Amyloid‐β transmission has been described in patients both with and without iatrogenic Creutzfeldt–Jakob disease; however, there is little information regarding the clinical impact of this acquired ...amyloid‐β pathology during life. Here, for the first time, we describe in detail the clinical and neuroimaging findings in 3 patients with early onset symptomatic amyloid‐β cerebral amyloid angiopathy following childhood exposure to cadaveric dura (by neurosurgical grafting in 2 patients and tumor embolization in a third). Our observations provide further in vivo evidence that cerebral amyloid angiopathy might be caused by transmission of amyloid‐β seeds (prions) present in cadaveric dura and have diagnostic relevance for younger patients presenting with suspected cerebral amyloid angiopathy. Ann Neurol 2019; 1–7 ANN NEUROL 2019;85:284–290.
Adult-onset leukodystrophies and genetic leukoencephalopathies comprise a diverse group of neurodegenerative disorders of white matter with a wide age of onset and phenotypic spectrum. Patients with ...white matter abnormalities detected on MRI often present a diagnostic challenge to both general and specialist neurologists. Patients typically present with a progressive syndrome including various combinations of cognitive impairment, movement disorders, ataxia and upper motor neuron signs. There are a number of important and treatable acquired causes for this imaging and clinical presentation. There are also a very large number of genetic causes which due to their relative rarity and sometimes variable and overlapping presentations can be difficult to diagnose. In this review, we provide a structured approach to the diagnosis of inherited disorders of white matter in adults. We describe clinical and radiological clues to aid diagnosis, and we present an overview of both common and rare genetic white matter disorders. We provide advice on testing for acquired causes, on excluding small vessel disease mimics, and detailed advice on metabolic and genetic testing available to the practising neurologist. Common genetic leukoencephalopathies discussed in detail include CSF1R, AARS2, cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and mitochondrial and metabolic disorders.
The natural history of clinical symptoms in the spinocerebellar ataxias (SCA)s has been well characterised. However there is little longitudinal data comparing cognitive changes in the most common ...SCA subtypes over time. The present study provides a preliminary longitudinal characterisation of the clinical and cognitive profiles in patients with SCA1, SCA2, SCA3, SCA6 and SCA7, with the aim of elucidating the role of the cerebellum in cognition.
13 patients with different SCAs all caused by CAG repeat expansion (SCA1, n = 2; SCA2, n = 2; SCA3, n = 2; SCA6, n = 4; and SCA7, n = 3) completed a comprehensive battery of cognitive and mood assessments at two time points, a mean of 7.35 years apart. All patients were evaluated clinically using the Scale for the Rating and Assessment of Ataxia (SARA) and the Inventory of Non-Ataxia Signs (INAS). Patients underwent structural MRI imaging at follow-up.
Clinical scale scores increased in all patients over time, most prominently in the SCA1 (SARA) and SCA3 (INAS) groups. New impairments on neuropsychological tests were most commonly observed with executive functions, speed, attention, visual memory and Theory of Mind. Results suggest possible differences in cognitive decline in SCA subtypes, with the most rapid cognitive decline observed in the SCA1 patients, and the least in the SCA6 patients, congruent with observed patterns of motor deterioration. Minimal changes in mood were observed, and MRI measures of atrophy did not correlate with cognitive decline.
As well as increasing physical impairment, cognitive decline over time appears to be a distinct aspect of the SCA phenotype, in keeping with the cerebellar cognitive-affective syndrome. Our data suggest a trend of cognitive decline that is different for each SCA subtype, and for the majority is related to the severity of cerebellar motor impairment.
