Subjects -> MEDICAL SCIENCES (Total: 8810 journals)
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INTERNAL MEDICINE (180 journals)                     

Showing 1 - 180 of 180 Journals sorted alphabetically
Abdomen     Open Access  
ACP Hospitalist     Full-text available via subscription   (Followers: 9)
ACP Internist     Full-text available via subscription   (Followers: 10)
ACP Journal Club     Full-text available via subscription   (Followers: 11)
Acta Clinica Belgica     Hybrid Journal   (Followers: 1)
Acute and Critical Care     Open Access   (Followers: 11)
Acute Medicine     Full-text available via subscription   (Followers: 9)
Advances in Hepatology     Open Access   (Followers: 4)
Advances in Integrative Medicine     Hybrid Journal   (Followers: 6)
African Journal of Primary Health Care & Family Medicine     Open Access   (Followers: 6)
African Journal of Thoracic and Critical Care Medicine     Open Access  
American Family Physician     Full-text available via subscription   (Followers: 38)
American Journal of Hypertension     Hybrid Journal   (Followers: 31)
Anales de Medicina Interna     Open Access   (Followers: 1)
Anatomy & Physiology : Current Research     Open Access   (Followers: 9)
Angiology     Hybrid Journal   (Followers: 5)
Annals of Colorectal Research     Open Access   (Followers: 1)
Annals of Internal Medicine     Full-text available via subscription   (Followers: 392)
AORN Journal     Hybrid Journal   (Followers: 27)
Apollo Medicine     Open Access  
Archives of Drug Information     Hybrid Journal   (Followers: 5)
Archivos de Medicina Interna     Open Access   (Followers: 1)
Asia Oceania Journal of Nuclear Medicine & Biology     Open Access   (Followers: 4)
Asian Pacific Journal of Tropical Disease     Full-text available via subscription   (Followers: 3)
Australasian Physical & Engineering Sciences in Medicine     Hybrid Journal   (Followers: 1)
BMI Journal : Bariátrica & Metabólica Iberoamericana     Open Access   (Followers: 1)
BMJ Open Diabetes Research & Care     Open Access   (Followers: 35)
BMJ Quality & Safety     Hybrid Journal   (Followers: 69)
Bone & Joint Journal     Hybrid Journal   (Followers: 138)
Brain Communications     Open Access   (Followers: 4)
Brain Science Advances     Open Access  
Canadian Journal of General Internal Medicine     Open Access   (Followers: 2)
Cardiovascular Medicine in General Practice     Full-text available via subscription   (Followers: 7)
Case Reports in Internal Medicine     Open Access   (Followers: 1)
Cell Death & Disease     Open Access   (Followers: 3)
Cellular and Molecular Gastroenterology and Hepatology     Open Access   (Followers: 3)
Cephalalgia     Hybrid Journal   (Followers: 8)
Cephalalgia Reports     Open Access   (Followers: 4)
Chronic Diseases and Injuries in Canada     Free   (Followers: 1)
Clinical Ethics     Hybrid Journal   (Followers: 13)
Clinical Liver Disease     Open Access   (Followers: 5)
Clinical Nutrition     Hybrid Journal   (Followers: 98)
Clinical Thyroidology     Full-text available via subscription   (Followers: 1)
CNE Pflegemanagement     Hybrid Journal  
Communication Law and Policy     Hybrid Journal   (Followers: 5)
Current Diabetes Reports     Hybrid Journal   (Followers: 30)
Current Hepatology Reports     Hybrid Journal  
Current Research: Integrative Medicine     Open Access  
CVIR Endovascular     Open Access   (Followers: 1)
Der Internist     Hybrid Journal   (Followers: 12)
Diabetes     Full-text available via subscription   (Followers: 603)
Diabetes Care     Full-text available via subscription   (Followers: 578)
Diabetes Internacional     Open Access  
Diabetes Spectrum     Full-text available via subscription   (Followers: 17)
Diagnosis     Hybrid Journal   (Followers: 1)
Egyptian Journal of Bronchology     Open Access  
Egyptian Journal of Internal Medicine     Open Access   (Followers: 1)
Egyptian Journal of Neurosurgery     Open Access  
Egyptian Liver Journal     Open Access   (Followers: 2)
Egyptian Spine Journal     Open Access  
EMC - Aparato Locomotor     Hybrid Journal  
Endovascular Neuroradiology / Ендоваскулярна нейрорентгенохірургія     Open Access   (Followers: 1)
eNeuro     Open Access   (Followers: 3)
Ergonomics     Hybrid Journal   (Followers: 24)
European Journal of Inflammation     Open Access   (Followers: 2)
European Journal of Internal Medicine     Full-text available via subscription   (Followers: 10)
European Journal of Translational Myology     Open Access  
European Radiology Experimental     Open Access   (Followers: 2)
Head and Neck Tumors     Open Access   (Followers: 1)
Health Sociology Review     Hybrid Journal   (Followers: 14)
HemaSphere     Open Access   (Followers: 2)
Hepatology Communications     Open Access  
Hepatoma Research     Open Access   (Followers: 3)
Human Physiology     Hybrid Journal   (Followers: 5)
ImmunoHorizons     Open Access  
Immunological Medicine     Open Access  
Infectious Diseases: Research and Treatment     Open Access   (Followers: 5)
Inflammation and Regeneration     Open Access   (Followers: 2)
Inflammatory Intestinal Diseases     Open Access  
Innere Medizin up2date     Hybrid Journal   (Followers: 1)
Internal and Emergency Medicine     Hybrid Journal   (Followers: 5)
Internal Medicine Journal     Hybrid Journal   (Followers: 9)
International Journal of Abdominal Wall and Hernia Surgery     Open Access   (Followers: 1)
International Journal of Anatomy and Research     Open Access   (Followers: 2)
International Journal of Angiology     Hybrid Journal  
International Journal of Artificial Organs     Hybrid Journal   (Followers: 3)
International Journal of Hyperthermia     Open Access  
International Journal of Internal Medicine     Open Access   (Followers: 3)
International Journal of Noncommunicable Diseases     Open Access  
International Journal of Psychiatry in Clinical Practice     Hybrid Journal   (Followers: 6)
Iranian Journal of Neurosurgery     Open Access   (Followers: 1)
Italian Journal of Anatomy and Embryology     Open Access   (Followers: 1)
JAC-Antimicrobial Resistance     Open Access   (Followers: 4)
JAMA Internal Medicine     Full-text available via subscription   (Followers: 364)
JCSM Clinical Reports     Open Access   (Followers: 3)
JHEP Reports     Open Access  
JIMD Reports     Open Access  
JMV - Journal de Médecine Vasculaire     Hybrid Journal   (Followers: 1)
Joint Commission Journal on Quality and Patient Safety     Hybrid Journal   (Followers: 41)
JOP. Journal of the Pancreas     Open Access   (Followers: 2)
Journal of Basic & Clinical Physiology & Pharmacology     Hybrid Journal   (Followers: 1)
Journal of Bone Oncology     Open Access   (Followers: 1)
Journal of Cancer & Allied Specialties     Open Access  
Journal of Clinical and Experimental Hepatology     Full-text available via subscription   (Followers: 3)
Journal of Clinical Movement Disorders     Open Access   (Followers: 3)
Journal of Community Hospital Internal Medicine Perspectives     Open Access  
Journal of Cutaneous Immunology and Allergy     Open Access  
Journal of Developmental Origins of Health and Disease     Hybrid Journal   (Followers: 2)
Journal of Endoluminal Endourology     Open Access  
Journal of Gastroenterology and Hepatology Research     Open Access   (Followers: 4)
Journal of General Internal Medicine     Hybrid Journal   (Followers: 23)
Journal of Hypertension     Hybrid Journal   (Followers: 14)
Journal of Infectious Diseases     Hybrid Journal   (Followers: 48)
Journal of Interdisciplinary Medicine     Open Access  
Journal of Internal Medicine     Hybrid Journal   (Followers: 11)
Journal of Liver : Disease & Transplantation     Hybrid Journal   (Followers: 7)
Journal of Medical Internet Research     Open Access   (Followers: 24)
Journal of Movement Disorders     Open Access   (Followers: 2)
Journal of Pain and Symptom Management     Hybrid Journal   (Followers: 46)
Journal of Pancreatic Cancer     Open Access  
Journal of Renal and Hepatic Disorders     Open Access  
Journal of Solid Tumors     Open Access   (Followers: 1)
Journal of Sports Medicine and Allied Health Sciences : Official Journal of the Ohio Athletic Trainers Association     Open Access   (Followers: 1)
Journal of the American Board of Family Medicine     Open Access   (Followers: 11)
Journal of the European Mosquito Control Association     Open Access  
Journal of Translational Internal Medicine     Open Access  
Jurnal Vektor Penyakit     Open Access  
La Revue de Medecine Interne     Full-text available via subscription   (Followers: 3)
Lege artis - Das Magazin zur ärztlichen Weiterbildung     Hybrid Journal   (Followers: 1)
Liver Cancer International     Open Access  
Liver Research     Open Access  
Molecular Diagnosis & Therapy     Hybrid Journal   (Followers: 3)
Molecular Therapy - Oncolytics     Open Access  
Multiple Sclerosis and Demyelinating Disorders     Open Access   (Followers: 7)
MYOPAIN. A journal of myofascial pain and fibromyalgia     Hybrid Journal   (Followers: 18)
Neuro-Oncology Advances     Open Access   (Followers: 1)
Neurobiology of Pain     Open Access   (Followers: 2)
Neurointervention     Open Access   (Followers: 6)
Neuromuscular Diseases     Open Access  
Nigerian Journal of Gastroenterology and Hepatology     Full-text available via subscription  
OA Alcohol     Open Access   (Followers: 5)
Oncological Coloproctology     Open Access  
Open Journal of Internal Medicine     Open Access  
Pleura and Peritoneum     Open Access  
Pneumo News     Full-text available via subscription  
Polish Archives of Internal Medicine     Full-text available via subscription   (Followers: 2)
Preventing Chronic Disease     Free   (Followers: 2)
Progress in Transplantation     Hybrid Journal   (Followers: 1)
Prostate International     Open Access   (Followers: 2)
Psychiatry and Clinical Psychopharmacology     Open Access   (Followers: 1)
Pulmonary Therapy     Open Access   (Followers: 2)
Quality of Life Research     Hybrid Journal   (Followers: 20)
Research and Practice in Thrombosis and Haemostasis     Open Access  
Revista Chilena de Fonoaudiología     Open Access   (Followers: 1)
Revista de la Sociedad Peruana de Medicina Interna     Open Access   (Followers: 4)
Revista del Instituto de Medicina Tropical     Open Access  
Revista Hispanoamericana de Hernia     Open Access   (Followers: 1)
Revista Médica Internacional sobre el Síndrome de Down     Full-text available via subscription   (Followers: 1)
Revista Virtual de la Sociedad Paraguaya de Medicina Interna     Open Access   (Followers: 1)
Romanian Journal of Diabetes Nutrition and Metabolic Diseases     Open Access   (Followers: 1)
Romanian Journal of Internal Medicine     Open Access  
Russian Journal of Child Neurology     Open Access   (Followers: 1)
Scandinavian Journal of Primary Health Care     Open Access   (Followers: 8)
Schlaf     Hybrid Journal  
Schmerzmedizin     Hybrid Journal  
Scientific Journal of the Foot & Ankle     Open Access   (Followers: 1)
SciMedicine Journal     Open Access   (Followers: 3)
SEMERGEN - Medicina de Familia     Full-text available via subscription   (Followers: 1)
The Journal of Critical Care Medicine     Open Access   (Followers: 9)
Therapeutic Advances in Chronic Disease     Open Access   (Followers: 8)
Therapeutic Advances in Musculoskeletal Disease     Hybrid Journal   (Followers: 6)
Thieme Case Report     Hybrid Journal   (Followers: 1)
Tijdschrift voor Urologie     Hybrid Journal  
Tissue Barriers     Hybrid Journal   (Followers: 1)
Transactions of the Royal Society of Tropical Medicine and Hygiene     Hybrid Journal   (Followers: 3)
Transgender Health     Open Access   (Followers: 3)
Trends in Anaesthesia and Critical Care     Full-text available via subscription   (Followers: 23)
US Cardiology Review     Open Access  
Vascular and Endovascular Review     Open Access   (Followers: 1)
Ожирение и метаболизм     Open Access  


