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Toxicon : Official Journal of the... Aug 2023Many studies have shown that botulinum toxin (BoNT) can be an option to treat motor and non-motor symptoms in Parkinson's disease (PD) and parkinsonian syndromes. The... (Review)
Review
Many studies have shown that botulinum toxin (BoNT) can be an option to treat motor and non-motor symptoms in Parkinson's disease (PD) and parkinsonian syndromes. The advantages of BoNT compared to oral medications include localized action and low incidence of systemic side effects, which is important in treating neurodegenerative disease. Motor symptoms that can be treated with BoNT include blepharospasm, apraxia of eyelid opening, tremor, cervical dystonia and limb dystonia. Other indications with less evidence include camptocormia, freezing of gait and dyskinesia. Non-motor symptoms that may improve with BoNT include sialorrhea, pain, overreactive bladder, dysphagia and constipation. However, the current evidence for use of BoNT in parkinsonism is mostly based on open-label studies and there are few randomized, controlled trials. BoNT can be a valuable tool to treat certain symptoms of PD and parkinsonian syndromes to improve the patient's quality of life. However, many of the uses are not supported by high quality studies and further studies are needed to provide further evidence of efficacy, define the optimal injection protocols such as doses and muscle selection.
Topics: Humans; Botulinum Toxins; Botulinum Toxins, Type A; Gait Disorders, Neurologic; Neurodegenerative Diseases; Parkinson Disease; Parkinsonian Disorders; Quality of Life; Torticollis
PubMed: 37429465
DOI: 10.1016/j.toxicon.2023.107209 -
Practical Neurology Nov 2023A 68-year-old Brazilian woman had 3 months of progressive fatigue, difficulty walking and 18 kg weight loss. On examination, there was gait apraxia and executive...
A 68-year-old Brazilian woman had 3 months of progressive fatigue, difficulty walking and 18 kg weight loss. On examination, there was gait apraxia and executive dysfunction. MR scan of brain showed communicating hydrocephalus and a cerebrospinal fluid showed 105 white cells/µL (≤5), predominantly lymphocytes, protein of 1.35 g/L (0.15-0.45) and the glucose content of 0.06 mmol/L (3.3-4.4). We suspected an infective cause and used of metagenomic next-generation sequencing to diagnose neurocysticercosis. This case highlights the challenge of diagnosing chronic meningitis and the relevance of genetic approaches in diagnosing neurological infections.
Topics: Female; Humans; Aged; Neurocysticercosis; Meningitis; Brain; Hydrocephalus; High-Throughput Nucleotide Sequencing
PubMed: 37468299
DOI: 10.1136/pn-2023-003795 -
Alzheimer's Research & Therapy Jul 2023Alzheimer's disease (AD) is a common age-related neurodegenerative disease in the central nervous system and is the primary cause of dementia. It is clinically... (Review)
Review
Alzheimer's disease (AD) is a common age-related neurodegenerative disease in the central nervous system and is the primary cause of dementia. It is clinically characterized by the memory impairment, aphasia, apraxia, agnosia, visuospatial and executive dysfunction, behavioral changes, and so on. Incidence of this disease was bound up with age, genetic factors, cardiovascular and cerebrovascular dysfunction, and other basic diseases, but the exact etiology has not been clarified. MicroRNAs (miRNAs) are small endogenous non-coding RNAs that were involved in the regulation of post-transcriptional gene expression. miRNAs have been extensively studied as noninvasive potential biomarkers for disease due to their relative stability in bodily fluids. In addition, they play a significant role in the physiological and pathological processes of various neurological disorders, including stroke, AD, and Parkinson's disease. MiR-155, as an important pro-inflammatory mediator of neuroinflammation, was reported to participate in the progression of β-amyloid peptide and tau via regulating immunity and inflammation. In this review, we put emphasis on the effects of miR-155 on AD and explore the underlying biological mechanisms which could provide a novel approach for diagnosis and treatment of AD.
