Background:Essential tremor (ET) is a complex neurological disorder with a strong genetic basis, yet there remains a disparity between its estimated heritability and currently known genetic risk. This missing heritability has led to a lack of appropriate treatments and has exacerbated the misdiagnosis of patients. Methods:To address the missing heritability of ET, we called copy number variants (CNVs) in a large cohort of ET patients (n = 1,853) and unaffected controls (n = 10,336). CNVs were called from single nucleotide polymorphism (SNP) microarray data using PennCNV and QuantiSNP and only rare CNVs (frequency < 1%) intersecting protein coding regions of the genome were analyzed. To investigate whether CNV occurrence was associated with ET, global burden, pathogenicity burden, gene set enrichment, and gene burden tests were conducted. Results:Global duplication burden by CNV number, CNV length, and number of genes affected by CNVs were all significantly elevated in ET patients compared to controls. Across gene-sets, duplications affecting Mendeliome genes, genes highly expressed in the brain, and genes expressed in the cerebellum were significantly enriched in patients compared to controls. Gene-based burden testing indicated that duplications involving ZNF813 were significantly less frequent in ET patients than in controls. No associations with deletion events were observed. Discussion:Our results point to rare copy number duplications affecting protein coding regions of the genome as likely contributors to ET genetic risk. However, specific susceptibility genes could not be reliably identified, highlighting the need for larger studies of diverse variant types to clarify the genetic architecture of ET.

Summary 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.

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.

INTRODUCTION:Parkinson's disease (PD) is the second most common neurodegenerative disorder. The main clinical features are bradykinesia, rigidity, and resting tremor. Other neurodegenerative disorders such as progressive supranuclear palsy and multiple system atrophy share some of these clinical manifestations. All those disorders are collectively known as parkinsonism or Parkinson syndrome (PS). Definite diagnosis of PD requires brain autopsy. There is no known cure for PD. Since its discovery in the 1960s, levodopa (LD) has remained the best and most widely used medication in PD. The impact of that is important to understanding the neuroepidemiology of PD. The incidence of PD rises with advancing age. In the last six decades, life expectancy in the general population has increased resulting in a larger pool of at-risk persons. Onset age of PD is the most reliable indicator of PD survival as older onset cases have shorter survival. We report on survival in autopsy-confirmed PD cases with onset age <70 years treated with LD and compare that with similar onset-age cases of PD before the discovery of LD. MATERIAL AND METHODS:The Saskatchewan Movement Disorders Program (SMDP) has operated uninterrupted since 1968. Long follow-up and autopsy studies are a special interest of the SMDP. All PS cases followed by the SMPD during 47 years (1968-2015) that came to autopsy were considered. Those with autopsy-confirmed PD and onset <70 years were included and were compared with pre-LD cases of similar age of onset. RESULTS:Overall, 392 PS cases were seen in our clinic between 1968 and 2015 and had brain pathology studies. A total of 314 (80%) of those had PD. Overall, 128 (41%) of the PD cases had onset <70 years and were included in this study. Their median survival was 18 years. CONCLUSION:Prior to widespread use of LD, nearly all PD cases had onset <70 years and mean survival was 9.4 years. Longer survival in our study is attributed primarily to modern treatment. Increased survival has resulted in a larger number of older, chronically treated, higher comorbidity, and complicated PD patients. These changes present new challenges. It requires a larger and increasingly diverse workforce for patient care and research.

OBJECTIVES:The aim of the study is to report a case with heat intolerance, complex motor fluctuations, and parkinsonism.MATERIALS AND METHODS:A male with onset of heat intolerance at the age of 46 years developed left upper limb tremor at the age of 58 years. He was diagnosed with Parkinson disease at the age of 62 years and presented to Movement Disorders Clinic Saskatchewan at the age of 65 years. He reported motor response fluctuations, including WO and dyskinesias. There was no history of dizziness on standing, bladder, or sexual dysfunction. We recorded an asymptomatic drop of orthostatic blood pressure. He reported loss of smell sensation for 5 years and REM behavior disorder characterized by talking in his sleep. He was assessed at the age of 65 years over the course of a day with 4 video recordings of his evolving findings and symptoms with his informed consent.RESULTS:Initial assessment after levodopa was withheld more than 14 hours revealed him to be 'off' with severe dystonic neck flexion and with bradykinesia and rigidity in the limbs. He was anhidrotic, felt hot, and needed a wet towel over his neck. Over the course of 4 hours, he turns "on" with improvement in heat intolerance, neck hypertonicity, and parkinsonian findings and develops evolving dyskinetic movements before turning "off" again. His overall clinical picture was most consistent with multiple system atrophy.CONCLUSIONS:Heat intolerance can precede onset of motor symptoms of parkinsonism by several years and supports a diagnosis of multiple system atrophy. To our knowledge, this is the first documented case of improvement in heat intolerance with levodopa.

Fatty acids play many critical roles in brain function but have not been investigated in essential tremor (ET), a frequent movement disorder suspected to involve cerebellar dysfunction. Here, we report a postmortem comparative analysis of fatty acid profiles by gas chromatography in the cerebellar cortex from ET patients (n = 15), Parkinson’s disease (PD) patients (n = 15) and Controls (n = 17). Phosphatidylcholine (PC), phosphatidylethanolamine (PE) and phosphatidylinositol (PI)/ phosphatidylserine (PS) were separated by thin-layer chromatography and analyzed separately. First, the total amounts of fatty acids retrieved from the cerebellar cortex were lower in ET patients compared with PD patients, including monounsaturated (MUFA) and polyunsaturated fatty acids (PUFA). The diagnosis of ET was associated with lower cerebellar levels of saturated fatty acids (SFA) and PUFA (DHA and ARA) in the PE fraction specifically, but with a higher relative content of dihomo-γ-linolenic acid (DGLA; 20:3 ω-6) in the PC fraction. In contrast, a diagnosis of PD was associated with higher absolute concentrations of SFA, MUFA and ω-6 PUFA in the PI + PS fractions. However, relative PI + PS contents of ω-6 PUFA were lower in both PD and ET patients. Finally, linear regression analyses showed that the ω-3:ω-6 PUFA ratio was positively associated with age of death, but inversely associated with insoluble α-synuclein. Although it remains unclear how these FA changes in the cerebellum are implicated in ET or PD pathophysiology, they may be related to an ongoing neurodegenerative process or to dietary intake differences. The present findings provide a window of opportunity for lipid-based therapeutic nutritional intervention.

