representing all major PPA syndromes (non-fluent/agrammatic variant, nfvPPA; logopenic variant, lvPPA; semantic variant, svPPA) and behavioural variant frontotemporal dementia (bvFTD). The prevalence of binary reversals and behavioural abnormalities, illness duration, parkinsonian features and neuropsychological test scores were compared between neurodegenerative syndromes, and the diagnostic predictive value of binary reversals was assessed using logistic regression. RESULTS: Data were obtained for 83 patients (21 nfvPPA, 13 lvPPA, 22 svPPA, 27 bvFTD). Binary reversals occurred in all patients with nfvPPA, but significantly less frequently and later in lvPPA (54%), svPPA (9%) and bvFTD (44%). Patients with bvFTD with binary reversals had significantly more severe language (but not general executive or behavioural) deficits than those without reversals. Controlling for potentially confounding variables, binary reversals strongly predicted a diagnosis of nfvPPA over other syndromes. CONCLUSIONS: Binary reversals are a sensitive (though not specific) neurolinguistic feature of nfvPPA, and should suggest this diagnosis if present as a prominent early symptom.

Differential Synaptic Loss in ß-Amyloid Positive Versus ß-Amyloid Negative Corticobasal Syndrome.

BACKGROUND/OBJECTIVE: The corticobasal syndrome (CBS) is a complex asymmetric movement disorder, with cognitive impairment. Although commonly associated with the primary 4-repeat-tauopathy of corticobasal degeneration, clinicopathological correlation is poor, and a significant proportion is due to Alzheimer's disease (AD). Synaptic loss is a pathological feature of many clinical and preclinical tauopathies. We therefore measured the degree of synaptic loss in patients with CBS and tested whether synaptic loss differed according to ß-amyloid status. METHODS: Twenty-five people with CBS, and 32 age-/sex-/education-matched healthy controls participated. Regional synaptic density was estimated by [11C]UCB-J non-displaceable binding potential (BPND), AD-tau pathology by [18F]AV-1451 BPND, and gray matter volume by T1-weighted magnetic resonance imaging. Participants with CBS had ß-amyloid imaging with 11C-labeled Pittsburgh Compound-B ([11C]PiB) positron emission tomography. Symptom severity was assessed with the progressive supranuclear palsy-rating-scale, the cortical basal ganglia functional scale, and the revised Addenbrooke's Cognitive Examination. Regional differences in BPND and gray matter volume between groups were assessed by ANOVA. RESULTS: Compared to controls, patients with CBS had higher [18F]AV-1451 uptake, gray matter volume loss, and reduced synaptic density. Synaptic loss was more severe and widespread in the ß-amyloid negative group. Asymmetry of synaptic loss was in line with the clinically most affected side. DISCUSSION: Distinct patterns of [11C]UCB-J and [18F]AV-1451 binding and gray matter volume loss, indicate differences in the pathogenic mechanisms of CBS according to whether it is associated with the presence of Alzheimer's disease or not. This highlights the potential for different therapeutic strategies in CBSs. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Longitudinal Synaptic Loss in Primary Tauopathies: An In Vivo [11 C]UCB-J Positron Emission Tomography Study.

BACKGROUND: Synaptic loss is characteristic of many neurodegenerative diseases; it occurs early and is strongly related to functional deficits. OBJECTIVE: In this longitudinal observational study, we determine the rate at which synaptic density is reduced in the primary tauopathies of progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD), and we test the relationship with disease progression. METHODS: Our cross-sectional cohort included 32 participants with probable PSP and 16 with probable CBD (all amyloid-negative corticobasal syndrome), recruited from tertiary care centers in the United Kingdom, and 33 sex- and age-matched healthy control subjects. Synaptic density was estimated by positron emission tomography imaging with the radioligand [11 C]UCB-J that binds synaptic vesicle 2A. Clinical severity and cognition were assessed by the PSP Rating Scale and the Addenbrooke's cognitive examination. Regional [11 C]UCB-J nondisplaceable binding potential was estimated in Hammersmith Atlas regions of interest. Twenty-two participants with PSP/CBD had a follow-up [11 C]UCB-J positron emission tomography scan after 1 year. We calculated the annualized change in [11 C]UCB-J nondisplaceable binding potential and correlated this with the change in clinical severity. RESULTS: We found significant annual synaptic loss within the frontal lobe (-3.5%, P = 0.03) and the right caudate (-3.9%, P = 0.046). The degree of longitudinal synaptic loss within the frontal lobe correlated with the rate of change in the PSP Rating Scale (R = 0.47, P = 0.03) and cognition (Addenbrooke's Cognitive Examination-Revised, R = -0.62, P = 0.003). CONCLUSIONS: We provide in vivo evidence for rapid progressive synaptic loss, correlating with clinical progression in primary tauopathies. Synaptic loss may be an important therapeutic target and outcome variable for early-phase clinical trials of disease-modifying treatments. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Ultrasound of peripheral nerves distinguishes inherited sensory neuronopathy of cerebellar ataxia with neuropathy and vestibular areflexia syndrome from inherited axonopathy.

