Pure Autonomic Failure Research Articles

Author response: A new potential biomarker for dementia with Lewy bodies: Skin nerve α-synuclein deposits.

The questions raised by Dr. Khan are interesting, but need clarification. First, skin nerve α-synuclein deposits are a reliable biomarker of synucleinopathies,1–3 helping to differentiate these disorders from diseases of different origins. Accordingly, through skin biopsy, pure autonomic failure was differentiated from acquired autonomic neuropathies,4 idiopathic Parkinson disease from tauopathies or vascular parkinsonisms,2 and dementia with Lewy bodies from Alzheimer disease, frontotemporal dementia, or vascular dementia.1 As postmortem studies demonstrated,5 current clinical diagnostic criteria for synucleinopathies have a considerable error rate, leading to possible misdiagnosis with disorders of different origins. A reliable biomarker is important to improve clinical management, decreasing the misdiagnosis of synucleinopathies. Furthermore, the possibility to differentiate different phenotypes of synucleinopathy by skin biopsy is an important aim, on which we are working. However, early data suggested that the distribution of α-synuclein deposits throughout proximal and distal skin sites may be helpful to identify peculiar patterns,3 although more data are needed to achieve an extensive picture of synucleinopathies.

Treatment of autonomic dysfunction in Parkinson disease and other synucleinopathies.

Dysfunction of the autonomic nervous system afflicts most patients with Parkinson disease and other synucleinopathies such as dementia with Lewy bodies, multiple system atrophy, and pure autonomic failure, reducing quality of life and increasing mortality. For example, gastrointestinal dysfunction can lead to impaired drug pharmacodynamics causing a worsening in motor symptoms, and neurogenic orthostatic hypotension can cause syncope, falls, and fractures. When recognized, autonomic problems can be treated, sometimes successfully. Discontinuation of potentially causative/aggravating drugs, patient education, and nonpharmacological approaches are useful and should be tried first. Pathophysiology-based pharmacological treatments that have shown efficacy in controlled trials of patients with synucleinopathies have been approved in many countries and are key to an effective management. Here, we review the treatment of autonomic dysfunction in patients with Parkinson disease and other synucleinopathies, summarize the nonpharmacological and current pharmacological therapeutic strategies including recently approved drugs, and provide practical advice and management algorithms for clinicians, with focus on neurogenic orthostatic hypotension, supine hypertension, dysphagia, sialorrhea, gastroparesis, constipation, neurogenic overactive bladder, underactive bladder, and sexual dysfunction. © 2018 International Parkinson and Movement Disorder Society.

Orthostatic heart rate changes in patients with autonomic failure caused by neurodegenerative synucleinopathies.

Blunted tachycardia during hypotension is a characteristic feature of patients with autonomic failure, but the range has not been defined. This study reports the range of orthostatic heart rate (HR) changes in patients with autonomic failure caused by neurodegenerative synucleinopathies. Patients evaluated at sites of the U.S. Autonomic Consortium (NCT01799915) underwent standardized autonomic function tests and full neurological evaluation. We identified 402 patients with orthostatic hypotension (OH) who had normal sinus rhythm. Of these, 378 had impaired sympathetic activation (ie, neurogenic OH) and based on their neurological examination were diagnosed with Parkinson disease, dementia with Lewy bodies, pure autonomic failure, or multiple system atrophy. The remaining 24 patients had preserved sympathetic activation and their OH was classified as nonneurogenic, due to volume depletion, anemia, or polypharmacy. Patients with neurogenic OH had twice the fall in systolic blood pressure (SBP; -44 ± 25 vs -21 ± 14 mmHg [mean ± standard deviation], p < 0.0001) but only one-third of the increase in HR of those with nonneurogenic OH (8 ± 8 vs 25 ± 11 beats per minute [bpm], p < 0.0001). A ΔHR/ΔSBP ratio of 0.492 bpm/mmHg had excellent sensitivity (91.3%) and specificity (88.4%) to distinguish between patients with neurogenic from nonneurogenic OH (area under the curve = 0.96, p < 0.0001). Within patients with neurogenic OH, HR increased more in those with multiple system atrophy (p = 0.0003), but there was considerable overlap with patients with Lewy body disorders. A blunted HR increase during hypotension suggests a neurogenic cause. A ΔHR/ΔSBP ratio < 0.5 bpm/mmHg is diagnostic of neurogenic OH. Ann Neurol 2018;83:522-531.

