pinecone/core-2020-05-10-deduplication huggingface dataset:
POLG2 deficiency causes adult-onset syndromic sensory neuropathy, ataxia and parkinsonism

Objective: Mitochondrial dysfunction plays a key role in the pathophysiology of neurodegenerative disorders such as ataxia and Parkinson's disease. We describe an extended Belgian pedigree where seven individuals presented with adult-onset cerebellar ataxia, axonal peripheral ataxic neuropathy, and tremor, in variable combination with parkinsonism, seizures, cognitive decline, and ophthalmoplegia. We sought to identify the underlying molecular etiology and characterize the mitochondrial pathophysiology of this neurological syndrome.
Methods: Clinical, neurophysiological, and neuroradiological evaluations were conducted. Patient muscle and cultured fibroblasts underwent extensive analyses to assess mitochondrial function. Genetic studies including genome-wide sequencing were conducted.
Results: Hallmarks of mitochondrial dysfunction were present in patients' tissues including ultrastructural anomalies of mitochondria, mosaic cytochrome c oxidase deficiency, and multiple mtDNA deletions. We identified a splice acceptor variant in POLG2, c.970-1G>C, segregating with disease in this family and associated with a concomitant decrease in levels of POLG2 protein in patient cells.
Interpretation: This work extends the clinical spectrum of POLG2 deficiency to include an overwhelming, adult-onset neurological syndrome that includes cerebellar syndrome, peripheral neuropathy, tremor, and parkinsonism. We therefore suggest to include POLG2 sequencing in the evaluation of ataxia and sensory neuropathy in adults, especially when it is accompanied by tremor or parkinsonism with white matter disease. The demonstration that deletions of mtDNA resulting from autosomal-dominant POLG2 variant lead to a monogenic neurodegenerative multicomponent syndrome provides further evidence for a major role of mitochondrial dysfunction in the pathomechanism of nonsyndromic forms of the component neurodegenerative disorders
Familial amyloid polyneuropathy in Portugal: New genes modulating age-at-onset

OBJECTIVES:

Familial amyloid polyneuropathy (FAP ATTRV30M) shows a wide variation in age-at-onset (AO) between clusters, families, and among generations. We will now explore some candidate genes involved in altered disease pathways in order to assess their role as genetic modifiers of AO, using a family-centered approach.
METHODS:

We analyzed 62 tagging SNPs from nine genes-NGAL,MMP-9,BGN,MEK1,MEK2,ERK1,ERK2,HSP27, and YWHAZ - in a sample of 318 V30M Portuguese patients (106 families), currently under follow-up. A generalized estimating equation analysis was used to take into account nonindependency of AO between relatives. Also, an in silico analysis was performed in order to assess the functional impact of significant variants associated with AO.
RESULTS:

We found for the first time variants from six genes (NGAL,BGN (in the female group), MEK1,MEK2,HSP27, and YWHAZ) that were significantly associated with early- and/or late-onset. Then, we confirmed a strong synergistic interaction between NGAL and MMP-9 genes. Additionally, by an in silico analysis, we found some variants for MEK1 gene that may alter binding of the transcription factors and that influence the regulation of gene expression regarding microRNA binding sites and splicing regulatory factors.
INTERPRETATION:

These findings showed that different genetic factors can modulate differently the onset of disease's symptoms and revealed new mechanisms with clinical implications in the genetic counseling and follow-up of mutation carriers and could contribute for development of potential therapeutical targets.info:eu-repo/semantics/publishedVersio
Antibodies to TRIM46 are associated with paraneoplastic neurological syndromes.

Paraneoplastic neurological syndromes (PNS) are often characterized by the presence of antineuronal antibodies in patient serum or cerebrospinal fluid. The detection of antineuronal antibodies has proven to be a useful tool in PNS diagnosis and the search for an underlying tumor. Here, we describe three patients with autoantibodies to several epitopes of the axon initial segment protein tripartite motif 46 (TRIM46). We show that anti-TRIM46 antibodies are easy to detect in routine immunohistochemistry screening and can be confirmed by western blotting and cell-based assay. Anti-TRIM46 antibodies can occur in patients with diverse neurological syndromes and are associated with small-cell lung carcinoma
Immune and myodegenerative pathomechanisms in inclusion body myositis