Similar Journals
Journal Cover
Brain Communications
Number of Followers: 4  

  This is an Open Access Journal Open Access journal
ISSN (Online) 2632-1297
Published by Oxford University Press Homepage  [416 journals]
  • Women can bear a bigger burden: ante- and post-mortem evidence for reserve
           in the face of tau

    • Authors: Digma L; Madsen J, Rissman R, et al.
      Abstract: In this study, we aimed to assess whether women are able to withstand more tau before exhibiting verbal memory impairment. Using data from 121 amyloid-β-positive Alzheimer’s Disease Neuroimaging Initiative participants, we fit a linear model with Rey Auditory Verbal Learning Test score as the response variable and tau-PET standard uptake value ratio as the predictor and took the residuals as an estimate of verbal memory reserve for each subject. Women demonstrated higher reserve (i.e. residuals), whether the Learning (t = 2.78, P = 0.006) or Delay (t = 2.14, P = 0.03) score from the Rey Auditory Verbal Learning Test was used as a measure of verbal memory ability. To validate these findings, we examined 662 National Alzheimer’s Coordinating Center participants with a C2/C3 score (Consortium to Establish a Registry for Alzheimer’s Disease) at autopsy. We stratified our National Alzheimer’s Coordinating Center sample into Braak 1/2, Braak 3/4 and Braak 5/6 subgroups. Within each subgroup, we compared Logical Memory scores between men and women. Men had worse verbal memory scores within the Braak 1/2 (Logical Memory Immediate: β = −5.960 ± 1.517, P < 0.001, Logical Memory Delay: β = −5.703 ± 1.677, P = 0.002) and Braak 3/4 (Logical Memory Immediate: β = −2.900 ± 0.938, P = 0.002, Logical Memory Delay: β = −2.672 ± 0.955, P = 0.006) subgroups. There were no sex differences in Logical Memory performance within the Braak 5/6 subgroup (Logical Memory Immediate: β = −0.314 ± 0.328, P = 0.34, Logical Memory Delay: β = −0.195 ± 0.287, P = 0.50). Taken together, our results point to a sex-related verbal memory reserve.
      PubDate: Tue, 14 Apr 2020 00:00:00 GMT
  • Association of neuroinflammation with episodic memory: a [11C]PBR28 PET
           study in cognitively discordant twin pairs

    • Authors: Lindgren N; Tuisku J, Vuoksimaa E, et al.
      Abstract: Alzheimer’s disease is associated with chronic response of innate immune system, referred as neuroinflammation. PET radioligands binding to the 18 kDa translocator protein are potential biomarkers of neuroinflammation. Translocator protein PET studies in mild cognitive impairment and Alzheimer’s disease have indicated controversial results, possibly reflecting interindividual variation and heterogeneity of study populations. We controlled for genetic and environmental effects by studying twin pairs discordant for episodic memory performance. Episodic memory impairment is a well-known cognitive hallmark of early Alzheimer’s disease process. Eleven same-sex twin pairs (four monozygotic pairs, six female pairs, age 72–77 years) underwent [11C]N-acetyl-N-(2-methoxybenzyl)-2-phenoxy-5-pyridinamine ([11C]PBR28) PET imaging, structural magnetic resonance imaging and neuropsychological testing in 2014–17. Main PET outcome was the volume-weighted average standardized uptake value of cortical regions vulnerable to Alzheimer’s disease pathology. Ten pairs were discordant for episodic memory performance. In the eight pairs with identical translocator protein genotype, twins with poorer episodic memory had ∼20% higher cortical [11C]PBR28 binding compared with their better-performing co-twins (mean intra-pair difference 0.21 standardized uptake value, 95% confidence interval 0.05–0.37, P = 0.017). The result remained the same when including all discordant pairs and controlling for translocator protein genotype. Increased translocator protein PET signal suggests that increased microglial activation is associated with poorer episodic memory performance. Twins with worse episodic memory performance compared with their co-twins had on average 20% higher uptake of the neuroinflammatory marker translocator protein PET tracer 11[11C]PBR28. The findings support a negative association between neuroinflammation and episodic memory and the use of translocator protein positron emission tomography as a useful indicator of Alzheimer’s disease process.
      PubDate: Tue, 14 Apr 2020 00:00:00 GMT
  • A toxic subset of soluble α-synuclein species in dementia with Lewy

    • Authors: Castillo-Carranza D.
      Abstract: This scientific commentary refers to ‘Analysis of α-synuclein species enriched from cerebral cortex of humans with sporadic dementia with Lewy bodies’, by Sanderson et al. (
      PubDate: Tue, 24 Mar 2020 00:00:00 GMT
  • Cerebellar lesions at a young age predict poorer long-term functional

    • Authors: Beuriat P; Cristofori I, Richard N, et al.
      Abstract: Early studies on long-term functional recovery after motor and premotor lesions showed better outcomes in younger monkeys than in older monkeys. This finding led to the widespread belief that brain injuries cause less impairment in children than adults. However, this view has limitations and a large body of evidence now indicates that cerebral damages can be more harmful when inflicted at young age, during critical periods of neural development. To date, this issue has been mainly investigated in the context of focal and diffuse cortical lesions. Much less is known about the potential influence of early cerebellar damages. Several studies exist in survivor of posterior fossa tumours. However, in these studies, critical confounders were not always considered and contradictory conclusions were provided. We studied the impact or early cerebellar damage on long-term functional recovery in three groups of 15 posterior fossa survivors, comparable with respect to their tumour characteristics (type, size and location) but operated at different ages: young (≤7 years), middle (>7 and ≤13 years) and older (>13 years). Daily (health-related quality of life scale, performance status scale), motor (International Cooperative Ataxia Rating Scale, Pegboard Purdue Test) and cognitive (full-scale intelligence quotient) functioning were assessed. A general linear model controlling for age at surgery, radiotherapy, preservation of deep cerebellar nuclei, tumour volume and delay between surgery and assessment was used to investigate significant variations in outcome measures. Early age at surgery, lesion of deep cerebellar nuclei and postoperative radiotherapy had a significant, independent negative influence on long-term recovery. Tumour volume and delay between surgery and assessment had no statistically detectable impact. The negative influence of early age at surgery was significant in all domains: daily functioning (health-related quality of life scale, performance status scale), motor functioning (International Cooperative Ataxia Rating Scale, Pegboard Purdue Test) and cognitive functioning (full-scale intelligence quotient). These results support the existence of an early critical period of development during which the cerebellar ‘learning machine’ is of critical importance. Although the extent to which the early deficits here observed can be reversed needs now to be established, our data plead for the implementation of prompt and intense rehabilitation interventions in children operated before 7 years of age.
      PubDate: Fri, 06 Mar 2020 00:00:00 GMT
  • Increased glutamate transporter-associated anion currents cause glial
           apoptosis in episodic ataxia 6

    • Authors: Kovermann P; Untiet V, Kolobkova Y, et al.
      Abstract: Episodic ataxia type 6 is an inherited neurological condition characterized by combined ataxia and epilepsy. A severe form of this disease with episodes combining ataxia, epilepsy and hemiplegia was recently associated with a proline to arginine substitution at position 290 of the excitatory amino acid transporter 1 in a heterozygous patient. The excitatory amino acid transporter 1 is the predominant glial glutamate transporter in the cerebellum. However, this glutamate transporter also functions as an anion channel and earlier work in heterologous expression systems demonstrated that the mutation impairs the glutamate transport rate, while increasing channel activity. To understand how these changes cause ataxia, we developed a constitutive transgenic mouse model. Transgenic mice display epilepsy, ataxia and cerebellar atrophy and, thus, closely resemble the human disease. We observed increased glutamate-activated chloride efflux in Bergmann glia that triggers the apoptosis of these cells during infancy. The loss of Bergmann glia results in reduced glutamate uptake and impaired neural network formation in the cerebellar cortex. This study shows how gain-of-function of glutamate transporter-associated anion channels causes ataxia through modifying cerebellar development.
      PubDate: Wed, 04 Mar 2020 00:00:00 GMT
  • Thinking fast or slow' Functional magnetic resonance imaging reveals
           stronger connectivity when experienced neurologists diagnose ambiguous

    • Authors: van den Berg B; de Bruin A, Marsman J, et al.
      Abstract: For ∼40 years, thinking about reasoning has been dominated by dual-process theories. This model, consisting of two distinct types of human reasoning, one fast and effortless and the other slow and deliberate, has also been applied to medical diagnosis. Medical experts are trained to diagnose patients based on their symptoms. When symptoms are prototypical for a certain diagnosis, practitioners may rely on fast, recognition-based reasoning. However, if they are confronted with ambiguous clinical information slower, analytical reasoning is required. To examine the neural underpinnings of these two hypothesized forms of reasoning, 16 highly experienced clinical neurologists were asked to diagnose two types of medical cases, straightforward and ambiguous cases, while functional magnetic resonance imaging was being recorded. Compared with reading control sentences, diagnosing cases resulted in increased activation in brain areas typically found to be active during reasoning such as the caudate nucleus and frontal and parietal cortical regions. In addition, we found vast increased activity in the cerebellum. Regarding the activation differences between the two types of reasoning, no pronounced differences were observed in terms of regional activation. Notable differences were observed, though, in functional connectivity: cases containing ambiguous information showed stronger connectivity between specific regions in the frontal, parietal and temporal cortex in addition to the cerebellum. Based on these results, we propose that the higher demands in terms of controlled cognitive processing during analytical medical reasoning may be subserved by stronger communication between key regions for detecting and resolving uncertainty.
      PubDate: Mon, 02 Mar 2020 00:00:00 GMT
  • Bortezomib at therapeutic doses poorly passes the blood–brain barrier
           and does not impair cognition

    • Authors: Huehnchen P; Springer A, Kern J, et al.
      Abstract: The 26S proteasome inhibitor bortezomib is currently used to treat multiple myeloma but also is effective in the treatment of antibody-mediated autoimmune disorders. One clinical concern is bortezomib’s toxicity towards the (central) nervous system. We used standardized neuropsychological testing to assess cognitive function in six patients with myasthenia gravis and systemic lupus erythematodes before and after treatment with a mean cumulative dose of 9.4 mg m−2 bortezomib. In addition, cognitive performance was measured in adult C57Bl/6 mice after treatment with a human equivalent cumulative dose of 15.6 mg m−2. Bortezomib concentrations were analysed in the human CSF as well as the brain tissue and serum of adult C57Bl/6 mice at various time points after the injection of 1.3 mg m−2 bortezomib with liquid chromatography–tandem mass spectrometry. Neither patients nor mice showed signs of cognitive impairment after bortezomib therapy. Bortezomib concentrations in the human CSF and murine brain tissue reached only 5–7% of serum concentrations with comparable concentrations measured in the hippocampus and the neocortex. Five-fold higher concentrations were needed to damage neuronal cells in vitro. In conclusion, penetration of the intact blood–brain barrier by bortezomib is low. Overall, our data show that bortezomib is a safe medication in terms of central nervous system toxicity.
      PubDate: Thu, 27 Feb 2020 00:00:00 GMT
  • Visual contrast sensitivity is associated with the presence of cerebral
           amyloid and tau deposition