Autonomic dysfunction in genetic forms of synucleinopathies

The discovery of genetic links between alpha-synuclein and PD has opened unprecedented opportunities for research into a new group of diseases, now collectively known as synucleinopathies. Autonomic dysfunction, including cardiac sympathetic denervation, has been reported in familial forms of synucleinopathies that have Lewy bodies at the core of their pathogenesis. SNCA mutations and multiplications, LRRK2 disease with Lewy bodies as well as other common, sporadic forms of idiopathic PD, MSA, pure autonomic failure, and dementia with Lewy bodies have all been associated with dysautonomia. By contrast, in familial cases of parkinsonism without Lewy bodies, such as in PARK2, the autonomic profile remains normal throughout the course of the disease. The degeneration of the central and peripheral autonomic systems in genetic as well as sporadic forms of neurodegenerative synucleinopathies correlates with the accumulation of alpha-synuclein immunoreactive-containing inclusions. Given that dysautonomia has a significant impact on the quality of life of sufferers and autonomic symptoms are generally treatable, a prompt diagnostic testing and treatment should be provided. Moreover, new evidence suggests that autonomic dysfunction can be used as an outcome prediction factor in some forms of synucleinopathies or premotor diagnostic markers that could be used in the future to define further research avenues. In this review, we describe the autonomic dysfunction of genetic synucleinopathies in comparison to the dysautonomia of sporadic forms of alpha-synuclein accumulation and provide the reader with an up-to-date overview of the current understanding in this fast-growing field. © 2018 International Parkinson and Movement Disorder Society.

Photocatalytic properties of amine functionalized Bi2Sn2O7/rGO nanocomposites

The binary metal oxide nanomaterials are having applications in various fields like sensors, optics, electrocatalyst and photocatalyst so on. Bi2Sn2O7 with pyrochlore structure is having low band gap energy; hence it is utilized in battery storage and gas sensor applications. In the present work, we have made an attempt to synthesis amine-functionalized Bi2Sn2O7/rGO nanocomposites by a thermal decomposition method and in-situ method; the synthesized nanocomposites were confirmed by XRD, FT-IR and Raman analysis. The AF-Bi2Sn2O7/rGO nanocomposites morphology was confirmed by FE-SEM along with EDX spectroscopy, we obtained different flowers and nest-like morphology. The pure and composite material band gap energy is decreases from 2.6 eV to 1.6 eV. All three nanomaterials Bi2Sn2O7, AF-Bi2Sn2O7, AF-Bi2Sn2O7/rGO nanocomposites (AF–amine functionalized) were utilized for the photocatalytic degradation of methylene blue dye under visible light irradiation. AF-Bi2Sn2O7/rGO nanocomposite showed an excellent photocatalytic activity than pure Bi2Sn2O7 and AF- Bi2Sn2O7.

Spectrum of abnormalities of sympathetic tyrosine hydroxylase and alpha-synuclein in chronic autonomic failure.