Inclusion Body Myositis (IBM) is a relatively common acquired inflammatory myopathy in patients above 50 years of age. Pathological hallmarks of IBM are intramyofiber protein inclusions and endomysial inflammation, indicating that both myodegenerative and inflammatory mechanisms contribute to its pathogenesis. Impaired protein degradation by the autophagic machinery, which regulates innate and adaptive immune responses, in skeletal muscle fibers has recently been identified as a potential key pathomechanism in IBM. Immunotherapies, which are successfully used for treating other inflammatory myopathies lack efficacy in IBM and so far no effective treatment is available. Thus, a better understanding of the mechanistic pathways underlying progressive muscle weakness and atrophy in IBM is crucial in identifying novel promising targets for therapeutic intervention. Here, we discuss recent insights into the pathomechanistic network of mutually dependent inflammatory and degenerative events during IBM
Cardiac responses to viewing facial emotion differentiate frontotemporal dementias

The Dementia Research Centre is supported by Alzheimer's Research UK, the Brain Research Trust and the Wolfson Foundation. This work was funded by the Alzheimer's Society, Leonard Wolfson Experimental Neurology Centre, Wellcome Trust, Medical Research Council UK, and the NIHR UCLH Biomedical Research Centre. CRM is supported by a Clinical Research Fellowship from the Leonard Wolfson Experimental Neurology Centre. CJDH and RLB hold MRC PhD studentships. CNC was supported by The National Brain Appeal – Frontotemporal Dementia Research Fund. KMD is supported by a grant from the Alzheimer's Society. JDR is an MRC Clinician Scientist. JDW was supported by a Wellcome Trust Senior Clinical Fellowship (Grant No 091673/Z/10/Z)
Preoperative cerebrospinal fluid β-Amyloid/Tau ratio and postoperative delirium

Objective: The neuropathogenesis of postoperative delirium remains unknown. Low cerebrospinal fluid (CSF) β-amyloid protein (Aβ) and high CSF Tau levels are associated with Alzheimer's disease. We, therefore, assessed whether lower preoperative CSF Aβ/Tau ratio was associated with higher incidence and greater severity of postoperative delirium. Methods: One hundred and fifty-three participants (71 ± 5 years, 53% men) who had total hip/knee replacement under spinal anesthesia were enrolled. CSF was obtained during initiation of spinal anesthesia. The incidence and severity of postoperative delirium were determined by Confusion Assessment Method (CAM) and Memorial Delirium Assessment Scale (MDAS) on postoperative day 1 and 2. Aβ40, Aβ42, and Tau levels in the CSF were measured by enzyme-linked immunosorbent assay. The relationships among these variables were determined, adjusting for age and gender. Results: Participants in the lowest quartile of preoperative CSF Aβ40/Tau and Aβ42/Tau ratio had higher incidence (32% vs. 17%, P = 0.0482) and greater symptom severity of postoperative delirium (Aβ40/Tau ratio: 4 vs. 3, P = 0.034; Aβ42/Tau ratio: 4 vs. 3, P = 0.062, the median of the highest MDAS score) as compared to the combination of the rest of the quartiles. The preoperative CSF Aβ40/Tau or Aβ42/Tau ratio was inversely associated with MDAS score (Aβ40/Tau ratio: −0.12 ± 0.05, P = 0.014, adj. −0.12 ± 0.05, P = 0.018; Aβ42/Tau ratio: −0.65 ± 0.26, P = 0.013, adj. −0.62 ± 0.27, P = 0.022). Interpretation Lower CSF Aβ/Tau ratio could be associated with postoperative delirium, pending confirmation of our preliminary results in further studies. These findings suggest potential roles of Aβ and/or Tau in postoperative delirium neuropathogenesis
Multiple prior concussions are associated with symptoms in high school athletes

Objectives: The purpose of this study was to evaluate the association of prior concussion on baseline computerized neurocognitive testing in a large cohort of high school athletes. Methods: This is a retrospective cohort study of student athletes from 49 Maine High Schools in 2010 who underwent baseline computerized neurocognitive evaluation with Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT®). As part of the ImPACT®, subjects reported a prior history of concussion as well as demographic information and a symptom questionnaire. We used linear regression to evaluate the association of prior concussion with baseline: (1) ImPACT® composite scores; and (2) symptom scores. Results: Six thousand seventy-five subjects were included in the study, of whom 57% were boys. The majority of student athletes (85.3%) reported no prior history of concussion while 4.6% reported having sustained two or more prior concussions. On simple linear regression, increasing number of concussions was related to worse performance in verbal memory (P = 0.039) and greater symptoms scores (P < 0.001). On multivariate modeling, only the association with baseline symptoms remained (P < 0.001). Other factors associated with baseline symptom reporting in the multivariate model included mental health history, headache/migraine history, gender, developmental and/or learning problems, and number of prior concussions. Interpretation In this large-scale, retrospective survey study, history of multiple prior concussions was associated with higher symptom burden but not baseline computerized neurocognitive testing. The association between baseline symptom reporting and clinical and demographic factors was greater than the association with a history of multiple concussions
Phosphodiesterase III inhibitor promotes drainage of cerebrovascular β-amyloid