Topics: Humans; Alzheimer Disease; Neurodegenerative Diseases; MicroRNAs; Amyloid beta-Peptides; Risk Factors
PubMed: 37452431
DOI: 10.1186/s13195-023-01264-z -
Brain Communications 2023Apraxia of eyelid opening (or eye-opening apraxia) is characterized by the inability to voluntarily open the eyes because of impaired supranuclear control. Here, we...
Apraxia of eyelid opening (or eye-opening apraxia) is characterized by the inability to voluntarily open the eyes because of impaired supranuclear control. Here, we examined the neural substrates implicated in eye-opening apraxia through lesion network mapping. We analysed brain lesions from 27 eye-opening apraxia stroke patients and compared them with lesions from 20 aphasia and 45 hemiballismus patients serving as controls. Lesions were mapped onto a standard brain atlas using resting-state functional MRI data derived from 966 healthy adults in the Harvard Dataverse. Our analyses revealed that most eye-opening apraxia-associated lesions occurred in the right hemisphere, with subcortical or mixed cortical/subcortical involvement. Despite their anatomical heterogeneity, these lesions functionally converged on the bilateral dorsal anterior and posterior insula. The functional connectivity map for eye-opening apraxia was distinct from those for aphasia and hemiballismus. Hemiballismus lesions predominantly mapped onto the putamen, particularly the posterolateral region, while aphasia lesions were localized to language-processing regions, primarily within the frontal operculum. In summary, in patients with eye-opening apraxia, disruptions in the dorsal anterior and posterior insula may compromise their capacity to initiate the appropriate eyelid-opening response to relevant interoceptive and exteroceptive stimuli, implicating a complex interplay between salience detection and motor execution.
PubMed: 37953849
DOI: 10.1093/braincomms/fcad288 -
Journal of Neural Transmission (Vienna,... Dec 2023Corticobasal degeneration (CBD) is a rare, sporadic, late-onset progressive neurodegenerative disorder of unknown etiology, clinically characterized by an akinetic-rigid... (Review)
Review
Corticobasal degeneration (CBD) is a rare, sporadic, late-onset progressive neurodegenerative disorder of unknown etiology, clinically characterized by an akinetic-rigid syndrome, behavior and personality disorders, language problems (aphasias), apraxia, executive and cognitive abnormalities and limb dystonia. The syndrome is not specific, as clinical features of pathologically proven CBD include several phenotypes. This 4-repeat (4R) tauopathy is morphologically featured by often asymmetric frontoparietal atrophy, ballooned/achromatic neurons containing filamentous 4R-tau aggregates in cortex and striatum, thread-like processes that are more widespread than in progressive supranuclear palsy (PSP), pathognomonic "astroglial plaques", and numerous inclusions in both astrocytes and oligodendroglia ("coiled bodies") in the white matter. Cognitive deficits in CBD are frequent initial presentations before onset of motor symptoms, depending on the phenotypic variant. They predominantly include executive and visuospatial dysfunction, sleep disorders and language deficits with usually preserved memory domains. Neuroimaging studies showed heterogenous locations of brain atrophy, particularly contralateral to the dominant symptoms, with disruption of striatal connections to prefrontal cortex and basal ganglia circuitry. Asymmetric hypometabolism, mainly involving frontal and parietal regions, is associated with brain cholinergic deficits, and dopaminergic nigrostriatal degeneration. Widespread alteration of cortical and subcortical structures causing heterogenous changes in various brain functional networks support the concept that CBD, similar to PSP, is a brain network disruption disorder. Putative pathogenic factors are hyperphosphorylated tau-pathology, neuroinflammation and oxidative injury, but the basic mechanisms of cognitive impairment in CBD, as in other degenerative movement disorders, are complex and deserve further elucidation as a basis for early diagnosis and adequate treatment of this fatal disorder.
Topics: Humans; Corticobasal Degeneration; Cerebral Cortex; Supranuclear Palsy, Progressive; Atrophy; Cognition; tau Proteins
PubMed: 37659990
DOI: 10.1007/s00702-023-02691-w -
Neurology Jul 2023Corticobasal syndrome (CBS) is a clinical phenotype characterized by asymmetric parkinsonism, rigidity, myoclonus, and apraxia. Originally believed secondary to...
