The role of manganese dysregulation in neurological disease: emerging evidence

Manganese is an essential trace metal. The dysregulation of manganese seen in a broad spectrum of neurological disorders reflects its importance in brain development and key neurophysiological processes. Historically, the observation of acquired manganism in miners and people who misuse drugs provided early evidence of brain toxicity related to manganese exposure. The identification of inherited manganese transportopathies, which cause neurodevelopmental and neurodegenerative syndromes, further corroborates the neurotoxic potential of this element. Moreover, manganese dyshomoeostasis is also implicated in Parkinson's disease and other neurodegenerative conditions, such as Alzheimer's disease and Huntington's disease. Ongoing and future research will facilitate the development of better targeted therapeutical strategies than are currently available for manganese-associated neurological disorders

Peripheral Display in Virtual Reality Environments involves Higher Cognitive Demands Compared to Centered Display during Dual-Tasking

Peripheral displays may require higher attention allocation compared to centered displays. This study investigated how cognitive load with peripheral dual-tasking affected gait variability in healthy young adults compared to centered dual-tasking. Eleven healthy young adults (23.8±1.25 years) participated in the experiment. Participants performed three trials of three different tests while walking on the treadmill. The tasks were randomly assigned as i) normal walking without dual tasking, ii) walking with a centered cognitive arithmetic test or centered dual-tasking (DTC) and iii) walking with peripheral cognitive arithmetic test or peripheral dual-tasking (DTP). Gait parameters were evaluated for all three task conditions. We found step width significantly increased during DTP compared to the control walking condition (p\u3c0.05). Our results revealed that DTP was challenging even for healthy young adults and thus leading to adaptations in step width. Our results show that DTP has clinical diagnostic values in revealing subtle gait deviations and can potentially be used to assess Parkinson’s disease and post-concussion disorders

Huntington’s disease in Finland. Epidemiologic, genetic and clinical studies

Huntington’s disease (HD) is a lethal, dominantly inherited neurodegenerative disorder reported to be unusually rare in Finland. The overall HD prevalence and the proportion of late-onset cases (LOHD) are increasing in many populations. The characteristics of LOHD are nevertheless poorly understood. Information on neurological comorbidity in patients with HD is also scarce. These retrospective studies analyzed a national Finnish HD cohort in the time frame 1987-2010 by searching national registries and archives. Data was extracted from medical records. Population genotypes were obtained from the 1000 Genomes project. The prevalence of HD in Finland was found to be 2.12/100,000, or over four times more common than reported previously. Nonetheless, HD is more uncommon than in other Western European countries. The national cohort of 207 patients included 52 (25%) patients with LOHD; they had poorer motor status at the time of diagnosis than patients with mid-age onset, possibly because of the diagnostic delay. No other differences were detected between these groups. Interestingly, only one individual (0.5% of all HD patients in Finland) with juvenile-onset HD was identified. The length of the affected CAG repeat or its intergenerational stability did not differ from those reported in other populations. However, the high risk chromosome 4 haplogroup A was relatively uncommon in the Finnish general population (39.2%), possibly partly explaining the relative rarity of HD in Finland. Patients with adult-onset HD had epilepsy and strokes as often as reported in the general population. HD patients were, however, at an increased risk of suffering subdural haematomas.Huntingtonin tauti Suomessa. Epidemiologisia, perinnöllisyystieteellisiä ja kliinisiä tutkimuksia. Huntingtonin tauti (HD) on autosomaalisesti vallitsevasti periytyvä, kuolemaan johtava hermoston rappeumasairaus. Taudin on todettu olevan poikkeuksellisen harvinainen Suomessa. Monissa väestöissä HD:n esiintyvyyden sekä myöhäisiällä alkavan HD:n (LOHD) osuuden on havaittu lisääntyneen. LOHD:n ominaispiirteet tunnetaan kuitenkin huonosti. Myös HD-potilaiden neurologisesta oheissairastavuudesta on käytettävissä vain hyvin vähän tietoja. Näissä takautuvissa tutkimuksissa analysoitiin kansallinen suomalainen HD-potilaiden kohortti vuosilta 1987-2010. Potilaat tunnistettiin kansallisista rekistereistä sekä tietyistä arkistoista. Tutkimustiedot kerättiin sairauskertomuksista. Väestön genotyyppitiedot saatiin 1000 Genomes –projektista. Huntingtonin taudin vallitsevuuden (2,12/100’000) havaittiin olevan Suomessa yli nelinkertainen aiempaan tutkimustietoon nähden. Silti HD on selvästi harvinaisempi Suomessa kuin muissa läntisen Euroopan maissa. Kansallisesta 207 HD-potilaan kohortista 52 (25%) oli LOHD-potilaita ja heidän motoriset oireensa ja löydöksensä olivat diagnoosinteon hetkellä vaikeampia kuin aiemmalla aikuisiällä sairastuneiden, mikä mahdollisesti johtui diagnoosien viivästymisestä LOHD-potilailla. Muuten näiden ryhmien välillä ei havaittu eroja. Yllättäen löysimme vain yhden (0,5%) potilaan, jolla HD alkoi nuoruusiällä. Tautialleelin CAG-toistojakson pituus tai sen sukupolvien välinen vakaus eivät eronneet muissa väestöissä raportoiduista. Kromosomin 4 korkean riskin haploryhmä A:n havaittiin kuitenkin olevan suomalaisessa väestössä verrattain harvinainen (39,2%), mikä saattaa osittain selittää HD:n suhteellista harvinaisuutta Suomessa. Aikuisiällä HD-diagnoosin saaneilla potilailla oli epilepsiaa ja aivoverenkiertohäiriöitä samassa määrin kuin valtaväestöllä. Kovakalvon alaisten verenvuotojen riski havaittiin HD-potilailla suurentuneeksi.Siirretty Doriast

