Oliver Bandmann

• Professor at The University of Sheffield

The Parkinson’s Families Project is a UK-wide study aimed at identifying genetic variation associated with familial and early-onset Parkinson’s disease (PD). We recruited individuals with a clinical diagnosis of PD and age at motor symptom onset ≤45 years and/or a family history of PD in up to third-degree relatives. Where possible, we also recruit...

Background Mitochondrial dysfunction is widely reported in models of Huntington’s disease (HD), including altered respiratory complex activity, altered mitochondrial membrane potential and changes in mitophagy. However, whether mitochondrial function could be rescued as a therapeutic target in HD is under explored. This study sought to determine wh...

Objective The aim of our study is to better understand the genetic architecture and pathological mechanisms underlying neurodegeneration in idiopathic Parkinson's disease (iPD). We hypothesized that a fraction of iPD patients may harbor a combination of common variants in nuclear‐encoded mitochondrial genes ultimately resulting in neurodegeneration...

The heterogenous aetiology of Parkinson's disease is increasingly recognized; both mitochondrial and lysosomal dysfunction have been implicated. Powerful, clinically applicable tools are required to enable mechanistic stratification for future precision medicine approaches. The aim of this study was to characterize bioenergetic dysfunction in Parki...

Background: Rescue of mitochondrial function is a promising neuroprotective strategy for Parkinson's disease (PD). Ursodeoxycholic acid (UDCA) has shown considerable promise as a mitochondrial rescue agent across a range of preclinical in vitro and in vivo models of PD. Objectives: To investigate the safety and tolerability of high-dose UDCA in...

Heterozygous variants in GBA1 encoding glucocerebrosidase (GCase) are the most common genetic risk factor for Parkinson's disease (PD). Moreover, sporadic PD patients also have a substantial reduction of GCase activity. Genetic variants in SMPD1 are also overrepresented in PD cohorts, whilst a reduction of its encoded enzyme (ASM) activity is linke...

Parkinson’s Disease is the most common neurodegenerative movement disorder globally, with prevalence increasing. There is an urgent need for new therapeutics which are disease-modifying rather than symptomatic. Mitochondrial dysfunction is a well-documented mechanism in both sporadic and familial Parkinson’s Disease. Furthermore, ursodeoxycholic ac...

Background Sporadic Parkinson’s disease (sPD) is an aetiologically heterogeneous disorder. Identification of distinct pathogenic mechanisms causing sPD will be crucial to develop future “Precision Medicine” approaches. 31P-MRS is a non-invasive tool that can quantify key bionenergetic metabolites in individual patients. Objective To determine whet...

Background: Cognitive impairment is common in neurological presentations of Wilson's disease (WD). Various domains can be affected, and subclinical deficits have been reported in patients with hepatic presentations. Associations with imaging abnormalities have not been systematically tested. Objective: The aim was to determine the neuroanatomica...

Introduction Chelation therapy is used to ‘de-copper’ patients with Wilson’s disease but neurological outcomes are unpredictable and biomarkers of end-organ damage are needed. Methods We prospectively performed clinical assessments, venepuncture and 3T MRI in 40 patients with Wilson’s disease. Using tract-based spatial statistics, we compared diff...

Background Serum and urine copper levels are used to monitor chelation therapy for Wilson’s disease (WD) but do not reflect neurological involvement. Biomarkers of end-organ damage are needed to optimise chelation therapy and prepare for clinical trials for gene therapy. Methods We measured neurofilament light (NfL) levels in plasma samples, Unifi...

Wilson's disease is an autosomal-recessive disorder of copper metabolism with hepatic, neurological, psychiatric, ophthalmological, haematological, renal, and rheumatological manifestations. Making a diagnosis can be challenging given that no single test can confirm or exclude the disease, and diagnostic delays are common. Treatment protocols vary...