Objective: Brain amyloidosis is a key feature of Alzheimer's disease (AD). It also incorporates cerebrovascular amyloid β (Aβ) in the form of cerebral amyloid angiopathy (CAA) involving neurovascular dysfunction. We have recently shown by retrospective analysis that patients with mild cognitive impairment receiving a vasoactive drug cilostazol, a selective inhibitor of phosphodiesterase (PDE) III, exhibit significantly reduced cognitive decline. Here, we tested whether cilostazol protects against the disruption of the neurovascular unit and facilitates the arterial pulsation-driven perivascular drainage of Aβ in AD/CAA. Methods: We explored the expression of PDE III in postmortem human brain tissue followed by a series of experiments examining the effects of cilostazol on Aβ metabolism in transgenic mice (Tg-SwDI mice) as a model of cerebrovascular β-amyloidosis, as well as cultured neurons. Results: We established that PDE III is abnormally upregulated in cerebral blood vessels of AD and CAA subjects and closely correlates with vascular amyloid burden. Furthermore, we demonstrated that cilostazol treatment maintained cerebral hyperemic and vasodilative responses to hypercapnia and acetylcholine, suppressed degeneration of pericytes and vascular smooth muscle cells, promoted perivascular drainage of soluble fluorescent Aβ1-40, and rescued cognitive deficits in Tg-SwDI mice. Although cilostazol decreased endogenous Aβ production in cultured neurons, C-terminal fragment of amyloid precursor protein expression was not altered in cilostazol-treated Tg-SwDI mice. Interpretation The predominant action of cilostazol on Aβ metabolism is likely to facilitate Aβ clearance due to the sustained cerebrovascular function in vivo. Our findings mechanistically demonstrate that cilostazol is a promising therapeutic approach for AD and CAA
Saffold cardiovirus and multiple sclerosis: no evidence for an association

Contains fulltext :
                  138713.pdf (publisher's version ) (Open Access)Saffold cardiovirus, a newly discovered human cardiovirus, has close similarity with Theiler's murine encephalomyelitis virus (TMEV) which can cause a chronic demyelinating encephalomyelitis in mice. In this study, we tested whether Saffold cardiovirus infection of the brain is associated with multiple sclerosis (MS). Autopsy white matter samples from 19 MS and 9 normal brain donors were tested by polymerase chain reaction. All were negative. Paired cerebrospinal fluid and serum samples from 24 MS patients and 27 controls were tested for Saffold cardiovirus-specific oligoclonal bands, two patients and two controls reacted positive. We conclude that an association between Saffold cardiovirus and MS is highly improbable
Brain diabetic neurodegeneration segregates with low intrinsic aerobic capacity

Objectives  Diabetes leads to cognitive impairment and is associated with age‐related neurodegenerative diseases including Alzheimer's disease ( AD ). Thus, understanding diabetes‐induced alterations in brain function is important for developing early interventions for neurodegeneration. Low‐capacity runner ( LCR ) rats are obese and manifest metabolic risk factors resembling human “impaired glucose tolerance” or metabolic syndrome. We examined hippocampal function in aged  LCR  rats compared to their high‐capacity runner ( HCR ) rat counterparts.    Methods  Hippocampal function was examined using proton magnetic resonance spectroscopy and imaging, unbiased stereology analysis, and a Y maze. Changes in the mitochondrial respiratory chain function and levels of hyperphosphorylated tau and mitochondrial transcriptional regulators were examined.    Results  The levels of glutamate,  myo ‐inositol, taurine, and choline‐containing compounds were significantly increased in the aged  LCR  rats. We observed a significant loss of hippocampal neurons and impaired cognitive function in aged  LCR  rats. Respiratory chain function and activity were significantly decreased in the aged  LCR  rats. Hyperphosphorylated tau was accumulated within mitochondria and peroxisome proliferator‐activated receptor‐gamma coactivator 1 α , the  NAD  + ‐dependent protein deacetylase sirtuin 1, and mitochondrial transcription factor A were downregulated in the aged  LCR  rat hippocampus.    Interpretation  These data provide evidence of a neurodegenerative process in the hippocampus of aged  LCR  rats, consistent with those seen in aged‐related dementing illnesses such as  AD  in humans. The metabolic and mitochondrial abnormalities observed in  LCR  rat hippocampus are similar to well‐described mechanisms that lead to diabetic neuropathy and may provide an important link between cognitive and metabolic dysfunction
Disproportionate subarachnoid space hydrocephalus-outcome and perivascular space