Development of an acute excitotoxic model of Huntington's disease in sheep

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder. The earliest and most severe neuropathological change in HD occurs within the striatum. Exogenous excitotoxic lesioning of the rodent and non-human primate (NHP) striatum is used to model HD. Apart from NHPs, no other excitotoxic large animal model of HD has been established. Sheep have the potential to be an important species for modelling neurodegenerative disease, primarily because of neuroanatomical similarities between the sheep and human brain. This thesis describes the development of an excitotoxic sheep model of HD using the excitotoxin, quinolinic acid (QA). QA is an N-methyl-D-aspartate (NMDA) glutamate receptor agonist that produces pathological changes within the striatum that resemble those seen in HD. Sixteen castrated-male, 18 month old, Merino-Border Leicester cross sheep underwent two surgical procedures, four weeks apart, to infuse 75 μl of 180 mM QA (experimental group) or 75 μl of saline (control group) into the left (first surgery) and then the right (second surgery) caudate nucleus of the striatum. Longitudinal magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS) and diffusion tensor imaging (DTI) of the brains of the sheep was performed on a 3-Tesla scanner pre-surgically, one week after the first surgery, five weeks after the first surgery and sixteen weeks after the first surgery to investigate the neuropathological changes that occur in vivo after QA lesioning of the sheep striatum. The phenotypic consequences of lesioning the sheep striatum with QA were investigated using a veterinary neurological examination, dopamine agonist induced rotation and a two-choice discrimination task. The author / investigator was blind to the treatment group. MRI revealed QA-lesion hyperintensity and dilation of the lateral ventricles, consistent with atrophy of the caudate nucleus. MRS and DTI revealed a significant decrease in the neuronal marker N-acetylaspartate (NAA), and in fractional anisotropy (FA) in the acutely-lesioned (one week after surgery) striatae of the QA-lesioned sheep, followed by recovery in NAA and a significant increase in FA in the chronic (five to sixteen weeks) QA-lesioned striatae. NAA and FA changes are consistent with neuronal loss and structural disruption in the acute lesion, followed by recovery of reversibly impaired neurons, structural reorganisation and gliosis in the chronic lesion. Heterogeneous neuronal loss and damage and gliosis were visible on histological analysis of the QA-lesioned sheep striatae, supporting the in vivo MRS and DTI detected changes. Neurological examination of the sheep revealed evidence of laterality and mild hind limb motor paresis in seven out of eight of the QA-lesioned sheep, however the examination was not informative of lesion characteristics. A directional bias was evident in the QA-lesioned sheep during rotation studies. However, the direction and magnitude of bias in individual sheep at any one timepoint varied markedly, making identification of QA-lesioned individuals difficult. There was no difference between the QA-lesioned and saline-treated sheep in performance of the acquisition and reversal phases of the two-choice discrimination task. The behavioural studies described in this thesis were not suitable for comprehensive identification and characterisation of QA lesions in the striatum of sheep. This is the first description of the development of an acute excitotoxic sheep model of HD. The experiments demonstrate that longitudinal analysis of the neuropathological changes in the QA-lesioned sheep striatum is possible using advanced magnetic resonance modalities performed on a clinically relevant 3-Tesla scanner and that neuropathological changes are consistent with HD-like pathology in other species. Furthermore, phenotypic investigation of the QA-lesioned sheep is possible, however more refined methods than those described need to be utilised. The excitotoxic sheep model of HD is clinically relevant HD model with potential for use in disease mechanism and therapy investigations.Thesis (Ph.D.) -- University of Adelaide, Adelaide Medical School, 202