The Parkinson’s disease (PD) risk gene GTP cyclohydrolase 1 (GCH1) catalyzes the rate-limiting step in tetrahydrobiopterin (BH4) synthesis, an essential cofactor in the synthesis of monoaminergic neurotransmitters. To investigate the mechanisms by which GCH1 deficiency may contribute to PD, we generated a loss of function zebrafish gch1 mutant (gch...

PGC-1α plays a central role in maintaining the mitochondrial and energy metabolism homeostasis, linking external stimuli to the transcriptional co-activation of genes involved in adaptive and age-related pathways. The carboxyl-terminus encodes a serine/arginine-rich (RS) region and a putative RNA recognition motif, however potential RNA-processing...

Wilson's disease is an autosomal-recessive disorder of copper metabolism caused by mutations in ATP7B and associated with neurological, psychiatric, ophthalmological and hepatic manifestations. Decoppering treatments are used to prevent disease progression and reduce symptoms, but neurological outcomes remain mixed. In this article, we review the c...

Wilson’s disease is an autosomal-recessive disorder of copper metabolism with neurological and hepatic presentations. Chelation therapy is used to ‘de-copper’ patients but neurological outcomes remain unpredictable. A range of neuroimaging abnormalities have been described and may provide insights into disease mechanisms, in addition to prognostic...

The development of interventions to slow or halt the progression of Parkinson's disease remains a priority for patients and researchers alike. To date, no agents have been shown to have unequivocal evidence of disease-modifying effects in Parkinson's disease. The absence of disease-modifying treatments might relate not only to inadequate approaches...

Visual hallucinations (VH) are common in dementia with Lewy bodies (DLB), and are among the core symptoms for its clinical diagnosis. VH have been associated with cognitive alterations, although research findings in this area are still limited. The present study aimed at investigating the cognitive correlates of VH in DLB, and the baseline neuropsy...

Visual hallucinations (VH) are common in Parkinson’s disease and dementia with Lewy bodies, two forms of Lewy body disease (LBD), but the neural substrates and mechanisms involved are still unclear. We conducted meta-analyses of voxel-based morphometry (VBM) and neuropsychological studies investigating the neuroanatomical and cognitive correlates o...

Recent evidence suggests neurogenesis is on-going throughout life but the relevance of these findings for neurodegenerative disorders such as Parkinson’s disease (PD) is poorly understood. Biallelic PINK1 mutations cause early onset, Mendelian inherited PD. We studied the effect of PINK1 deficiency on adult neurogenesis of dopaminergic (DA) neurons...

Background Outcomes are unpredictable for neurological presentations of Wilson's disease (WD). Dosing regimens for chelation therapy vary and monitoring depends on copper indices, which do not reflect end‐organ damage. Objective To identify a biomarker for neurological involvement in WD. Methods Neuronal and glial‐specific proteins were measured...

Background The additive mechanistic effect of genetic risk variants for Parkinson’s disease (PD) is a plausible but largely unproven hypothesis. We investigated the mechanistic interaction between the two lysosomal PD risk genes glucocerebrosidase 1 (GBA1) and sphingomyelinase 1 (SMPD1) in complementing model systems. Methods Using CRISPR/Cas gene...

Introduction There are no disease-modifying treatments for Parkinson’s disease (PD). We undertook the first drug screen in PD patient tissue and idntified ursodeoxycholic acid (UDCA) as a promising mitochondrial rescue agent. The aims of this trial are to determine safety and tolerability of UDCA in PD at 30 mg/kg, confirm the target engagement of...

Mechanistic disease stratification will be crucial to develop a precision medicine approach for future disease modifying therapy in sporadic Parkinson's disease (sPD). Mitochondrial and lysosomal dysfunction are key mechanisms in the pathogenesis of sPD and therefore promising targets for therapeutic intervention. We investigated mitochondrial and...

It is important to understand how the disease process affects the metabolic pathways in amyotrophic lateral sclerosis and whether these pathways can be manipulated to ameliorate disease progression. To analyse the basis of the metabolic defect in amyotrophic lateral sclerosis we used a phenotypic metabolic profiling approach. Using fibroblasts and...

