Seeing the Woods for the Trees? Applying Diagnostic Criteria for Dementia with Lewy Bodies to Patients Presenting with Posterior Cortical Atrophy.

Posterior cortical atrophy (PCA) is a clinico-radiological syndrome characterised by progressive decline in visual processing and other posterior cognitive functions, relatively preserved memory and language in the early stages, and atrophy of posterior brain regions. Often considered a "visual variant" of Alzheimer's disease, a number of other pathological substrates are recognised. Dementia with Lewy Bodies is the second most common neurodegenerative dementia and there is increasing recognition of presentations with little or no parkinsonism, highlighting significant under-recognition of this condition. To complicate matters, some patients with PCA exhibit additional features consistent with other neurodegenerative conditions. We present a series of three such patients presenting with features satisfying the recent consensus criteria for "PCA-Plus (DLB)". We review the current classification of PCA and highlight the importance of deep clinico-radiological phenotyping in neurodegenerative disease to guide targeted interventions and establish future trial-ready cohorts.

MicroRNA inhibition using antimiRs in acute human brain tissue sections.

Antisense inhibition of microRNAs is an emerging preclinical approach to pharmacoresistant epilepsy. A leading candidate is an "antimiR" targeting microRNA-134 (ant-134), but testing to date has used rodent models. Here, we develop an antimiR testing platform in human brain tissue sections. Brain specimens were obtained from patients undergoing resective surgery to treat pharmacoresistant epilepsy. Neocortical specimens were submerged in modified artificial cerebrospinal fluid (ACSF) and dissected for clinical neuropathological examination, and unused material was transferred for sectioning. Individual sections were incubated in oxygenated ACSF, containing either ant-134 or a nontargeting control antimiR, for 24 h at room temperature. RNA integrity was assessed using BioAnalyzer processing, and individual miRNA levels were measured using quantitative reverse transcriptase polymerase chain reaction. Specimens transported in ACSF could be used for neuropathological diagnosis and had good RNA integrity. Ant-134 mediated a dose-dependent knockdown of miR-134, with approximately 75% reduction of miR-134 at 1 µmol L-1 and 90% reduction at 3 µmol L-1 . These doses did not have off-target effects on expression of a selection of three other miRNAs. This is the first demonstration of ant-134 effects in live human brain tissues. The findings lend further support to the preclinical development of a therapy that targets miR-134 and offer a flexible platform for the preclinical testing of antimiRs, and other antisense oligonucleotide therapeutics, in human brain.

Neurophysiological correlates of dual tasking in people with Parkinson's disease and freezing of gait.

Freezing of gait in people with Parkinson's disease (PwP) is associated with executive dysfunction and motor preparation deficits. We have recently shown that electrophysiological markers of motor preparation, rather than decision-making, differentiate PwP with freezing of gait (FOG +) and without (FOG -) while sitting. To examine the effect of locomotion on these results, we measured behavioural and electrophysiological responses in PwP with and without FOG during a target response time task while sitting (single-task) and stepping-in-place (dual-task). Behavioural and electroencephalographic data were acquired from 18 PwP (eight FOG +) and seven young controls performing the task while sitting and stepping-in-place. FOG + had slower response times while stepping compared with sitting. However, response times were significantly faster while stepping compared with sitting for controls. Electrophysiological responses showed no difference in decision-making potentials (centroparietal positivity) between groups or conditions but there were differences in neurophysiological markers of response inhibition (N2) and motor preparation (lateralized readiness potential, LRP) in FOG + while performing a dual-task. This suggests that the addition of a second complex motor task (stepping-in-place) impacts automatic allocation of resources in FOG +, resulting in delayed response times. The impact of locomotion on the generation of the N2 and LRP potentials, particularly in freezers, indirectly implies that these functions compete with locomotion for resources. In the setting of multiple complex tasks or cognitive impairment, severe motor dysfunction may result, leading to freezing of gait.

KMT2B-related disorders: expansion of the phenotypic spectrum and long-term efficacy of deep brain stimulation.

