Eduardo De Pablo-Fernandez

Neuroendocrine abnormalities in Parkinson's disease

Neuroendocrine abnormalities are common in Parkinsons disease (PD) and include disruption of melatonin secretion, disturbances of glucose, insulin resistance and bone metabolism, and body weight changes. They have been associated with multiple non-motor symptoms in PD and have important clinical consequences, including therapeutics. Some of the underlying mechanisms have been implicated in the pathogenesis of PD and represent promising targets for the development of disease biomarkers and neuroprotective therapies. In this systems-based review, we describe clinically relevant neuroendocrine abnormalities in Parkinsons disease to highlight their role in overall phenotype. We discuss pathophysiological mechanisms, clinical implications, and pharmacological and non-pharmacological interventions based on the current evidence. We also review recent advances in the field, focusing on the potential targets for development of neuroprotective drugs in Parkinsons disease and suggest future areas for research.

Association of Autonomic Dysfunction With Disease Progression and Survival in Parkinson Disease

Importance Evidence suggests that development of autonomic dysfunction (AutD) may negatively affect disease course and survival in patients with synucleinopathies. However, the few available studies on Parkinson disease (PD) have conflicting results, comprise a small number of patients, have short follow-up periods, and lack pathologic confirmation of the diagnosis. Objective To examine the association of time of onset of AutD with disease progression and survival in PD. Design, Setting, and Participants This retrospective review of clinical data from 100 consecutive patients with an autopsy-confirmed diagnosis of PD from the archives of the Queen Square Brain Bank in London, United Kingdom, from January 1, 2006, to June 3, 2016, included patients with PD regularly seen by hospital specialists (neurologists or geriatricians) in the United Kingdom throughout their disease until death. Patients with dementia before or within 1 year after onset of motor symptoms, monogenic forms of PD, comorbidities that affect autonomic function, a coexisting neuropathologic diagnosis, or insufficient clinical information were excluded. Main Outcomes and Measures Survival and time from diagnosis to specific disease milestones were calculated to assess disease progression. Autonomic dysfunction was defined as autonomic failure at autonomic function testing or 2 of the following symptoms: urinary symptoms, constipation, upper gastrointestinal tract dysfunction, orthostatic hypotension, sweating abnormalities, or erectile dysfunction. Multivariable Cox proportional hazards regression models on the risk of a disease milestone and death were used. Results A total of 100 patients (60 [60.0%] male; mean [SD] age at diagnosis, 63.9 [10.3] years; mean [SD] disease duration, 14.6 [7.7] years) were studied. Autonomic dysfunction developed in 85 patients (mean [SD] time from diagnosis, 6.7 [7.7] years) and was associated with older age at diagnosis, male sex, poor initial levodopa treatment response, and postural instability and gait difficulty motor PD subtype in linear regression analysis, but staging of &agr;-synuclein pathologic changes was unrelated. Earlier AutD increased the risk of reaching the first milestone (hazard ratio, 0.86; 95% CI, 0.83-0.89; P < .001) and shortened survival (hazard ratio, 0.92; 95% CI, 0.88-0.96; P < .001). Older age at diagnosis and poorer levodopa treatment response were the other factors associated with shorter survival in adjusted multivariate analysis. Conclusions and Relevance Earlier AutD is associated with a more rapid development of disease milestones and shorter survival in patients with PD.

Hypothalamic α-synuclein and its relation to weight loss and autonomic symptoms in Parkinson's disease

FIG. 1. Images of representative sections of the infundibular (A), paraventricular (B), and supraoptic (C) hypothalamic nuclei. Immunohistochemistry for specific hypothalamic cell populations was used to help identification of hypothalamic nuclei: agouti-related peptide (D), cocaineand amphetamine-regulated transcript (E), and oxytocin (F). Tyrosine hydroxylase as a dopamine marker (G-I) and a-synuclein immunoreactivity (J-L) were assessed for each nucleus. Bar represents 260 lm in A-C, 50 lm in D-I, and 25 lm in J-L. [Color figure can be viewed at wileyonlinelibrary.com]

Concomitant fragile X-associated tremor ataxia syndrome and Parkinson's disease: a clinicopathological report of two cases