Next‐generation sequencing in the diagnosis of Dementia and Huntington’s disease Phenocopy Syndromes

Dementia is a major cause of disability worldwide, especially in the elderly. While Mendelian causes of dementia only account for a small proportion of cases, their role in elucidating the pathophysiology has been paramount. Genetically defined cohorts also offer opportunities for trials of disease‐modifying treatments, even before the onset of symptoms. Previously, only a small number of genes could be selected for genetic testing because of cost‐restrictions, but the advent of next‐generation sequencing has enabled its more widespread use. This thesis explored the use of next‐generation sequencing in patients living with dementia and HD phenocopy (HDPC) syndromes, who include patients with mixed presentations of dementia and motor symptoms. Using a validated 17 gene Dementia Gene panel supplemented by C9orf72 expansion testing and Apolipoprotein (ApoE) genotyping in over 3000 patients and controls, I determined the success rate of genetic panel testing in dementia; I developed an algorithm for the selection of patients for genetic testing based on the clinical presentation and common predictors of genetic causes of dementia. A detailed analysis of the ApoE data in the frontotemporal dementia cohort revealed strong effects of ApoE4 on age at onset in the subset with proven or suspected tau neuropathology, as well as opposite effects of amyloid‐beta pathology. In order to improve the definition and diagnostic rate of HDPC syndromes, patients who were referred for HD testing from two clinics were compared based on their clinical presentation; patients could not be distinguished based on clinical presentation alone, even if analysed as patterns. Given the low success rate of dementia gene panel testing in the HDPC cohort, 50 patients were selected for whole‐genome sequencing based on their HD‐likeness and their likelihood of harbouring a Mendelian variant. The results revealed a number of variants of interest but require replication

Rat Model of Pre-Motor Parkinson\u27s Disease: Behavioral and MRI Characterization.