    • Authors: Risacher S; WuDunn D, Tallman E, et al.
      Abstract: Visual deficits are common in neurodegenerative diseases including Alzheimer’s disease. We sought to determine the association between visual contrast sensitivity and neuroimaging measures of Alzheimer’s disease-related pathophysiology, including cerebral amyloid and tau deposition and neurodegeneration. A total of 74 participants (7 Alzheimer’s disease, 16 mild cognitive impairment, 20 subjective cognitive decline, 31 cognitively normal older adults) underwent the frequency doubling technology 24-2 examination, a structural MRI scan and amyloid PET imaging for the assessment of visual contrast sensitivity. Of these participants, 46 participants (2 Alzheimer’s disease, 9 mild cognitive impairment, 12 subjective cognitive decline, 23 cognitively normal older adults) also underwent tau PET imaging with [18F]flortaucipir. The relationships between visual contrast sensitivity and cerebral amyloid and tau, as well as neurodegeneration, were assessed using partial Pearson correlations, covaried for age, sex and race and ethnicity. Voxel-wise associations were also evaluated for amyloid and tau. The ability of visual contrast sensitivity to predict amyloid and tau positivity were assessed using forward conditional logistic regression and receiver operating curve analysis. All analyses first were done in the full sample and then in the non-demented at-risk individuals (subjective cognitive decline and mild cognitive impairment) only. Significant associations between visual contrast sensitivity and regional amyloid and tau deposition were observed across the full sample and within subjective cognitive decline and mild cognitive impairment only. Voxel-wise analysis demonstrated strong associations of visual contrast sensitivity with amyloid and tau, primarily in temporal, parietal and occipital brain regions. Finally, visual contrast sensitivity accurately predicted amyloid and tau positivity. Alterations in visual contrast sensitivity were related to cerebral deposition of amyloid and tau, suggesting that this measure may be a good biomarker for detecting Alzheimer’s disease-related pathophysiology. Future studies in larger patient samples are needed, but these findings support the power of these measures of visual contrast sensitivity as a potential novel, inexpensive and easy-to-administer biomarker for Alzheimer’s disease-related pathology in older adults at risk for cognitive decline.
      PubDate: Wed, 26 Feb 2020 00:00:00 GMT
  • Interactive effects of HIV and ageing on neural oscillations: independence
           from neuropsychological performance

    • Authors: Lew B; O’Neill J, Rezich M, et al.
      Abstract: HIV infection is associated with increased age-related co-morbidities including cognitive deficits, leading to hypotheses of HIV-related premature or accelerated ageing. Impairments in selective attention and the underlying neural dynamics have been linked to HIV-associated neurocognitive disorder; however, the effect of ageing in this context is not yet understood. Thus, the current study aimed to identify the interactive effects of ageing and HIV on selective attention processing. A total of 165 participants (92 controls, 73 participants with HIV) performed a visual selective attention task while undergoing magnetoencephalography and were compared cross-sectionally. Spectrally specific oscillatory neural responses during task performance were imaged and linked with selective attention function. Reaction time on the task and regional neural activity were analysed with analysis of covariance (ANCOVA) models aimed at examining the age-by-HIV interaction term. Finally, these metrics were evaluated with respect to clinical measures such as global neuropsychological performance, duration of HIV infection and medication regimen. Reaction time analyses showed a significant HIV-by-age interaction, such that in controls older age was associated with greater susceptibility to attentional interference, while in participants with HIV, such susceptibility was uniformly high regardless of age. In regard to neural activity, theta-specific age-by-HIV interaction effects were found in the prefrontal and posterior parietal cortices. In participants with HIV, neuropsychological performance was associated with susceptibility to attentional interference, while time since HIV diagnosis was associated with parietal activity above and beyond global neuropsychological performance. Finally, current efavirenz therapy was also related to increased parietal interference activity. In conclusion, susceptibility to attentional interference in younger participants with HIV approximated that of older controls, suggesting evidence of HIV-related premature ageing. Neural activity serving attention processing indicated compensatory recruitment of posterior parietal cortex as participants with HIV infection age, which was related to the duration of HIV infection and was independent of neuropsychological performance, suggesting an altered trajectory of neural function.
      PubDate: Thu, 20 Feb 2020 00:00:00 GMT
  • Adenosine kinase inhibition promotes proliferation of neural stem cells
           after traumatic brain injury

    • Authors: Gebril H; Rose R, Gesese R, et al.
      Abstract: Traumatic brain injury (TBI) is a major public health concern and remains a leading cause of disability and socio-economic burden. To date, there is no proven therapy that promotes brain repair following an injury to the brain. In this study, we explored the role of an isoform of adenosine kinase expressed in the cell nucleus (ADK-L) as a potential regulator of neural stem cell proliferation in the brain. The rationale for this hypothesis is based on coordinated expression changes of ADK-L during foetal and postnatal murine and human brain development indicating a role in the regulation of cell proliferation and plasticity in the brain. We first tested whether the genetic disruption of ADK-L would increase neural stem cell proliferation after TBI. Three days after TBI, modelled by a controlled cortical impact, transgenic mice, which lack ADK-L (ADKΔneuron) in the dentate gyrus (DG) showed a significant increase in neural stem cell proliferation as evidenced by significant increases in doublecortin and Ki67-positive cells, whereas animals with transgenic overexpression of ADK-L in dorsal forebrain neurons (ADK-Ltg) showed an opposite effect of attenuated neural stem cell proliferation. Next, we translated those findings into a pharmacological approach to augment neural stem cell proliferation in the injured brain. Wild-type C57BL/6 mice were treated with the small molecule adenosine kinase inhibitor 5-iodotubercidin for 3 days after the induction of TBI. We demonstrate significantly enhanced neural stem cell proliferation in the DG of 5-iodotubercidin-treated mice compared to vehicle-treated injured animals. To rule out the possibility that blockade of ADK-L has any effects in non-injured animals, we quantified baseline neural stem cell proliferation in ADKΔneuron mice, which was not altered, whereas baseline neural stem cell proliferation in ADK-Ltg mice was enhanced. Together these findings demonstrate a novel function of ADK-L involved in the regulation of neural stem cell proliferation after TBI.
      PubDate: Thu, 20 Feb 2020 00:00:00 GMT
  • The rise and fall of fasciculations in amyotrophic lateral sclerosis

    • Authors: Bashford J; Wickham A, Iniesta R, et al.
      Abstract: Amyotrophic lateral sclerosis is a devastating neurodegenerative disease with a median survival of 3 years from symptom onset. Accessible and reliable biomarkers of motor neuron decline are urgently needed to quicken the pace of drug discovery. Fasciculations represent an early pathophysiological hallmark of amyotrophic lateral sclerosis and can be reliably detected by high-density surface electromyography. We set out to quantify fasciculation potentials prospectively over 14 months, seeking comparisons with established markers of disease progression. Twenty patients with amyotrophic lateral sclerosis and five patients with benign fasciculation syndrome underwent up to seven assessments each. At each assessment, we performed the amyotrophic lateral sclerosis-functional rating scale, sum power score, slow vital capacity, 30-min high-density surface electromyography recordings from biceps and gastrocnemius and the motor unit number index. We employed the Surface Potential Quantification Engine, which is an automated analytical tool to detect and characterize fasciculations. Linear mixed-effect models were employed to account for the pseudoreplication of serial measurements. The amyotrophic lateral sclerosis-functional rating scale declined by 0.65 points per month (P < 0.0001), 35% slower than average. A total of 526 recordings were analysed. Compared with benign fasciculation syndrome, biceps fasciculation frequency in amyotrophic lateral sclerosis was 10 times greater in strong muscles and 40 times greater in weak muscles. This was coupled with a decline in fasciculation frequency among weak muscles of –7.6/min per month (P = 0.003), demonstrating the rise and fall of fasciculation frequency in biceps muscles. Gastrocnemius behaved differently, whereby strong muscles in amyotrophic lateral sclerosis had fasciculation frequencies five times greater than patients with benign fasciculation syndrome while weak muscles were increased by only 1.5 times. Gastrocnemius demonstrated a significant decline in fasciculation frequency in strong muscles (−2.4/min per month, P < 0.0001), which levelled off in weak muscles. Fasciculation amplitude, an easily quantifiable surrogate of the reinnervation process, was highest in the biceps muscles that transitioned from strong to weak during the study. Pooled analysis of >900 000 fasciculations revealed inter-fasciculation intervals <100 ms in the biceps of patients with amyotrophic lateral sclerosis, particularly in strong muscles, consistent with the occurrence of doublets. We hereby present the most comprehensive longitudinal quantification of fasciculation parameters in amyotrophic lateral sclerosis, proposing a unifying model of the interactions between motor unit loss, muscle power and fasciculation frequency. The latter showed promise as a disease biomarker with linear rates of decline in strong gastrocnemius and weak biceps muscles, reflecting the motor unit loss that drives clinical progression.
      PubDate: Thu, 20 Feb 2020 00:00:00 GMT
  • Tadalafil may improve cerebral perfusion in small-vessel occlusion
           stroke—a pilot study

    • Authors: Ölmestig J; Marlet I, Hansen R, et al.
      Abstract: New treatments for cerebral small-vessel disease are needed to reduce the risk of small-vessel occlusion stroke and vascular cognitive impairment. We investigated an approach targeted to the signalling molecule cyclic guanosine monophosphate, using the phosphodiesterase 5 inhibitor tadalafil, to explore if it improves cerebral blood flow and endothelial function in patients with cerebral small-vessel disease and stroke. In a randomized, double-blinded, placebo-controlled, cross-over pilot trial (NCT02801032), we included patients who had a previous (>6 months) small-vessel occlusion stroke. They received a single dose of either 20 mg tadalafil or placebo on 2 separate days at least 1 week apart. We measured the following: baseline MRI for lesion load, repeated measurements of blood flow velocity in the middle cerebral artery by transcranial Doppler, blood oxygen saturation in the cortical microvasculature by near-infrared spectroscopy, peripheral endothelial response by EndoPAT and endothelial-specific blood biomarkers. Twenty patients with cerebral small-vessel disease stroke (3 women, 17 men), mean age 67.1 ± 9.6, were included. The baseline mean values ± standard deviations were as follows: blood flow velocity in the middle cerebral artery, 57.4 ± 10.8 cm/s; blood oxygen saturation in the cortical microvasculature, 67.0 ± 8.2%; systolic blood pressure, 145.8 ± 19.5 mmHg; and diastolic blood pressure, 81.3 ± 9.1 mmHg. We found that tadalafil significantly increased blood oxygen saturation in the cortical microvasculature at 180 min post-administration with a mean difference of 1.57 ± 3.02%. However, we saw no significant differences in transcranial Doppler measurements over time. Tadalafil had no effects on peripheral endothelial function assessed by EndoPAT and endothelial biomarker results conflicted. Our findings suggest that tadalafil may improve vascular parameters in patients with cerebral small-vessel disease stroke, although the effect size was small. Increased oxygenation of cerebral microvasculature during tadalafil treatment indicated improved perfusion in the cerebral microvasculature, theoretically presenting an attractive new therapeutic target in cerebral small-vessel disease. Future studies of the effect of long-term tadalafil treatment on cerebrovascular reactivity and endothelial function are needed to evaluate general microvascular changes and effects in cerebral small-vessel disease and stroke.
      PubDate: Thu, 20 Feb 2020 00:00:00 GMT
  • Monocytes and neutrophils are associated with clinical features in
           amyotrophic lateral sclerosis