Heterozygous mutations in KMT2B are associated with an early-onset, progressive and often complex dystonia (DYT28). Key characteristics of typical disease include focal motor features at disease presentation, evolving through a caudocranial pattern into generalized dystonia, with prominent oromandibular, laryngeal and cervical involvement. Although KMT2B-related disease is emerging as one of the most common causes of early-onset genetic dystonia, much remains to be understood about the full spectrum of the disease. We describe a cohort of 53 patients with KMT2B mutations, with detailed delineation of their clinical phenotype and molecular genetic features. We report new disease presentations, including atypical patterns of dystonia evolution and a subgroup of patients with a non-dystonic neurodevelopmental phenotype. In addition to the previously reported systemic features, our study has identified co-morbidities, including the risk of status dystonicus, intrauterine growth retardation, and endocrinopathies. Analysis of this study cohort (n = 53) in tandem with published cases (n = 80) revealed that patients with chromosomal deletions and protein truncating variants had a significantly higher burden of systemic disease (with earlier onset of dystonia) than those with missense variants. Eighteen individuals had detailed longitudinal data available after insertion of deep brain stimulation for medically refractory dystonia. Median age at deep brain stimulation was 11.5 years (range: 4.5-37.0 years). Follow-up after deep brain stimulation ranged from 0.25 to 22 years. Significant improvement of motor function and disability (as assessed by the Burke Fahn Marsden's Dystonia Rating Scales, BFMDRS-M and BFMDRS-D) was evident at 6 months, 1 year and last follow-up (motor, P = 0.001, P = 0.004, and P = 0.012; disability, P = 0.009, P = 0.002 and P = 0.012). At 1 year post-deep brain stimulation, >50% of subjects showed BFMDRS-M and BFMDRS-D improvements of >30%. In the long-term deep brain stimulation cohort (deep brain stimulation inserted for >5 years, n = 8), improvement of >30% was maintained in 5/8 and 3/8 subjects for the BFMDRS-M and BFMDRS-D, respectively. The greatest BFMDRS-M improvements were observed for trunk (53.2%) and cervical (50.5%) dystonia, with less clinical impact on laryngeal dystonia. Improvements in gait dystonia decreased from 20.9% at 1 year to 16.2% at last assessment; no patient maintained a fully independent gait. Reduction of BFMDRS-D was maintained for swallowing (52.9%). Five patients developed mild parkinsonism following deep brain stimulation. KMT2B-related disease comprises an expanding continuum from infancy to adulthood, with early evidence of genotype-phenotype correlations. Except for laryngeal dysphonia, deep brain stimulation provides a significant improvement in quality of life and function with sustained clinical benefit depending on symptoms distribution.

Very-late-onset Friedreich's ataxia: diagnosis in a kindred with late-onset cerebellar ataxia.

Friedreich's ataxia is classically considered a disease with onset in the first or second decade. However, late-onset (age of onset 25-39 years) and very-late-onset (age of onset >40 years) forms do occur rarely. Misdiagnosis is common, particularly because the later onset forms of Friedreich's ataxia commonly do not show characteristic features of the disorder (areflexia, dysarthria, sensory neuropathy, extensor plantars, amyotrophy, cardiac involvement, diabetes mellitus, scoliosis). Also, there may be atypical features such as spasticity, brisk reflexes and laryngeal dystonia. We present the clinical, imaging and genetic findings of a kindred with very-late-onset Friedreich's ataxia and discuss the pitfalls and risk of misdiagnosis.

Autoimmune Movement Disorders.