Chorea is a hyperkinetic movement disorder resulting from dysfunction of striatal medium spiny neurons (MSNs), which form the main output projections from the basal ganglia. Here, we used whole-exome ...sequencing to unravel the underlying genetic cause in three unrelated individuals with a very similar and unique clinical presentation of childhood-onset chorea and characteristic brain MRI showing symmetrical bilateral striatal lesions. All individuals were identified to carry a de novo heterozygous mutation in PDE10A (c.898T>C p.Phe300Leu in two individuals and c.1000T>C p.Phe334Leu in one individual), encoding a phosphodiesterase highly and selectively present in MSNs. PDE10A contributes to the regulation of the intracellular levels of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Both substitutions affect highly conserved amino acids located in the regulatory GAF-B domain, which, by binding to cAMP, stimulates the activity of the PDE10A catalytic domain. In silico modeling showed that the altered residues are located deep in the binding pocket, where they are likely to alter cAMP binding properties. In vitro functional studies showed that neither substitution affects the basal PDE10A activity, but they severely disrupt the stimulatory effect mediated by cAMP binding to the GAF-B domain. The identification of PDE10A mutations as a cause of chorea further motivates the study of cAMP signaling in MSNs and highlights the crucial role of striatal cAMP signaling in the regulation of basal ganglia circuitry. Pharmacological modulation of this pathway could offer promising etiologically targeted treatments for chorea and other hyperkinetic movement disorders.
Dizziness is a highly prevalent complaint with wide-ranging causes and resultant morbidity. Whether symptomatic dizziness and its various manifestations are associated with all-cause and ...cause-specific mortality is unknown.
To examine the associations of symptomatic dizziness and its manifestations with all-cause and cause-specific mortality.
This cohort study is a mortality follow-up study based on the 1999-2004 National Health and Nutrition Examination Survey. The study cohort included adults 40 years and older who completed questions about symptomatic dizziness, including problems with dizziness, balance, falling, and positional dizziness, within the past 12 months. Respondents were linked to mortality data through December 31, 2019. Data were analyzed from February to August 2023.
Self-reported symptomatic dizziness.
All-cause and cause-specific (cardiovascular disease, diabetes, cancer, and unintentional injuries) mortality. Cox proportional hazard regression models were used to examine associations between symptomatic dizziness and all-cause and cause-specific mortality while adjusting for demographics and medical history.
In this nationally representative cohort of 9000 middle-aged and older US adults (mean SD age, 61.8 13.8 years; 4570 50.8% female), prevalence of symptomatic dizziness was 23.8%. Specifically, 18.3% reported problems with dizziness, 14.5% reported problems with balance, 5.7% reported problems with falling, and 3.8% reported dizziness when turning in bed (positional dizziness). At a median (range) of 16.2 (0.1-20.6) years of follow-up, all-cause mortality for adults with symptomatic dizziness was higher than for those without (45.6% vs 27.1%). Symptomatic dizziness was associated with elevated risk for cause-specific mortality from diabetes (hazard ratio HR, 1.66; 95% CI, 1.23-2.25), cardiovascular disease (HR, 1.33; 95% CI, 1.12-1.55), and cancer (HR, 1.21; 95% CI, 0.99-1.47) but not unintentional injuries (HR, 0.98; 95% CI, 0.51-1.88). Reporting problems with balance or falling was associated with increased all-cause mortality (balance: HR, 1.27; 95% CI, 1.17-1.39; and falling: HR, 1.52; 95% CI, 1.33-1.73), cardiovascular disease-specific mortality (balance: HR, 1.41; 95% CI, 1.20-1.66; and falling: HR, 1.49; 95% CI, 1.15-1.94), and diabetes-specific mortality risks (balance: HR, 1.74; 95% CI, 1.26-2.39; and falling: HR, 2.01; 95% CI, 1.26-3.18). There was no association between positional dizziness and mortality (HR, 0.98; 95% CI, 0.82-1.19).
In this cohort study, symptomatic dizziness was associated with increased risk for all-cause and diabetes-, cardiovascular disease-, and cancer-specific mortality. The imprecision of the effect size estimate for cancer-specific mortality prevents making a definitive conclusion. Future studies are needed to determine whether symptomatic dizziness indicates underlying health conditions contributing to mortality or if early intervention for imbalance and falls can reduce mortality risk.