    • Authors: McGill R; Steyn F, Ngo S, et al.
      Abstract: Immunity has emerged as a key player in neurodegenerative diseases such as amyotrophic lateral sclerosis, with recent studies documenting aberrant immune changes in patients and animal models. A challenging aspect of amyotrophic lateral sclerosis research is the heterogeneous nature of the disease. In this study, we investigate the associations between peripheral blood myeloid cell populations and clinical features characteristic of amyotrophic lateral sclerosis. Peripheral blood leukocytes from 23 healthy controls and 48 patients with amyotrophic lateral sclerosis were analysed to measure myeloid cell alterations. The proportion of monocytes (classical, intermediates and non-classical subpopulations) and neutrophils, as well as the expression of select surface markers, were quantitated using flow cytometry. Given the heterogeneous nature of amyotrophic lateral sclerosis, multivariable linear analyses were performed to investigate associations between patients’ myeloid profile and clinical features, such as the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale, bulbar subscore of the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale, change in Revised Amyotrophic Lateral Sclerosis Functional Rating Scale over disease duration and respiratory function. We demonstrate a shift in monocyte subpopulations in patients with amyotrophic lateral sclerosis, with the ratio of classical to non-classical monocytes increased compared with healthy controls. In line with this, patients with greater disease severity, as determined by a lower Revised Amyotrophic Lateral Sclerosis Functional Rating Scale score, had reduced non-classical monocytes. Interestingly, patients with greater bulbar involvement had a reduction in the proportions of classical, intermediate and non-classical monocyte populations. We also revealed several notable associations between myeloid marker expression and clinical features in amyotrophic lateral sclerosis. CD16 expression on neutrophils was increased in patients with greater disease severity and a faster rate of disease progression, whereas HLA-DR expression on all monocyte populations was elevated in patients with greater respiratory impairment. This study demonstrates that patients with amyotrophic lateral sclerosis with distinct clinical features have differential myeloid cell signatures. Identified cell populations and markers may be candidates for targeted mechanistic studies and immunomodulation therapies in amyotrophic lateral sclerosis.
      PubDate: Fri, 14 Feb 2020 00:00:00 GMT
  • Bridging integrator 1 protein loss in Alzheimer’s disease promotes
           synaptic tau accumulation and disrupts tau release

    • Authors: Glennon E; Lau D, Gabriele R, et al.
      Abstract: Polymorphisms associated with BIN1 (bridging integrator 1) confer the second greatest risk for developing late-onset Alzheimer’s disease. The biological consequences of this genetic variation are not fully understood; however, BIN1 is a binding partner for tau. Tau is normally a highly soluble cytoplasmic protein, but in Alzheimer’s disease, tau is abnormally phosphorylated and accumulates at synapses to exert synaptotoxicity. The purpose of this study was to determine whether alterations in BIN1 and tau in Alzheimer’s disease promote the damaging redistribution of tau to synapses, as a mechanism by which BIN1 polymorphisms may increase the risk of developing Alzheimer’s disease. We show that BIN1 is lost from the cytoplasmic fraction of Alzheimer’s disease cortex, and this is accompanied by the progressive mislocalization of phosphorylated tau to synapses. We confirmed proline 216 in tau as critical for tau interaction with the BIN1-SH3 domain and showed that the phosphorylation of tau disrupts this binding, suggesting that tau phosphorylation in Alzheimer’s disease disrupts tau–BIN1 associations. Moreover, we show that BIN1 knockdown in rat primary neurons to mimic BIN1 loss in Alzheimer’s disease brain causes the damaging accumulation of phosphorylated tau at synapses and alterations in dendritic spine morphology. We also observed reduced release of tau from neurons upon BIN1 silencing, suggesting that BIN1 loss disrupts the function of extracellular tau. Together, these data indicate that polymorphisms associated with BIN1 that reduce BIN1 protein levels in the brain likely act synergistically with increased tau phosphorylation to increase the risk of Alzheimer’s disease by disrupting cytoplasmic tau–BIN1 interactions, promoting the damaging mis-sorting of phosphorylated tau to synapses to alter synapse structure and reducing the release of physiological forms of tau to disrupt tau function.
      PubDate: Fri, 14 Feb 2020 00:00:00 GMT
  • Brain phenotyping in Moebius syndrome and other congenital facial weakness
           disorders by diffusion MRI morphometry

    • Authors: Sadeghi N; Hutchinson E, Van Ryzin C, et al.
      Abstract: In this study, we used a novel imaging technique, DTI (diffusion tensor imaging)-driven tensor-based morphometry, to investigate brain anatomy in subjects diagnosed with Moebius syndrome (n = 21), other congenital facial weakness disorders (n = 9) and healthy controls (n = 15). First, we selected a subgroup of subjects who satisfied the minimum diagnostic criteria for Moebius syndrome with only mild additional neurological findings. Compared to controls, in this cohort, we found a small region of highly significant volumetric reduction in the paramedian pontine reticular formation and the medial longitudinal fasciculus, important structures for the initiation and coordination of conjugate horizontal gaze. Subsequently, we tested if volume measurements from this region could help differentiate individual subjects of the different cohorts that were included in our study. We found that this region allowed discriminating Moebius syndrome subjects from congenital facial weakness disorders and healthy controls with high sensitivity (94%) and specificity (89%). Interestingly, this region was normal in congenital facial weakness subjects with oculomotor deficits of myopathic origin, who would have been classified as Moebius on the basis of purely clinical diagnostic criteria, indicating a potential role for diffusion MRI morphometry for differential diagnosis in this condition. When the entire Moebius syndrome cohort was compared to healthy controls, in addition to this ‘landmark’ region, other areas of significantly reduced volume in the brainstem emerged, including the location of the nuclei and fibres of cranial nerve VI (abducens nerve), and fibres of cranial nerve VII (facial nerve), and a more rostral portion of the medial longitudinal fasciculus. The high sensitivity and specificity of DTI-driven tensor-based morphometry in reliably detecting very small areas of volumetric abnormality found in this study suggest broader applications of this analysis in personalized medicine to detect hypoplasia or atrophy of small pathways and/or brainstem nuclei in other neurological disorders.
      PubDate: Fri, 14 Feb 2020 00:00:00 GMT
  • Intraepidermal nerve fibre density as biomarker in
           Charcot–Marie–Tooth disease type 1A

    • Authors: Hartmannsberger B; Doppler K, Stauber J, et al.
      Abstract: Charcot–Marie–Tooth disease type 1A, caused by a duplication of the gene peripheral myelin protein 22 kDa, is the most frequent subtype of hereditary peripheral neuropathy with an estimated prevalence of 1:5000. Patients suffer from sensory deficits, muscle weakness and foot deformities. There is no treatment approved for this disease. Outcome measures in clinical trials were based mainly on clinical features but did not evaluate the actual nerve damage. In our case–control study, we aimed to provide objective and reproducible outcome measures for future clinical trials. We collected skin samples from 48 patients with Charcot–Marie–Tooth type 1A, 7 patients with chronic inflammatory demyelinating polyneuropathy, 16 patients with small fibre neuropathy and 45 healthy controls. To analyse skin innervation, 40-µm cryosections of glabrous skin taken from the lateral index finger were double-labelled by immunofluorescence. The disease severity of patients with Charcot–Marie–Tooth type 1A was assessed by the Charcot–Marie–Tooth neuropathy version 2 score, which ranged from 3 (mild) to 27 (severe) and correlated with age (P < 0.01, R = 0.4). Intraepidermal nerve fibre density was reduced in patients with Charcot–Marie–Tooth type 1A compared with the healthy control group (P < 0.01) and negatively correlated with disease severity (P < 0.05, R = −0.293). Meissner corpuscle (MC) density correlated negatively with age in patients with Charcot–Marie–Tooth type 1A (P < 0.01, R = −0.45) but not in healthy controls (P = 0.07, R = 0.28). The density of Merkel cells was reduced in patients with Charcot–Marie–Tooth type 1A compared with healthy controls (P < 0.05). Furthermore, in patients with Charcot–Marie–Tooth type 1A, the fraction of denervated Merkel cells was highly increased and correlated with age (P < 0.05, R = 0.37). Analysis of nodes of Ranvier revealed shortened paranodes and a reduced fraction of long nodes in patients compared with healthy controls (both P < 0.001). Langerhans cell density was increased in chronic inflammatory demyelinating polyneuropathy, but not different in Charcot–Marie–Tooth type 1A compared with healthy controls. Our data suggest that intraepidermal nerve fibre density might be used as an outcome measure in Charcot–Marie–Tooth type 1A disease, as it correlates with disease severity. The densities of Meissner corpuscles and Merkel cells might be an additional tool for the evaluation of the disease progression. Analysis of follow-up biopsies will clarify the effects of Charcot–Marie–Tooth type 1A disease progression on cutaneous innervation.
      PubDate: Wed, 12 Feb 2020 00:00:00 GMT
  • Analysis of α-synuclein species enriched from cerebral cortex of humans
           with sporadic dementia with Lewy bodies

    • Authors: Sanderson J; De S, Jiang H, et al.
      Abstract: Since researchers identified α-synuclein as the principal component of Lewy bodies and Lewy neurites, studies have suggested that it plays a causative role in the pathogenesis of dementia with Lewy bodies and other ‘synucleinopathies’. While α-synuclein dyshomeostasis likely contributes to the neurodegeneration associated with the synucleinopathies, few direct biochemical analyses of α-synuclein from diseased human brain tissue currently exist. In this study, we analysed sequential protein extracts from a substantial number of patients with neuropathological diagnoses of dementia with Lewy bodies and corresponding controls, detecting a shift of cytosolic and membrane-bound physiological α-synuclein to highly aggregated forms. We then fractionated aqueous extracts (cytosol) from cerebral cortex using non-denaturing methods to search for soluble, disease-associated high molecular weight species potentially associated with toxicity. We applied these fractions and corresponding insoluble fractions containing Lewy-type aggregates to several reporter assays to determine their bioactivity and cytotoxicity. Ultimately, high molecular weight cytosolic fractions enhances phospholipid membrane permeability, while insoluble, Lewy-associated fractions induced morphological changes in the neurites of human stem cell-derived neurons. While the concentrations of soluble, high molecular weight α-synuclein were only slightly elevated in brains of dementia with Lewy bodies patients compared to healthy, age-matched controls, these observations suggest that a small subset of soluble α-synuclein aggregates in the brain may drive early pathogenic effects, while Lewy body-associated α-synuclein can drive neurotoxicity.
      PubDate: Tue, 11 Feb 2020 00:00:00 GMT
  • Neuroanatomical spread of amyloid β and tau in Alzheimer’s disease:
           implications for primary prevention