OBJECTIVE: We sought to identify the prevalence of MRI features of disproportionately enlarged subarachnoid space hydrocephalus in possible idiopathic normal pressure hydrocephalus (DESH-iNPH) and to describe the clinico-radiological features and outcomes of a community-based investigation (The Vienna Trans-Danube Aging study).\ud
METHODS: Of the 697 inhabitants (all 75 years old), 503 completed extensive neurological examinations at baseline and were followed up every 30 months thereafter with MRIs, mini-mental state examination (MMSE), and the Unified Parkinson Disease Rating Scale-Motor Section (UPDRSM). The DESH-iNPH participant data were compared with the data from participants with Evans index ratios >0.3 (ex vacuo hydrocephalus), cerebral small-vessel diseases, and normal MRIs. The widening of perivascular space was also evaluated by MRI in these groups.\ud
RESULTS: Eight participants with DESH-iNPH (1.6%) and 76 with ex vacuo hydrocephalus (16.1%) at baseline were identified. The mean MMSE in DESH-iNPH, ex vacuo hydrocephalus, and normal MRIs was 26.4, 27.9, and 28.3, respectively, and the mean UPDRSM was 9.75, 2.96, and 1.87, respectively. After a 90-month follow-up, the mortality rates for DESH-iNPH, ex vacuo hydrocephalus, and normal MRIs were 25.0%, 21.3%, and 10.9%, respectively. The perivascular-space widening scores were significantly smaller in the DESH-iNPH cases, particularly at the centrum semiovale, compared to cerebral small-vessel disease and ex vacuo hydrocephalus cases.\ud
INTERPRETATION: The prevalence of DESH-iNPH was 1.6% for participants aged 75 years and revealed significantly lower MMSE and higher UPDRSM scores compared to the ex vacuo hydrocephalus and controls. Moreover, it is suggested that perivascular-space narrowing is a morphological and pathophysiological marker of DESH-iNPH
Molecular mechanism underlying the impact of vitamin D on disease activity of MS

Objective: Some previous studies suggest modest to strong effects of 25-hydroxyvitamin D (25(OH)D) on multiple sclerosis (MS) activity. The objective of this study was to explore the mechanistic rationale that may explain potential clinical effects of 25(OH)D. Methods: This study measured serum 25(OH)D levels and global gene expression profiles over a course of up to 2 years in patients starting treatment with interferon beta-1b (IFNB-1b) after a clinically isolated syndrome. MS disease activity was assessed by the number of gadolinium-enhancing lesions present on repeated magnetic resonance imaging (MRIs). Results: The number of gadolinium-enhancing lesions was highly significantly associated with 25(OH)D levels. Conducting various systems-level analyses on the molecular level, multiple lines of evidence indicated that 25(OH)D regulates expression dynamics of a large gene–gene interaction system which primarily regulates immune modulatory processes modulating MS activity. The vitamin D response element was significantly enriched in this system, indicating a direct regulation of this gene interaction network through the vitamin D receptor. With increasing 25(OH)D levels, resulting regulation of this system was associated with a decrease in MS activity. Within the complex network of genes that are regulated by 25(OH)D, well-described targets of IFNB-1b and a regulator of sphingosine-1-phosphate bioavailability were found. The 25(OH)D effects on MS activity were additively enhanced by IFNB-1b. Interpretation Here, we provide mechanistic evidence that an unbalanced 25(OH)D gene expression system may affect MS activity. Our findings support a potential benefit of monitoring and managing vitamin D levels (e.g., through supplementation) in early MS patients treated with IFN-beta-1b
Subplate in a rat model of preterm hypoxia-ischemia.