Introduction/Aims Recent studies have shown that ultrasound of peripheral nerves can distinguish inherited sensory neuronopathy from acquired axonopathy with a high degree of accuracy. In this study we aimed to determine whether ultrasound can also distinguish inherited sensory neuronopathy from inherited axonopathy. Methods We compared the ultrasound cross-sectional areas (CSAs) of the median, ulnar, sural, and tibial nerves of retrospectively recruited patients with cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS), in whom sensory neuronopathy is a cardinal feature, with Charcot-Marie-Tooth type 2 (CMT2) disease patients, who have an inherited axonopathy, using the Kruskal-Wallis test and receiver-operating characteristic curves. Results There were 17 patients with CANVAS and 18 with CMT2. The upper limb nerve CSAs were significantly smaller in CANVAS than in CMT2 (P < .001), with the CSAs of the median nerve at mid-forearm and ulnar nerve at mid-arm being a third or less the size of those of the CMT2 patients. Nerve ultrasound reliably distinguished CANVAS from CMT2 with ROC areas under the curve between 0.97 and 0.99. The lower limb CSAs of the two patient groups were not significantly different. Discussion Ultrasound of the upper limb nerves distinguishes CANVAS sensory neuronopathy from inherited axonopathy with high accuracy and can therefore be proposed as a reliable additional tool in the investigation of these diseases.

Dissecting the Phenotype and Genotype of PLA2G6-Related Parkinsonism.

BACKGROUND: Complex parkinsonism is the commonest phenotype in late-onset PLA2G6-associated neurodegeneration. OBJECTIVES: The aim of this study was to deeply characterize phenogenotypically PLA2G6-related parkinsonism in the largest cohort ever reported. METHODS: We report 14 new cases of PLA2G6-related parkinsonism and perform a systematic literature review. RESULTS: PLA2G6-related parkinsonism shows a fairly distinct phenotype based on 86 cases from 68 pedigrees. Young onset (median age, 23.0 years) with parkinsonism/dystonia, gait/balance, and/or psychiatric/cognitive symptoms were common presenting features. Dystonia occurred in 69.4%, pyramidal signs in 77.2%, myoclonus in 65.2%, and cerebellar signs in 44.6% of cases. Early bladder overactivity was present in 71.9% of cases. Cognitive impairment affected 76.1% of cases and psychiatric features 87.1%, the latter being an isolated presenting feature in 20.1%. Parkinsonism was levodopa responsive but complicated by early, often severe dyskinesias. Five patients benefited from deep brain stimulation. Brain magnetic resonance imaging findings included cerebral (49.3%) and/or cerebellar (43.2%) atrophy, but mineralization was evident in only 28.1%. Presynaptic dopaminergic terminal imaging was abnormal in all where performed. Fifty-four PLA2G6 mutations have hitherto been associated with parkinsonism, including four new variants reported in this article. These are mainly nontruncating, which may explain the phenotypic heterogeneity of childhood- and late-onset PLA2G6-associated neurodegeneration. In five deceased patients, median disease duration was 13.0 years. Brain pathology in three cases showed mixed Lewy and tau pathology. CONCLUSIONS: Biallelic PLA2G6 mutations cause early-onset parkinsonism associated with dystonia, pyramidal and cerebellar signs, myoclonus, and cognitive impairment. Early psychiatric manifestations and bladder overactivity are common. Cerebro/cerebellar atrophy are frequent magnetic resonance imaging features, whereas brain iron deposition is not. Early, severe dyskinesias are a tell-tale sign. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Utility of neuromuscular ultrasound in the investigation of common mononeuropathies in everyday neurophysiology practice.

INTRODUCTION: In everyday clinical neurophysiology practice, mononeuropathies are evaluated primarily by traditional electrodiagnostic testing. We sought to assess the additional benefit of neuromuscular ultrasound (US) in this scenario. METHODS: All consecutive mononeuropathies undergoing combined US and electrodiagnostic evaluation over a 23-mo period at a single neurophysiology practice were reviewed. Three independent examiners assessed how often US was: (a) "contributory" - enabling a definite diagnosis not made by electrophysiology alone and/or impacting on the therapeutic decision, (b) "confirmatory" of the electrodiagnostic findings, but not adding further diagnostic or therapeutic information, or (c) "negative" - missed the diagnosis. RESULTS: There were 385 studies included. US was "contributory" in 36%, "confirmatory" in 61% and "negative" in 3%. DISCUSSION: In this study of everyday neurophysiology practice, neuromuscular US contributed significant diagnostic or therapeutic information in over 1/3 of the investigations for common mononeuropathies. False negative US studies were uncommon in this setting.