    • Authors: Insel P; Mormino E, Aisen P, et al.
      Abstract: With recent advances in our understanding of the continuous pathophysiological changes that begin many years prior to symptom onset, it is now apparent that Alzheimer’s disease cannot be adequately described by discrete clinical stages, but should also incorporate the continuum of biological changes that precede and underlie the clinical representation of the disease. By jointly considering longitudinal changes of all available biomarkers and clinical assessments, variation within individuals can be integrated into a single continuous measure of disease progression and used to identify the earliest pathophysiological changes. Disease time, a measure of disease severity, was estimated using a Bayesian latent time joint mixed-effects model applied to an array of imaging, biomarker and neuropsychological data. Trajectories of regional amyloid β and tau PET uptake were estimated as a function of disease time. Regions with early signs of elevated amyloid β uptake were used to form an early, focal composite and compared to a commonly used global composite, in a separate validation sample. Disease time was estimated in 279 participants (183 cognitively unimpaired individuals, 61 mild cognitive impairment and 35 Alzheimer’s disease dementia patients) with available amyloid β and tau PET data. Amyloid β PET uptake levels in the posterior cingulate and precuneus start high and immediately increase with small increases of disease time. Early elevation in tau PET uptake was found in the inferior temporal lobe, amygdala, banks of the superior temporal sulcus, entorhinal cortex, middle temporal lobe, inferior parietal lobe and the fusiform gyrus. In a separate validation sample of 188 cognitively unimpaired individuals, the early, focal amyloid β PET composite showed a 120% increase in the accumulation rate of amyloid β compared to the global composite (P < 0.001), resulting in a 60% increase in the power to detect a treatment effect in a primary prevention trial design. Ordering participants on a continuous disease time scale facilitates the inspection of the earliest signs of amyloid β and tau pathology. To detect early changes in amyloid β pathology, focusing on the earliest sites of amyloid β accumulation results in more powerful and efficient study designs in early Alzheimer’s disease. Targeted composites could be used to re-examine the thresholds for amyloid β-related study inclusion, especially as the field shifts to focus on primary and secondary prevention. Clinical trials of anti-amyloid β treatments may benefit from the use of focal composites when estimating drug effects on amyloid β and tau changes in populations with minimal amyloid β and tau pathology and limited expected short-term accumulation.
      PubDate: Thu, 06 Feb 2020 00:00:00 GMT
  • Circadian and multiday seizure periodicities, and seizure clusters in
           canine epilepsy

    • Authors: Gregg N; Nasseri M, Kremen V, et al.
      Abstract: Advances in ambulatory intracranial EEG devices have enabled objective analyses of circadian and multiday seizure periodicities, and seizure clusters in humans. This study characterizes circadian and multiday seizure periodicities, and seizure clusters in dogs with naturally occurring focal epilepsy, and considers the implications of an animal model for the study of seizure risk patterns, seizure forecasting and personalized treatment protocols. In this retrospective cohort study, 16 dogs were continuously monitored with ambulatory intracranial EEG devices designed for humans. Detailed medication records were kept for all dogs. Seizure periodicity was evaluated with circular statistics methods. Circular non-uniformity was assessed for circadian, 7-day and approximately monthly periods. The Rayleigh test was used to assess statistical significance, with correction for multiple comparisons. Seizure clusters were evaluated with Fano factor (index of dispersion) measurements, and compared to a Poisson distribution. Relationships between interseizure interval (ISI) and seizure duration were evaluated. Six dogs met the inclusion criteria of having at least 30 seizures and were monitored for an average of 65 weeks. Three dogs had seizures with circadian seizure periodicity, one dog had a 7-day periodicity, and two dogs had approximately monthly periodicity. Four dogs had seizure clusters and significantly elevated Fano factor values. There were subject-specific differences in the dynamics of ISI and seizure durations, both within and between lead and clustered seizure categories. Our findings show that seizure timing in dogs with naturally occurring epilepsy is not random, and that circadian and multiday seizure periodicities, and seizure clusters are common. Circadian, 7-day, and monthly seizure periodicities occur independent of antiseizure medication dosing, and these patterns likely reflect endogenous rhythms of seizure risk.
      PubDate: Thu, 06 Feb 2020 00:00:00 GMT
  • Improved detection of RNA foci in C9orf72 amyotrophic lateral sclerosis
           post-mortem tissue using BaseScope™ shows a lack of association with
           cognitive dysfunction

    • Authors: Mehta A; Selvaraj B, Barton S, et al.
      Abstract: The C9orf72 hexanucleotide repeat expansion is the commonest known genetic mutation in amyotrophic lateral sclerosis. A neuropathological hallmark is the intracellular accumulation of RNA foci. The role that RNA foci play in the pathogenesis of amyotrophic lateral sclerosis is widely debated. Historically, C9orf72 RNA foci have been identified using in situ hybridization. Here, we have implemented BaseScope™, a high-resolution modified in situ hybridization technique. We demonstrate that previous studies have underestimated the abundance of RNA foci in neurons and glia. This improved detection allowed us to investigate the abundance, regional distribution and cell type specificity of antisense C9orf72 RNA foci in post-mortem brain and spinal cord tissue of six deeply clinically phenotyped C9orf72 patients and six age- and sex-matched controls. We find a correlation between RNA foci and the accumulation of transactive response DNA-binding protein of 43 kDa in spinal motor neurons (rs = 0.93; P = 0.008), but not in glia or cortical motor neurons. We also demonstrate that there is no correlation between the presence of RNA foci and the accumulation of transactive response DNA binding protein of 43 kDa in extra-motor brain regions. Furthermore, there is no association between the presence of RNA foci and cognitive indices. These results highlight the utility of BaseScope™ in the clinicopathological assessment of the role of antisense RNA foci in C9orf72.
      PubDate: Fri, 31 Jan 2020 00:00:00 GMT
  • Differential effects of deep brain stimulation and levodopa on brain
           activity in Parkinson’s disease

    • Authors: Mueller K; Urgošík D, Ballarini T, et al.
      Abstract: Levodopa is the first-line treatment for Parkinson’s disease, although the precise mechanisms mediating its efficacy remain elusive. We aimed to elucidate treatment effects of levodopa on brain activity during the execution of fine movements and to compare them with deep brain stimulation of the subthalamic nuclei. We studied 32 patients with Parkinson’s disease using functional MRI during the execution of finger-tapping task, alternating epochs of movement and rest. The task was performed after withdrawal and administration of a single levodopa dose. A subgroup of patients (n = 18) repeated the experiment after electrode implantation with stimulator on and off. Investigating levodopa treatment, we found a significant interaction between both factors of treatment state (off, on) and experimental task (finger tapping, rest) in bilateral putamen, but not in other motor regions. Specifically, during the off state of levodopa medication, activity in the putamen at rest was higher than during tapping. This represents an aberrant activity pattern probably indicating the derangement of basal ganglia network activity due to the lack of dopaminergic input. Levodopa medication reverted this pattern, so that putaminal activity during finger tapping was higher than during rest, as previously described in healthy controls. Within-group comparison with deep brain stimulation underlines the specificity of our findings with levodopa treatment. Indeed, a significant interaction was observed between treatment approach (levodopa, deep brain stimulation) and treatment state (off, on) in bilateral putamen. Our functional MRI study compared for the first time the differential effects of levodopa treatment and deep brain stimulation on brain motor activity. We showed modulatory effects of levodopa on brain activity of the putamen during finger movement execution, which were not observed with deep brain stimulation.
      PubDate: Wed, 29 Jan 2020 00:00:00 GMT
  • Deep phenotyping classical galactosemia: clinical outcomes and biochemical

    • Authors: Welsink-Karssies M; Ferdinandusse S, Geurtsen G, et al.
      Abstract: Early diagnosis and dietary treatment do not prevent long-term complications, which mostly affect the central nervous system in classical galactosemia patients. The clinical outcome of patients is highly variable, and there is an urgent need for prognostic biomarkers. The aim of this study was first to increase knowledge on the natural history of classical galactosemia by studying a cohort of patients with varying geno- and phenotypes and second to study the association between clinical outcomes and two possible prognostic biomarkers. In addition, the association between abnormalities on brain MRI and clinical outcomes was investigated. Classical galactosemia patients visiting the galactosemia expertise outpatient clinic of the Amsterdam University Medical Centre were evaluated according to the International Classical Galactosemia guideline with the addition of an examination by a neurologist, serum immunoglobulin G N-glycan profiling and a brain MRI. The biomarkers of interest were galactose-1-phosphate levels and N-glycan profiles, and the clinical outcomes studied were intellectual outcome and the presence or absence of movement disorders and/or primary ovarian insufficiency. Data of 56 classical galactosemia patients are reported. The intellectual outcome ranged from 45 to 103 (mean 77 ± 14) and was <85 in 62%. Movement disorders were found in 17 (47%) of the 36 tested patients. In females aged 12 years and older, primary ovarian insufficiency was diagnosed in 12 (71%) of the 17 patients. Significant differences in N-glycan peaks were found between controls and patients. However, no significant differences in either N-glycans or galactose-1-phosphate levels were found between patients with a poor (intellectual outcome < 85) and normal intellectual outcome (intellectual outcome ≥ 85), and with or without movement disorders or primary ovarian insufficiency. The variant patients detected by newborn screening, with previously unknown geno- and phenotypes and currently no long-term complications, demonstrated significantly lower galactose-1-phospate levels than classical patients (P < 0.0005). Qualitative analysis of the MRI’s demonstrated brain abnormalities in 18 of the 21 patients, more severely in patients with a lower intellectual outcome and/or with movement disorders. This study demonstrates a large variability in clinical outcome, which varies from a below average intelligence, movement disorders and in females primary ovarian insufficiency to a normal clinical outcome. In our cohort of classical galactosemia patients, galactose-1-phosphate levels and N-glycan variations were not associated with clinical outcomes, but galactose-1-phosphate levels did differentiate between classical and variant patients detected by newborn screening. The correlation between brain abnormalities and clinical outcome should be further investigated by quantitative analysis of the MR images. The variability in clinical outcome necessitates individual and standardized evaluation of all classical galactosemia patients.
      PubDate: Wed, 29 Jan 2020 00:00:00 GMT
  • Cardiac sympathetic denervation and synucleinopathy in Alzheimer’s
           disease with brain Lewy body disease

    • Authors: Serrano G; Shprecher D, Callan M, et al.
      Abstract: Comorbid Lewy body pathology is very common in Alzheimer’s disease and may confound clinical trial design, yet there is no in vivo test to identify patients with this. Tissue (and/or radioligand imaging) studies have shown cardiac sympathetic denervation in Parkinson’s disease and dementia with Lewy bodies, but this has not been explored in Alzheimer’s subjects with Lewy bodies not meeting dementia with Lewy bodies clinicopathological criteria. To determine if Alzheimer’s disease with Lewy bodies subjects show sympathetic cardiac denervation, we analysed epicardial and myocardial tissue from autopsy-confirmed cases using tyrosine hydroxylase and neurofilament immunostaining. Comparison of tyrosine hydroxylase fibre density in 19 subjects with Alzheimer’s disease/dementia with Lewy bodies, 20 Alzheimer’s disease with Lewy bodies, 12 Alzheimer’s disease subjects without Lewy body disease, 19 Parkinson’s disease, 30 incidental Lewy body disease and 22 cognitively normal without Alzheimer’s disease or Lewy body disease indicated a significant group difference (P < 0.01; Kruskal–Wallis analysis of variance) and subsequent pair-wise Mann–Whitney U tests showed that Parkinson’s disease (P < 0.05) and Alzheimer’s disease/dementia with Lewy bodies (P < 0.01) subjects, but not Alzheimer’s disease with Lewy bodies subjects, had significantly reduced tyrosine hydroxylase fibre density as compared with cognitively normal. Both Parkinson’s disease and Alzheimer’s disease/dementia with Lewy bodies subjects also showed significant epicardial losses of neurofilament protein-immunoreactive nerve fibre densities within the fibre bundles as compared with cognitively normal subjects (P < 0.01) and both groups showed high pathologic alpha-synuclein densities (P < 0.0001). Cardiac alpha-synuclein densities correlated significantly with brain alpha-synuclein (P < 0.001), while cardiac tyrosine hydroxylase and neurofilament immunoreactive nerve fibre densities were negatively correlated with the densities of both brain and cardiac alpha-synuclein, as well as Unified Parkinson’s Disease Rating Scale scores (P < 0.05). The clear separation of Alzheimer’s disease/dementia with Lewy bodies subjects from Alzheimer’s disease and cognitively normal, based on cardiac tyrosine hydroxylase fibre density, is the first report of a statistically significant difference between these groups. Our data do not show significant sympathetic cardiac denervation in Alzheimer’s disease with Lewy bodies, but strongly confirm that cardiac nuclear imaging with a noradrenergic radioligand is worthy of further study as a potential means to separate Alzheimer’s disease from Alzheimer’s disease/dementia with Lewy bodies during life.
      PubDate: Tue, 28 Jan 2020 00:00:00 GMT
  • The ‘creatures’ of the human cortical somatosensory system