Autoimmune movement disorders are rare but potentially treatable entities. They can present with an excess or paucity of movement and may have other associated neurological symptoms. These disorders were originally recognized by their classic clinical presentations and the cancers associated with them. Recent emphasis has been targeted on associated, and sometimes causative, antibodies. Although some disorders have stereotypical presentations, the spectrum of abnormalities reported in association with antibodies is widening. Determining whether antibodies are incidental or pathogenic and, hence, foregoing or commencing immunotherapy treatment can be challenging for practicing neurologists. Physicians often have to make the decision to empirically treat patients while awaiting test results. Due to the lack of randomized controlled trials, the ideal immunotherapy treatments and regimens are unknown. Patients with intracellularly targeted antibodies tend to fare less well, while those with extracellularly targeted antibody disorders often respond to treatments reducing antibody production. This review aims to summarize reported adult-onset autoimmune movement disorders to date, and to provide a template for the workup and treatment of suspected disorders. Rarer antibodies that are not yet fully characterized, or reported in a few cases only, will not be covered in detail as these are not likely to be readily commercially available. Childhood disorders will be only be mentioned briefly in the discussion, as there is a separate article in this issue on autoimmune neurologic diseases in children.

The effects of immunologic brainstem encephalopathy on cognitive function following awakening from a progressive autoimmune coma.

We describe a unique patient who experienced a progressive autoimmune coma from age 14 to 17. The patient awoke after treatment with immunosuppressant medication. Although alertness, verbalization, and mobilization markedly improved, the patient reported persistent cognitive difficulties. Neuropsychological assessment from age 21 showed impairments in selective attention, distractibility, and memory. Conversely, higher-order executive functions were preserved. Electrophysiological analysis also identified abnormal neural signatures of selective attention. Eighteen months after the neuropsychological assessment, voxel-based morphometry revealed reduced white matter in the medulla compared to controls. The findings are discussed in terms of the impact of brainstem encephalopathy on cognitive mechanisms.

Treatment of Apathy in Parkinson's Disease and Implications for Underlying Pathophysiology.

Apathy is a prevalent and highly debilitating non-motor symptom of Parkinson's disease (PD) that is often overlooked in clinical practice due to its subtle nature. This review aims to provide a comprehensive overview of the current evidence for the treatment of apathy in PD, highlighting recent advancements and emerging therapeutic avenues. In this review, we analyse a diverse array of treatment strategies for apathy in PD, including pharmacological interventions, non-pharmacological approaches, and emerging neuromodulation techniques. We evaluate the efficacy, safety, and limitations of established pharmacotherapies, such as dopaminergic agents, antidepressants, and cognitive enhancers. Additionally, we examine the promising role of non-pharmacological interventions, encompassing psychotherapies and behavioural interventions, in ameliorating apathetic symptoms. Furthermore, this review explores the effects of neuromodulation techniques on apathy, including the modulation of apathy via deep brain stimulation and emerging data on the potential influence of transcranial magnetic stimulation (TMS) on apathy in PD. Ultimately, a deeper understanding of effective treatment strategies for apathy has the potential to significantly improve the quality of life and overall well-being of individuals living with PD.

Arm Swing while Walking and Running: A New Clinical Feature to Separate Parkinson's Disease from Functional Parkinsonism.

BACKGROUND: Functional parkinsonism is an important differential diagnosis of Parkinson's disease (PD). Based on anecdotal experience, we hypothesized that arm swing while walking and running could differentiate these two conditions, but this assumption has not been previously explored systematically. OBJECTIVES: To examine differences in arm swing while walking and running between patients with PD and functional parkinsonism. METHODS: We analyzed blinded video assessments of arm swing and other gait parameters in patients with asymmetrical PD (n = 81) and functional parkinsonism (n = 8) while walking and running. The groups were matched for age, sex and disease duration. RESULTS: In contrast to those with PD, patients with functional parkinsonism (i) were more likely to have a marked asymmetry in arm swing while walking (5/8 vs. 25/81; P = 0.06), (ii) were less likely to improve arm swing while running with full effort (3/8 vs. 72/81; P < 0.001) and (iii) demonstrated normal passive arm swing even when asymmetry of arm swing was marked during running/walking (6/6 vs. 9/33; P = 0.002). CONCLUSIONS: Assessment of arm swing while walking and running and passive arm swing could be important differentiating clinical features between functional parkinsonism and PD.