ABSTRACT Background Multiple System Atrophy is a rare neurodegenerative disease with alpha‐synuclein aggregation in glial cytoplasmic inclusions and either predominant olivopontocerebellar atrophy or striatonigral degeneration, leading to dysautonomia, parkinsonism, and cerebellar ataxia. One prior genome‐wide association study in mainly clinically diagnosed patients with Multiple System Atrophy failed to identify genetic variants predisposing for the disease. Objective Since the clinical diagnosis of Multiple System Atrophy yields a high rate of misdiagnosis when compared to the neuropathological gold standard, we studied only autopsy‐confirmed cases. Methods We studied common genetic variations in Multiple System Atrophy cases (N = 731) and controls (N = 2898). Results The most strongly disease‐associated markers were rs16859966 on chromosome 3, rs7013955 on chromosome 8, and rs116607983 on chromosome 4 with P ‐values below 5 × 10 −6 , all of which were supported by at least one additional genotyped and several imputed single nucleotide polymorphisms. The genes closest to the chromosome 3 locus are ZIC1 and ZIC4 encoding the zinc finger proteins of cerebellum 1 and 4 (ZIC1 and ZIC4). Interpretation Since mutations of ZIC1 and ZIC4 and paraneoplastic autoantibodies directed against ZIC4 are associated with severe cerebellar dysfunction, we conducted immunohistochemical analyses in brain tissue of the frontal cortex and the cerebellum from 24 Multiple System Atrophy patients. Strong immunohistochemical expression of ZIC4 was detected in a subset of neurons of the dentate nucleus in all healthy controls and in patients with striatonigral degeneration, whereas ZIC4‐immunoreactive neurons were significantly reduced inpatients with olivopontocerebellar atrophy. These findings point to a potential ZIC4‐mediated vulnerability of neurons in Multiple System Atrophy. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Multiple System Atrophy is a rare neurodegenerative disease with alpha-synuclein aggregation in glial cytoplasmic inclusions and either predominant olivopontocerebellar atrophy or striatonigral degeneration, leading to dysautonomia, parkinsonism, and cerebellar ataxia. One prior genome-wide association study in mainly clinically diagnosed patients with Multiple System Atrophy failed to identify genetic variants predisposing for the disease. Since the clinical diagnosis of Multiple System Atrophy yields a high rate of misdiagnosis when compared to the neuropathological gold standard, we studied common genetic variation in only autopsy-confirmed cases (N = 731) and controls (N = 2,898). The most strongly disease-associated markers were rs16859966 on chromosome 3 (P = 8.6 * 10-7, odds ratio (OR) = 1.58, [95% confidence interval (CI) = 1.32-1.89]), rs7013955 on chromosome 8 (P = 3.7 * 10-6, OR = 1.8 [1.40-2.31]), and rs116607983 on chromosome 4 (P = 4.0 * 10-6, OR = 2.93 [1.86-4.63]), all of which were supported by at least one additional genotyped and several imputed single nucleotide polymorphisms with P-values below 5 * 10-5. The genes closest to the chromosome 3 locus are ZIC1 and ZIC4 encoding the zinc finger proteins of cerebellum 1 and 4 (ZIC1 and ZIC4). Since mutations of ZIC1 and ZIC4 and paraneoplastic autoantibodies directed against ZIC4 are associated with severe cerebellar dysfunction, we conducted immunohistochemical analyses in brain tissue of the frontal cortex and the cerebellum from 24 Multiple System Atrophy patients. Strong immunohistochemical expression of ZIC4 was detected in a subset of neurons of the dentate nucleus in all healthy controls and in patients with striatonigral degeneration, whereas ZIC4 positive neurons were significantly reduced in patients with olivopontocerebellar atrophy. These findings point to a potential ZIC4-mediated vulnerability of neurons in Multiple System Atrophy.

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.