    • Authors: Saadon-Grosman N; Loewenstein Y, Arzy S.
      Abstract: Penfield’s description of the ‘homunculus’, a ‘grotesque creature’ with large lips and hands and small trunk and legs depicting the representation of body-parts within the primary somatosensory cortex (S1), is one of the most prominent contributions to the neurosciences. Since then, numerous studies have identified additional body-parts representations outside of S1. Nevertheless, it has been implicitly assumed that S1’s homunculus is representative of the entire somatosensory cortex. Therefore, the distribution of body-parts representations in other brain regions, the property that gave Penfield’s homunculus its famous ‘grotesque’ appearance, has been overlooked. We used whole-body somatosensory stimulation, functional MRI and a new cortical parcellation to quantify the organization of the cortical somatosensory representation. Our analysis showed first, an extensive somatosensory response over the cortex; and second, that the proportional representation of body parts differs substantially between major neuroanatomical regions and from S1, with, for instance, much larger trunk representation at higher brain regions, potentially in relation to the regions’ functional specialization. These results extend Penfield’s initial findings to the higher level of somatosensory processing and suggest a major role for somatosensation in human cognition.
      PubDate: Fri, 17 Jan 2020 00:00:00 GMT
  • Clinical efficacy of haematopoietic stem cell transplantation for adult

    • Authors: Matsukawa T; Yamamoto T, Honda A, et al.
      Abstract: Accumulated experience supports the efficacy of allogenic haematopoietic stem cell transplantation in arresting the progression of childhood-onset cerebral form of adrenoleukodystrophy in early stages. For adulthood-onset cerebral form of adrenoleukodystrophy, however, there have been only a few reports on haematopoietic stem cell transplantation and the clinical efficacy and safety of that for adulthood-onset cerebral form of adrenoleukodystrophy remain to be established. To evaluate the clinical efficacy and safety of haematopoietic stem cell transplantation, we conducted haematopoietic stem cell transplantation on 12 patients with adolescent-/adult-onset cerebral form/cerebello-brainstem form of adrenoleukodystrophy in a single-institution-based prospective study. Through careful prospective follow-up of 45 male adrenoleukodystrophy patients, we aimed to enrol patients with adolescent-/adult-onset cerebral form/cerebello-brainstem form of adrenoleukodystrophy at early stages. Indications for haematopoietic stem cell transplantation included cerebral form of adrenoleukodystrophy or cerebello-brainstem form of adrenoleukodystrophy with Loes scores up to 13, the presence of progressively enlarging white matter lesions and/or lesions with gadolinium enhancement on brain MRI. Clinical outcomes of haematopoietic stem cell transplantation were evaluated by the survival rate as well as by serial evaluation of clinical rating scale scores and neurological and MRI findings. Clinical courses of eight patients who did not undergo haematopoietic stem cell transplantation were also evaluated for comparison of the survival rate. All the patients who underwent haematopoietic stem cell transplantation survived to date with a median follow-up period of 28.6 months (4.2–125.3 months) without fatality. Neurological findings attributable to cerebral/cerebellar/brainstem lesions became stable or partially improved in all the patients. Gadolinium-enhanced brain lesions disappeared or became obscure within 3.5 months and the white matter lesions of MRI became stable or small. The median Loes scores before haematopoietic stem cell transplantation and at the last follow-up visit were 6.0 and 5.25, respectively. Of the eight patients who did not undergo haematopoietic stem cell transplantation, six patients died 69.1 months (median period; range 16.0–104.1 months) after the onset of the cerebral/cerebellar/brainstem lesions, confirming that the survival probability was significantly higher in patients with haematopoietic stem cell transplantation compared with that in patients without haematopoietic stem cell transplantation (P = 0.0089). The present study showed that haematopoietic stem cell transplantation was conducted safely and arrested the inflammatory demyelination in all the patients with adolescent-/adult-onset cerebral form/cerebello-brainstem form of adrenoleukodystrophy when haematopoietic stem cell transplantation was conducted in the early stages. Further studies are warranted to optimize the procedures of haematopoietic stem cell transplantation for adolescent-/adult-onset cerebral form/cerebello-brainstem form of adrenoleukodystrophy.
      PubDate: Tue, 14 Jan 2020 00:00:00 GMT
  • Editorial

    • Authors: Spires-Jones T.
      Abstract: Happy New Year and welcome to our second volume of Brain Communications.
      PubDate: Mon, 13 Jan 2020 00:00:00 GMT
  • Exercise alters cerebellar and cortical activity related to working memory
           in phenotypes of Gulf War Illness

    • Authors: Washington S; Rayhan R, Garner R, et al.
      Abstract: Gulf War Illness affects 25–32% of veterans from the 1990–91 Persian Gulf War. Post-exertional malaise with cognitive dysfunction, pain and fatigue following physical and/or mental effort is a defining feature of Gulf War Illness. We modelled post-exertional malaise by assessing changes in functional magnetic resonance imaging at 3T during an N-Back working memory task performed prior to a submaximal bicycle stress test and after an identical stress test 24 h later. Serial trends in postural changes in heart rate between supine and standing defined three subgroups of veterans with Gulf War Illness: Postural Orthostatic Tachycardia Syndrome (GWI-POTS, 15%, n = 11), Stress Test Associated Reversible Tachycardia (GWI-START, 31%, n = 23) and Stress Test Originated Phantom Perception (GWI-STOPP, no postural tachycardia, 54%, n = 46). Before exercise, there were no differences in blood oxygenation level-dependent activity during the N-Back task between control (n = 31), GWI-START, GWI-STOPP and GWI-POTS subgroups. Exercise had no effects on blood oxygenation level-dependent activation in controls. GWI-START had post-exertional deactivation of cerebellar dentate nucleus and vermis regions associated with working memory. GWI-STOPP had significant activation of the anterior supplementary motor area that may be a component of the anterior salience network. There was a trend for deactivation of the vermis in GWI-POTS after exercise. These patterns of cognitive dysfunction were apparent in Gulf War Illness only after the exercise stressor. Mechanisms linking the autonomic dysfunction of Stress Test Associated Reversible Tachycardia and Postural Orthostatic Tachycardia Syndrome to cerebellar activation, and Stress Test Originated Phantom Perception to cortical sensorimotor alterations, remain unclear but may open new opportunities for understanding, diagnosing and treating Gulf War Illness.
      PubDate: Sun, 12 Jan 2020 00:00:00 GMT
  • Monotherapy efficacy of blood–brain barrier permeable small molecule
           reactivators of protein phosphatase 2A in glioblastoma

    • Authors: Merisaari J; Denisova O, Doroszko M, et al.
      Abstract: Glioblastoma is a fatal disease in which most targeted therapies have clinically failed. However, pharmacological reactivation of tumour suppressors has not been thoroughly studied as yet as a glioblastoma therapeutic strategy. Tumour suppressor protein phosphatase 2A is inhibited by non-genetic mechanisms in glioblastoma, and thus, it would be potentially amendable for therapeutic reactivation. Here, we demonstrate that small molecule activators of protein phosphatase 2A, NZ-8-061 and DBK-1154, effectively cross the in vitro model of blood–brain barrier, and in vivo partition to mouse brain tissue after oral dosing. In vitro, small molecule activators of protein phosphatase 2A exhibit robust cell-killing activity against five established glioblastoma cell lines, and nine patient-derived primary glioma cell lines. Collectively, these cell lines have heterogeneous genetic background, kinase inhibitor resistance profile and stemness properties; and they represent different clinical glioblastoma subtypes. Moreover, small molecule activators of protein phosphatase 2A were found to be superior to a range of kinase inhibitors in their capacity to kill patient-derived primary glioma cells. Oral dosing of either of the small molecule activators of protein phosphatase 2A significantly reduced growth of infiltrative intracranial glioblastoma tumours. DBK-1154, with both higher degree of brain/blood distribution, and more potent in vitro activity against all tested glioblastoma cell lines, also significantly increased survival of mice bearing orthotopic glioblastoma xenografts. In summary, this report presents a proof-of-principle data for blood–brain barrier—permeable tumour suppressor reactivation therapy for glioblastoma cells of heterogenous molecular background. These results also provide the first indications that protein phosphatase 2A reactivation might be able to challenge the current paradigm in glioblastoma therapies which has been strongly focused on targeting specific genetically altered cancer drivers with highly specific inhibitors. Based on demonstrated role for protein phosphatase 2A inhibition in glioblastoma cell drug resistance, small molecule activators of protein phosphatase 2A may prove to be beneficial in future glioblastoma combination therapies.
      PubDate: Sat, 11 Jan 2020 00:00:00 GMT
  • 11β-Hydroxysteroid dehydrogenase type 1 inhibition in idiopathic
           intracranial hypertension: a double-blind randomized controlled trial

    • Authors: Markey K; Mitchell J, Botfield H, et al.
      Abstract: Treatment options for idiopathic intracranial hypertension are limited. The enzyme 11β-hydroxysteroid dehydrogenase type 1 has been implicated in regulating cerebrospinal fluid secretion, and its activity is associated with alterations in intracranial pressure in idiopathic intracranial hypertension. We assessed therapeutic efficacy, safety and tolerability and investigated indicators of in vivo efficacy of the 11β-hydroxysteroid dehydrogenase type 1 inhibitor AZD4017 compared with placebo in idiopathic intracranial hypertension. A multicenter, UK, 16-week phase II randomized, double-blind, placebo-controlled trial of 12-week treatment with AZD4017 or placebo was conducted. Women aged 18–55 years with active idiopathic intracranial hypertension (>25 cmH2O lumbar puncture opening pressure and active papilledema) were included. Participants received 400 mg of oral AZD4017 twice daily compared with matching placebo over 12 weeks. The outcome measures were initial efficacy, safety and tolerability. The primary clinical outcome was lumbar puncture opening pressure at 12 weeks analysed by intention-to-treat. Secondary clinical outcomes were symptoms, visual function, papilledema, headache and anthropometric measures. In vivo efficacy was evaluated in the central nervous system and systemically. A total of 31 subjects [mean age 31.2 (SD = 6.9) years and body mass index 39.2 (SD = 12.6) kg/m2] were randomized to AZD4017 (n = 17) or placebo (n = 14). At 12 weeks, lumbar puncture pressure was lower in the AZD4017 group (29.7 cmH2O) compared with placebo (31.3 cmH2O), but the difference between groups was not statistically significant (mean difference: −2.8, 95% confidence interval: −7.1 to 1.5; P = 0.2). An exploratory analysis assessing mean change in lumbar puncture pressure within each group found a significant decrease in the AZD4017 group [mean change: −4.3 cmH2O (SD = 5.7); P = 0.009] but not in the placebo group [mean change: −0.3 cmH2O (SD = 5.9); P = 0.8]. AZD4017 was safe, with no withdrawals related to adverse effects. Nine transient drug-related adverse events were reported. One serious adverse event occurred in the placebo group (deterioration requiring shunt surgery). In vivo biomarkers of 11β-hydroxysteroid dehydrogenase type 1 activity (urinary glucocorticoid metabolites, hepatic prednisolone generation, serum and cerebrospinal fluid cortisol:cortisone ratios) demonstrated significant enzyme inhibition with the reduction in serum cortisol:cortisone ratio correlating significantly with reduction in lumbar puncture pressure (P = 0.005, R = 0.70). This is the first phase II randomized controlled trial in idiopathic intracranial hypertension evaluating a novel therapeutic target. AZD4017 was safe and well tolerated and inhibited 11β-hydroxysteroid dehydrogenase type 1 activity in vivo. Reduction in serum cortisol:cortisone correlated with decreased intracranial pressure. Possible clinical benefits were noted in this small cohort. A longer, larger study would now be of interest.
      PubDate: Fri, 10 Jan 2020 00:00:00 GMT
  • Structural brain networks and functional motor outcome after
           stroke—a prospective cohort study

