Parkinsonism in essential tremor cases: A clinicopathological study.

BACKGROUND: Essential tremor and Parkinson's syndrome are two common movement disorders that may co-occur in some individuals. There is no diagnostic neuropathology for essential tremor, but in PD and other Parkinson's syndrome variants, the neuropathology is well known. The spectrum of Parkinson's syndrome variants associated with essential tremor, their clinical features, and course have not been determined in autopsy-confirmed cases. OBJECTIVES: To identify: diagnostic features of essential tremor/Parkinson's syndrome, different Parkinson's syndrome variants, and long-term clinical profile in such cases. METHODS: Patients that had an essential tremor diagnosis and a subsequent clinical or pathological diagnosis of Parkinson's syndrome seen in our clinic during 50 years were included. The diagnosis of parkinsonism was made when bradykinesia, rigidity, and resting tremor were all clinically evident. RESULTS: Twenty-one cases were included. All the common variants of parkinsonism co-occurred with essential tremor. The most common was PD (67%) followed by PSP. The pathological findings were not predicted clinically in 2 cases that had essential tremor/PD and in all 5 essential tremor/PSP cases. CONCLUSION: In most essential tremor/Parkinson's syndrome patients, the main motor features of parkinsonism-bradykinesia, rigidity, and resting tremor-were identifiable. All known degenerative Parkinson's syndrome variants co-occurred in essential tremor patients. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

KCC3 axonopathy: neuropathological features in the central and peripheral nervous system.

Hereditary motor and sensory neuropathy associated with agenesis of the corpus callosum (HMSN/ACC) is an autosomal recessive disease of the central and peripheral nervous system that presents as early-onset polyneuropathy. Patients are hypotonic and areflexic from birth, with abnormal facial features and atrophic muscles. Progressive peripheral neuropathy eventually confines them to a wheelchair in the second decade of life, and death occurs by the fourth decade. We here define the neuropathologic features of the disease in autopsy tissues from eight cases. Both developmental and neurodegenerative features were found. Hypoplasia or absence of the major telencephalic commissures and a hypoplasia of corticospinal tracts to half the normal size, were the major neurodevelopmental defects we observed. Despite being a neurodegenerative disease, preservation of brain weight and a conspicuous absence of neuronal or glial cell death were signal features of this disease. Small tumor-like overgrowths of axons, termed axonomas, were found in the central and peripheral nervous system, indicating attempted axonal regeneration. We conclude that the neurodegenerative deficits in HMSN/ACC are primarily caused by an axonopathy superimposed upon abnormal development, affecting peripheral but also central nervous system axons, all ultimately because of a genetic defect in the axonal cotransporter KCC3.

Recommended Methods for Brain Processing and Quantitative Analysis in Rodent Developmental Neurotoxicity Studies.

Neuropathology methods in rodent developmental neurotoxicity (DNT) studies have evolved with experience and changing regulatory guidance. This article emphasizes principles and methods to promote more standardized DNT neuropathology evaluation, particularly procurement of highly homologous brain sections and collection of the most reproducible morphometric measurements. To minimize bias, brains from all animals at all dose levels should be processed from brain weighing through paraffin embedding at one time using a counterbalanced design. Morphometric measurements should be anchored by distinct neuroanatomic landmarks that can be identified reliably on the faced block or in unstained sections and which address the region-specific circuitry of the measured area. Common test article-related qualitative changes in the developing brain include abnormal cell numbers (yielding altered regional size), displaced cells (ectopia and heterotopia), and/or aberrant differentiation (indicated by defective myelination or synaptogenesis), but rarely glial or inflammatory reactions. Inclusion of digital images in the DNT pathology raw data provides confidence that the quantitative analysis was done on anatomically matched (i.e., highly homologous) sections. Interpreting DNT neuropathology data and their presumptive correlation with neurobehavioral data requires an integrative weight-of-evidence approach including consideration of maternal toxicity, body weight, brain weight, and the pattern of findings across brain regions, doses, sexes, and ages.

Lactate storm marks cerebral metabolism following brain trauma.