Movement DisordersVolume 35, Issue 11 p. 1916-1921 In MemoriamOpen Access Professor Oleh Hornykiewicz, MD (1926–2020): Remembering the Father of the Modern Treatment of Parkinson's Disease and the Man Ali H. Rajput FRCPC, Corresponding Author Ali H. Rajput FRCPC ali.rajput@usask.ca Saskatchewan Movement Disorders Program, University of Saskatchewan/Saskatchewan Health Region, Saskatoon, Saskatchewan, Canada Correspondence to: Dr. Ali H. Rajput, Division of Neurology, Royal University Hospital 103 Hospital Drive Saskatoon, SK S7N 0W8, Canada; E-mail: ali.rajput@usask.ca; or Dr. Stephen J. Kish, Human Brain Laboratory Centre for Addiction and Mental Health 250 College Street Toronto, ON M8Y 2L, Canada; E-mail: stephen.kish@camh.caSearch for more papers by this authorStephen J. Kish PhD, Corresponding Author Stephen J. Kish PhD stephen.kish@camh.ca Human Brain Laboratory, Centre for Addiction and Mental Health, Toronto, Ontario, Canada Correspondence to: Dr. Ali H. Rajput, Division of Neurology, Royal University Hospital 103 Hospital Drive Saskatoon, SK S7N 0W8, Canada; E-mail: ali.rajput@usask.ca; or Dr. Stephen J. Kish, Human Brain Laboratory Centre for Addiction and Mental Health 250 College Street Toronto, ON M8Y 2L, Canada; E-mail: stephen.kish@camh.caSearch for more papers by this author Ali H. Rajput FRCPC, Corresponding Author Ali H. Rajput FRCPC ali.rajput@usask.ca Saskatchewan Movement Disorders Program, University of Saskatchewan/Saskatchewan Health Region, Saskatoon, Saskatchewan, Canada Correspondence to: Dr. Ali H. Rajput, Division of Neurology, Royal University Hospital 103 Hospital Drive Saskatoon, SK S7N 0W8, Canada; E-mail: ali.rajput@usask.ca; or Dr. Stephen J. Kish, Human Brain Laboratory Centre for Addiction and Mental Health 250 College Street Toronto, ON M8Y 2L, Canada; E-mail: stephen.kish@camh.caSearch for more papers by this authorStephen J. Kish PhD, Corresponding Author Stephen J. Kish PhD stephen.kish@camh.ca Human Brain Laboratory, Centre for Addiction and Mental Health, Toronto, Ontario, Canada Correspondence to: Dr. Ali H. Rajput, Division of Neurology, Royal University Hospital 103 Hospital Drive Saskatoon, SK S7N 0W8, Canada; E-mail: ali.rajput@usask.ca; or Dr. Stephen J. Kish, Human Brain Laboratory Centre for Addiction and Mental Health 250 College Street Toronto, ON M8Y 2L, Canada; E-mail: stephen.kish@camh.caSearch for more papers by this author First published: 28 September 2020 https://doi.org/10.1002/mds.28317 Relevant conflicts of interests/financial disclosures: Nothing to report. AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat This tribute provides thoughts and recollections by Saskatoon neurologist Ali Rajput and Toronto scientist Stephen Kish on the life of Professor Oleh Hornykiewicz, who passed away on May 26, 2020, in Vienna at the age of 93. 1 Early Years and Education Oleh Hornykiewicz was born in Sychow (Lvov), Ukraine (formerly Poland). When he was 13 years old, his family migrated to Vienna, Austria, during the Second World War. All of his future education was in Vienna. He graduated with a doctorate in medicine from the University of Vienna in 1951.1 During undergraduate medical school, he was highly impressed with his professors of organic chemistry, neuroanatomy, and pharmacology. He decided to pursue research that combined those disciplines rather than train for clinical practice. 2 First Research Project After graduation, Oleh joined the Pharmacological Institute at the University of Vienna as an unpaid research assistant to work with Professor Franz von Brucke.1 The institute attracted many leading European experts, including Professor Hermann Blaschko of Oxford University, England. Oleh's first research project was the study of ceruloplasmin in Wilson disease. Because Wilson disease involved the basal ganglia, he developed a special interest in their functions.1 3 A Focus on Dopamine Research In 1956, he was awarded a British Council Scholarship to work with Professor Blaschko at Oxford University. Dopamine (DA) had been discovered recently but was generally regarded as an intermediate step in the synthesis of adrenaline with no physiological function of its own. Blaschko, on the other hand, believed that DA had some independent regulatory function and directed Oleh to work on DA.1 His research project was the study of DA's effect on blood pressure in the guinea pig. He confirmed a previous report that, contrary to the action of adrenaline, which elevated blood pressure, DA lowered blood pressure. He and his supervisor were now convinced that DA played a distinct but unknown physiological role. While at Oxford, he also determined that levodopa (l-dopa) behaved very much like DA.1 When he finished his studies 18 months later, Professor Blaschko advised him to continue working on DA. 4 The Role of DA in Human Brain and Parkinson's Disease (PD) A major goal of medical research is to carry out studies with possible application to human health and disease. Hence, laboratory/animal studies must pass through the phase of validation in human subjects before application to medical teaching and practice. Even today, there is no perfect animal model of PD. The experts in the 1950s and 1960s had serious reservations about biochemical studies of autopsied human brains, such as fresh frozen material, and raised doubt that it would yield any meaningful information, such as pertaining to neurotransmitters.1 By the time Oleh returned to Vienna in 1958, he was well versed in laboratory methodology and animal studies, and he had a sound knowledge of biochemistry, pharmacology, and human brain anatomy. He also had an understanding of some physiological functions of DA and l-dopa. Having confirmed the peripheral physiological effect of DA, he decided to study the role of DA using autopsied human brains. He was now an independent investigator and had postdoctoral students working with him. With his knowledge of neuroanatomy and the conviction that brain tissue must be well suited for laboratory studies of neurological disorders, he devised a method to dissect tissue of research interest from frozen brain for biochemical analysis. By early 1959, he and his research student, Herbert Ehringer, started systematically analyzing specimens of frozen human brains for their DA and noradrenaline content. With remarkable efficiency, they studied 31 brains in 1 year.1 These included brains from neurologically normal human adults, fetuses, parkinsonism cases, and other degenerative disorders such as Huntington's disease. They detected a marked reduction of DA in the striatum of persons with PD and postencephalitic parkinsonism. Their article was published in German2 and later translated into English.3 For the first time, they demonstrated that freshly frozen postmortem brain could be studied for reliable assessment of neurotransmitter levels. They also demonstrated that striatal DA deficiency was specific for the neurological condition of parkinsonism. 5 DA Replacement Experiment Oleh's next undertaking was to explore whether brain DA deficiency in PD could be corrected pharmacologically. He already knew that DA did not cross the blood–brain barrier, but its precursor l-dopa did, and the 2 substances had similar physiological effects. In collaboration with a clinical neurologist, Professor Walter Birkmayer, he performed an elegant clinical neuropharmacological experiment. Oleh had access to only 2 g of pure l-dopa. To determine its efficacy in as many patients with parkinsonian as possible, they decided to use levodopa intravenously. They administered the drug to 20 patients using different dosages: 50, 100, and 150 mg. The patients' responses were “spectacular,” as he would often describe them. The bedridden patients could stand up, and those who previously could not walk could now do so.4 The weakest response was on 50 mg, and the most pronounced was with 150 mg.4 That article was also published in German in 19614 and later translated in English.5 To document their clinical observations, Oleh and colleagues made movies of untreated and post-l-dopa-treated patients; he loaned those movies to experts upon request. The observation that l-dopa benefit was dose dependent was subsequently incorporated by Cotzias and colleagues into their clinical trials.6 They reported dramatic improvements in patients with PD on large oral doses of D-L-DOPA.6 In the remarkably short span of 2 years, Oleh had established that (1) striatal DA deficiency was a major biochemical abnormality in PD and (2) l-dopa corrected that deficiency, thereby resulting in major symptomatic benefit. Both were new observations at the time. With those 2 studies, Oleh revolutionized the approach to chronic neurological disease research and laid the foundation of science-based treatment of the disease. Until then, it was believed that neurodegenerative disorders were untreatable.1 Hornykiewicz's model was later adopted for other neurodegenerative diseases such as Alzheimer's disease.1 He was also the first scientist to speculate that a pathway from the anterior midbrain to the basal ganglia in the forebrain would underlie the DA content of the striatum in normal human brain. Oleh was young—in his early 30s—when he made those groundbreaking observations. Many senior scientists were skeptical of his findings. His first 2 articles were published in German in a journal to which few international scientists paid attention. Thus, the English-speaking world could not fully appreciate the importance of his findings. Nevertheless, the original observations of Oleh Hornykiewicz have stood the test of time. In essentially 60 years, there has never been a publication contradicting either of those 2 studies. Many clinicians and basic scientists made pilgrimages to Professor Hornykiewicz's laboratory for firsthand visits of his set up and to see the movies that he and Birkmayer had made of the treated patients. The acceptance of his work was slow but steady. His future work consolidated the validity of the earlier studies. 6 Some Related Questions Resolved Oleh and his colleagues subsequently established that the severity of striatal DA loss correlated with the severity of substantia nigra neuronal loss and, in turn, with the severity of parkinsonism.1, 7 He continued studies of human brain and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine—treated monkey models with support from his very capable junior colleagues: Drs. Ken Lloyd (Toronto), Stephen Kish (Toronto), and Christian Pifl (Vienna).1 Oleh also established that brain enzyme dihydroxyphenylalanine (DOPA) decarboxylase converted l-dopa to DA.1 He demonstrated that DA deficiency in PD was specific and not simply a result of normal aging.8, 9 He studied the biochemical basis of l-dopa–induced dyskinesia and wearing-off phenomena.10, 11 He advanced the idea that PD could be a vesicular storage disorder.12 7 Second Institution and Second Citizenship In 1967, Oleh moved to Clarke Institute at the University of Toronto in Ontario, Canada, as a neuropsychopharmacologist to head a newly formed research institute.1 He stayed in Toronto for the next 10 years. He also became a dual citizen of Canada and Austria. 8 Recollections of the Toronto Years by Dr. Stephen Kish Professor Oleh Hornykiewicz was my teacher, constant mentor, and scientific colleague. Our association spanned the period from 1979 to 2020, the year of his death. I was based in Toronto, originally in his laboratory at the Clarke Institute of Psychiatry. For part of his career (1967–1977), Oleh headed the psychopharmacology section at Toronto's Clarke Institute of Psychiatry (now the Centre for Addiction and Mental Health). In 1977, he returned to the University of Vienna and began splitting his time between Vienna and Toronto, where he continued to supervise the Clarke's Human Brain Laboratory until 1992. Oleh mentioned in the late 1960s (some 10 years following his initial discoveries) that some scientists still expressed skepticism regarding the usefulness of l-dopa in PD. For amusement purposes, he kept a Medical Post article on a debate hosted by the Canadian Royal College of Physicians and Surgeons between a researcher and a neurologist on the benefit of l-dopa in PD. The researcher expressed “skepticism” because l-dopa in her animal model failed to show an increase in brain DA levels, whereas the neurologist opined that “proving the drug's efficacy is no longer an issue” and that “the results he has had with l-dopa are so outstanding that it holds the promise of being the most important advance in the treatment of parkinsonism.” Hornykiewicz's article of brain DA deficiency in PD was, by today's standards, a “preliminary” finding.2 Likely, the first independent replication study was conducted 11 years later in 1971 by Dr. Stanley Fahn.13 In Toronto, working with Ken Lloyd, Oleh largely disposed of the question of the role of DA in the therapeutic effect by l-dopa by showing in a logistically challenging postmortem brain study that brain levels of DA in patients with PD who had received l-dopa were 0 to 15 times higher than those who had not received such treatment and that the levels were higher in the “good” versus “poor” clinical responders.14 9 Toronto Studies From 1980 to the Present I first encountered Oleh in 1979 as a graduate student in the Pharmacology Department at the University of British Columbia in Vancouver. My doctorate thesis was focused (unusually at the time) entirely on biochemical studies of autopsied human brain, and my supervisor agreed to send me to Toronto for a week in 1979 to learn from the master himself, Professor Hornykiewicz, how to carry out the dissection procedure. I found Hornykiewicz to be kind, supportive, and very much a gentleman, but with his conservative dress (including on weekends) and his unusual, double lens-carrying, flip-one-up spectacles, he represented a rather imposing Austrian professor. He was my constant scientific colleague from 1980 until his death in 2020. Among the Toronto studies that Oleh considered especially important was the demonstration of the highly specific, subregional pattern of DA loss in the striatum of patients with idiopathic PD9 compared with those patterns observed in persons with other parkinsonian conditions. He also discovered that the topographic pattern of DA loss in normal aging was distinct from that in idiopathic PD.8 Accordingly, he felt that these findings suggested that the cause of degeneration of DA-producing neurons in idiopathic PD is likely not the same as that responsible for loss in other parkinsonian conditions (or in normal aging). Along these lines, he would insist that in our joint manuscripts we clarify explicitly that the parkinsonian disorder we studied is idiopathic PD, which is likely to have a specific cause. Oleh also argued for the remainder of his career that studies of hereditary parkinsonism might not be helpful in understanding the cause of idiopathic PD. However, as a colleague, Oleh was a stickler in joint publications to ensure that we cite the very first person who made a finding “ …because this is how it should be done.” We both enjoyed going back to the very early literature from the 1930s and 1940s (often in German) to discover the now forgotten fellow who was the first person to describe a key finding. Oleh's recollection of scientific facts and research discoveries was astounding right up to the end. The conversations that I had with him in 2020 were at the same level as those 40 years earlier. 