Unravelling the enigma of cortical tremor and other forms of cortical myoclonus.

Cortical tremor is a fine rhythmic oscillation involving distal upper limbs, linked to increased sensorimotor cortex excitability, as seen in cortical myoclonus. Cortical tremor is the hallmark feature of autosomal dominant familial cortical myoclonic tremor and epilepsy (FCMTE), a syndrome not yet officially recognized and characterized by clinical and genetic heterogeneity. Non-coding repeat expansions in different genes have been recently recognized to play an essential role in its pathogenesis. Cortical tremor is considered a rhythmic variant of cortical myoclonus and is part of the 'spectrum of cortical myoclonus', i.e. a wide range of clinical motor phenomena, from reflex myoclonus to myoclonic epilepsy, caused by abnormal sensorimotor cortical discharges. The aim of this update is to provide a detailed analysis of the mechanisms defining cortical tremor, as seen in FCMTE. After reviewing the clinical and genetic features of FCMTE, we discuss the possible mechanisms generating the distinct elements of the cortical myoclonus spectrum, and how cortical tremor fits into it. We propose that the spectrum is due to the evolution from a spatially limited focus of excitability to recruitment of more complex mechanisms capable of sustaining repetitive activity, overcoming inhibitory mechanisms that restrict excitatory bursts, and engaging wide areas of cortex. Finally, we provide evidence for a possible common denominator of the elements of the spectrum, i.e. the cerebellum, and discuss its role in FCMTE, according to recent genetic findings.

A Maori specific RFC1 pathogenic repeat configuration in CANVAS, likely due to a founder allele.

Cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS) is a recently recognized neurodegenerative disease with onset in mid- to late adulthood. The genetic basis for a large proportion of Caucasian patients was recently shown to be the biallelic expansion of a pentanucleotide (AAGGG)n repeat in RFC1. Here, we describe the first instance of CANVAS genetic testing in New Zealand Maori and Cook Island Maori individuals. We show a novel, possibly population-specific CANVAS configuration (AAAGG)10-25(AAGGG)exp, which was the cause of CANVAS in all patients. There were no apparent phenotypic differences compared with European CANVAS patients. Presence of a common disease haplotype among this cohort suggests this novel repeat expansion configuration is a founder effect in this population, which may indicate that CANVAS will be especially prevalent in this group. Haplotype dating estimated the most recent common ancestor at ∼1430 ce. We also show the same core haplotype as previously described, supporting a single origin of the CANVAS mutation.

Tardive syndromes.

Dopamine receptor-blocking antipsychotics, first introduced into clinical practice in 1952, were hailed as a panacea in the treatment of a number of psychiatric disorders. However, within 5 years, this notion was to be shattered by the recognition of both acute and chronic drug-induced movement disorders which can accompany their administration. Tardive syndromes, denoting the delayed onset of movement disorders following administration of dopamine receptor-blocking (and also other) drugs, have diverse manifestations ranging from the classic oro-bucco-lingual dyskinesia, through dystonic craniocervical and trunk posturing, to abnormal breathing patterns. Although tardive syndromes have been an important part of movement disorder clinical practice for over 60 years, their pathophysiologic basis remains poorly understood and the optimal treatment approach remains unclear. This review summarises the current knowledge relating to these syndromes and provides clinicians with pragmatic, clinically focused guidance to their management.

Carpal tunnel syndrome in advanced age: A sonographic and electrodiagnostic study.

INTRODUCTION: After noting inconsistent sonographic median nerve cross-sectional area (CSA) enlargement at the wrist in very elderly patients with carpal tunnel syndrome (CTS), we systematically reviewed ultrasound, electrodiagnostic, and clinical data collected over a 12-month period in patients from 2 age groups: 80-95 years and 40-65 years old. METHODS: Clinical and electrodiagnostic CTS severity, sensitivity of ultrasound CSA (against both electrodiagnostic and clinical reference standards), and correlations between ultrasound CSA and clinical and electrodiagnostic severity were compared in both groups. RESULTS: In very elderly patients, despite a higher prevalence of severe CTS, nerve ultrasound was less sensitive than in the younger group (54% vs. 87%, using clinical reference standard), and did not correlate with clinical (r = 0.28, P = 0.10) or electrodiagnostic (r = 0.09, P = 0.60) severity. DISCUSSION: Median nerve ultrasound CSA at the wrist is not a sensitive marker of CTS in very elderly populations. In this work we detail and discuss potential pathophysiological underpinnings of this unexpected finding. Muscle Nerve, 2019.