Brain metabolism is thought to be maintained by neuronal-glial metabolic coupling. Glia take up glutamate from the synaptic cleft for conversion into glutamine, triggering glial glycolysis and lactate production. This lactate is shuttled into neurons and further metabolized. The origin and role of lactate in severe traumatic brain injury (TBI) remains controversial. Using a modified weight drop model of severe TBI and magnetic resonance (MR) spectroscopy with infusion of (13)C-labeled glucose, lactate, and acetate, the present study investigated the possibility that neuronal-glial metabolism is uncoupled following severe TBI. Histopathology of the model showed severe brain injury with subarachnoid and hemorrhage together with glial cell activation and positive staining for Tau at 90 min post-trauma. High resolution MR spectroscopy of brain metabolites revealed significant labeling of lactate at C-3 and C-2 irrespective of the infused substrates. Increased (13)C-labeled lactate in all study groups in the absence of ischemia implied activated astrocytic glycolysis and production of lactate with failure of neuronal uptake (i.e. a loss of glial sensing for glutamate). The early increase in extracellular lactate in severe TBI with the injured neurons rendered unable to pick it up probably contributes to a rapid progression toward irreversible injury and pan-necrosis. Hence, a method to detect and scavenge the excess extracellular lactate on site or early following severe TBI may be a potential primary therapeutic measure.

The Story Behind the First Mini-BEAM Photon Radiation Treatment: What is the Mini-Beam and Why is it Such an Advance?

Radiation treatment has been the cornerstone in cancer management. However, long term treatment-related morbidity always accompanies tumor control which has significant impact on quality of life of the patient who has survived the cancer. Spatially fractionated radiation has the potential to achieve both cure and to avoid dreaded long term sequelae. The first ever randomized study of mini-beam radiation treatment (MBRT) of canine brain tumor has clearly shown the ability to achieve this goal. Dogs have gyrencephalic brains functionally akin to human brain. We here report long term follow-up and final outcome of the dogs, revealing both tumor control and side effects on normal brain. The results augur potential for conducting human studies with MBRT.

A pathogenic variant in RAB32 causes autosomal dominant Parkinson's disease and activates LRRK2 kinase.

Background: Parkinson's disease (PD) is a progressive neurodegenerative disorder. Mendelian forms have revealed multiple genes, with a notable emphasis on membrane trafficking; RAB GTPases play an important role in PD as a subset are both regulators and substrates of LRRK2 protein kinase. To explore the role of RAB GTPases in PD, we undertook a comprehensive examination of their genetic variability in familial PD. Methods: Affected probands from 130 multi-incident PD families underwent whole-exome sequencing and genotyping, Potential pathogenic variants in 61 RAB GTPases were genotyped in relatives to assess disease segregation. These variants were also genotyped in a larger case-control series, totaling 3,078 individuals (2,734 with PD). The single most significant finding was subsequently validated within genetic data (6,043 with PD). Clinical and pathologic findings were summarized for gene-identified patients, and haplotypes were constructed. In parallel, wild-type and mutant RAB GTPase structural variation, protein interactions, and resultant enzyme activities were assessed. Findings: We found RAB32 c.213C>G (Ser71Arg) to co-segregate with autosomal dominant parkinsonism in three multi-incident families. RAB32 Ser71Arg was also significantly associated with PD in case-control samples: genotyping and database searches identified thirteen more patients with the same variant that was absent in unaffected controls. Notably, RAB32 Ser71Arg heterozygotes share a common haplotype. At autopsy, one patient had sparse neurofibrillary tangle pathology in the midbrain and thalamus, without Lewy body pathology. In transfected cells the RAB32 Arg71 was twice as potent as Ser71 wild type to activate LRRK2 kinase. Interpretation: Our study provides unequivocal evidence to implicate RAB32 Ser71Arg in PD. Functional analysis demonstrates LRRK2 kinase activation. We provide a mechanistic explanation to expand and unify the etiopathogenesis of monogenic PD. Funding: National Institutes of Health, the Canada Excellence Research Chairs program, Aligning Science Across Parkinson's, the Michael J. Fox Foundation for Parkinson's Research, and the UK Medical Research Council.

RAB32 Ser71Arg in autosomal dominant Parkinson's disease: linkage, association, and functional analyses.