10 How Will Professor Hornykiewicz Be Remembered? Oleh made a seminal discovery,2 and in the space of less than 2 years translated that pivotal finding into the clinic.4 In so doing, he became the founding father of a new era in neuroscience. In the 40 years that I knew Oleh Hornykiewicz, we discussed only once how he would like to be remembered. During this exchange, he mentioned that, if I were to write an obituary of him, I should consider the statement by the much admired British neurologist and scientist, Dr. C. David Marsden. David had summed it up simply and accurately, namely, that for a person with PD, there was a before and after Oleh Hornykiewicz15 Marsden said that his “discovery… changed everything.” 11 In Toronto, “What Made Hornykiewicz Tick”? What made Oleh “really excited” I feel, more than anything else, was in discovering “new regions” of the brain, or better, old regions with new functions, and trying to figure out whether they might be involved in PD. An example was the small, noradrenaline-rich nucleus accumbens,16 which Hornykiewicz subdivided even more, and which only he could reliably dissect from frozen autopsied human brain using his special standardized dissection procedure. 12 …and Then There Was the Claustrum At the age of 90, he spearheaded a study, entirely his own and with little moral support from his junior colleagues, on the behavior of claustrum, with its still uncertain functions, in PD. Sometimes Oleh jokingly pointed to the claustrum during a brain dissection and suggested that the soul of man must be located in that region. Hornykiewicz published the article on the claustrum in 2017 at the age of 90.17 13 Back to Vienna and a Dual Role In 1977, he returned to Vienna as Head of the Institute of Biochemical Pharmacology and was appointed Professor of Biochemical Pharmacology.1 Henceforth, he split his time between the University of Vienna and the University of Toronto until his mandatory retirement in the 1990s at both institutions. However, his scientific productivity was far from over. His tenure at the helm of neuroscientific research activities in Vienna has recently been summarized by others.18 14 Recollections of Saskatoon Years by Dr. Ali Rajput 14.1 Third Institutional Affiliation In 1996, Oleh Hornykiewicz was appointed Distinguished Professor of Brain Disorder Research at the University of Saskatchewan in Saskatoon, Canada, a position he retained for the rest of his life. He was my colleague and friend from 1975 to 2020. In late 1968, we started a movement disorders program in Saskatoon. We conducted longitudinal patient follow-ups with detailed clinical documentation of each subject that included videography in most cases. By 1970, we started performing autopsies on the deceased patients and soon decided to use a half of the brain for standard pathology and preserve the other half at −80°C for future research.19 By the mid-1970s, Oleh and I had established a collaboration that continued for the rest of his life. Our first article together was published in the journal Nature in 1978.20 After he left Toronto in 1992, the intensity of our collaboration declined. At a meeting in 1996, I asked Oleh, “Where should we send someone for training to study our postmortem frozen human brains?” Without hesitation he asked, “Do you want me to come to Saskatoon?”, to which he added, “You do not have to pay me.” We could not have wished for a more qualified scientist and at that price! He came to Saskatoon for approximately 1 week at a time, once or twice a year. He had a private office and his own laboratory. We would discuss manuscripts and plan future research, and he would dissect frozen half-brain samples that were sent to his laboratory in Vienna or to other researchers (Drs. Paul Bedard, Therese Di Paolo, and Frederic Calon) for further studies.11 The critical link between my clinical operations and his laboratory work was access to suitable frozen brain samples for analysis. He trained Dr. Alex Rajput who is now the Director of the Saskatchewan Movement Disorders Program in brain dissection here in Saskatoon, ensuring future research. Oleh was a gentleman and a scholar in the best sense of those words. He was shy, unselfish, and did not promote himself. He had very high professional ethical standards. When we discussed manuscripts, Oleh would go out of his way to give credit to individuals who had done some related work. At times, I would ask him for a reference and he would say, “I heard him say that.” He gave credit without consideration of reciprocity. He was a meticulous writer; he checked every word and every sentence in the manuscript for accuracy. In his autobiographic piece, Oleh noted his association with me: “Without his unique brain material we would not have been able to do even one-tenth of our human brain research.”1 As important as it seems, he turned down my initial proposal to collaborate for ethical reasons. He was told (inaccurately) that I was collaborating with someone else. During his visits to Saskatoon, my wife would arrange dinners at our house, where Oleh would relax and meet new friends. Coincidentally, my wife's grandfather was born in the same area of Ukraine as Oleh. Oleh's son served as a Ukrainian church minister in Saskatoon. Over the years, our families got to know each other well. An Afterthought by the Authors: Significance of Oleh's Work to Humanity To understand the impact of Dr. Oleh Hornykiewicz's contribution to chronic progressive neurological disease, we need to understand the status prior to his seminal discoveries. The clinical diagnosis of PD was not difficult to make for a neurologist. After the diagnosis, the neurologist would tell the patient that PD is a progressive disease for which there is no cure. The only treatment available was via anticholinergic drugs that had modest symptomatic benefit in some cases. By contrast, the effect of l-dopa therapy was and remains “miraculous.” Oleh's initial observations led to oral l-dopa as the standard treatment for PD. After more than 5 decades, it remains the best symptomatic drug treatment for PD. There are more than 7 million parkinsonian patients in the world at any time. Every patient with PD who can afford it is being treated with l-dopa. If only 5 million patients were being treated at a given time, with significant improvement of their symptoms during a 50-year interval, l-dopa therapy would have improved 250 million person-years of human life. There is no other drug for chronic progressive neurodegenerative diseases that can approach that impact. Even for other common diseases, there are not many drugs that remain the gold standard for such a long time. 14.2 Special Awards For his extraordinary contributions, Oleh received both numerous and major awards such as the following: The Wolf Foundation Award in Medicine, American Parkinson's Disease Association Award, and Warren Alpert Foundation Prize. Most of us working in the PD field expected that some day Oleh Hornykiewicz would be recognized by the Nobel Prize committee for his outstanding contribution to the fields of medicine, neuroscience, and pharmacology. Inexplicably, he was overlooked for the 2000 Nobel Prize for Medicine or Physiology, which was awarded to 3 other scientists on the topic of PD and molecular neurosciences. A number of individuals wrote personal letters to different journals, and 275 scientists from around the world wrote an open letter to the Nobel Prize committee that had overseen the 2000 decision, indicating their disapproval for his omission.21 Consistent with the historical records, the outcome remained unchanged; however, Oleh was pleased that so many of his colleagues valued his work so much that they put their signature on this open letter. Former colleagues, trainees, and fellow scientists around the globe are confident that Oleh's contribution to the medical sciences will remain a major milestone in the history of PD. To us, the collective body of work he produced remains the most significant contribution to the understanding and treatment of chronic brain disorders. On behalf of millions of patients and scientists who have benefited from your discoveries, we collectively express, thank you, Oleh! Acknowledgment The authors thank Dr. M. Schlossmacher for comments and edits. Full financial disclosures for the previous 12 months Dr. Ali Rajput has no disclosures. Dr. Stephen Kish has received funding from the US National Institutes of Health NIAAA 026680 and from an investigator-sponsored grant from Jazz Pharmaceuticals, which are both unrelated to the research covered in this article. References 1Hornykiewicz O. Oleh Hornykiewicz. In: LR Squire, ed. The History of Neuroscience in Autobiography. Vol 4th ed. Amsterdam: Elsevier Academic Press; 2004: 240– 281. 2Ehringer H, Hornykiewicz O. Distribution of noradrenaline and dopamine (3-hydroxytyramine) in human brain: their behaviour in extrapyramidal system diseases. Klin Wochenschr 1960; 38: 1236– 1239. 3Ehringer H, Hornykiewicz O. Distribution of noradrenaline and dopamine (3-hydroxytyramine) in the human brain and their behavior in diseases of the extrapyramidal system. Parkinsonism Relat Disord 1998; 4: 53– 57. 4Birkmayer W, Hornykiewicz O. The effect of L-3,4-dihydroxyphenylalanine (=L-DOPA) on akinesia in parkinsonism. Wiener Klinische Wochenschrift 1961; 73: 787– 788. 5Birkmayer W, Hornykiewicz O. The effect of L-3,4-dihydroxyphenylalanine (=DOPA) on akinesia in parkinsonism. Parkinsonism Relat Disord 1998; 4: 59– 60. 6Cotzias GC, Van Woert MH, Schiffer LM. Aromatic amino acids and modification of parkinsonism. N Engl J Med 1967; 276: 374– 379. 7Bernheimer H, Birkmayer W, Jellinger K, Seitelberger F, Hornykiewicz O. Brain dopamine and the syndromes of Parkinson and Huntington: clinical, morphological and neurochemical correlations. J Neurol Sci 1973; 20: 415– 455. 8Kish SJ, Shannak K, Rajput A, Deck JHN, Hornykiewicz O. Aging produces a specific pattern of striatal dopamine loss: implications for the etiology of idiopathic Parkinson's disease. J Neurochem 1992; 58: 642– 648. 9Kish SJ, Shannak K, Hornykiewicz O. Uneven pattern of dopamine loss in the striatum of patients with idiopathic Parkinson's disease. N Engl J Med 1988; 318: 876– 880. 10Rajput AH, Fenton ME, Di Paolo T, Sitte H, Pifl C, Hornykiewicz O. Human brain dopamine metabolism in levodopa-induced dyskinesia and wearing-off. Parkinsonism Relat Disord 2004; 10: 221– 226. 11Calon F, Dridi M, Hornykiewicz O, Bedard PJ, Rajput AH, DiPaolo T. Increased adenosine A2A receptors in the brain of Parkinson's disease patients with dyskinesias. Brain 2004; 127: 1075– 1084. 12Pifl C, Rajput A, Reither H, et al. Is Parkinson's disease a vesicular dopamine storage disorder? Evidence from a study in isolated synaptic vasicles of human and nonhuman primate striatum. J Neurosci 2014; 34: 8210– 8218. 13Fahn S, Libsch LR, Cutler RW. Monoamines in the human neostriatum: topographic distribution in normals and in Parkinson's disease and their role in akinesia, rigidity, chorea, and tremor. J Neurol Sci 1971; 14: 427– 455. 14Lloyd KG, Davidson L, Hornykiewicz O. The neurochemistry of Parkinson's disease: effect of L-dopa therapy. J Pharmacol Exp Ther 1975; 195: 453– 464. 15Hornykiewicz O. L-DOPA. J Parkinsons Dis 2017; 7: S3– S10. 16Tong J, Hornykiewicz O, Kish SJ. Identification of a noradrenaline-rich subdivision of the human nucleus accumbens. J Neurochem 2006; 96: 349– 354. 17Sitte HH, Pifl C, Rajput AH, et al. Dopamine and noradrenaline, but not serotonin, in the human claustrum are greatly reduced in patients with Parkinson's disease: possible functional implications. Eur J Neurosci 2017; 45: 192– 197. 18Pifl C, Sitte HH. A tribute to Oleh Hornykiewicz (1926-2020). Trends Pharmacol Sci 2020; 41: 499– 501. 19Rajput AH, Rajput A. Saskatchewan Movement Disorders Program. Can J Neurol Sci 2015; 42: 74– 87. 20Lee T, Seeman P, Rajput AH, Farley IJ, Hornykiewicz O. Receptor basis for dopeminergic supersensitivity in Parkinson's disease. Nature 1978; 273: 59– 61. 21Rajput AH. An open letter to the committee on the Nobel Prize in Medicine. Parkinsonism Relat Disord 2001; 7: 149– 155. Volume35, Issue11November 2020Pages 1916-1921 ReferencesRelatedInformation