Parkinsonism is common in fragile X-associated tremor/ataxia syndrome (FXTAS) but its underlying pathophysiology remains unknown. Our group reported a patient with FXTAS and parkinsonism, and in vivo evidence of presynaptic and postsynaptic nigrostriatal dysfunction.1 We report the histological findings of this case (case 1) and another case with dual pathologies of FXTAS and Lewy body Parkinsons disease (PD). Genetic testing for FXTAS was requested in seven cases from the Queen Square Brain Bank for Neurological Disorders (QSBB) based on the characteristic radiological ‘middle cerebellar peduncle’ (MCP) sign (case 1, diagnosis confirmed in life) and histological findings of round, eosinophilic p62-positive neuronal intranuclear inclusions in the hippocampus or unexplained cerebellar degeneration (6 postmortem cases were tested). Two cases were positive for FMR1 premutation and both showed histological features of FXTAS and PD. The QSBB brain donor programme was approved by a Research Ethics Committee and written consent for research was obtained from all cases. ### Case 1 A 68-year-old man presented with a 10-year history of slowly progressive right-hand tremor. There was no family history of neurological disorders or mental retardation. Examination showed hypomimia, asymmetric rest and kinetic tremor, rigidity, mild bradykinesia and inability to tandem walk. The patient was diagnosed with tremor-predominant PD but did not respond to L-dopa (600 mg/day). Over the next few years he developed mild cognitive impairment, gait ataxia and intention tremor. Brain MRI demonstrated the MCP sign and diffuse atrophy. Genetic analysis confirmed FMR1 premutation with 87 CGG expansion. 123I-FP-CIT SPECT revealed …

Association between diabetes and subsequent Parkinson disease: A record-linkage cohort study

Objective To investigate the association between type 2 diabetes mellitus (T2DM) and subsequent Parkinson disease (PD). Methods Linked English national Hospital Episode Statistics and mortality data (1999–2011) were used to conduct a retrospective cohort study. A cohort of individuals admitted for hospital care with a coded diagnosis of T2DM was constructed, and compared to a reference cohort. Subsequent PD risk was estimated using Cox regression models. Individuals with a coded diagnosis of cerebrovascular disease, vascular parkinsonism, drug-induced parkinsonism, and normal pressure hydrocephalus were excluded from the analysis. Results A total of 2,017,115 individuals entered the T2DM cohort and 6,173,208 entered the reference cohort. There were significantly elevated rates of PD following T2DM (hazard ratio [HR] 1.32, 95% confidence interval [CI] 1.29–1.35; p < 0.001). The relative increase was greater in those with complicated T2DM (HR 1.49, 95% CI 1.42–1.56) and when comparing younger individuals (HR 3.81, 95% CI 2.84–5.11 in age group 25–44 years). Conclusions We report an increased rate of subsequent PD following T2DM in this large cohort study. These findings may reflect shared genetic predisposition and/or disrupted shared pathogenic pathways with potential clinical and therapeutic implications.

MSA-C or SCA 17? A clinicopathological case update.