BACKGROUND: Parkinson's disease is a progressive neurodegenerative disorder with multifactorial causes, among which genetic risk factors play a part. The RAB GTPases are regulators and substrates of LRRK2, and variants in the LRRK2 gene are important risk factors for Parkinson's disease. We aimed to explore genetic variability in RAB GTPases within cases of familial Parkinson's disease. METHODS: We did whole-exome sequencing in probands from families in Canada and Tunisia with Parkinson's disease without a genetic cause, who were recruited from the Centre for Applied Neurogenetics (Vancouver, BC, Canada), an international consortium that includes people with Parkinson's disease from 36 sites in 24 countries. 61 RAB GTPases were genetically screened, and candidate variants were genotyped in relatives of the probands to assess disease segregation by linkage analysis. Genotyping was also done to assess variant frequencies in individuals with idiopathic Parkinson's disease and controls, matched for age and sex, who were also from the Centre for Applied Neurogenetics but unrelated to the probands or each other. All participants were aged 18 years or older. The sequencing and genotyping findings were validated by case-control association analyses using bioinformatic data obtained from publicly available clinicogenomic databases (AMP-PD, GP2, and 100 000 Genomes Project) and a private German clinical diagnostic database (University of Tübingen). Clinical and pathological findings were summarised and haplotypes were determined. In-vitro studies were done to investigate protein interactions and enzyme activities. FINDINGS: Between June 1, 2010, and May 31, 2017, 130 probands from Canada and Tunisia (47 [36%] female and 83 [64%] male; mean age 72·7 years [SD 11·7; range 38-96]; 109 White European ancestry, 18 north African, two east Asian, and one Hispanic] underwent whole-exome sequencing. 15 variants in RAB GTPase genes were identified, of which the RAB32 variant c.213C>G (Ser71Arg) cosegregated with autosomal dominant Parkinson's disease in three families (nine affected individuals; non-parametric linkage Z score=1·95; p=0·03). 2604 unrelated individuals with Parkinson's disease and 344 matched controls were additionally genotyped, and five more people originating from five countries (Canada, Italy, Poland, Turkey, and Tunisia) were identified with the RAB32 variant. From the database searches, in which 6043 individuals with Parkinson's disease and 62 549 controls were included, another eight individuals were identified with the RAB32 variant from four countries (Canada, Germany, UK, and USA). Overall, the association of RAB32 c.213C>G (Ser71Arg) with Parkinson's disease was significant (odds ratio [OR] 13·17, 95% CI 2·15-87·23; p=0·0055; I2=99·96%). In the people who had the variant, Parkinson's disease presented at age 54·6 years (SD 12·75, range 31-81, n=16), and two-thirds had a family history of parkinsonism. RAB32 Ser71Arg heterozygotes shared a common haplotype, although penetrance was incomplete. Findings in one individual at autopsy showed sparse neurofibrillary tangle pathology in the midbrain and thalamus, without Lewy body pathology. In functional studies, RAB32 Arg71 activated LRRK2 kinase to a level greater than RAB32 Ser71. INTERPRETATION: RAB32 Ser71Arg is a novel genetic risk factor for Parkinson's disease, with reduced penetrance. The variant was found in individuals with Parkinson's disease from multiple ethnic groups, with the same haplotype. In-vitro assays show that RAB32 Arg71 activates LRRK2 kinase, which indicates that genetically distinct causes of familial parkinsonism share the same mechanism. The discovery of RAB32 Ser71Arg also suggests several genetically inherited causes of Parkinson's disease originated to control intracellular immunity. This shared aetiology should be considered in future translational research, while the global epidemiology of RAB32 Ser71Arg needs to be assessed to inform genetic counselling. FUNDING: National Institutes of Health, the Canada Excellence Research Chairs program, Aligning Science Across Parkinson's, the Michael J Fox Foundation for Parkinson's Research, and the UK Medical Research Council.

Sequence of synaptogenesis in the fetal and neonatal cerebellar system - part 1: Guillain-Mollaret triangle (dentato-rubro-olivo-cerebellar circuit).