•Discovery of dopamine deficiency in Parkinson’s disease.•First, ever evidence that levodopa is effective in Parkinson’s disease.•A new model of neurodegenerative diseases research.

BACKGROUND:Elevated brain iron has been observed in Idiopathic Parkinson's disease (IPD) within the deep gray matter. Using quantitative susceptibility mapping (QSM) and a thresholded high-iron region, we quantified iron content in the midbrain of patients with Parkinson's disease as a function of age.METHODS:We used MRI to scan 24 IPD patients at 3-Tesla. Susceptibility-weighted images were collected with the following parameters, TE: 6 and 20 ms, TR: 30 ms, FA: 15°, and resolution: 0.5 × 0.5 × 2.0 mm3. QSM images were reconstructed from the source phase images. Whole-region and thresholded high-iron (RII) region boundaries for the Substantia Nigra (SN) and Red Nucleus (RN) were traced. Iron content was measured via mean susceptibilities and volumes, which were compared between the groups, as well as between right and left side of the structures within groups.RESULTS:Twenty patients with mild to moderate IPD were used in this study. For the SN, mean RII and whole-region iron and volumes were higher in the IPD group compared to HC, as well as mean RII for the RN, while no differences were seen between the groups when considering whole-region mean susceptibility bilaterally for the RN.CONCLUSION:Using a two-region of interest analysis on QSM, we showed that abnormal iron occurs in IPD patients in the SN and with greater volumes compared to HC. This method may have application as a biomarker for disease diagnosis and early intervention.

