PROJECT 1 NYU Pure autonomic failure (PAF) is a neurodegenerative disorder characterized clinically by orthostatic hypotension (OH) and pathologically by intracellular deposits of the protein alpha synuclein. As in Parkinson disease (PD), in PAF alpha synuclein aggregates in neuronal cytoplasmic inclusions called Lewy bodies (LBs). LB in PAF are numerous in peripheral autonomic neurons with only a few in the substantia nigra and scattered in the CNS. PAF is one of three LB disorders, a category that includes PD and dementia with Lewy bodies (DLB). Each of these disorders affects different neuronal groups relatively selectively, resulting in distinct but overlapping autonomic, motor, and cognitive phenotypes. Because of paucity of data on the natural history of PAF, however, it is not known whether the striatum and other cortical areas remain intact in PAF over time.
Specific Aim 1 of this project is to conduct a prospective, longitudinal study to define the natural history of PAF and determine whether the disease remains confined to autonomic neurons or develops eventually into one of the other LB disorders, i.e., PD or DLB. If PAF patients sustain the """"""""pure"""""""" autonomic phenotype, PAF might entail neuroprotective features that prevent the disorder from spreading to the brain affecting motor and cognitive function. Understanding the mechanisms of this neuroprotection could aid in the development of treatments for all LB disorders. The characteristic clinical manifestation of PAF, neurogenic orthostatic hypotension, can also be the initial manifestation of multiple system atrophy (MSA), a neurodegenerative disorder in which alpha synuclein accumulates in glial cytoplasmic inclusions rather than in Lewy bodies. Whereas the three LB disorders involve loss of postganglionic noradrenergic neurons in the heart, these neurons are usually spared in MSA. Therefore, peripheral noradrenergic involvement detected by neurochemical or neuroimaging studies, might be useful as a biomarker of PAF vs. early """"""""premotor"""""""" MSA.
In Specific aim 2 we will test the hypothesis that patients who have the clinical phenotype of PAF but have preserved postganglionic sympathetic neurons do not have PAF but have early MSA or other as vet undefined disorders.

Public Health Relevance

PAF is the only synucleinopathy not associated with clinical evidence of central neurodegeneration. Defining its natural history is a first step to identify features that may protect the CNS from neurodegeneration. Identifying biomarkers of LB disorders may allow therapeutic neuroprotective interventions when the disease is in its premotor stage. This natural history study also provides a unique opportunuty to study genotpyephenotype relationships in novel autonomic disorders.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Specialized Center--Cooperative Agreements (U54)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-HOP-Y)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Vanderbilt University Medical Center
United States
Zip Code
Singer, Wolfgang; Berini, Sarah E; Sandroni, Paola et al. (2017) Pure autonomic failure: Predictors of conversion to clinical CNS involvement. Neurology 88:1129-1136
Palma, Jose-Alberto; Spalink, Christy; Barnes, Erin P et al. (2017) Neurogenic dysphagia with undigested macaroni and megaesophagus in familial dysautonomia. Clin Auton Res :
Wallach, Asya I; Park, Hannah; Rucker, Janet C et al. (2017) Supranuclear gaze palsy and horizontal ocular oscillations in Creutzfeldt-Jakob disease. Neurology 89:749
Palma, Jose-Alberto; Norcliffe-Kaufmann, Lucy; Perez, Miguel A et al. (2017) Sudden Unexpected Death During Sleep in Familial Dysautonomia: A Case-Control Study. Sleep 40:
Coon, Elizabeth A; Low, Phillip A (2017) Pure autonomic failure without alpha-synuclein pathology: an evolving understanding of a heterogeneous disease. Clin Auton Res 27:67-68
Mendoza-Santiesteban, Carlos E; Palma, Jose-Alberto; Hedges 3rd, Thomas R et al. (2017) Pathological Confirmation of Optic Neuropathy in Familial Dysautonomia. J Neuropathol Exp Neurol 76:238-244
Kaufmann, Horacio; Jordan, Jens (2017) The Clinical Autonomic Research journal 2017 and onward. Clin Auton Res 27:1-2
Spalink, Christy L; Barnes, Erin; Palma, Jose-Alberto et al. (2017) Intranasal dexmedetomidine for adrenergic crisis in familial dysautonomia. Clin Auton Res 27:279-282
Bajaj, Sweta; Krismer, Florian; Palma, Jose-Alberto et al. (2017) Diffusion-weighted MRI distinguishes Parkinson disease from the parkinsonian variant of multiple system atrophy: A systematic review and meta-analysis. PLoS One 12:e0189897
Mendoza-Santiesteban, Carlos E; Palma, Jose-Alberto; Norcliffe-Kaufmann, Lucy et al. (2017) Familial dysautonomia: a disease with hidden tears. J Neurol 264:1290-1291

Showing the most recent 10 out of 133 publications