BACKGROUND AND OBJECTIVES
Corticobasal syndrome (CBS) is a clinical phenotype characterized by asymmetric parkinsonism, rigidity, myoclonus, and apraxia. Originally believed secondary to corticobasal degeneration (CBD), mounting clinicopathologic studies have revealed heterogenous neuropathologies. The objectives of this study were to determine the pathologic heterogeneity of CBS, the clinicoradiologic findings associated with different underlying pathologies causing CBS, and the positive predictive value (PPV) of current diagnostic criteria for CBD among patients with a CBS.
METHODS
Clinical data, brain MRI, and neuropathologic data of patients followed at Mayo Clinic and diagnosed with CBS antemortem were reviewed according to neuropathology category at autopsy.
RESULTS
The cohort consisted of 113 patients with CBS, 61 (54%) female patients. Mean ± SD disease duration was 7 ± 3.7 years; mean ± SD age at death was 70.5 ± 9.1 years. The primary neuropathologic diagnoses were 43 (38%) CBD, 27 (24%) progressive supranuclear palsy (PSP), 17 (15%) Alzheimer disease (AD), 10 (9%) frontotemporal lobar degeneration (FTLD) with TAR DNA-binding protein 43 (TDP) inclusions, 7 (6%) diffuse Lewy body disease (DLBD)/AD, and 9 (8%) with other diagnoses. Patients with CBS-AD or CBS-DLBD/AD were youngest at death (median [interquartile range]: 64 [13], 64 [11] years) while CBS-PSP were oldest (77 [12.5] years, = 0.024). Patients with CBS-DLBD/AD had the longest disease duration (9 [6] years), while CBS-other had the shortest (3 [4.25] years, = 0.04). Posterior cortical signs and myoclonus were more characteristic of patients with CBS-AD and patients with CBS-DLBD/AD. Patients with CBS-DLBD/AD displayed more features of Lewy body dementia. Voxel-based morphometry revealed widespread cortical gray matter loss characteristic of CBS-AD, while CBS-CBD and CBS-PSP predominantly involved premotor regions with greater amount of white matter loss. Patients with CBS-DLBD/AD showed atrophy in a focal parieto-occipital region, and patients with CBS-FTLD-TDP had predominant prefrontal cortical loss. Patients with CBS-PSP had the lowest midbrain/pons ratio ( = 0.012). Of 67 cases meeting clinical criteria for possible CBD at presentation, 27 were pathology-proven CBD, yielding a PPV of 40%.
DISCUSSION
A variety of neurodegenerative disorders can be identified in patients with CBS, but clinical and regional imaging differences aid in predicting underlying neuropathology. PPV analysis of the current CBD diagnostic criteria revealed suboptimal performance. Biomarkers adequately sensitive and specific for CBD are needed.
Topics: Female; Male; Humans; Corticobasal Degeneration; Myoclonus; Supranuclear Palsy, Progressive; Alzheimer Disease; Magnetic Resonance Imaging; Lewy Body Disease
PubMed: 37268436
DOI: 10.1212/WNL.0000000000207397 -
Brain : a Journal of Neurology May 2024Progressive apraxia of speech (PAOS) is a neurodegenerative motor-speech disorder that most commonly arises from a four-repeat tauopathy. Recent studies have established...