Movement DisordersVolume 34, Issue 11 p. 1749-1749 Letters: Published Articles Parkinsonism in essential tremor cases: A clinicopathological study—were they really essential tremor? Eoin Mulroy FRACP, Corresponding Author Eoin Mulroy FRACP eoin.mulroy@nhs.net Department of Clinical and Movement Neurosciences, University College London Queen Square Institute of Neurology, London, UKCorrespondence to: Eoin Mulroy, Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK; E-mail: eoin.mulroy@nhs.netSearch for more papers by this authorAnna Latorre MD, Anna Latorre MD orcid.org/0000-0001-7103-5209 Department of Clinical and Movement Neurosciences, University College London Queen Square Institute of Neurology, London, UKSearch for more papers by this authorKailash P. Bhatia FRCP, Kailash P. Bhatia FRCP orcid.org/0000-0001-8185-286X Department of Clinical and Movement Neurosciences, University College London Queen Square Institute of Neurology, London, UKSearch for more papers by this author Eoin Mulroy FRACP, Corresponding Author Eoin Mulroy FRACP eoin.mulroy@nhs.net Department of Clinical and Movement Neurosciences, University College London Queen Square Institute of Neurology, London, UKCorrespondence to: Eoin Mulroy, Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK; E-mail: eoin.mulroy@nhs.netSearch for more papers by this authorAnna Latorre MD, Anna Latorre MD orcid.org/0000-0001-7103-5209 Department of Clinical and Movement Neurosciences, University College London Queen Square Institute of Neurology, London, UKSearch for more papers by this authorKailash P. Bhatia FRCP, Kailash P. Bhatia FRCP orcid.org/0000-0001-8185-286X Department of Clinical and Movement Neurosciences, University College London Queen Square Institute of Neurology, London, UKSearch for more papers by this author First published: 19 November 2019 https://doi.org/10.1002/mds.27835 Relevant conflicts of interests/financial disclosures: Nothing to report. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume34, Issue11November 2019Pages 1749-1749 RelatedInformation