Lewy body forms of primary chronic autonomic failure (CAF) such as incidental Lewy body disease (ILBD), Parkinson's disease (PD), and pure autonomic failure evolving into dementia with Lewy bodies (PAF+DLB) feature cardiac sympathetic denervation, whereas multiple system atrophy (MSA) in most cases does not. What links Lewy bodies with cardiac sympathetic denervation in CAF? In familial PD, abnormalities of the alpha-synuclein (AS) gene cause CAF and cardiac sympathetic denervation; and in sporadic PD, brainstem Lewy bodies contain AS co-localized with tyrosine hydroxylase (TH), a marker of catecholaminergic neurons. Cytotoxicity from AS deposition within sympathetic neurons might explain noradrenergic denervation in Lewy body forms of CAF. We used immunofluorescence microscopy (IM) to explore this possibility in sympathetic ganglia obtained at autopsy from CAF patients. Immunoreactive AS and TH were imaged in sympathetic ganglion tissue from 6 control subjects (2 with ILBD), 5 PD patients (1 with concurrent PSP), and 3 patients with CAF (2 PAF+DLB, 1 MSA). MSA involved normal ganglionic TH and no AS deposition. In ILBD TH was variably decreased, and TH and AS were co-localized in Lewy bodies. In PD TH was substantially decreased, and TH and AS were co-localized in Lewy bodies. In PAF+DLB TH was virtually absent, but AS was present in Lewy bodies. The PD+PSP patient had AS co-localized with tau but not TH. Sympathetic denervation and intraneuronal AS deposition are correlated across CAF syndromes, consistent with a pathogenic contribution of synucleinopathy to cardiac noradrenergic deficiency in Lewy body diseases.

Neuropathology of autonomic dysfunction in synucleinopathies.

The synucleinopathies-Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, and pure autonomic failure-result from distinct patterns of abnormal α-synuclein aggregation throughout the nervous system. Autonomic dysfunction in these disorders results from variable involvement of the central and peripheral autonomic networks. The major pathologic hallmark of Parkinson's disease and dementia with Lewy bodies is Lewy bodies and Lewy neurites; of multiple system atrophy, oligodendroglial cytoplasmic inclusions; and of pure autonomic failure, peripheral neuronal cytoplasmic inclusions. Clinical manifestations include orthostatic hypotension, thermoregulatory dysfunction, gastrointestinal dysmotility, and urogenital dysfunction with neurogenic bladder and sexual dysfunction. Strong evidence supports isolated idiopathic rapid eye movement sleep disorder as a significant risk factor for the eventual development of synucleinopathies with autonomic and/or motor involvement. In contrast, some neurologically normal elderly individuals have Lewy-related pathology. Future work may reveal protective or vulnerability factors that allow some patients to harbor Lewy pathology without overt autonomic dysfunction. © 2018 International Parkinson and Movement Disorder Society.

Does sympathetic dysfunction occur before denervation in pure autonomic failure?

Pure autonomic failure (PAF) is a rare sporadic disorder characterized by autonomic failure in the absence of a movement disorder or dementia and is associated with very low plasma norepinephrine (NE) levels-suggesting widespread sympathetic denervation, however due to its rarity the pathology remains poorly elucidated. We sought to correlate clinical and neurochemical findings with sympathetic nerve protein abundances, accessed by way of a forearm vein biopsy, in patients with PAF and in healthy controls and patients with multiple systems atrophy (MSA) in whom sympathetic nerves are considered intact. The abundance of sympathetic nerve proteins, extracted from forearm vein biopsy specimens, in 11 patients with PAF, 8 patients with MSA and 9 age-matched healthy control participants was performed following a clinical evaluation and detailed evaluation of sympathetic nervous system function, which included head-up tilt (HUT) testing with measurement of plasma catecholamines and muscle sympathetic nerve activity (MSNA) in addition to haemodynamic assessment to confirm the clinical phenotype. PAF participants were found to have normal abundance of the NE transporter (NET) protein, together with very low levels of tyrosine hydroxylase (TH) (P<0.0001) and reduced vesicular monoamine transporter 2 (VMAT2) (P<0.05) protein expression compared with control and MSA participants. These findings were associated with a significantly higher ratio of plasma 3,4-dihydroxyphenylglycol (DHPG):NE in PAF participants when compared with controls (P<0.05). The finding of normal NET abundance in PAF suggests intact sympathetic nerves but with reduced NE synthesis. The finding of elevated plasma ratio of DHPG:NE and reduced VMAT2 in PAF indicates a shift towards intraneuronal NE metabolism over sequestration in sympathetic nerves and suggests that sympathetic dysfunction may occur ahead of denervation.