Progressive apraxia of speech (PAOS) is a neurodegenerative motor-speech disorder that most commonly arises from a four-repeat tauopathy. Recent studies have established that progressive apraxia of speech is not a homogenous disease but rather there are distinct subtypes: the phonetic subtype is characterized by distorted sound substitutions, the prosodic subtype by slow and segmented speech and the mixed subtype by a combination of both but lack of predominance of either. There is some evidence that cross-sectional patterns of neurodegeneration differ across subtypes, although it is unknown whether longitudinal patterns of neurodegeneration differ. We examined longitudinal patterns of atrophy on MRI, hypometabolism on 18F-fluorodeoxyglucose-PET and tau uptake on flortaucipir-PET in a large cohort of subjects with PAOS that had been followed for many years. Ninety-one subjects with PAOS (51 phonetic, 40 prosodic) were recruited by the Neurodegenerative Research Group. Of these, 54 (27 phonetic, 27 prosodic) returned for annual follow-up, with up to seven longitudinal visits (total visits analysed = 217). Volumes, metabolism and flortaucipir uptake were measured for subcortical and cortical regions, for all scans. Bayesian hierarchical models were used to model longitudinal change across imaging modalities with PAOS subtypes being compared at baseline, 4 years from baseline, and in terms of rates of change. The phonetic group showed smaller volumes and worse metabolism in Broca's area and the striatum at baseline and after 4 years, and faster rates of change in these regions, compared with the prosodic group. There was also evidence of faster spread of hypometabolism and flortaucipir uptake into the temporal and parietal lobes in the phonetic group. In contrast, the prosodic group showed smaller cerebellar dentate, midbrain, substantia nigra and thalamus volumes at baseline and after 4 years, as well as faster rates of atrophy, than the phonetic group. Greater hypometabolism and flortaucipir uptake were also observed in the cerebellar dentate and substantia nigra in the prosodic group. Mixed findings were observed in the supplementary motor area and precentral cortex, with no clear differences observed across phonetic and prosodic groups. These findings support different patterns of disease spread in PAOS subtypes, with corticostriatal patterns in the phonetic subtype and brainstem and thalamic patterns in the prosodic subtype, providing insight into the pathophysiology and heterogeneity of PAOS.
Topics: Humans; Carbolines; Male; Female; Aged; Apraxias; Positron-Emission Tomography; Middle Aged; Longitudinal Studies; Magnetic Resonance Imaging; Brain; Atrophy; Fluorodeoxyglucose F18; Phonetics; Aged, 80 and over; tau Proteins
PubMed: 38217867
DOI: 10.1093/brain/awae016 -
Molecular Cell Oct 2023The senataxin (SETX, Sen1 in yeasts) RNA-DNA hybrid resolving helicase regulates multiple nuclear transactions, including DNA replication, transcription, and DNA repair,...
The senataxin (SETX, Sen1 in yeasts) RNA-DNA hybrid resolving helicase regulates multiple nuclear transactions, including DNA replication, transcription, and DNA repair, but the molecular basis for Sen1 activities is ill defined. Here, Sen1 cryoelectron microscopy (cryo-EM) reconstructions reveal an elongated inchworm-like architecture. Sen1 is composed of an amino terminal helical repeat Sen1 N-terminal (Sen1N) regulatory domain that is flexibly linked to its C-terminal SF1B helicase motor core (Sen1) via an intrinsically disordered tether. In an autoinhibited state, the Sen1 domain regulates substrate engagement by promoting occlusion of the RNA substrate-binding cleft. The X-ray structure of an activated Sen1 engaging single-stranded RNA and ADP-SO shows that the enzyme encircles RNA and implicates a single-nucleotide power stroke in the Sen1 RNA translocation mechanism. Together, our data unveil dynamic protein-protein and protein-RNA interfaces underpinning helicase regulation and inactivation of human SETX activity by RNA-binding-deficient mutants in ataxia with oculomotor apraxia 2 neurodegenerative disease.