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. (c) 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

The identification of genetic causes for Mendelian disorders has been based on the collection of multi-incident families, linkage analysis, and sequencing of genes in candidate intervals. This study describes the application of next-generation sequencing technologies to a Swiss kindred presenting with autosomal-dominant, late-onset Parkinson disease (PD). The family has tremor-predominant dopa-responsive parkinsonism with a mean onset of 50.6 ± 7.3 years. Exome analysis suggests that an aspartic-acid-to-asparagine mutation within vacuolar protein sorting 35 (VPS35 c.1858G>A; p.Asp620Asn) is the genetic determinant of disease. VPS35 is a central component of the retromer cargo-recognition complex, is critical for endosome-trans-golgi trafficking and membrane-protein recycling, and is evolutionarily highly conserved. VPS35 c.1858G>A was found in all affected members of the Swiss kindred and in three more families and one patient with sporadic PD, but it was not observed in 3,309 controls. Further sequencing of familial affected probands revealed only one other missense variant, VPS35 c.946C>T; (p.Pro316Ser), in a pedigree [...] VILARIÑO-GÜELL, Carles, et al. VPS35 mutations in Parkinson disease. American Journal of Human Genetics, 2011, vol. 89, no. 1, p. 162-7 DOI : 10.1016/j.ajhg.2011.06.001

