Neurodegenerative Diseases最新文献

Introduction: Herpesviruses might play a role in the pathogenesis of neurodegenerative disorders. We sought to examine a possible association between alpha herpesvirus infections and Parkinson's disease.

Methods: We conducted a population-based case-control study of incident Parkinson's disease in 2009 Medicare beneficiaries age 66-90 years (89,790 cases, 118,095 randomly selected comparable controls). We classified beneficiaries with any diagnosis code for "herpes simplex" and/or "herpes zoster" in the previous 5 years as having had the respective alpha herpesviruses. In beneficiaries with Part D prescription coverage, we also identified those prescribed anti-herpetic medications. We calculated odds ratios (OR) and 95% CI between alpha herpesvirus diagnosis/treatment and Parkinson's disease with logistic regression, with adjustment for age, sex, race/ethnicity, smoking, and use of medical care.

Results: Parkinson's disease risk was inversely associated with herpes simplex (OR 0.79, 95% CI 0.74-0.84), herpes zoster (OR 0.88, 95% CI 0.85-0.91), and anti-herpetic medications (OR 0.87, 95% CI 0.80-0.96).

Conclusion: Herpesvirus infection or treatment might reduce risk of Parkinson's disease, but future studies will be required to explore whether this inverse association is causal.

Objective: The electrocortical activities associated with the neuropsychiatric symptoms (NPSs) of Alzheimer's disease (AD) were investigated using frequency-domain electroencephalography (EEG) spectral source analysis, and the potential electrocortical indices identified.

Materials and methods: Scalp EEG data were obtained from 51 patients with AD to investigate the presence of four NPS subdomains, hyperactivity, psychosis, affective symptoms, and apathy. EEG power spectra and the standardized low-resolution brain electromagnetic tomography (sLORETA)-localized EEG cortical sources were compared between the groups with and without the four NPS subdomains in eight frequency bands: 1-4, 4-8, 8-10, 10-12, 12-18, 18-20, 20-30, and 30-45 Hz.

Results: The power spectral analysis of EEG data showed that AD patients with psychosis had lower values at the α2-band in most areas. In patients with apathy, the θ-to-β power ratio showed a greater activity over the frontal and central regions. The cortical source analysis using sLORETA revealed that patients with psychosis showed decreased values in the α2-band and patients with apathy showed higher δ-values, especially in the right frontal and temporal regions.

Conclusion: The results of the present study showed that both classical EEG spectral and EEG source analysis could differentiate patients with and without NPSs, especially psychosis and apathy subdomains. Spectral and sLORETA analyses provided information helpful for a better characterization in patients with NPSs.

Introduction: Familial isolated deficiency of vitamin E (VED or AVED; MIM #277460) is a progressive neurodegenerative disorder resembling Friedreich ataxia. It is caused by the deficiency of α-tocopherol transfer protein that prevents patients from retaining vitamin E. Oral vitamin E supplements are an accepted treatment, but detailed dosage recommendations and reports on long-term therapeutic results are scarce.

Methods: The first patient with VED was discovered at our institution at the age of 12 years and has since been followed with clinical, neurophysiological, neuroradiological, and biochemical investigations to his present age of 52 years. For the last 36 years, the patient has scrupulously followed a custom-made high-dose vitamin E supplement regimen that we devised on the basis of studies of his metabolism of vitamin E.

Results: Over the long period of observation, the patient has remained in good general health and has not shown progression of neurological symptoms and signs. His vitamin E plasma levels were always moderately above the normal range. During short interruptions of vitamin E supplements, vitamin E levels fell rapidly, even after years of massive supplementation.

Discussion: In this VED patient, a specified and carefully controlled high-dose vitamin E therapy has prevented any recognizable progression of the neurodegenerative process over more than 3 decades of observation.

Introduction: We investigated the association between atrophy subtypes of Alzheimer's disease (AD), the ATN classification scheme, and key demographic and clinical factors in 2 cohorts with different source characteristics (a highly selective research-oriented cohort, the Alzheimer's Disease Neuroimaging Initiative [ADNI]; and a naturalistic heterogeneous clinically oriented cohort, Karolinska Imaging Dementia Study [KIDS]).

Methods: A total of 382 AD patients were included. Factorial analysis of mixed data was used to investigate associations between AD subtypes based on brain atrophy patterns, ATN profiles based on cerebrospinal fluid biomarkers, and age, sex, Mini Mental State Examination (MMSE), cerebrovascular disease (burden of white matter signal abnormalities, WMSAs), and APOE genotype.

Results: Older patients with high WMSA burden, belonging to the typical AD subtype and showing A+T+N+ or A+T+N- profiles clustered together and were mainly from ADNI. Younger patients with low WMSA burden, limbic-predominant or minimal atrophy AD subtypes, and A+T-N- or A+T-N+ profiles clustered together and were mainly from KIDS. APOE ε4 carriers more frequently showed the A+T-N- and A+T+N- profiles.

Conclusions: Our findings align with the recent framework for biological subtypes of AD: the combination of risk factors, protective factors, and brain pathologies determines belonging of AD patients to distinct subtypes.