In the last 6 years, following the first pathological description of presumed amyloid-beta (Aβ) transmission in humans (in 2015) and subsequent experimental confirmation (in 2018), clinical cases of ...iatrogenic cerebral amyloid angiopathy (CAA)—attributed to the transmission of Aβ seeds—have been increasingly recognised and reported. This newly described form of CAA is associated with early disease onset (typically in the third to fifth decade), and often presents with intracerebral haemorrhage, but also seizures and cognitive impairment. Although assumed to be rare, it is important that clinicians remain vigilant for potential cases, particularly as the optimal management, prognosis, true incidence and public health implications remain unknown. This review summarises our current understanding of the clinical spectrum of iatrogenic CAA and provides a diagnostic framework for clinicians. We provide clinical details for three patients with pathological evidence of iatrogenic CAA and present a summary of the published cases to date (n=20), identified following a systematic review. Our aims are: (1) To describe the clinical features of iatrogenic CAA, highlighting important similarities and differences between iatrogenic and sporadic CAA; and (2) To discuss potential approaches for investigation and diagnosis, including suggested diagnostic criteria for iatrogenic CAA.
Summary Background In May, 2013, an outbreak of symptomatic hepatitis A virus infections occurred in the USA. Federal, state, and local public health officials investigated the cause of the outbreak ...and instituted actions to control its spread. We investigated the source of the outbreak and assessed the public health measures used. Methods We interviewed patients, obtained their shopping information, and did genetic analysis of hepatitis A virus recovered from patients' serum and stool samples. We tested products for the virus and traced supply chains. Findings Of 165 patients identified from ten states, 69 (42%) were admitted to hospital, two developed fulminant hepatitis, and one needed a liver transplant; none died. Illness onset occurred from March 31 to Aug 12, 2013. The median age of patients was 47 years (IQR 35–58) and 91 (55%) were women. 153 patients (93%) reported consuming product B from retailer A. 40 patients (24%) had product B in their freezers, and 113 (68%) bought it according to data from retailer A. Hepatitis A virus genotype IB, uncommon in the Americas, was recovered from specimens from 117 people with hepatitis A virus illness. Pomegranate arils that were imported from Turkey—where genotype IB is common—were identified in product B. No hepatitis A virus was detected in product B. Interpretation Imported frozen pomegranate arils were identified as the vehicle early in the investigation by combining epidemiology—with data from several sources—genetic analysis of patient samples, and product tracing. Product B was removed from store shelves, the public were warned not to eat product B, product recalls took place, and postexposure prophylaxis with both hepatitis A virus vaccine and immunoglobulin was provided. Our findings show that modern public health actions can help rapidly detect and control hepatitis A virus illness caused by imported food. Our findings show that postexposure prophylaxis can successfully prevent hepatitis A illness when a specific product is identified. Imported food products combined with waning immunity in some adult populations might make this type of intervention necessary in the future. Funding US Centers for Disease Control and Prevention, US Food and Drug Administration, and US state and local public health departments.
Loss-of-function of DDX3X is a leading cause of neurodevelopmental disorders (NDD) in females. DDX3X is also a somatically mutated cancer driver gene proposed to have tumour promoting and suppressing ...effects. We perform saturation genome editing of DDX3X, testing in vitro the functional impact of 12,776 nucleotide variants. We identify 3432 functionally abnormal variants, in three distinct classes. We train a machine learning classifier to identify functionally abnormal variants of NDD-relevance. This classifier has at least 97% sensitivity and 99% specificity to detect variants pathogenic for NDD, substantially out-performing in silico predictors, and resolving up to 93% of variants of uncertain significance. Moreover, functionally-abnormal variants can account for almost all of the excess nonsynonymous DDX3X somatic mutations seen in DDX3X-driven cancers. Systematic maps of variant effects generated in experimentally tractable cell types have the potential to transform clinical interpretation of both germline and somatic disease-associated variation.
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