Precise temporal and spatial sequences of synaptogenesis occur in the cerebellar system, as in other synaptic circuits of the brain. In postmortem brain sections of 172 human fetuses and neonates, synaptophysin immunoreactivity was studied in nuclei of the Guillain-Mollaret triangle: dentato-olivo-rubro-cerebellar circuit. Synaptophysin demonstrates not only progressive increase in synaptic vesicles in each structure, but also shows the development of shape from amorphous globular neuronal aggregates to undulated nuclei. Intensity of synaptophysin reactivity is strong before the mature shape of these nuclei is achieved. Accessory olivary and deep cerebellar nuclei are intensely stained earlier than the principal olivary and dentate nuclei. The dorsal blades of both form earlier than the ventral, with reactivity initially peripheral. Initiation of synaptophysin reactivity is at 13 weeks in the inferior olive (r6, r7) and at 16 weeks in the dentate (r2). Initial synaptic vesicles are noted at 13 weeks in the red nucleus (r0); synapses form initially on the small neurons at 13 weeks but thereafter simultaneously on small and large neurons. Form and reactivity follow caudorostral, dorsoventral and mediolateral gradients in the axes of the rhombencephalon. This study provides control data to serve as a basis for interpreting aberrations in synaptogenesis in malformations of the cerebellar system, genetic disorders and acquired insults to the cerebellum and brainstem during fetal life, applicable to tissue sections and complementing biochemical and molecular techniques.

Synaptogenesis in the foetal and neonatal cerebellar system. 2. Pontine nuclei and cerebellar cortex.

Precise temporal and spatial sequences of synaptogenesis were demonstrated in 172 human foetuses and neonates post-mortem in transverse paraffin sections of pons and cerebellar vermis and hemispheres, using synaptophysin immunoreactivity of this protein of synaptic vesicular walls. The pontine nuclei exhibit a transitory patchy pattern not predicted from the uniform histology and reminiscent of the corpus striatum; synaptic vesicle reactivity appears at 20 weeks and is uniform by 34 weeks. In the cerebellar cortex, the vermis matures sooner than the cerebellar hemispheres and the paravermal portions earlier than the lateral folia. The earliest synapses occur around the somata of Purkinje neurons and later in the internal granular layer, but synaptic glomeruli are not well formed until after 26 weeks. The normal patterns here shown, together with earlier data of the Guillain-Mollaret triangle, provide controls for the interpretation of synaptic delay or precociousness and other pathological patterns in malformations, genetic/metabolic conditions and prenatal acquired insults affecting the human foetus.

Pediatric intracranial tuberculoma: illustrative case.

BACKGROUND: Tuberculosis is an airborne disease caused by Mycobacterium tuberculosis. Intracranial tuberculoma is a rare complication of extrapulmonary tuberculosis due to hematogenous spread to subpial and subependymal regions. Intracranial tuberculoma can occur with or without meningitis. OBSERVATIONS: A 3-year-old male who had recently emigrated from Sudan presented to the emergency department with right-sided seizures lasting 30 minutes, which were aborted with levetiracetam and midazolam. Head computed tomography revealed a multilobulated left supratentorial mass with solid and cystic components and measuring 8.0 × 4.8 × 6.5 cm. The patient had successful resection of the mass, which was positive for M. tuberculosis. He was started on rifampin, isoniazid, pyrazinamide, ethambutol, and fluoroquinolone and was discharged home in stable condition. LESSONS: A literature review on pediatric intracranial tuberculoma was performed, which included 48 studies (n = 49). The mean age was 8.8 ± 5.4 years with a slight female predilection (59%). Predominant solitary tuberculomas (63%) were preferentially managed with both resection and antituberculosis therapy (ATT), whereas multifocal tuberculomas were preferentially managed with ATT. Intracranial tuberculoma is a rare but treatable cause of space-occupying lesions in children. Clinicians should maintain a high level of suspicion in patients from endemic regions and involve the infectious disease service early.

Simultaneous Presentation of Glioblastoma Multiforme in Divorced Spouses.