Topics: Humans; RNA; Neurodegenerative Diseases; Cryoelectron Microscopy; RNA Helicases; Multifunctional Enzymes; DNA; Homeostasis; DNA Helicases
PubMed: 37832548
DOI: 10.1016/j.molcel.2023.09.024 -
Brain Sciences Jan 2024Rett syndrome (RTT) is a neurological disorder that mostly affects females, with a frequency of 1 in 10,000 to 20,000 live birth cases. Symptoms include stereotyped hand... (Review)
Review
Rett syndrome (RTT) is a neurological disorder that mostly affects females, with a frequency of 1 in 10,000 to 20,000 live birth cases. Symptoms include stereotyped hand movements; impaired learning, language, and communication skills; sudden loss of speech; reduced lifespan; retarded growth; disturbance of sleep and breathing; seizures; autism; and gait apraxia. Pneumonia is the most common cause of death for patients with Rett syndrome, with a survival rate of 77.8% at 25 years of age. Survival into the fifth decade is typical in Rett syndrome, and the leading cause of death is cardiorespiratory compromise. Rett syndrome progression has multiple stages; however, most phenotypes are associated with the nervous system and brain. In total, 95% of Rett syndrome cases are due to mutations in the gene, an X-linked gene that encodes for the methyl CpG binding protein, a regulator of gene expression. In this review, we summarize the recent developments in the field of Rett syndrome and therapeutics targeting MECP2.
PubMed: 38391695
DOI: 10.3390/brainsci14020120 -
Brain : a Journal of Neurology Apr 2024It is debated whether primary progressive apraxia of speech (PPAOS) and progressive agrammatic aphasia (PAA) belong to the same clinical spectrum, traditionally termed...
It is debated whether primary progressive apraxia of speech (PPAOS) and progressive agrammatic aphasia (PAA) belong to the same clinical spectrum, traditionally termed non-fluent/agrammatic variant primary progressive aphasia (nfvPPA), or exist as two completely distinct syndromic entities with specific pathologic/prognostic correlates. We analysed speech, language and disease severity features in a comprehensive cohort of patients with progressive motor speech impairment and/or agrammatism to ascertain evidence of naturally occurring, clinically meaningful non-overlapping syndromic entities (e.g. PPAOS and PAA) in our data. We also assessed if data-driven latent clinical dimensions with aetiologic/prognostic value could be identified. We included 98 participants, 43 of whom had an autopsy-confirmed neuropathological diagnosis. Speech pathologists assessed motor speech features indicative of dysarthria and apraxia of speech (AOS). Quantitative expressive/receptive agrammatism measures were obtained and compared with healthy controls. Baseline and longitudinal disease severity was evaluated using the Clinical Dementia Rating Sum of Boxes (CDR-SB). We investigated the data's clustering tendency and cluster stability to form robust symptom clusters and employed principal component analysis to extract data-driven latent clinical dimensions (LCD). The longitudinal CDR-SB change was estimated using linear mixed-effects models. Of the participants included in this study, 93 conformed to previously reported clinical profiles (75 with AOS and agrammatism, 12 PPAOS and six PAA). The remaining five participants were characterized by non-fluent speech, executive dysfunction and dysarthria without apraxia of speech or frank agrammatism. No baseline clinical features differentiated between frontotemporal lobar degeneration neuropathological subgroups. The Hopkins statistic demonstrated a low cluster tendency in the entire sample (0.45 with values near 0.5 indicating random data). Cluster stability analyses showed that only two robust subgroups (differing in agrammatism, executive dysfunction and overall disease severity) could be identified. Three data-driven components accounted for 71% of the variance [(i) severity-agrammatism; (ii) prominent AOS; and (iii) prominent dysarthria]. None of these data-driven LCDs allowed an accurate prediction of neuropathology. The severity-agrammatism component was an independent predictor of a faster CDR-SB increase in all the participants. Higher dysarthria severity, reduced words per minute and expressive and receptive agrammatism severity at baseline independently predicted accelerated disease progression. Our findings indicate that PPAOS and PAA, rather than exist as completely distinct syndromic entities, constitute a clinical continuum. In our cohort, splitting the nfvPPA spectrum into separate clinical phenotypes did not improve clinical-pathological correlations, stressing the need for new biological markers and consensus regarding updated terminology and clinical classification.
Topics: Humans; Aphasia, Broca; Dysarthria; Apraxias; Language; Speech; Aphasia, Primary Progressive; Primary Progressive Nonfluent Aphasia
PubMed: 37988272
DOI: 10.1093/brain/awad396