Spinocerebellar ataxia type 2-neuronopathy or neuropathy?

INTRODUCTION: Use of peripheral nerve ultrasound alongside standard electrodiagnostic tests may help to gain insight into the pathophysiology of peripheral nerve involvement in type 2 spinocerebellar ataxia (SCA2). METHODS: Twenty-seven patients with SCA2 underwent ultrasound cross-sectional area (CSA) measurement of median, ulnar, sural and tibial nerves, and motor (median, ulnar, tibial) and sensory (median, ulnar, radial, sural) nerve conduction studies. RESULTS: Twenty patients had pathologically small-nerve CSAs, suggestive of sensory neuronopathy. In these patients, electrophysiology showed non-length-dependent sensory neuropathy (14 of 20), "possible sensory neuropathy" (1 of 20), or normal findings (5 of 20). Four different patients had length-dependent sensory neuropathy on electrophysiology, and 1 had enlarged nerve CSAs. Regression analysis showed an inverse relationship between ataxia scores and upper limb nerve CSA (P < 0.03). DISCUSSION: Our findings suggest that a majority of patients with SCA2 (74%) have a sensory neuronopathy and this correlates with disability. A minority of patients have findings consistent with axonal neuropathy (18%). Muscle Nerve, 2019.

Peripheral nerve ultrasound in Friedreich ataxia.

INTRODUCTION: Sensory impairment in Friedreich ataxia (FRDA) is generally accepted as being due to a ganglionopathy. The degree of contribution from axonal pathology remains a matter of debate. Nerve ultrasound may be able to differentiate these processes. METHODS: The ultrasound cross-sectional area of median, ulnar, tibial, and sural nerves of 8 patients with FRDA was compared with 8 age- and gender-matched healthy controls and with reference values in our population. RESULTS: The nerves of the patients with FRDA were significantly larger than those of healthy controls at all upper limb sites (P < 0.05) but not significantly different in the lower limbs. DISCUSSION: Our findings add additional weight to the theory that dorsal root ganglionopathy is not the sole cause of peripheral sensory loss in FRDA. Peripheral neuropathic processes are also likely to play a role. Muscle Nerve 57: 852-856, 2018.

Peripheral nerve ultrasound findings in mucolipidosis type 3.

PURPOSE: The mucolipidoses are rare autosomal recessive lysosomal storage disorders. Neurologic involvement in these conditions is generally thought to be limited to cognitive delay and entrapment neuropathies (primarily carpal tunnel syndrome). We sought to evaluate peripheral nerves in this condition using nerve ultrasound. METHODS: We performed peripheral nerve ultrasound in two siblings with genetically confirmed mucolipidosis type 3 (alpha/beta). RESULTS: Peripheral nerves in mucolipidosis type 3 (alpha/beta) exhibit multifocal enlargement. CONCLUSION: The peripheral nerve ultrasound has a role in the evaluation of this, and possibly other lysosomal storage disorders.

Peripheral nerve ultrasound in cerebellar ataxia neuropathy vestibular areflexia syndrome (CANVAS).

INTRODUCTION: We report preliminary findings of nerve ultrasound in patients with cerebellar ataxia neuropathy vestibular areflexia syndrome (CANVAS) who have sensory impairment due to dorsal root ganglionopathy. METHODS: The ultrasound cross-sectional area (CSA) of median and ulnar nerves of 7 CANVAS patients was compared with 7 age- and gender-matched controls and with the mean CSA of our reference population. RESULTS: The nerve CSA of CANVAS patients was significantly smaller than that of controls at all sites (P < 0.01). All but 1 individual measurement of CSA at the mid-forearm level in the CANVAS patients fell outside the normal control range and was >2 standard deviations below the reference mean. CONCLUSIONS: The small nerves in CANVAS probably reflect nerve thinning from axonal loss secondary to ganglion cell loss. Our data show a role for ultrasound in the diagnosis of CANVAS ganglionopathy. This may also be applicable to ganglionopathy from other causes. Muscle Nerve 56: 160-162, 2017.

Symptomatic intracranial hypertension during recovery from the syndrome of headache with neurologic deficits and cerebrospinal fluid lymphocytosis (HANDL).

The syndrome of headache with neurologic deficits and cerebrospinal fluid lymphocytosis (HANDL) is rare; it comprises migrainous headaches (generally in headache-naïve people), fluctuating neurological symptoms and cerebrospinal fluid (CSF) lymphocytosis. The syndrome generally runs a benign, self-limiting course over weeks. A small proportion of patients develop intracranial hypertension as a consequence of the illness. Recurrence of headaches or development of visual symptoms following apparent recovery from HANDL should prompt urgent re-evaluation for elevated intracranial pressure. Short-to-medium term management with CSF drainage and acetazolamide may be necessary to prevent visual loss.