High-grade gliomas are the most common primary brain tumors in adults. However, with an incidence of 4/100,000 per year, glioblastoma multiforme is uncommon enough to make simultaneous presentation of identical tumors in husband and wife exceedingly rare. We report the fourth couple in the literature presenting with malignant astrocytomas concurrently. Despite being divorced and living apart for two decades, they presented on the same day, overhearing and recognizing each other's voice in the emergency room. We include here the molecular characteristics of the tumors in both husband and wife, favoring the independent development of concurrent primary glioblastomas. Despite the number of conjugal presentations reported, genotoxicity and gliomagenesis may remain a completely independent event in spouses, dependent on endogenous factors damaging DNA. The slowly increasing incidence of gliomas, with nearly 100% correct nosologic recognition of this tumor entity, may lead to further recognition of independent but concurrent brain tumors in spouses.

Evolving resting head tremor in parkinsonism: Clinicopathological study of a case.

INTRODUCTION: Resting limb tremor (RLT) is a well known feature in parkinsonism. There is very little information on resting head tremor (RHT) in parkinsonism, and none in pathologically confirmed cases. The association between RLT and RHT remains uncertain. METHODS: A Caucasian male developed upper limb tremor and voice changes at age 70. He was first assessed at our clinic at age 72. At age 73 he developed resting head tremor (RHT) which prevented him from falling asleep. His status was documented in longitudinal follow-up at our clinic. He had a total of 14 clinical evaluations and four videos made over 6 years. Autopsy of the brain and spinal cord was performed. RESULTS: The resting head tremor improved on antiparkinsonian drugs and resolved completely after four years. Coincident with RHT remission, the upper limb tremor worsened and interfered with feeding, and his lower limb resting tremor became more pronounced. During his course he developed slow, scanning speech and all the cardinal motor findings of parkinsonism. There was no ophthalmoplegia. Post-mortem neuropathological examination revealed prominent progressive supranuclear palsy (PSP) changes and minor Lewy body pathology. CONCLUSION: This is the first autopsy confirmed case of parkinsonism with RHT. He had dual pathology. Dissociation between RHT and RLT indicates that the oscillatory brain centers for the two were different in this case.

Proliferation of human glioblastoma stem cells occurs independently of exogenous mitogens.

Primary glial tumors of the central nervous system, most commonly glioblastoma multiforme (GBM), are aggressive lesions with a dismal prognosis. Despite identification and isolation of human brain tumor stem cells (BTSCs), characteristics that distinguish BTSCs from neural stem cells remain to be elucidated. We cultured cells isolated from gliomas, using the neurosphere culture system, to understand their growth requirements. Both CD133(+) and CD133(-) adult GBM BTSCs proliferated in the absence of exogenous mitogenic stimulation and gave rise to multipotent GBM spheres that were capable of self-renewal. Epidermal growth factor (EGF) and fibroblast growth factor-2 enhanced GBM BTSC survival, proliferation, and subsequent sphere size. Blockade of EGF receptor (EGFR) signaling reduced exogenous mitogen-independent GBM sphere growth. Implantation of as few as 10 exogenous mitogen-independent GBM BTSCs led to the formation of highly invasive intracranial tumors, which closely resembled human GBMs, in immunocompromised mice. These results demonstrate that exogenous mitogen independence, mediated in part through EGFR signaling, is one characteristic that distinguishes CD133(+) and CD133(-) GBM BTSCs from neural stem cells. This novel experimental system will permit the elucidation of additional constitutively activated mechanisms that promote GBM BTSC survival, self-renewal, and proliferation.

Neuronal Intranuclear Inclusion Disease presenting as juvenile Parkinsonism.

BACKGROUND: Diagnostic considerations for juvenile onset Parkinsonism (onset at < 21 years of age) include juvenile Huntington disease, Wilson disease, dentatorubral-pallidoluysian atrophy (DRPLA), storage diseases, and mitochondrial cytopathies. Neuronal Intranuclear Inclusion Disease (NIID) must also be considered. CASE REPORT: We present a case of juvenile onset NIID with a predominantly Parkinsonian presentation, followed later by corticospinal, cerebellar, and lower motor neuron symptoms. CONCLUSION: Diagnosis of NIID can be made antemortem through rectal biopsy, however it was missed in this case. Rectal biopsy should be performed in all suspected cases, reviewed by an experienced neuropathologist and repeated if the suspicion for NIID is high. Pathologically, SUMO-1 immunohistochemistry appears to reliably label the neuronal inclusions and abnormal SUMOylation may play a part in the pathogenesis.