We reported a case of late onset cerebellar ataxia mimicking multiple system atrophy–cerebellar type (MSA-C), which was attributed to an intermediate range expansion of the TATA-binding protein gene, causing a phenotypically restricted spinocerebellar ataxia 17 (SCA 17). This patient has now come to postmortem, and we present the neuropathological findings. In summary, the patient’s disease onset was at 59 years of age with dysarthria and gait ataxia. He had erectile dysfunction, but no other autonomic symptoms. Examination throughout the disease revealed a pure cerebellar syndrome. Structural imaging showed cerebellar atrophy and the “hot cross bun” sign. Dopamine transporter single photon emission computerized tomography was normal. After extensive investigations, an intermediate range expansion (41 CAG/CAA repeats) at the SCA 17 locus was found with proposed penetrance of 50%. A restricted SCA 17 phenotype was suggested as a more likely clinical diagnosis. Symptoms gradually progressed, and he died of aspiration pneumonia 8 years from disease onset. The key findings on macroscopic examination of the brain were mild pallor of the substantia nigra and marked cerebellar atrophy. Histological study (Figure 1) revealed moderate neuronal loss in the ventrolateral tier of the substantia nigra and severe Purkinje cell depletion and gliosis of the cerebellar dentate nucleus. The basal ganglia (putamen, caudate, globus pallidus, subthalamic nucleus), cerebral cortices, and hippocampal formation showed good preservation of neuronal populations. There was no amyloid beta or TAR DNA-binding protein-43 pathology. Phospho-tau immunohistochemistry showed Braak and Braak stage I pathology. a-synuclein immunohistochemistry demonstrated frequent glial cytoplasmic inclusions in the motor cortex, dorsal putamen, substantia nigra, and cerebellar white matter, confirming a pathological diagnosis of MSA of the olivopontocerebellar subtype. Further immunohistochemistry for expanded polyglutamine tracts using anti-1C2 antibody revealed occasional cortical, subcortical (caudate and putamen), and cerebellar (Purkinje cell and dentate nucleus) neurons with diffuse nuclear immunoreactivity, indicating subtle pathology of the type associated with SCA 17. Considering the possibility of somatic mosaicism with dissimilar repeat sizes between the central and peripheral tissues, accounting for the neuropathological changes, DNA was extracted from frozen tissue samples from the cerebellum and frontal and parietal cortices and the SCA 17 locus was tested. However, results showed similar intermediate repeat expansions of the TATA-binding protein allele in brain tissue when compared with blood (Supplementary Figure). This is the first intermediate range expansion SCA 17 case neuropathologically examined and analyzed for somatic mosaicism. The definitive diagnosis is MSA-C, but the finding of antipolyglutamine positivity in neuronal nuclei of select brain regions contests the argument that this case was MSA-C with coincidental CAG/CAA expansion. Currently there is no clear cut-off value for SCA 17 repeats, and the pathogenic role of intermediate repeat expansions is under debate. This case demonstrates for the first time that CAG expansions of 41 repeats can be associated with polyglutamine neuronal intranuclear inclusions supporting a pathogenic role of intermediate expansions. The clinical correlation of these histopathological findings is complicated in our case given the presence of concomitant MSA pathology. Further neuropathological studies of such cases are required to understand the pathogenic role of partially penetrant alleles and establish a phenotype correlation.

A Histologic Study of the Circadian System in Parkinson Disease, Multiple System Atrophy, and Progressive Supranuclear Palsy

Importance Circadian dysfunction may be associated with the symptoms and neurodegeneration in Parkinson disease (PD), multiple system atrophy (MSA), and progressive supranuclear palsy (PSP), although the underlying neuroanatomical site of disruption and pathophysiological mechanisms are not fully understood. Objective To perform a neuropathological analysis of disease-specific inclusions in the key structures of the circadian system in patients with PD, MSA, and PSP. Design, Setting, and Participants This investigation was a brain bank case-control study assessing neuropathological inclusions in the suprachiasmatic nucleus (SCN) of the hypothalamus and pineal gland in healthy controls, PD (Lewy pathology), MSA (glial cytoplasmic inclusions), and PSP (tau inclusions). The study analyzed 12 healthy control, 28 PD, 11 MSA, and 21 PSP samples from consecutive brain donations (July 1, 2010, to June 30, 2016) to the Queen Square Brain Bank for Neurological Disorders and the Parkinson’s UK Brain Bank, London, United Kingdom. Cases were excluded if neither SCN nor pineal tissue was available. Main Outcomes and Measures Disease-specific neuropathological changes were graded using a standard semiquantitative scoring system (absent, mild, moderate, severe, or very severe) and compared between groups. Results Because of limited tissue availability, the following total samples were examined in a semiquantitative histologic analysis: 5 SCNs and 7 pineal glands in the control group (6 male; median age at death, 83.8 years; interquartile range [IQR], 78.2-88.0 years), 13 SCNs and 17 pineal glands in the PD group (22 male; median age at death, 78.8 years; IQR, 75.5-83.8 years), 5 SCNs and 6 pineal glands in the MSA group (7 male; median age at death, 69.5 years; IQR, 61.6-77.7 years), and 5 SCNs and 19 pineal glands in the PSP group (13 male; median age at death, 74.3 years; IQR, 69.7-81.1 years). No neuropathological changes were found in either the SCN or pineal gland in healthy controls or MSA cases. Nine PD cases had Lewy pathology in the SCN, and only 2 PD cases had Lewy pathology in the pineal gland. All PSP cases showed inclusions in the SCN, but no PSP cases had pathology in the pineal gland. Conclusions and Relevance Disease-related neuropathological changes were found in the SCN but not in the pineal gland in PD and PSP, while both structures were preserved in MSA, reflecting different pathophysiological mechanisms that may have important therapeutic implications.