Author response: Effects of orthostatic hypotension on cognition in Parkinson disease.

We thank Guaraldi et al. for their comment on our article,1 and for drawing our attention to their work assessing cognitive function in patients with peripheral autonomic disorders, pure autonomic failure (PAF), and autoimmune autonomic neuropathy.2 The results in their study are similar to our results in Parkinson disease (PD),2 and to data we reported earlier on reversible cognitive impairment in individuals with orthostatic hypotension (OH) due to the peripheral disorder autoimmune autonomicganglionopathy.3 Cognitive changes in all of these studies are most significant in the domains of attention and executive functioning; while disease-specific decrements vary across each participant group regardless of posture, the totality of these data strongly suggest an independent effect of OH that may go unnoticed during standard clinical assessment. This is perhaps most relevant for PD, where the management focus tends to be on motor features and OH may be unrecognized whereas dysautonomic signs are prioritized in autoimmune autonomic ganglionopathy, autonomic neuropathies, and PAF. All these studies highlight the need for clinical awareness of cognitive impairment in association with OH, and for additional work to delineate the pathophysiologic mechanisms underlying OH-induced cognitive impairment.1–3

3. Immunofluorescence characterization of skin nerve misfolded α-synuclein in different synucleinopathies: A confocal study

Intraneural misfolded α-synuclein (syn) characterized different synucleinopathies such as pure autonomic failure (PAF), idiopathic Parkinson disease (IPD) and dementia with Lewy Bodies (DLB). The aim of this study is to characterize by immunofluorescence the skin intraneural α-synuclein (syn) deposits in PAF, IPD and DLB to ascertain conformation-specific differences which may justify a different clinical phenotype. We identified a total of 21 skin intraneural abnormal syn deposits in PAF (3 patients), 22 in IPD (8 patients) and 40 in DLB (7 patients). Ten healthy subjects were used controls. Skin biopsy was performed on proximal (C7 paravertebral) and distal (thigh and leg) sites. To characterize abnormal syn deposits we used primary antibodies against native α-synuclein (NAC) and against C-terminal α-synuclein epitopes involved in post-translational modifications such as phosphorylation at serine 129 (pS129) and tyrosine 125 (pY125), nitrate α-synuclein at tyr125-133 (nY125-133) and advanced glycation end products (AGEs). Furthermore, the mature amyloid α-synuclein fibrils were characterized by using a non-commercial antibody (Syn-F) and ubiquitin deposits were identified by a specific antibody (UBI). Antibody raised against pS129 disclosed abnormal skin nerves syn deposits in all patients and never in the control group. Abnormal pS129 syn deposits were often (80–90% of all analysed deposits) stained by the antibody recognizing a fibril conformation, seldom (around 40%) by native antibodies and very occasionally by antibodies against nY125-133. Furthermore, abnormal syn deposits were not stained by antibodies against pY125, AGEs and UBI. The immunofluorescence characterization of abnormal syn deposits showed similar findings in IPD, PAF and DLB although in these latter abnormal deposits were quantitatively higher than in IPD. Phosphorylation at serine 129 was the most sensitive and specific epitope to identify skin nerves abnormal syn deposits for the in vivo diagnosis of synucleinopathies; (2) skin syn neuritis showed no relevant immunofluorescence differences in PAF, IPD and DLB suggesting a similar conformation among different clinical phenotypes.

Diagnosis of multiple system atrophy.

