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Skin Biopsy Detection of Phosphorylated α-Synuclein in Patients With Synucleinopathies

Gibbons, Christopher H; Levine, Todd; Adler, Charles; Bellaire, Bailey; Wang, Ningshan; Stohl, Jade; Agarwal, Pinky; Aldridge, Georgina M; Barboi, Alexandru; Evidente, Virgilio G H; Galasko, Douglas; Geschwind, Michael D; Gonzalez-Duarte, Alejandra; Gil, Ramon; Gudesblatt, Mark; Isaacson, Stuart H; Kaufmann, Horacio; Khemani, Pravin; Kumar, Rajeev; Lamotte, Guillaume; Liu, Andy J; McFarland, Nikolaus R; Miglis, Mitchell; Reynolds, Adam; Sahagian, Gregory A; Saint-Hillaire, Marie-Helene; Schwartzbard, Julie B; Singer, Wolfgang; Soileau, Michael J; Vernino, Steven; Yerstein, Oleg; Freeman, Roy
IMPORTANCE/UNASSIGNED:Finding a reliable diagnostic biomarker for the disorders collectively known as synucleinopathies (Parkinson disease [PD], dementia with Lewy bodies [DLB], multiple system atrophy [MSA], and pure autonomic failure [PAF]) is an urgent unmet need. Immunohistochemical detection of cutaneous phosphorylated α-synuclein may be a sensitive and specific clinical test for the diagnosis of synucleinopathies. OBJECTIVE/UNASSIGNED:To evaluate the positivity rate of cutaneous α-synuclein deposition in patients with PD, DLB, MSA, and PAF. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:This blinded, 30-site, cross-sectional study of academic and community-based neurology practices conducted from February 2021 through March 2023 included patients aged 40 to 99 years with a clinical diagnosis of PD, DLB, MSA, or PAF based on clinical consensus criteria and confirmed by an expert review panel and control participants aged 40 to 99 years with no history of examination findings or symptoms suggestive of a synucleinopathy or neurodegenerative disease. All participants completed detailed neurologic examinations and disease-specific questionnaires and underwent skin biopsy for detection of phosphorylated α-synuclein. An expert review panel blinded to pathologic data determined the final participant diagnosis. EXPOSURE/UNASSIGNED:Skin biopsy for detection of phosphorylated α-synuclein. MAIN OUTCOMES/UNASSIGNED:Rates of detection of cutaneous α-synuclein in patients with PD, MSA, DLB, and PAF and controls without synucleinopathy. RESULTS/UNASSIGNED:Of 428 enrolled participants, 343 were included in the primary analysis (mean [SD] age, 69.5 [9.1] years; 175 [51.0%] male); 223 met the consensus criteria for a synucleinopathy and 120 met criteria as controls after expert panel review. The proportions of individuals with cutaneous phosphorylated α-synuclein detected by skin biopsy were 92.7% (89 of 96) with PD, 98.2% (54 of 55) with MSA, 96.0% (48 of 50) with DLB, and 100% (22 of 22) with PAF; 3.3% (4 of 120) of controls had cutaneous phosphorylated α-synuclein detected. CONCLUSIONS AND RELEVANCE/UNASSIGNED:In this cross-sectional study, a high proportion of individuals meeting clinical consensus criteria for PD, DLB, MSA, and PAF had phosphorylated α-synuclein detected by skin biopsy. Further research is needed in unselected clinical populations to externally validate the findings and fully characterize the potential role of skin biopsy detection of phosphorylated α-synuclein in clinical care.
PMCID:10955354
PMID: 38506839
ISSN: 1538-3598
CID: 5640572

Phenoconversion in pure autonomic failure: a multicentre prospective longitudinal cohort study