    • Authors: Schlemm E; Schulz R, Bönstrup M, et al.
      Abstract: The time course of topological reorganization that occurs in the structural connectome after an ischaemic stroke is currently not well understood. We aimed to determine the evolution of structural brain networks in stroke patients with motor deficits and relate changes in their global topology to residual symptom burden and functional impairment. In this prospective cohort study, ischaemic stroke patients with supratentorial infarcts and motor symptoms were assessed longitudinally by advanced diffusion MRI and detailed clinical testing of upper extremity motor function at four time points from the acute to the chronic stage. For each time point, structural connectomes were reconstructed, and whole-hemisphere global network topology was quantified in terms of integration and segregation parameters. Using non-linear joint mixed-effects regression modelling, network evolution was related to lesion volume and clinical outcome. Thirty patients were included for analysis. Graph-theoretical analysis demonstrated that, over time, brain networks became less integrated and more segregated with decreasing global efficiency and increasing modularity. Changes occurred in both stroke and intact hemispheres and, in the latter, were positively associated with lesion volume. Greater change in topology was associated with larger residual symptom burden and greater motor impairment 1, 3 and 12 months after stroke. After ischaemic stroke, brain networks underwent characteristic changes in both ipsi- and contralesional hemispheres. Topological network changes reflect the severity of damage to the structural network and are associated with functional outcome beyond the impact of lesion volume.
      PubDate: Fri, 10 Jan 2020 00:00:00 GMT
  • Neuron-autonomous susceptibility to induced synuclein aggregation is
           exacerbated by endogenous Lrrk2 mutations and ameliorated by Lrrk2 genetic

    • Authors: MacIsaac S; Quevedo Melo T, Zhang Y, et al.
      Abstract: Neuronal aggregates containing α-synuclein are a pathological hallmark of several degenerative diseases; including Parkinson’s disease, Parkinson’s disease with dementia and dementia with Lewy bodies. Understanding the process of α-synuclein aggregation, and discovering means of preventing it, may help guide therapeutic strategy and drug design. Recent advances provide tools to induce α-synuclein aggregation in neuronal cultures. Application of exogenous pre-formed fibrillar α-synuclein induces pathological phosphorylation and accumulation of endogenous α-synuclein, typical of that seen in disease. Genomic variability and mutations in α-synuclein and leucine-rich repeat kinase 2 proteins are the major genetic risk factors for Parkinson’s disease. Reports demonstrate fibril-induced α-synuclein aggregation is increased in cells from leucine-rich repeat kinase 2 pathogenic mutant (G2019S) overexpressing mice, and variously decreased by leucine-rich repeat kinase 2 inhibitors. Elsewhere in vivo antisense knock-down of leucine-rich repeat kinase 2 protein has been shown to protect mice from fibril-induced α-synuclein aggregation, whereas kinase inhibition did not. To help bring clarity to this issue, we took a purely genetic approach in a standardized neuron-enriched culture, lacking glia. We compared fibril treatment of leucine-rich repeat kinase 2 germ-line knock-out, and G2019S germ-line knock-in, mouse cortical neuron cultures with those from littermates. We found leucine-rich repeat kinase 2 knock-out neurons are resistant to α-synuclein aggregation, which predominantly forms within axons, and may cause axonal fragmentation. Conversely, leucine-rich repeat kinase 2 knock-in neurons are more vulnerable to fibril-induced α-synuclein accumulation. Protection and resistance correlated with basal increases in a lysosome marker in knock-out, and an autophagy marker in knock-in cultures. The data add to a growing number of studies that argue leucine-rich repeat kinase 2 silencing, and potentially kinase inhibition, may be a useful therapeutic strategy against synucleinopathy.
      PubDate: Tue, 07 Jan 2020 00:00:00 GMT
  • Haemoglobin causes neuronal damage in vivo which is preventable by

    • Authors: Garland P; Morton M, Haskins W, et al.
      Abstract: After subarachnoid haemorrhage, prolonged exposure to toxic extracellular haemoglobin occurs in the brain. Here, we investigate the role of haemoglobin neurotoxicity in vivo and its prevention. In humans after subarachnoid haemorrhage, haemoglobin in cerebrospinal fluid was associated with neurofilament light chain, a marker of neuronal damage. Most haemoglobin was not complexed with haptoglobin, an endogenous haemoglobin scavenger present at very low concentration in the brain. Exogenously added haptoglobin bound most uncomplexed haemoglobin, in the first 2 weeks after human subarachnoid haemorrhage, indicating a wide therapeutic window. In mice, the behavioural, vascular, cellular and molecular changes seen after human subarachnoid haemorrhage were recapitulated by modelling a single aspect of subarachnoid haemorrhage: prolonged intrathecal exposure to haemoglobin. Haemoglobin-induced behavioural deficits and astrocytic, microglial and synaptic changes were attenuated by haptoglobin. Haptoglobin treatment did not attenuate large-vessel vasospasm, yet improved clinical outcome by restricting diffusion of haemoglobin into the parenchyma and reducing small-vessel vasospasm. In summary, haemoglobin toxicity is of clinical importance and preventable by haptoglobin, independent of large-vessel vasospasm.
      PubDate: Fri, 03 Jan 2020 00:00:00 GMT
  • Is tau in the absence of amyloid on the Alzheimer’s continuum': A
           study of discordant PET positivity

    • Authors: Weigand A; Bangen K, Thomas K, et al.
      Abstract: The amyloid cascade model of Alzheimer’s disease posits the primacy of amyloid beta deposition preceding tau-mediated neurofibrillary tangle formation. The amyloid-tau-neurodegeneration biomarker-only diagnostic framework similarly requires the presence of amyloid beta for a diagnosis on the Alzheimer’s continuum. However, medial temporal lobe tau pathology in the absence of amyloid beta is frequently observed at autopsy in cognitively normal individuals, a phenomenon that may reflect a consequence of aging and has been labelled ‘primary age-related tauopathy’. Alternatively, others argue that this tauopathy reflects an early stage of the developmental continuum leading to Alzheimer’s disease. We used positron emission tomography imaging to investigate amyloid beta and tau positivity and associations with cognition to better inform the conceptualization of biomarker changes in Alzheimer’s pathogenesis. Five hundred twenty-three individuals from the Alzheimer’s Disease Neuroimaging Initiative who had undergone flortaucipir positron emission tomography imaging were selected to derive positron emission tomography positivity thresholds using conditional inference decision tree regression. A subsample of 301 individuals without dementia (i.e. those with normal cognition or mild cognitive impairment) had also undergone florbetapir positron emission tomography imaging within 12 months and were categorized into one of the four groups based on cortical amyloid and Braak stage I/II tau positivity: A−/T−, A+/T−, A−/T+, or A+/T+. Tau positivity in the absence of amyloid beta positivity (i.e. A−/T+) comprised the largest group, representing 45% of the sample. In contrast, only 6% of the sample was identified as A+/T−, and the remainder of the sample fell into A−/T− (22%) or A+/T+ (27%) categories. A−/T− and A+/T− groups had the best cognitive performances across memory, language and executive function; the A−/T+ group showed small-to-moderate relative decreases in cognition; and the A+/T+ group had the worst cognitive performances. Furthermore, there were negative associations between Braak stage I/II tau values and all cognitive domains only in the A−/T+ and A+/T+ groups, with strongest associations for the A+/T+ group. Among our sample of older adults across the Alzheimer’s pathological spectrum, 7-fold fewer individuals have positron emission tomography evidence of amyloid beta pathology in the absence of tau pathology than the converse, challenging prevailing models of amyloid beta’s primacy in Alzheimer’s pathogenesis. Given that cognitive performance in the A−/T+ group was poorer than in individuals without either pathology, our results suggest that medial temporal lobe tau without cortical amyloid beta may reflect an early stage on the Alzheimer’s pathological continuum.
      PubDate: Fri, 20 Dec 2019 00:00:00 GMT
  • Mechanical property alterations across the cerebral cortex due to
           Alzheimer’s disease

    • Authors: Hiscox L; Johnson C, McGarry M, et al.
      Abstract: Alzheimer’s disease is a personally devastating neurodegenerative disorder and a major public health concern. There is an urgent need for medical imaging techniques that better characterize the early stages and monitor the progression of the disease. Magnetic resonance elastography (MRE) is a relatively new and highly sensitive MRI technique that can non-invasively assess tissue microstructural integrity via measurement of brain viscoelastic mechanical properties. For the first time, we use high-resolution MRE methods to conduct a voxel-wise MRE investigation and state-of-the-art post hoc region of interest analysis of the viscoelastic properties of the cerebral cortex in patients with Alzheimer’s disease (N = 11) compared with cognitively healthy older adults (N = 12). We replicated previous findings that have reported significant volume and stiffness reductions at the whole-brain level. Significant reductions in volume were also observed in Alzheimer’s disease when white matter, cortical grey matter and subcortical grey matter compartments were considered separately; lower stiffness was also observed in white matter and cortical grey matter, but not in subcortical grey matter. Voxel-based morphometry of both cortical and subcortical grey matter revealed localized reductions in volume due to Alzheimer’s disease in the hippocampus, fusiform, middle, superior temporal gyri and precuneus. Similarly, voxel-based MRE identified lower stiffness in the middle and superior temporal gyri and precuneus, although the spatial distribution of these effects was not identical to the pattern of volume reduction. Notably, MRE additionally identified stiffness deficits in the operculum and precentral gyrus located within the frontal lobe; regions that did not undergo volume loss identified through voxel-based morphometry. Voxel-based-morphometry and voxel-based MRE results were confirmed by a complementary post hoc region-of-interest approach in native space where the viscoelastic changes remained significant even after statistically controlling for regional volumes. The pattern of reduction in cortical stiffness observed in Alzheimer’s disease patients raises the possibility that MRE may provide unique insights regarding the neural mechanisms which underlie the development and progression of the disease. The measured mechanical property changes that we have observed warrant further exploration to investigate the diagnostic usefulness of MRE in cases of Alzheimer’s disease and other dementias.
      PubDate: Tue, 17 Dec 2019 00:00:00 GMT
  • A comprehensive analysis of methods for assessing polygenic burden on
           Alzheimer’s disease pathology and risk beyond APOE