Multiple system atrophy (MSA) may be difficult to distinguish clinically from other disorders, particularly in the early stages of the disease. An autonomic-only presentation can be indistinguishable from pure autonomic failure. Patients presenting with parkinsonism may be misdiagnosed as having Parkinson disease. Patients presenting with the cerebellar phenotype of MSA can mimic other adult-onset ataxias due to alcohol, chemotherapeutic agents, lead, lithium, and toluene, or vitamin E deficiency, as well as paraneoplastic, autoimmune, or genetic ataxias. A careful medical history and meticulous neurological examination remain the cornerstone for the accurate diagnosis of MSA. Ancillary investigations are helpful to support the diagnosis, rule out potential mimics, and define therapeutic strategies. This review summarizes diagnostic investigations useful in the differential diagnosis of patients with suspected MSA. Currently used techniques include structural and functional brain imaging, cardiac sympathetic imaging, cardiovascular autonomic testing, olfactory testing, sleep study, urological evaluation, and dysphagia and cognitive assessments. Despite advances in the diagnostic tools for MSA in recent years and the availability of consensus criteria for clinical diagnosis, the diagnostic accuracy of MSA remains sub-optimal. As other diagnostic tools emerge, including skin biopsy, retinal biomarkers, blood and cerebrospinal fluid biomarkers, and advanced genetic testing, a more accurate and earlier recognition of MSA should be possible, even in the prodromal stages. This has important implications as misdiagnosis can result in inappropriate treatment, patient and family distress, and erroneous eligibility for clinical trials of disease-modifying drugs.

The heart of PD: Lewy body diseases as neurocardiologic disorders

This review provides an update about cardiac sympathetic denervation in Lewy body diseases. The family of Lewy body diseases includes Parkinson’s disease (PD), pure autonomic failure (PAF), and dementia with Lewy bodies (DLB). All three feature intra-neuronal cytoplasmic deposits of the protein, alpha-synuclein. Multiple system atrophy (MSA), the parkinsonian form of which can be difficult to distinguish from PD with orthostatic hypotension, involves glial cytoplasmic inclusions that contain alpha-synuclein. By now there is compelling neuroimaging, neuropathologic, and neurochemical evidence for cardiac sympathetic denervation in Lewy body diseases. In addition to denervation, there is decreased storage of catecholamines in the residual terminals. The degeneration develops in a centripetal, retrograde, “dying back” sequence. Across synucleinopathies the putamen and cardiac catecholaminergic lesions seem to occur independently of each other, whereas non-motor aspects of PD (e.g., anosmia, dementia, REM behavior disorder, OH) are associated with each other and with cardiac sympathetic denervation. Cardiac sympathetic denervation can be caused by synucleinopathy in inherited PD. According to the catecholaldehyde hypothesis, 3,4-dihydroxyphenylacetaldehyde (DOPAL), an intermediary metabolite of dopamine, causes or contributes to the death of catecholamine neurons, especially by interacting with proteins such as alpha-synuclein. DOPAL oxidizes spontaneously to DOPAL-quinone, which probably converts alpha-synuclein to its toxic oligomeric form. Decreasing DOPAL production and oxidation might slow the neurodegenerative process. Tracking cardiac sympathetic innervation over time could be the basis for a proof of principle experimental therapeutics trial targeting DOPAL.

Striatal dopamine transporter abnormalities in pure autonomic failure and speculation about the relationship with Lewy bodies

Background: Whether pure autonomic failure (PAF) is a prodromal state of PD and DLB is not clear. However, dopamine transporter (DAT) function in PAF will help elucidate why the majority of patients with PAF experience only autonomic dysfunction and seldom progress to motor dysfunction and dementia.

Abstract P382: Management and Treatment of Neurogenic Orthostatic Hypotension: Results From a Survey of Patients and Caregivers