The loss of dopaminergic neurons (DA) is a pathological hallmark of sporadic and familial forms of Parkinson's Disease (PD). We had previously shown that inhibiting mitochondrial calcium uniporter (mcu) using morpholinos can rescue DA neurons in pink1-/- zebrafish model of PD. In this study, we are showing results from our studies in mcu knockout z...

Background: Strong evidence of mitochondrial dysfunction exists for both familial and sporadic Parkinson disease (PD). A simple test, reliably identifying mitochondrial dysfunction, could be important for future stratified medicine trials in PD. We previously undertook a comparison of serum biomarkers in classic mitochondrial diseases and establis...

The additive effect of genetic risk variants on overall disease risk is a plausible but frequently unproven hypothesis. To test this hypothesis, we assessed the biological effect of combined glucocerebrosidase (GCase) and acid sphingomyelinase (ASM) deficiency. Variants in both glucocerebrosidase1 ( GBA1 ) and sphingomyelinase ( SMPD1 ) are genetic...

Background: Studies on early-onset presentations of progressive supranuclear palsy (PSP) have been limited to those where a rare monogenic cause has been identified. Here, we have defined early-onset PSP (EOPSP) and investigated its genetic and clinico-pathological profile in comparison with late-onset PSP (LOPSP) and Parkinson's disease (PD). Me...

Background Although health-related quality of life is key for patients with long-term neurodegenerative conditions, measuring this is less straightforward and complex in Huntington’s disease (HD). Objectives To refine and validate a fully patient-derived instrument, the Huntington’s Disease health-related Quality of Life questionnaire (HDQoL), and...

Bi-allelic mutations in the glucocerebrosidase gene (GBA1) cause Gaucher's disease, the most common human lysosomal storage disease. We previously reported a marked increase in miR-155 transcript levels and early microglial activation in a zebrafish model of Gaucher's disease (gba1 −/− ). miR-155 is a master regulator of inflammation and has been i...

Parkinson’s Disease can be understood as a disorder of motor habits. A prediction of this theory is that early stage Parkinson’s patients will display fewer errors caused by interference from previously over-learned behaviours. We test this prediction in the domain of skilled typing, where actions are easy to record and errors easy to identify. We...

Background: The frequency of late-onset Huntington's disease (>59 years) is assumed to be low and the clinical course milder. However, previous literature on late-onset disease is scarce and inconclusive. Objective: Our aim is to study clinical characteristics of late-onset compared to common-onset HD patients in a large cohort of HD patients fr...

Neurovascular coupling (through which local cerebral blood flow changes in response to neural activation are mediated) is impaired in many diseases including diabetes. Current preclinical rodent models of neurovascular coupling rely on invasive surgery and instrumentation, but transgenic zebrafish coupled with advances in imaging techniques allow n...

Background: We previously reported up-regulation of tigarb (the zebrafish orthologue? of human TIGAR, TP53 -Induced Glycolysis and Apoptosis Regulator) in a zebrafish pink1-/- model of Parkinson's disease (PD). Genetic inactivation of tigarb led to the rescue of dopaminergic neurons and mitochondrial function in pink-/- zebrafish. The aim of this...

Alzheimer's disease (AD) is the leading cause of dementia worldwide. Mitochondrial abnormalities have been identified in many cell types in AD, with deficits preceding the development of the classical pathological aggregations. Ursodeoxycholic acid (UDCA), a treatment for primary biliary cirrhosis, improves mitochondrial function in fibroblasts der...

Parkinson’s Disease has been proposed as a disorder of motor habits. A prediction of this theory is that early stage Parkinson’s patients will display fewer errors caused by interference from previously over-learned behaviours. We test this prediction in the domain of skilled typing, where actions are easy to record and errors easy to identify. We...

While mitochondrial dysfunction is emerging as key in Parkinson's disease (PD), a central question remains whether mitochondria are actual disease drivers and whether boosting mitochondrial biogenesis and function ameliorates pathology. We address these questions using patient-derived induced pluripotent stem cells and Drosophila models of GBA-rela...