    • Authors: Altmann A; Scelsi M, Shoai M, et al.
      Abstract: Genome-wide association studies have identified dozens of loci that alter the risk to develop Alzheimer’s disease. However, with the exception of the APOE-ε4 allele, most variants bear only little individual effect and have, therefore, limited diagnostic and prognostic value. Polygenic risk scores aim to collate the disease risk distributed across the genome in a single score. Recent works have demonstrated that polygenic risk scores designed for Alzheimer’s disease are predictive of clinical diagnosis, pathology confirmed diagnosis and changes in imaging biomarkers. Methodological innovations in polygenic risk modelling include the polygenic hazard score, which derives effect estimates for individual single nucleotide polymorphisms from survival analysis, and methods that account for linkage disequilibrium between genomic loci. In this work, using data from the Alzheimer’s disease neuroimaging initiative, we compared different approaches to quantify polygenic disease burden for Alzheimer’s disease and their association (beyond the APOE locus) with a broad range of Alzheimer’s disease-related traits: cross-sectional CSF biomarker levels, cross-sectional cortical amyloid burden, clinical diagnosis, clinical progression, longitudinal loss of grey matter and longitudinal decline in cognitive function. We found that polygenic scores were associated beyond APOE with clinical diagnosis, CSF-tau levels and, to a minor degree, with progressive atrophy. However, for many other tested traits such as clinical disease progression, CSF amyloid, cognitive decline and cortical amyloid load, the additional effects of polygenic burden beyond APOE were of minor nature. Overall, polygenic risk scores and the polygenic hazard score performed equally and given the ease with which polygenic risk scores can be derived; they constitute the more practical choice in comparison with polygenic hazard scores. Furthermore, our results demonstrate that incomplete adjustment for the APOE locus, i.e. only adjusting for APOE-ε4 carrier status, can lead to overestimated effects of polygenic scores due to APOE-ε4 homozygous participants. Lastly, on many of the tested traits, the major driving factor remained the APOE locus, with the exception of quantitative CSF-tau and p-tau measures.
      PubDate: Mon, 16 Dec 2019 00:00:00 GMT
  • The dynamic of basal ganglia activity with a multiple covariance method:
           influences of Parkinson’s disease

    • Authors: Rodriguez-Sabate C; Morales I, Puertas-Avendaño R, et al.
      Abstract: The closed-loop cortico-subcortical pathways of basal ganglia have been extensively used to describe the physiology of these centres and to justify the functional disorders of basal ganglia diseases. This approach justifies some experimental and clinical data but not others, and furthermore, it does not include a number of subcortical circuits that may produce a more complex basal ganglia dynamic than that expected for closed-loop linear networks. This work studied the functional connectivity of the main regions of the basal ganglia motor circuit with magnetic resonance imaging and a new method (functional profile method), which can analyse the multiple covariant activity of human basal ganglia. The functional profile method identified the most frequent covariant functional status (profiles) of the basal ganglia motor circuit, ordering them according to their relative frequency and identifying the most frequent successions between profiles (profile transitions). The functional profile method classified profiles as input profiles that accept the information coming from other networks, output profiles involved in the output of processed information to other networks and highly interconnected internal profiles that accept transitions from input profiles and send transitions to output profiles. Profile transitions showed a previously unobserved functional dynamic of human basal ganglia, suggesting that the basal ganglia motor circuit may work as a dynamic multiple covariance network. The number of internal profiles and internal transitions showed a striking decrease in patients with Parkinson’s disease, a fact not observed for input and output profiles. This suggests that basal ganglia of patients with Parkinson’s disease respond to requirements coming from other neuronal networks, but because the internal processing of information is drastically weakened, its response will be insufficient and perhaps also self-defeating. These marked effects were found in patients with few motor disorders, suggesting that the functional profile method may be an early procedure to detect the first stages of the Parkinson’s disease when the motor disorders are not very evident. The multiple covariance activity found presents a complementary point of view to the cortico-subcortical closed-loop model of basal ganglia. The functional profile method may be easily applied to other brain networks, and it may provide additional explanations for the clinical manifestations of other basal ganglia disorders.
      PubDate: Wed, 11 Dec 2019 00:00:00 GMT
  • A neurophysiological model of speech production deficits in fragile X

    • Authors: Schmitt L; Wang J, Pedapati E, et al.
      Abstract: Fragile X syndrome is the most common inherited intellectual disability and monogenic cause of autism spectrum disorder. Expressive language deficits, especially in speech production, are nearly ubiquitous among individuals with fragile X, but understanding of the neurological bases for these deficits remains limited. Speech production depends on feedforward control and the synchronization of neural oscillations between speech-related areas of frontal cortex and auditory areas of temporal cortex. Interaction in this circuitry allows the corollary discharge of intended speech generated from an efference copy of speech commands to be compared against actual speech sounds, which is critical for making adaptive adjustments to optimize future speech. We aimed to determine whether alterations in coherence between frontal and temporal cortices prior to speech production are present in individuals with fragile X and whether they relate to expressive language dysfunction. Twenty-one participants with full-mutation fragile X syndrome (aged 7–55 years, eight females) and 20 healthy controls (matched on age and sex) completed a talk/listen paradigm during high-density EEG recordings. During the talk task, participants repeated pronounced short vocalizations of ‘Ah’ every 1–2 s for a total of 180 s. During the listen task, participants passively listened to their recordings from the talk task. We compared pre-speech event-related potential activity, N1 suppression to speech sounds, single trial gamma power and fronto-temporal coherence between groups during these tasks and examined their relation to performance during a naturalistic language task. Prior to speech production, fragile X participants showed reduced pre-speech negativity, reduced fronto-temporal connectivity and greater frontal gamma power compared to controls. N1 suppression during self-generated speech did not differ between groups. Reduced pre-speech activity and increased frontal gamma power prior to speech production were related to less intelligible speech as well as broader social communication deficits in fragile X syndrome. Our findings indicate that coordinated pre-speech activity between frontal and temporal cortices is disrupted in individuals with fragile X in a clinically relevant way and represents a mechanism contributing to prominent speech production problems in the disorder.
      PubDate: Mon, 09 Dec 2019 00:00:00 GMT
  • Phagocytic glioblastoma-associated microglia and macrophages populate
           invading pseudopalisades

    • Authors: Saavedra-López E; Roig-Martínez M, Cribaro G, et al.
      Abstract: Hypoxic pseudopalisades are a pathological hallmark of human glioblastoma, which is linked to tumour malignancy and aggressiveness. Yet, their function and role in the tumour development have scarcely been explored. It is thought that pseudopalisades are formed by malignant cells escaping from the hypoxic environment, although evidence of the immune component of pseudopalisades has been elusive. In the present work, we analyse the immunological constituent of hypoxic pseudopalisades using high-resolution three-dimensional confocal imaging in tissue blocks from excised tumours of glioblastoma patients and mimic the hypoxic gradient in microfluidic platforms in vitro to understand the cellular motility. We visualize that glioblastoma-associated microglia and macrophages abundantly populate pseudopalisades, displaying an elongated kinetic morphology across the pseudopalisades, and are oriented towards the necrotic focus. In vitro experiments demonstrate that under hypoxic gradient, microglia show a particular motile behaviour characterized by the increase of cellular persistence in contrast with glioma cells. Importantly, we show that glioblastoma-associated microglia and macrophages utilize fibres of glioma cells as a haptotactic cue to navigate along the anisotropic structure of the pseudopalisades and display a high phagocytic activity at the necrotic border of the pseudopalisades. In this study, we demonstrate that glioblastoma-associated microglia and macrophages are the main immune cells of pseudopalisades in glioblastoma, travelling to necrotic areas to clear the resulting components of the prothrombotic milieu, suggesting that the scavenging features of glioblastoma-associated microglia and macrophages at the pseudopalisades serve as an essential counterpart for glioma cell invasion.
      PubDate: Wed, 04 Dec 2019 00:00:00 GMT
  • Relationship of amyloid-β1–42 in blood and brain amyloid: Ginkgo
           Evaluation of Memory Study

    • Authors: Lopez O; Klunk W, Mathis C, et al.
      Abstract: A blood test that predicts the extent of amyloid plaques in the brain and risk of Alzheimer’s disease would have important benefits for the early identification of higher risk of dementia and Alzheimer’s disease and the evaluation of new preventative therapies. The goal of this study was to determine whether plasma levels of amyloid-β1–42, 1–40 and the amyloid-β1–42/1–40 ratio among participants in the Pittsburgh centre of the Ginkgo Evaluation of Memory Study were related to the extent of brain fibrillar amyloid plaques measured in 2009 using Pittsburgh compound-B PET imaging, hippocampal volume, cortical thickness in the temporal lobe and white matter lesions. There were 194 participants who had Pittsburgh compound-B measurements in 2009 with the mean age of 85 years; 96% were white and 60% men. Pittsburgh compound-B positivity was defined as a standardized uptake value ratio of ≥1.57. Amyloid-β in blood was measured using a sandwich enzyme-linked immunosorbent assay developed by Eli Lilly and modified at the University of Vermont. All participants were nondemented as of 2008 at the time of study close out. The study sample included 160 with blood samples drawn in 2000–02 and 133 from 2009 and also had brain amyloid measured in 2009. All blood samples were analysed at the same time in 2009. Plasma amyloid-β1–42 was inversely related to the percent Pittsburgh compound-B positive (standardized uptake value ratio ≥1.57), β −0.04, P = 0.005. Practically all participants who were apolipoprotein-E4 positive at older ages were also Pittsburgh compound-B positive for fibrillar amyloid. Among apolipoprotein-E4-negative participants, quartiles of amyloid-β1–42 were inversely related to Pittsburgh compound-B positivity. In multiple regression models, plasma amyloid-β1–42 measured in 2000–02 or 2009 were significantly and inversely related to Pittsburgh compound-B positivity as was the amyloid-β1–42/1–40 ratio. There was a 4-fold increase in the odds ratio for the presence of Pittsburgh compound-B positivity in the brain in 2009 for the first quartile of amyloid-β1–42 as compared with the fourth quartile in the multiple logistic model. This is one of the first longitudinal studies to evaluate the relationship between amyloid-β1–42 in the blood and the extent of brain amyloid deposition measured by PET imaging using Pittsburgh compound-B. Our findings showed that remote and recent low plasma amyloid-β1–42 levels were inversely associated with brain amyloid deposition in cognitively normal individuals. However, changes in plasma amyloid-β1–42 over time (8 years) were small and not related to the amount of Pittsburgh compound-B.
      PubDate: Wed, 27 Nov 2019 00:00:00 GMT
  • Blood-based protein mediators of senility with replications across
           biofluids and cohorts

    • Authors: Royall D; Palmer R, .
      Abstract: Dementia severity can be quantitatively described by the latent dementia phenotype ‘δ’ and its various composite ‘homologues’. We have explored δ’s blood-based protein biomarkers in the Texas Alzheimer’s Research and Care Consortium. However, it would be convenient to replicate them in the Alzheimer’s Disease Neuroimaging Initiative. To that end, we have engineered a δ homologue from the observed cognitive performance measures common to both projects [i.e. ‘d:Texas Alzheimer’s Research and Care Consortium to Alzheimer’s Disease Neuroimaging Initiative’ (dT2A)]. In this analysis, we confirm 13/22 serum proteins as partial mediators of age’s effect on dementia severity as measured by dT2A in the Texas Alzheimer’s Research and Care Consortium and then replicate 4/13 in the Alzheimer’s Disease Neuroimaging Initiative’s plasma data. The replicated mediators of age-specific effects on dementia severity are adiponectin, follicle-stimulating hormone, pancreatic polypeptide and resistin. In their aggregate, the 13 confirmed age-specific mediators suggest that ‘cognitive frailty’ pays a role in dementia severity as measured by δ. We provide both discriminant and concordant support for that hypothesis. Weight, calculated low-density lipoprotein and body mass index are partial mediators of age’s effect in the Texas Alzheimer’s Research and Care Consortium. Biomarkers related to other disease processes (e.g. cerebrospinal fluid Alzheimer’s disease-specific biomarkers in the Alzheimer’s Disease Neuroimaging Initiative) are not. It now appears that dementia severity is the sum of multiple independent processes impacting δ. Each may have a unique set of mediating biomarkers. Age’s unique effect appears to be at least partially mediated through proteins related to frailty. Age-specific mediation effects can be replicated across cohorts and biofluids. These proteins may offer targets for the remediation of age-specific cognitive decline (aka ‘senility’), help distinguish it from other determinants of dementia severity and/or provide clues to the biology of Aging Proper.
      PubDate: Fri, 22 Nov 2019 00:00:00 GMT
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