Millar Vernetti, Patricio; Norcliffe-Kaufmann, Lucy; Palma, Jose-Alberto; Biaggioni, Italo; Shibao, Cyndya A; Peltier, Amanda; Freeman, Roy; Gibbons, Christopher; Goldstein, David S; Low, Phillip A; Singer, Wolfgang; Coon, Elizabeth A; Miglis, Mitchell G; Wenning, Gregor K; Fanciulli, Alessandra; Vernino, Steven; Betensky, Rebecca A; Kaufmann, Horacio
We aimed to describe the clinical features of patients with pure autonomic failure (PAF) preceding phenoconversion that could be useful as predictive markers for advancing α-synuclein-associated neurodegeneration of the brain. Patients diagnosed with PAF were evaluated at 8 Centers (7-US based and 1 European) and enrolled in a longitudinal observational cohort study (NCT01799915). Subjects underwent detailed assessments of motor, sleep, olfactory, cognitive, and autonomic function and were followed prospectively to determine whether they developed parkinsonism or dementia for up to 10 years. We identified incident cases of Parkinson disease (PD), dementia with Lewy bodies (DLB), or multiple system atrophy (MSA) and computed hazard ratios for phenoconversion as functions of clinical features. A total of 209 participants with PAF with a median disease duration of 6 years (IQR: 3-10) were enrolled. Of those, 149 provided follow-up information at an office or telemedicine visit. After a mean follow-up duration of 3 years, 48 (33%) participants phenoconverted (42% to PD, 35% to DLB, and 23% to MSA). Faster phenoconversion from study enrollment to any diagnosis was associated with urinary and sexual dysfunction [HR 5.9, 95%CI: 1.6-22, and HR: 3.6, 95%CI: 1.1-12] followed by subtle motor signs [HR: 2.7, 95%CI: 1.2-6], trouble swallowing [HR 2.5, 95%CI: 1.4-4.5], and changes in speech [HR:2.4, 95%CI:1.1-4.8] at enrollment. Subjects reporting deterioration of handwriting were more likely to phenoconvert to PD (HR: 2.6, 95%CI: 1.1-5.9, ) and those reporting difficulty handling utensils were more likely to phenoconvert to DLB (HR: 6.8, 95%CI: 1.2-38). Patients with a younger age of PAF onset [HR: 11, 95%CI: 2.6-46], preserved olfaction [HR: 8.7, 95%CI: 1.7-45], anhidrosis [HR: 1.8, 95%CI: 1-3.1, p=0.042], and severe urinary problems [HR 1.6, 95%CI: 1-2.5, p=0.033] were more likely to phenoconvert to MSA. The best autonomic predictor of PD was a blunted heart rate increase during the tilt-table test (HR: 6.1, 95%CI: 1.4-26). Patients with PAF have an estimated 12% (95% CI: 9%-15%) per year annual risk following study entry of phenoconverting to a manifest CNS synucleinopathy.
PMID: 38366572
ISSN: 1460-2156
CID: 5636112

Pharmacologic Treatment for High BP and Risk of CVD [Comment]

Palma, Jose-Alberto; Kaufmann, Horacio
PMID: 38349377
ISSN: 1538-3598
CID: 5635282

Sensorimotor control in the congenital absence of functional muscle spindles

Macefield, Vaughan G; Smith, Lyndon J; Norcliffe-Kaufmann, Lucy; Palma, Jose-Alberto; Kaufmann, Horacio
NEW FINDINGS/RESULTS:What is the topic of this review? Hereditary sensory and autonomic neuropathy type III (HSAN III). What advances does it highlight? In individuals with (HSAN III) functional muscle spindles appear to be absent throughout the body, though myelinated cutaneous afferents are present. The former may explain the poor proprioception at the knee joint, while the latter may explain why increasing cutaneous feedback improves proprioception at the knee. Reaching and lifting small objects was greatly compromised, arguing for an important role of muscles spindles in sensorimotor control. ABSTRACT/UNASSIGNED:Hereditary sensory and autonomic neuropathy type III (HSAN III), also known as familial dysautonomia or Riley-Day syndrome, results from an autosomal recessive genetic mutation that causes a selective loss of specific sensory neurones, leading to greatly elevated pain and temperature thresholds, poor proprioception, marked ataxia and disturbances in blood pressure control. Stretch reflexes are absent throughout the body, which can be explained by the absence of functional muscle spindle afferents - assessed by intraneural microelectrodes inserted into peripheral nerves in the upper and lower limbs. This also explains the greatly compromised proprioception at the knee joint, as assessed by passive joint-angle matching. Moreover, there is a tight correlation between loss of proprioceptive acuity at the knee and the severity of gait impairment. Surprisingly, proprioception is normal at the elbow, suggesting that participants are relying more on sensory cues from the overlying skin; microelectrode recordings have shown that myelinated tactile afferents in the upper and lower limbs appear to be normal. Nevertheless, the lack of muscle spindles does affect sensorimotor control in the upper limb: in addition to poor performance in the finger-to-nose test, manual performance in the Purdue pegboard task is much worse than in age-matched healthy controls. Unlike those rare individuals with large-fibre sensory neuropathy, in which both muscle spindle and cutaneous afferents are absent, those with HSAN III present as a means of assessing sensorimotor control following the selective loss of muscle spindle afferents.
PMID: 37029664
ISSN: 1469-445x
CID: 5463982