Pathogenic and risk variants in the LRRK2 gene are among the main genetic contributors to Parkinson's disease (PD) worldwide, and LRRK2-targeted therapies for patients with PARK-LRRK2are now entering clinical trials. However, in contrast to the LRRK2 G2019S mutation commonly found in Caucasians, North-African Arabs, and Ashkenazi Jews, relatively little is known about other causative LRRK2 mutations, and data on genotype-phenotype correlations are largely lacking. This report is from an ongoing multicentre study in which next-generation sequencing-based PD gene panel testing has so far been conducted on 499 PD patients of various ethnicities from Malaysia. We describe 2 sisters of Chinese ancestry with PD who carry the R1441C mutation in LRRK2 (which in Asians has been reported in only 2 Chinese patients previously), and highlight interesting clinical observations made over a decade of close follow-up. We further explored the feasibility of using a brief, expert-administered rating scale (the Clinical Impression of Severity Index; CISI-PD) to capture data on global disease severity in a large (n = 820) unselected cohort of PD patients, including severely disabled individuals typically excluded from research studies. All patients in this study were managed and evaluated by the same PD neurologist, and these data were used to make broad comparisons between the monogenic PD cases versus the overall "real world" PD cohort. This report contributes to the scarce literature on R1441C PARK-LRRK2, offering insights into natural history and epidemiological aspects, and provides support for the application of a simple and reliable clinical tool that can improve the inclusion of under-represented patient groups in PD research.

Introduction: Rapid-onset dystonia parkinsonism (RDP), also referred to as Dystonia 12, is a rare autosomal dominant genetic disease characterized by abrupt onset of a rostrocaudal gradient of dystonia with prominent bulbar symptoms, and parkinsonian features, primarily bradykinesia and postural instability without tremor. The purpose of this study was to identify the genetic defect in a Chinese pedigree with familial RDP and to explore genotype-phenotype correlation.

Methods: A 3-generation Chinese Han pedigree consisting of 9 members and 3 patients with RDP, and 200 unrelated ethnically matched normal subjects were recruited in this study. Exome sequencing was performed in the proband, and Sanger sequencing was then conducted in other family members and 200 normal controls.

Results: In addition to the typical clinical manifestations of RDP, the proband and her sister presented tongue tremor which developed at the onset, and intriguingly the proband showed a "re-emergent" tongue tremor. Both the proband and her sister had a medical history of hyperthyroidism, and at the psychiatric interview they both received diagnoses of depression and anxiety. Excessive grammar errors existed in most sentences written by the proband, and this written-expression disorder occurred years before the onset of RDP. The mother of the proband presented tongue enlargement, oromandibular dystonia, and limb dystonia, which were not observed in her 2 daughters at the time of study. A missense variant, c.1838C>T (p.T613M), in the ATP1A3 gene, was identified in the 3 patients in the family and in 2 young children but was absent in family members without RDP and in the 200 normal controls.

Conclusion: These findings may broaden the phenotypic spectrums of RDP with mutations in the ATP1A3 gene, provide new insights into the diagnosis of RDP, and have implications for genetic counseling.

Objectives: The present study aimed to study whether combined inflow-based vascular-space-occupancy (iVASO) MR imaging (MRI) and diffusion-weighted imaging (DWI) improve the diagnostic accuracy in the preoperative grading of gliomas.

Methods: Fifty-one patients with histopathologically confirmed diffuse gliomas underwent preoperative structural MRI, iVASO, and DWI. We performed 2 qualitative consensus reviews: (1) structural MR images alone and (2) structural MR images with iVASO and DWI. Relative arteriolar cerebral blood volume (rCBVa) and minimum apparent diffusion coefficient (mADC) were compared between low-grade and high-grade gliomas. Receiver operating characteristic (ROC) curve analysis was performed to compare the tumor grading efficiency of rCBVa, mADC, and the combination of the two parameters.

Results: Two observers diagnosed accurate tumor grade in 40 of 51 (78.4%) patients in the first review and in 46 of 51 (90.2%) in the second review. Both rCBVa and mADC showed significant differences between low-grade and high-grade gliomas. ROC analysis gave a threshold value of 1.52 for rCBVa and 0.85 × 10-3 mm2/s for mADC to provide a sensitivity and specificity of 88.0 and 81.2% and 100.0 and 68.7%, respectively. The area under the ROC curve (AUC) was 0.87 and 0.85 for rCBVa and mADC, respectively. The combination of rCBVa and mADC values increased the AUC to 0.92.

Conclusion: The combined application of iVASO and DWI may improve the diagnostic accuracy of glioma grading.