The Concept of an Epilepsy Brain Bank.

Epilepsy comprises more than 40 clinical syndromes affecting millions of patients and families worldwide. To decode the molecular and pathological framework of epilepsy researchers, need reliable human epilepsy and control brain samples. Brain bank organizations collecting and supplying well-documented clinically and pathophysiologically tissue specimens are important for high-quality neurophysiology and neuropharmacology studies for epilepsy and other neurological diseases. New development in molecular mechanism and new treatment methods for neurological disorders have evoked increased demands for human brain tissue. An epilepsy brain bank is a storage source for both the frozen samples as well as the formaldehyde fixed paraffin embedded (FFPE) tissue from epilepsy surgery resections. In 2014, the University of Saskatchewan have started collecting human epilepsy brain tissues for the first time in Canada. This review highlights the necessity and importance of Epilepsy Brain bank that provides unique access for research to valuable source of brain tissue and blood samples from epilepsy patients.

Calcification and endothelialization of thrombi in acute stroke.

We report chronic histopathological features in thrombi mechanically retrieved from five acute ischemic stroke patients with a median age of 68 years and a median pretreatment National Institutes of Health Stroke Scale score of 13. Early endothelialization occurred over and within the thrombus, and calcifications were seen, in addition to the usual acute laminar fibrin, intervening red blood cells, and neutrophils. The effectiveness of tissue plasminogen activator in clot dissolution might be affected by these features, if extensive. Thrombus composition could critically determine the success of chemical thrombolysis. Our results should stimulate the development of imaging modalities to determine thrombus composition.

Non-toxicity of IV injected perfluorocarbon oxygen carrier in an animal model of liver regeneration following surgical injury.

Lethal dose experiments in animals have demonstrated that second-generation perfluorocarbon oxygen carriers are remarkably non-toxic. However, this non-toxicity has not previously been demonstrated in a liver failure scenario. A surgical liver damage and regeneration model in rats was selected using a well-controlled cross tabulated study design. A large number of physiological, biochemical, and hematological parameters were measured. No indications were found that intravenously injected perfluorooctyl bromide emulsion was toxic at the concentrations employed, in either healthy or severe liver injury scenarios. Neither was there any significant impact on the rate of liver regeneration following the injuries. Bearing in mind prior human clinical studies, it is therefore safe to assume that perfluorocarbon emulsions are also non-toxic in bioartificial liver treatments.

Near-Newtonian Blood Behavior - Is It Good to Be a Camel?

From a certain level of exercise-intensity onward, hematocrit increases in horses, which brings more oxygen carriers into the bloodstream. Camels, however, when used in competitive racing could be even in need of iron supplementation and blood transfusions due to a severe reduction of their available hematocrit compared to their resting hematocrit. Since the extrinsic and intrinsic mechanical properties of camel erythrocytes (RBC) are so different compared to RBCs of other mammals, the question arises whether this observation might be a response to endurance exercise aiming at keeping the RBC count low. Rheometry indicated dromedary camel blood to behave almost Newtonian, which is unique amongst mammals. Shear thinning did increase with the hematocrit, but remained marginal compared to horses. As a result, camel whole blood viscosity (WBV) exceeded horse WBV at high shear rates, an effect, which was significantly augmented when the packed cell volume (PCV) was increased. Therefore, in camels any infusion of RBCs into the bloodstream can increase the cardiac work and the energy input into the endothelium more effectively, which should generate vascular remodeling in the long term. Yielding, however, was completely absent in camel blood, confirming low cohesion between its components at quasi-static flow. Camel blood remained a viscous liquid without a threshold even at unphysiologically high PCVs. This can help to washout lactate when camels start to dehydrate and might contribute to the sustained working ability of these animals. The subtle pseudoplastic behavior and the high viscosity contrast across the RBC membrane point to weak coupling between blood flow and red cell behavior. We predict that RBCs flow as separate entities and can show various types of motion, which can lead to friction instead of being collectively aligned to the flow direction. In comparison to horses, this behavior will become relevant at higher RBC counts in front of flow obstacles and possibly cause vascular remodeling if the PCV rises during strenuous exercise, a matter that should be avoided.