Neuron-derived extracellular vesicles to examine brain mTOR target engagement with sirolimus in patients with multiple system atrophy

Pucha, Krishna A; Ma, Thong C; York, William; Kang, Un Jung; Kaufmann, Horacio; Kapogiannis, Dimitrios; Palma, Jose-Alberto
INTRODUCTION/BACKGROUND:Impaired autophagy is a pathogenic mechanism in the synucleinopathies. Sirolimus, a potent mTOR inhibitor and autophagy activator, had no beneficial effects in a randomized placebo-controlled trial in patients with multiple system atrophy (MSA). Whether sirolimus effectively inhibited brain mTOR activity was unknown. We aimed to evaluate if patients with MSA treated with sirolimus had evidence of inhibited brain mTOR pathways by measuring neuron-derived serum extracellular vesicles (NEVs). METHODS:Serum samples were collected from participants of the sirolimus-MSA trial, which randomized patients to sirolimus (2-6 mg/day) or placebo for 48 weeks. NEVs were immunoprecipitated with three antibodies-against neurons. Brain mTOR engagement was quantified as the change in the NEV phosphorylated mTOR (p-mTOR) to total-mTOR (tot-mTOR) ratio after 48 weeks of sirolimus. RESULTS:Samples from 27 patients [mean (±SD) age, 59.2±7 years, 15 (55.5%) men] were analyzed (19 sirolimus, 8 placebo). Treated- and placebo-patients had similar p-mTOR:tot-mTOR ratio at 24 (placebo: 0.248 ± 0.03, sirolimus: 0.289 ± 0.02; P = 0.305) and 48 weeks (placebo: 0.299 ± 0.05, sirolimus: 0.261 ± 0.03; P = 0.544). The tot-mTOR, p-mTOR, or their ratio levels were not associated with Unified MSA Rating Scale (UMSARS) worsening. DISCUSSION/CONCLUSIONS:These results are consistent with no brain mTOR engagement by oral sirolimus up to 6 mg/day. NEV-based biomarkers are a rational approach to investigating target engagement in clinical trials of brain-targeted therapeutics.
PMCID:10592064
PMID: 37643509
ISSN: 1873-5126
CID: 5618472

Meropenem-Induced Facial Myoclonus [Case Report]

Millar Vernetti, Patricio; Dalamo, Kaia; Khan, Zenith; Gonzalez-Duarte, Alejandra; Frucht, Steven; Kaufmann, Horacio
PMCID:10448627
PMID: 37636233
ISSN: 2330-1619
CID: 5618502

Familial dysautonomia

González-Duarte, Alejandra; Cotrina-Vidal, Maria; Kaufmann, Horacio; Norcliffe-Kaufmann, Lucy
Familial dysautonomia (FD) is an autosomal recessive hereditary sensory and autonomic neuropathy (HSAN, type 3) expressed at birth with profound sensory loss and early death. The FD founder mutation in the ELP1 gene arose within the Ashkenazi Jews in the sixteenth century and is present in 1:30 Jews of European ancestry. The mutation yield a tissue-specific skipping of exon 20 and a loss of function of the elongator-1 protein (ELP1), which is essential for the development and survival of neurons. Patients with FD produce variable amounts of ELP1 in different tissues, with the brain producing mostly mutant transcripts. Patients have excessive blood pressure variability due to the failure of the IXth and Xth cranial nerves to carry baroreceptor signals. Neurogenic dysphagia causes frequent aspiration leading to chronic pulmonary disease. Characteristic hyperadrenergic "autonomic crises" consisting of brisk episodes of severe hypertension, tachycardia, skin blotching, retching, and vomiting occur in all patients. Progressive features of the disease include retinal nerve fiber loss and blindness, and proprioceptive ataxia with severe gait impairment. Chemoreflex failure may explain the high frequency of sudden death in sleep. Although 99.5% of patients are homozygous for the founder mutation, phenotypic severity varies, suggesting that modifier genes impact expression. Medical management is currently symptomatic and preventive. Disease-modifying therapies are close to clinical testing. Endpoints to measure efficacy have been developed, and the ELP1 levels are a good surrogate endpoint for target engagement. Early intervention may be critical for treatment to be successful.
PMID: 37204536
ISSN: 1619-1560
CID: 5503652

Cutaneous α-Synuclein Signatures in Patients With Multiple System Atrophy and Parkinson Disease