In the human brain, the claustrum is a small subcortical telencephalic nucleus, situated between the insular cortex and the putamen. A plethora of neuroanatomical studies have shown the existence of dense, widespread, bidirectional and bilateral monosynaptic interconnections between the claustrum and most cortical areas. A rapidly growing body of experimental evidence points to the integrative role of claustrum in complex brain functions, from motor to cognitive. Here, we examined for the first time, the behaviour of the classical monoamine neurotransmitters dopamine, noradrenaline and serotonin in the claustrum of the normal autopsied human brain and of patients who died with idiopathic Parkinson's disease (PD). We found in the normal claustrum substantial amounts of all three monoamine neurotransmitters, substantiating the existence of the respective brain stem afferents to the claustrum. In PD, the levels of dopamine and noradrenaline were greatly reduced by 93 and 81%, respectively. Serotonin levels remained unchanged. We propose that by virtue of their projections to the claustrum, the brain stem dopamine, noradrenaline and serotonin systems interact directly with the cortico-claustro-cortical information processing mechanisms, by-passing their (parallel) routes via the basal ganglia-thalamo-cortical circuits. We suggest that loss of dopamine and noradrenaline in the PD claustrum is critical in the aetiology of both the motor and the non-motor symptoms of PD.

OBJECTIVE:To identify the significance of baseline motor features to the lifelong prognostic motor subtypes in a Parkinson disease (PD) cohort.METHODS:In a previous study of 166 PD cases, we observed different prognosis in tremor-dominant, akinetic-rigid, and mixed subtypes. This study includes the same cases, but we excluded 10 cases with symptoms of ≥15 years duration at baseline. Relative severity of tremor, bradykinesia/akinesia, and rigidity at baseline were evaluated as predictors of the motor subtypes, which are known to have different prognosis.RESULTS:The most common motor subtype was mixed, followed by akinetic-rigid and then the tremor-dominant. Seventy cases were not receiving antiparkinsonian drugs at baseline. The prognostic subtypes could be predicted at baseline in 85% of all and in 91% of the treatment-naive cases. Sensitivity, specificity, and positive predictive values were strong for the mixed and the akinetic-rigid but weak for the tremor-dominant subtype.CONCLUSIONS:Our data show that motor profile at baseline can predict prognosis in most PD cases. These findings can be incorporated into clinical practice.

Biallelic DNAJC12 mutations were described in children with hyperphenylalaninemia, neurodevelopmental delay, and dystonia. We identified DNAJC12 homozygous null variants (c.187A>T;p.K63* and c.79‐2A>G;p.V27Wfs*14) in two kindreds with early‐onset parkinsonism. Both probands had mild intellectual disability, mild nonprogressive, motor symptoms, sustained benefit from small dose of levodopa, and substantial worsening of symptoms after levodopa discontinuation. Neuropathology (Proband‐A) revealed no alpha‐synuclein pathology, and substantia nigra depigmentation with moderate cell loss. DNAJC12 transcripts were reduced in both patients. Our results suggest that DNAJC12 mutations (absent in 500 early‐onset patients with Parkinson's disease) rarely cause dopa‐responsive nonprogressive parkinsonism in adulthood, but broaden the clinical spectrum of DNAJC12 deficiency. Ann Neurol 2017;82:640–646

BACKGROUND:Parkinson's disease is the second most common neurodegenerative disorder for which old age is the best known risk. The proportion of elderly in the world is increasing, resulting in larger pool of people at risk for Parkinson's disease. Several other neurodegenerative disorders also produce Parkinson syndrome. Distinguishing between those variants is only possible with pathological examination of brain. No autopsy confirmed study of 80 years and older onset in parkinsonism cases has been reported. Clinical features of different PS variants, response to treatment and progression of disease in this age group remain to be determined.METHODS:Patients evaluated at Movement Disorders Clinic Saskatchewan are offered a choice of autopsy at no cost. The brain is studied by board certified neuropathologist.RESULTS:Thirty cases with clinical diagnosis of parkinsonism (onset ≥80 years) came to autopsy. Twenty-one (70%) had Parkinson's disease alone and two (6.7%) had an additional movement disorder. The progression of Parkinson's disease was accelerated, and dementia evolved earlier than reported in the younger onset cases. Most cases that tolerated an adequate dose improved on levodopa.CONCLUSION:Parkinson's disease is the most common variant in the octogenarian population. Most patients benefit from levodopa, and should be tried on the drug when diagnosis of parkinsonism is made.

L-DOPA-induced dyskinesias (LID) appear in the majority of Parkinson's disease (PD) patients. Nicotinic acetylcholine (nACh) receptor-mediated signaling has been implicated in PD and LID and modulation of brain α7 nACh receptors might be a potential therapeutic target for PD. This study used [(125)I]α-Bungarotoxin autoradiography to investigate α7 nACh receptors in LID in post-mortem brains from PD patients (n=14) and control subjects (n=11), and from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys treated with saline (n=5), L-DOPA (n=4) or L-DOPA+2-methyl-6-(phenylethynyl)pyridine (MPEP) (n=5), and control monkeys (n=4). MPEP is the prototypal metabotropic glutamate 5 (mGlu5) receptor antagonist; it reduced the development of LID in these monkeys. [(125)I]α-Bungarotoxin specific binding to striatal and pallidal α7 nACh receptors were only increased in L-DOPA-treated dyskinetic MPTP monkeys as compared to controls, saline and L-DOPA+MPEP MPTP monkeys; dyskinesia scores correlated positively with this binding. The total group of Parkinsonian patients had higher [(125)I]α-Bungarotoxin specific binding compared to controls in the caudate nucleus but not in the putamen. PD patients without motor complications had higher [(125)I]α-Bungarotoxin specific binding compared to controls only in the caudate nucleus. PD patients with LID only had higher [(125)I]α-Bungarotoxin specific binding compared to controls in the caudate nucleus and compared to those without motor complications and controls in the putamen. PD patients with wearing-off only, had [(125)I]α-Bungarotoxin specific binding at control values in the caudate nucleus and lower in the putamen. Reduced motor complications were associated with normal striatal α7 nACh receptors, suggesting the potential of this receptor to manage motor complications in PD.