Background: Parkinson\u27s disease (PD) is a chronic, progressive, neurodegenerative disorder with currently no known cure. PD has a significant impact on quality of life of the patients, as well as, the caregivers and family members. It is the second most common cause of chronic neurological disability in US and Europe. According to National Parkinson\u27s Foundation, there are almost 1 million patients in the Unites States and 50,000 to 60,000 new cases of PD are diagnosed each year. The total number of cases of PD is predicted to double by 2030. The annual cost associated with this disease is estimated to be $10.8 billion in the United States, including the cost of treatment and the cost of the disability. Although it is primarily thought of as a movement-disorder and is clinically diagnosed based on motor symptoms, non-motor symptoms such as cognitive and emotional deficits are thought to precede the clinical diagnosis by almost 20 years. By the time of clinical diagnosis, there is 80% loss in the dopamine content in the striatum and 50% degeneration of the substantia nigra dopamine cells. The research presented in this thesis was an attempt to develop an animal model of PD in its pre-motor stages. Such a model would allow us to develop pre-clinical markers for PD, and facilitate the development and testing of potential treatment strategies for the non-motor symptoms of the disorder. Specific Aims: There were five specific aims for this research: * The first specific aim dealt with development of a rat model of PD with slow, progressive onset of motor deficits, determination of timeline for future studies, and quantification the dopamine depletion in this model at a pre-motor stage. * The second and the third specific aims focused on testing for emotional (aversion) deficits and cognitive (executive functioning) deficits in this rat model at the 3 week timepoint determined during specific aim 1. * The fourth specific aim was to determine the brain network changes associated with the behavioral changes observed our rat model using resting state connectivity as a measure. * The fifth and the final specific aim was to test sodium butyrate, a drug from the histone deacetylase inhibitor family, as a potential treatment option for cognitive deficits in PD. Results: The 6-hydroxy dopamine based stepwise striatal lesion model of pre-motor PD, developed during this research, exhibits delayed onset of Parkinsonian gait like symptoms by week 4 after the lesions. At 3 weeks post lesion (3WKPD), the rats exhibit 27% reduction in striatal dopamine and 23%reduction in substantia nigra dopamine cells, with lack of any apparent motor deficits. The 3WKPD rats also exhibited changes in aversion. The fMRI study with the aversive scent pointed towards possible amygdala dysfunction sub-serving the aversion deficits. The executive function deficits tested using a rat analog of the Wisconsin card sorting test, divulged an extra-dimensional set shifting deficit in the 3WKPD rats similar to those reported in PD patients. The resting state connectivity study indicated significant changes in the 3WKPD rats compared to age matched controls. We observed increased overall connectivity of the motor cortex and increased CPu connectivity with prefrontal cortex, cingulate cortex, and hypothalamus in the 3WKPD rats compared to the controls. These observations parallel the observations in unmedicated early-stage PD patients. We also observed negative correlation between amygdala and prefrontal cortex as reported in humans. This negative correlation was lost in 3WKPD rats. Sodium butyrate treatment, tested in the cognitive deficit study, was able to ameliorate the extra-dimensional set shifting deficit observed in this model. This treatment also improved the attentional set formation. Conclusion: Taken together, our observations indicate that, the model of pre-motor stage PD developed during this research is a very high face validity rat model of late Braak stage 2 or early Braak stage 3 PD. Sodium butyrate was able to alleviate the cognitive deficits observed in our rat model. Hence, along with the prior reports of anti-depressant and neuroprotective effects of this drug, our results point towards a possible treatment strategy for the non-motor deficits of PD

Predictive testing and clinical genetic counselling services for Huntington disease in the Western Cape : an evaluation over eleven years

Includes bibliographical references (leaves 273-325)

Development of Translational Imaging Biomarkers in Mouse Models of Huntington's Disease

Huntington’s disease (HD) is a genetic neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin (HTT) gene that results in movement disorders and cognitive and psychiatric decline. To better track disease onset and progression, biomarkers that precede irreversible structural changes are needed. Alterations in metabolic processes detectable using magnetic resonance imaging (MRI) and other MR approaches may provide such biomarkers but need characterisation in HD mouse models to improve their clinical translatability. The aim of this thesis was to develop imaging biomarkers in transgenic R6/2 and knock-in zQ175 mice, two commonly used HD mouse models. To undertake the most comprehensive time-course analyses of metabolite concentrations in these models so far, proton magnetic resonance spectroscopy (1H-MRS) was acquired in selected brain regions throughout disease progression. Significant metabolic alterations were observed in zQ175 and R6/2 mice, with fluctuations at early disease stages. These changes suggested diminished neuronal integrity and reactive gliosis, which were confirmed using histology. Brain regions also exhibited specific metabolic profiles, many of said profiles being observed across both mouse models (albeit with some discrepancies). Chemical Exchange Saturation Transfer (CEST), which ought to overcome the limited sensitivity of 1H-MRS, was also acquired. However, we show CEST is not sensitive to HD pathology and do not recommend it for biomarker development in HD. Lastly, we acquired diffusion-weighted MRS (DW-MRS) in zQ175 mice to assess the diffusion of metabolites confined to cell-specific compartments. We found no changes in metabolite diffusion properties, but given the experimental nature of the protocol we used, DW-MRS needs further investigation in the context of HD. Overall, we have moved the field of HD forward by evaluating in detail the metabolic consequences of the disease in two mouse models that are widely used to investigate HD pathogenesis and evaluate therapeutic targets