Autonomic Dysfunction in Parkinson's Disease: The Hidden Game Changer?: Autonomic Dysfunction in PD

We read with interest the article by Merola et al evaluating the progression of autonomic symptoms in a prospective cohort of 122 Parkinson’s disease (PD) patients and welcome the addition of these results to a growing body of evidence suggesting a key role of autonomic dysfunction (AutD) on disability, disease progression, and survival in PD. PD is clinically heterogeneous, and it is now well accepted that AutD, although classically associated to multiple system atrophy (MSA), can be an early and prominent clinical feature in PD. A main challenge faced by clinicians is differentiating between these 2 conditions in a patient presenting with AutD and parkinsonism. The importance of diagnostic certainty in prospective clinical studies, which can only be definitively achieved with postmortem confirmation, should not be underestimated. The possibility of either clinical misdiagnosis or the inappropriate exclusion of patients must be considered in design and data interpretation, as it may lead to potential bias affecting the conclusions of the study. Merola and colleagues included PD patients based on the widely accepted UK PD Brain Bank clinical criteria. Although these criteria have demonstrated high diagnostic accuracy (up to 90% when applied by movement disorder experts), clinicopathological case series still showed a degree of misdiagnosis, with MSA the most common alternative disease. We recently reviewed the progression of AutD in 100 consecutive pathologically confirmed PD cases at the Queen Square Brain Bank, which showed results in agreement with this, with 12% of patients clinically misdiagnosed as MSA. Key reasons for misdiagnosis in this subgroup of patients were the presence of early and severe AutD, rapid disease progression, and poor tolerability (and consequently response) to treatment with levodopa, which are fundamental factors impacting on disability and disease course in any parkinsonian disorder. Therefore, prospective clinical studies, such as that by Merola and colleagues, may underestimate the impact of AutD on PD by excluding PD patients with early AutD, and it is important that the overview of research in this field include studies of patients with diagnostic certainty, ideally with postmortem confirmation. Most of the previous research on AutD in PD has focused on orthostatic hypotension and not other autonomic symptoms that may also play important roles. As shown by Merola et al and our group, gastrointestinal disturbances, genitourinary symptoms, and sweating abnormalities may also be associated with increasing disability, rapid disease progression, and reduced survival in PD. Despite the growing evidence, the pathophysiological mechanisms driving the negative impact of AutD on PD progression, whether by increasing comorbidity and/or affecting the neurodegenerative process, are poorly understood. We encourage additional research to elucidate (i) whether a better symptomatic control of autonomic symptoms could improve the disease course in PD patients and (ii) a better understanding of the pathophysiological mechanisms involved that may provide new therapeutic targets to slow disease progression.

No evidence of iatrogenic human transmission in autopsy confirmed multiple system atrophy: Iatrogenic Transmission in Multiple System Atrophy

Converging evidence suggests that a-synuclein aggregates may share some important properties with prion proteins (including template seeding and pathogenic spreading between cells), and a potential transmission between humans has been speculated leading to intense scientific debate. Despite this experimental evidence, no human-to-human transmission has ever been reported, although epidemiological studies are scarce and limited by potentially prolonged incubation periods. We would like to add more evidence to this controversial topic by reporting data on potential exposure to medical procedures associated with human-to-human prion-related disease transmission in a large group of neuropathologyconfirmed MSA patients (n 5 192) from the Queen Square Brain Bank. Inoculation of brain homogenates and insertion of surgical devices from patients with MSA, but not from patients with Parkinson’s disease (PD), have been demonstrated to induce a-synuclein neurodegeneration in TgM83 transgenic mice, so we compared the results with a group of consecutive patients with autopsy-confirmed PD (n 5 125) and controls (n 5 54). Formalin-fixed brain tissue samples were processed using standard protocols, and

Young-onset multiple system atrophy: Clinical and pathological features: Young-Onset Msa

Background: The onset of multiple system atrophy (MSA) before age 40 years is referred to as “young‐onset MSA.” We identified clinical and pathological characteristics that might help with its early diagnosis and distinction from young‐onset Parkinsons disease and late‐onset MSA.