OBJECTIVE: Hypoxia-ischemia (HI) in preterm infants primarily leads to injuries in the cerebral white matter. However, there is growing evidence that perinatal injury in preterms can also involve other zones including the cortical gray matter. In a neonatal rat model of HI, selective vulnerability of subplate has been suggested using BrdU birth-dating methods. In this study, we aimed to investigate the neuropathological changes of the subplate and deep layers of the cortex following cerebral HI in neonatal rats with specific cell markers.
METHODS: P2 rats underwent permanent occlusion of the right common carotid artery followed by a period of hypoxia. P8 rats were analyzed using immunohistochemistry; subplate and deep layers cells were quantified and compared with sham-operated case.
RESULTS: A large variability in the extent of the cerebral injury was apparent. For the three analyzed subplate populations (Nurr1+, Cplx3+, and Ctgf+ cells), no significant cell reduction was observed in mild and moderate cases. Only in severe cases, subplate cells were strongly affected, but these injuries were always accompanied by the cell reductions in layers VI and V.
INTERPRETATION: We could therefore not confirm a specific vulnerability of subplate cells compared to other deep layers or the white matter in our model
Do strict rules and moving images increase the reliability of sequential identification procedures?.

Live identification procedures in England and Wales have been replaced by use of video, which provides a sequential presentation of facial images. Sequential presentation of photographs provides some protection to innocent suspects from mistaken identification when used with strict instructions designed to prevent relative judgements (Lindsay, Lea & Fulford, 1991). However, the current procedure in England and Wales is incompatible with these strict instructions. The reported research investigated whether strict instructions would enhance the reliability of identification from video. The effect of using moving rather than still video clips was also investigated. Participants witnessed a live staged incident, and attempted to identify the culprit later from police video lineups, which were run double-blind. Strict instructions produced a significantly lower rate of correct identifications in culprit present lineups, but did not significantly reduce the rate of mistaken identification in culprit absent lineups. Moving images yielded fewer mistaken identifications in culprit absent lineups
Attention Cueing as a Means to Enhance Learning from an Animation

The question how animations should be designed so that learning is optimised, is still under
discussion. Animations are often cognitively very demanding, resulting in decreased learning
outcomes. In this study, we tried to prevent cognitive overload and foster learning by focusing
the learners’ attention to one element (i.e. process) of an animation using a cueing technique.
Psychology students viewed an animation of the cardiovascular system and were subsequently given
a comprehension test and a transfer test. One group studied the animation without a visual cue, while
for another group a visual cue was added to the animation. Results indicated that cueing not only
enhanced comprehension and transfer performance for cued information, but also for uncued
information. It is concluded that cueing can be used as a technique to improve learning from an
animation. Results are interpreted in terms of cognitive load theory (CLT)
Police officers' views of effective interview tactics with suspects: The effects of weight of case evidence and discomfort with ambiguity

This study examined the effects of case-specific facts and individual discomfort with ambiguity (DA) on investigators' beliefs concerning effective interviewing tactics for suspects. Violent crime investigators (n쳰) responded to a questionnaire including the Need for Closure Scale (NFCS) and ratings of the importance of 39 interrogation tactics in two hypothetical interrogations with a homicide suspect, where the evidence consisted of either technical evidence or soft information. Twenty tactics were analysed with a multidimensional scaling procedure which confirmed two discrete interviewing themes: humane and dominant. More tactics, both dominant and humane, were rated as important if the evidence was soft compared with technical. In the soft evidence condition, investigators who were high on DA rated both types of tactics as more important than did low-DA investigators. In the technical evidence condition, no such difference emerged.Full Tex
Innocent But Proven Guilty: Eliciting Internalized False Confessions Using Doctored-Video Evidence

More powerful computers and affordable digital-video equipment means that desktop-video editing is now accessible and popular. In two experiments, we investigated whether seeing fake-video evidence, or simply being told that video evidence exists, could lead people to believe they committed an act they never did. Subjects completed a computerized gambling task, and when they returned later the same day, we falsely accused them of cheating on the task. All of the subjects were told that incriminating video evidence existed, and half were also exposed to a fake video. See-video subjects were more likely to confess without resistance, and to internalize the act than told-video subjects, and see-video subjects tended to confabulate details more often than told-video subjects. We offer a metacognitive-based account of our results. Copyright (C) 2008 John Wiley & Sons, Ltd