A low prevalence of Parkinson’s disease (PD) has been reported in the Sub-Saharan Africa (SSA) region. The genetic causes and clinical features of PD in this region have been poorly described. Very few reports have examined the availability and access to evidence-based quality care for people living with PD in this region. We reviewed all publicati...

Background: For (123I)FP-CIT imaging, a number of algorithms have shown high performance in distinguishing normal patient images from those with disease, but none have yet been tested as part of reporting workflows. This study aims to evaluate the impact on reporters' performance of a computer-aided diagnosis (CADx) tool developed from established...

The diagnosis of acute intermittent porphyria (AIP) is often overlooked. We describe a patient with this condition who had all the ‘bells and whistles’, in whom the diagnosis was only made after considerable delay. Far from an esoteric condition haunting examination candidates, AIP is an important cause of a broad spectrum of neurological symptoms....

Wilson disease (WD) is an autosomal recessive disorder of copper metabolism manifesting with hepatic, neurological and psychiatric symptoms. The limitations of the currently available therapy for WD (particularly in the management of neuropsychiatric disease), together with our limited understanding of key aspects of this illness (e.g. neurological...

The Alderson striatal phantom is frequently used to assess I-FP-CIT (Ioflupane) image quality and to test semi-quantification software. However, its design is associated with a number of limitations, in particular: unrealistic image appearances and inflexibility. A new physical phantom approach is proposed on the basis of subresolution phantom tech...

Our understanding of the epidemiology of Wilson disease has steadily grown since Sternlieb and Scheinberg's first prevalence estimate of 5 per million individuals in 1968. Increasingly sophisticated genetic techniques have led to revised genetic prevalence estimates of 142 per million. Various population isolates exist where the prevalence of Wilso...

Background We and others have demonstrated marked abnormalities of mitochondrial and lysosomal function in peripheral tissue of patients with familial Parkinson’s disease (fPD). Aim The aim of this project was to determine whether similar changes can also be detected in subgroups of patients with sporadic PD (sPD). Methods Fibroblast cultures wer...

There is strong evidence of a key role for mitochondrial dysfunction in both sporadic and all forms of familial Parkinson's disease (PD). However, none of the clinical trials carried out with putative mitochondrial rescue agents has been successful. Firm establishment of a wet biomarker or a reliable readout from imaging studies detecting mitochond...

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify...

Background: In Huntington's Disease (HD) cognitive decline can occur before unequivocal motor signs become apparent. As cognitive decline often starts early in the course of the disease and has a progressive nature over time, cognition can be regarded as a key target for symptomatic treatment. The specific progressive profile of cognitive decline...

Patients with Lewy body disease (LBD) frequently experience visual hallucinations (VH), well-formed images perceived without the presence of real stimuli. The structural and functional brain mechanisms underlying VH in LBD are still unclear. The present review summarises the current literature on the neural correlates of VH in LBD, namely Parkinson...

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify...

Objectives.: REM sleep behaviour disorder (RBD) is the most specific marker of prodromal alpha-synucleinopathies. We sought to delineate the baseline clinical characteristics of RBD and evaluate risk stratification models. Methods.: Clinical assessments were performed in 171 RBD, 296 control and 119 untreated Parkinson's (PD) subjects. Putative...

Mutations in PTEN-induced putative kinase 1 (PINK1) are a cause of early onset Parkinson's disease (PD). Loss of PINK1 function causes dysregulation of mitochondrial calcium homeostasis, resulting in mitochondrial dysfunction and neuronal cell death. We report that both genetic and pharmacological inactivation of the mitochondrial calcium uniporter...

A large body of evidence confirms that mitochondria play an important role in the development and progression of Parkinson’s disease (PD). PTEN-induced putative kinase 1 (PINK1) is a mitochondrial serine/threonine-protein kinase and loss of function mutation in PINK1 leads to familial PD. We used a pink1 mutant zebrafish line with a premature stop...