Gibbons, Christopher; Wang, Ningshan; Rajan, Sharika; Kern, Drew; Palma, Jose-Alberto; Kaufmann, Horacio; Freeman, Roy
BACKGROUND AND OBJECTIVES:Multiple system atrophy (MSA) is a progressive neurodegenerative disorder caused by the abnormal accumulation of α-synuclein in the nervous system. Clinical features include autonomic and motor dysfunction, which overlap with those of Parkinson disease (PD), particularly at early disease stages. There is an unmet need for accurate diagnostic and prognostic biomarkers for MSA and, specifically, a critical need to distinguish MSA from other synucleinopathies, particularly PD. The purpose of the study was to develop a unique cutaneous pathologic signature of phosphorylated α-synuclein that could distinguish patients with MSA from patients with PD and healthy controls. METHODS:We studied 31 patients with MSA and 54 patients with PD diagnosed according to current clinical consensus criteria. We also included 24 matched controls. All participants underwent neurologic examinations, autonomic testing, and skin biopsies at 3 locations. The density of intraepidermal, sudomotor, and pilomotor nerve fibers was measured. The deposition of phosphorylated α-synuclein was quantified. Results were compared with clinical rating assessments and autonomic function test results. RESULTS:< 0.0001) than patients with PD. These results provided >90% sensitivity and specificity in distinguishing between the 2 disorders. DISCUSSION:α-synuclein is present in the peripheral autonomic nerves of patients with MSA and when combined with synuclein distribution accurately distinguishes MSA from PD. CLASSIFICATION OF EVIDENCE:This study provides Class II evidence that measurement of phosphorylated α-synuclein in skin biopsies can differentiate patients with MSA from those with PD.
PMID: 36657992
ISSN: 1526-632x
CID: 5466502

Gastrointestinal bleeding in children with familial dysautonomia: a case-control study

Ramprasad, Chethan; Palma, Jose-Alberto; Norcliffe-Kaufmann, Lucy; Levy, Joseph; Chen, Lea Ann; Kaufmann, Horacio
OBJECTIVE:Familial dysautonomia (FD) is a rare inherited autosomal recessive disorder with abnormal somatosensory, enteric, and afferent autonomic neurons. We aimed to define the incidence of gastrointestinal bleeding and its associated risk factors in patients with FD. METHODS:In this retrospective case-control study, we identified all episodes of gastrointestinal bleeding in patients with FD, occurring over four decades (January 1980-December 2017), using the New York University FD registry. RESULTS:We identified 104 episodes of gastrointestinal bleeding occurring in 60 patients with FD. The estimated incidence rate of gastrointestinal bleeds in the FD population rate was 4.20 episodes per 1000 person-years. We compared the 60 cases with 94 age-matched controls. Bleeding in the upper gastrointestinal tract from gastric and duodenal ulcers occurred most frequently (64 bleeds, 75.6%). Patients were more likely to have a gastrostomy (G)-tube and a Nissen fundoplication [odds ratio (OR) 3.73, 95% confidence interval (CI) 1.303-13.565] than controls. The mean time from G-tube placement to first gastrointestinal bleed was 7.01 years. The mean time from Nissen fundoplication to bleed was 7.01 years. Cases and controls had similar frequency of intake of nonsteroidal antiinflammatory drugs (NSAID) and selective serotonin reuptake inhibitors (SSRI). CONCLUSION/CONCLUSIONS:The incidence of gastrointestinal bleeding in the pediatric FD population was estimated to be 4.20 per 1000 person-years, 21 times higher than in the general pediatric population (0.2 per 1000 person-years). Patients with FD with a G-tube and a Nissen fundoplication had a higher risk of a subsequent gastrointestinal bleeding.
PMID: 36735101
ISSN: 1619-1560
CID: 5426782

Toward a biomarker panel measured in CNS-originating extracellular vesicles for improved differential diagnosis of Parkinson's disease and multiple system atrophy [Letter]

Taha, Hash Brown; Hornung, Simon; Dutta, Suman; Fenwick, Leony; Lahgui, Otmane; Howe, Kathryn; Elabed, Nour; Del Rosario, Irish; Wong, Darice Y; Duarte Folle, Aline; Markovic, Daniela; Palma, Jose-Alberto; Kang, Un Jung; Alcalay, Roy N; Sklerov, Miriam; Kaufmann, Horacio; Fogel, Brent L; Bronstein, Jeff M; Ritz, Beate; Bitan, Gal
PMCID:10026428
PMID: 36935518
ISSN: 2047-9158
CID: 5466992