Orthostatic tremor (OT) is not an uncommon symptom in various neurodegenerative diseases. However, the nature and pathophysiology of OT involve a complex network of tremors and dopaminergic pathways. We assessed patients who complained of prominent leg tremors described as "shaky leg." We analyzed their characteristics and evaluated them with neuroimaging and electrophysiological tools. A total of 23 patients who experienced an uncomfortable symptom of leg tremor were retrospectively enrolled from April 2014 to October 2019. Previous medical history, brain MRI, and surface electromyography (EMG) data were analyzed. The [18F]-FP-CIT brain positron emission tomography (PET) and the Unified Parkinson's Disease Rating Scale (UPDRS) were assessed for patients who showed parkinsonism. The causes of OT varied: parkinsonism (n = 5), idiopathic causes (n = 4), secondary causes (n = 3, trauma, brain lesion, arteriovenous malformation), drug reactions (n = 3, valproate, perphenazine, haloperidol), other neurological disorders (n = 5, essential tremor, dystonia, restless leg syndrome, REM sleep behavior disorder, dementia), alcohol withdrawal (n = 1), functional movement disorder (n = 1), and an unknown cause (n = 1). The frequency range varied (2.6-15 Hz) and according to the new consensus statement on the classification of OT, 4 patients had primary OT, 2 had "primary OT plus," 12 had slow OT, and 5 had orthostatic myoclonus. The prognosis associated with the use of medication was generally poor; however, clonazepam and levodopa were the most effective drugs. In conclusion, we found that different types of OT and orthostatic myoclonus were diagnosed by electrophysiological evaluation and neuroimaging tools even if they showed the same symptoms as "shaky leg." In addition, it is possible to roughly estimate the response to medication according to the type of OT and the cause. To clarify the pathophysiology of OT, a large number of longitudinal cohort studies and detailed neuroimaging and electrophysiological evaluations are needed.

Introduction: Saliva problems are common and distressing for people with motor neuron disease (pwMND). Despite clinical guidelines for assessment and treatment, management of saliva problems has received little research attention.

Objective: We aimed to investigate the prevalence of saliva problems in pwMND, their association with clinical factors, and their management practice using a highly curated population-based register for motor neuron disease (MND) with 99% case ascertainment.

Methods: We conducted an analysis of pwMND diagnosed between January 2015 and October 2019 using the Scottish MND Register (CARE-MND [Clinical, Audit, Research, and Evaluation of MND]). The association between clinical factors and saliva problems was investigated using univariate and multivariable logistic regression; results are reported as odds ratio (OR) and 95% confidence intervals. A survey of health-care professionals involved in the care of pwMND was performed to contextualize the findings.

Results: 939 pwMND were included. Prevalence of saliva problems was 31.3% (294). Bulbar onset (OR 9.46 [4.7, 19.2]; p < 0.001) but not age, sex, time to diagnosis, or MND subtype were independently associated with the presence of saliva problems in multivariable regression, and 52.7% (155) of those with saliva problems received pharmacological management. The most commonly used medications were hyoscine, amitriptyline, carbocisteine, glycopyrrolate, and atropine. Evidence base (8, 72.7%) and local guidelines (10, 90.9%) were cited as the most important factors influencing treatment decision by survey respondents (n = 11).

Conclusion: Saliva problems are common and associated with bulbar onset MND. A substantial proportion of pwMND with saliva problems did not receive recommended treatments. Future research is required to determine the relative efficacy of individual pharmacological treatments.

Introduction: Traumatic brain injury (TBI) is the most relevant external risk factor for dementia and a major global health burden. Mild TBI (mTBI) contributes to up to 90% of all TBIs, and the classification "mild" often misrepresents the patient's burden who suffer from neuropsychiatric long-term sequelae. Magnetic resonance spectroscopy (MRS) allows in vivo detection of compromised brain metabolism although it is not routinely used after TBI.

Objective: Thus, we performed a systematic review and meta-analysis to elucidate if MRS has the potential to identify changes in brain metabolism in adult patients after a single mTBI with a negative routine brain scan (CCT and/or MRI scan) compared to aged- and sex-matched healthy controls (HC) during the acute or subacute postinjury phase (≤90 days after mTBI).

Methods: A comprehensive literature search was conducted from the first edition of electronic databases until January 31, 2020. Group analyses were performed per metabolite using a random-effects model.

Results: Four and 2 out of 5,417 articles met the inclusion criteria for the meta-analysis and systematic review, respectively. For the meta-analysis, 50 mTBI patients and 51 HC with a mean age of 31 and 30 years, respectively, were scanned using N-acetyl-aspartate (NAA), a marker for neuronal integrity. Glutamate (Glu), a marker for disturbed brain metabolism, choline (Cho), a marker for increased cell membrane turnover, and creatine (Cr) were used in 2 out of the 4 included articles. Regions of interests were the frontal lobe, the white matter around 1 cm above the lateral ventricles, or the whole brain. NAA was decreased in patients compared to HC with an effect size (ES) of -0.49 (95% CI -1.08 to 0.09), primarily measured in the frontal lobe. Glu was increased in the white matter in 22 mTBI patients compared to 22 HC (ES 0.79; 95% CI 0.17-1.41). Cho was decreased in 31 mTBI patients compared to 31 HC (ES -0.31; 95% CI -0.81 to 0.19). Cr was contradictory and, therefore, potentially not suitable as a reference marker after mTBI.

Conclusions: MRS pinpoints changes in posttraumatic brain metabolism that correlate with cognitive dysfunction and, thus, might possibly help to detect mTBI patients at risk for unfavorable outcome or posttraumatic neurodegeneration early.