PTEN-induced putative kinase 1 (PINK1) is a mitochondrial serine/threonine-protein kinase and loss of function mutation in PINK1 leads to familial PD. In order to investigate abnormal calcium efflux/influx in neurons of the pink1-/- zebrafish model of Parkinson’s disease, we analyzed with light sheet microscope whole brains of zebrafish with geneti...

Multiple system atrophy (MSA) typically presents with a combination of parkinsonism, cerebellar ataxia, and autonomic failure.¹ Its incidence is estimated at 3 cases per 100,000 patients per year for people aged 50–99 years.² Median survival from symptom onset is less than 10 years, while time from diagnosis to death is often considerably shorter....

Mutations in parkin cause autosomal recessive Parkinsonism and mitochondrial defects. A recent drug screen identified a class of steroid-like hydrophobic compounds able to rescue mitochondrial function in parkin-mutant fibroblasts. Whilst these possess therapeutic potential, the size and high hydrophobicity of some may limit their ability to penetr...

Recent advances in molecular genetics have enabled a fundamentally new approach in establishing the prevalence of neurogenetic disorders. Rather than relying on traditional epidemiologic approaches, increasingly available and rapid genetic testing methods can now determine the genetic prevalence of a particular disorder in large cohorts with great...

Objective: To further elucidate the interaction between mitochondrial calcium homeostasis and PINK1 deficiency in a zebrafish (Danio rerio) model of Parkinson’s disease (PD). Background: Loss of PINK1 function causes dysregulation of mitochondrial calcium homeostasis, resulting in mitochondrial dysfunction and neuronal cell death. The voltage-depe...

Imaging the dynamic activity of the brain in vivo becomes possible with the state-of-the-art calcium probes and ultra-fast light sheet microscopes. To investigate if there is abnormal calcium efflux/influx in neurons of the zebrafish model of Parkinson’s disease (pink1 -/-mutant), we analyzed whole brains of fish with genetically encoded calcium in...

Autosomal recessively inherited glucocerebrosidase 1 (GBA1) mutations cause the lysosomal storage disorder Gaucher's disease (GD). Heterozygous GBA1 mutations (GBA1+/−) are the most common risk factor for Parkinson's disease (PD). Previous studies typically focused on the interaction between the reduction of glucocerebrosidase (enzymatic) activity...

Objectives To establish and characterise glucocerebrosidase 1 (GBA1) mutant zebrafish line. Background Homozygous GBA1 mutations (GBA1−/−) cause Gaucher disease (GD), heterozygote GBA1 mutations (GBA+/−) are the most common risk factor for Parkinson's disease (PD). The aim of this project was to develop a zebrafish model of GBA1 deficiency and stud...

Objective To determine if glucocerebrosidase 1 deficiency is a susceptibility factor to 1-methyl-4-phenylpyridinium (MPP+) toxicity using a zebrafish model. Background and hypothesis Heterozygous mutations in the glucocerebrosidase gene (GBA1) are a strong genetic risk factor for Parkinson's disease (PD). Genetic risk factors may increase susceptib...

Autosomal recessively inherited glucocerebrosidase 1 (GBA1) mutations cause the lysosomal storage disorder Gaucher's Disease (GD). Heterozygous GBA1 mutations (GBA+/-) are the most common risk factor for Parkinson's disease (PD). Previous studies typically focused on the interaction between the reduction of glucocerebrosidase (enzymatic) activity i...

To further characterize mitochondrial dysfunction in LRRK2(G2019S) mutant Parkinson disease (PD) patient tissue (M-LRRK2(G2019S)), determine whether ursodeoxycholic acid (UDCA) also exerts a beneficial effect on mitochondrial dysfunction in nonmanifesting LRRK2(G2019S) mutation carriers (NM-LRRK2(G2019S)), and assess UDCA for its beneficial effect...

The zebrafish has become a popular experimental model organism for biomedical research. In this paper, a unique framework is proposed for automatically detecting Tyrosine Hydroxylase-containing (TH-labeled) cells in larval zebrafish brain z-stack images recorded through the wide-field microscope. In this framework, a supervised max-pooling Con-volu...

The copper metabolism disorder Wilson's disease was first defined in 1912. Wilson's disease can present with hepatic and neurological deficits, including dystonia and parkinsonism. Early-onset presentations in infancy and late-onset manifestations in adults older than 70 years of age are now well recognised. Direct genetic testing for ATP7B mutatio...

Zebrafish, as a popular experimental model or-ganism, has been frequently used in biomedical research. For observing, analysing and recording labelled transparent features in zebrafish images, it is often efficient and convenient to adopt the fluorescence microscopy. However, the acquired z-stack im-ages are always blurred, which makes deblurring/d...

Optimizing the shape of a nanovector influences its interaction with a cell and determines the internalization kinetics. Block copolymer amphiphiles self-assemble into monodisperse structures in aqueous solutions and have been explored extensively as drug delivery vectors. However, the structure of self-assembled block copolymers has mainly been li...

Neurogenetic tests are increasingly requested by clinical neurologists without any formal training in clinical genetics. The aim of our study was to assess the documentation of consent and disclosure of genetic test results in a large regional clinical neuroscience centre. Documentation of some form of consent was evident in only 26/132 (20 %) of t...

Objective Loss of function mutations in PINK1 typically lead to early onset Parkinson disease (PD). Zebrafish (Danio rerio) are emerging as a powerful new vertebrate model to study neurodegenerative diseases. We used a pink1 mutant (pink(-/-)) zebrafish line with a premature stop mutation (Y431*) in the PINK1 kinase domain to identify molecular mec...

Objective Loss of function mutations in PINK1 typically lead to early onset Parkinson's Disease (EOPD). Zebrafish (Danio rerio) are emerging as a powerful new vertebrate model to study neurodegenerative diseases. We used a pink1 mutant (pink–/–) zebrafish line with a premature stop mutation (Y431*) in the PINK1 kinase domain to identify molecular m...

MicroRNAs (miRNAs) are small, abundant RNA molecules that constitute part of the cell's non-coding RNA "dark matter." In recent years, the discovery of miRNAs has revolutionised the traditional view of gene expression and our understanding of miRNA biogenesis and function has expanded. Altered expression of miRNAs is increasingly recognized as a fe...

This resource covers the basic science and clinical concepts underlying the movement disorders, as well as the diagnosis and treatment of individual hypokinetic and hyperkinetic movement disorders. Specifically written to aid understanding and treatment of a wide range of movement disorders, it includes a useful section covering miscellaneous cause...

Previous drug screens aiming to identify disease-modifying compounds for Parkinson's disease have typically been based on toxin-induced in vitro and in vivo models of this neurodegenerative condition. All these compounds have failed to have a reliable disease-modifying effect in subsequent clinical trials. We have now established a novel approach,...

To determine the histopathologic bases for the observed incidence of parkinsonism in families with C9ORF72 expansions, which typically cause amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia. DNA was extracted from 377 brains with the histopathologic diagnosis of idiopathic Parkinson disease or related disorders and analyzed for C9...

The cause of Huntington disease (HD) is a polyglutamine repeat expansion of more than 36 units in the huntingtin protein, which is inversely correlated with the age at onset of the disease. However, additional genetic factors are believed to modify the course and the age at onset of HD. Recently, we identified the V471A polymorphism in the autophag...

Objectives: The previous finding of an immunologic response primarily directed against transglutaminase (TG)6 in patients with gluten ataxia (GA) led us to investigate the role of TG6 antibodies in diagnosing GA. Methods: This was a prospective cohort study. We recruited patients from the ataxia, gluten/neurology, celiac disease (CD), and moveme...

Previous studies have failed to identify mutations in the Wilson's disease gene ATP7B in a significant number of clinically diagnosed cases. This has led to concerns about genetic heterogeneity for this condition but also suggested the presence of unusual mutational mechanisms. We now present our findings in 181 patients from the United Kingdom wit...