Objective: To understand the patient and caregiver experience with the management of neurogenic orthostatic hypotension (nOH) Background: nOH is a sustained reduction in blood pressure (BP) with postural change associated with autonomic dysfunction. Clinical symptoms may include falls, leading to activity limits and a diminished sense of well-being. Methods: A US-based survey designed by the authors was conducted by Harris Poll. Eligible participants had Parkinson disease (PD), multiple system atrophy, or pure autonomic failure and ≥1 of the following: orthostatic hypotension (OH), nOH, low BP, OH/nOH symptoms, or were caregivers of eligible patients. Descriptive statistics are reported. Results: PD was the most frequent underlying diagnosis (Table 1) . Healthcare provider (HCP) communication with patients was rated as satisfactory by ≥75% of respondents, yet when nOH symptoms were first discussed with the HCP, only 35% of patients and 31% of caregivers reported the patient received guidance on management. The most frequently recommended interventions are listed in Table 1 ; 25% of patients reported that no interventions were recommended. Medication prescribed to treat nOH was reported by 34% of patients and 45% of caregivers. Among patients treated, 79% of patients and 71% of caregivers said that the patient’s symptoms were somewhat to very well managed. Conclusions: Survey findings suggest the need for increased awareness of nOH and engagement with patients and caregivers regarding symptom management. A variety of interventions were recommended; no single treatment approach was noted. Respondents felt nOH symptoms were at least somewhat well managed with treatment.

Droxidopa for Symptomatic Neurogenic Hypotension.

Droxidopa is a first-in-class, orally available, synthetic amino acid precursor of norepinephrine that received accelerated Food and Drug Administration approval in February 2014 after Orphan Drug status for a debilitating condition known as symptomatic neurogenic orthostatic hypotension. Neurogenic disorders often lead to postural hypotension as a result of poor norepinephrine release from its storage sites. Clinical data suggest increases in standing systolic blood pressure and improvements in many other markers for subjective relief in patients with symptomatic neurogenic hypotension who received droxidopa therapy over 1-2 weeks. Studies evaluating the sustained effects of droxidopa are ongoing. With minimal drug interactions (even with carbidopa use) or adverse effects, droxidopa therapy can be used safely in patients with a variety of neurologic conditions; however, more data are needed to determine its appropriate pharmacotherapeutic role. In all, droxidopa is a safe and effective medication for the treatment of orthostatic dizziness/lightheadedness, or the "feeling that you are about to black out" in adult patients with symptomatic neurogenic orthostatic hypotension secondary to primary autonomic failure (Parkinson's disease, multiple system atrophy, and pure autonomic failure), dopamine beta-hydroxylase deficiency, and nondiabetic autonomic neuropathy.

Abstract P379: Patient and Caregiver Experiences With the Diagnosis of Neurogenic Orthostatic Hypotension

Objective: To understand the challenges to diagnosis in patients with neurogenic orthostatic hypotension (nOH) Background: nOH is a sustained reduction in blood pressure (BP) with postural change associated with autonomic dysfunction. Despite symptoms of nOH, many patients struggle to find an accurate diagnosis. Methods: An online, US-based survey designed by the authors was conducted by Harris Poll. Eligible participants were ≥18 years of age with Parkinson disease, multiple system atrophy, or pure autonomic failure and ≥1 of the following: orthostatic hypotension (OH), nOH, low BP, OH/nOH symptoms, or were caregivers of eligible participants. Results: The survey included 363 patients and 128 caregivers. Groups were separate, where caregivers were not the caregivers to patient responders. Respondents indicated that patients experienced nOH symptoms long term (Table 1) . Most patients (69%) and caregivers (59%) reported discussing nOH symptoms with a healthcare provider (HCP) within the first year of symptom onset, but only 36% of patients and 16% of caregivers reported a formal diagnosis of OH or nOH. Of those with a formal diagnosis, the majority of patients (50%) were frustrated by the path to diagnosis and more than 40% of patients and caregivers reported that the patient saw ≥3 HCPs before diagnosis. After diagnosis, most patients (70%) and caregivers (60%) reported improved symptom management. Conclusions: This survey reveals that patients and caregivers may find the path to nOH diagnosis challenging and suggests increased awareness among HCPs is needed. Once a diagnosis is made nOH symptoms are better managed.

Abstract P381: Understanding the Symptoms of Neurogenic Orthostatic Hypotension: Results From a Survey of Patients and Caregivers

Objective: To understand the burden and impact of symptoms of neurogenic orthostatic hypotension (nOH) on patients Background: nOH and its symptoms such as dizziness/lightheadedness are common in patients with Parkinson disease (PD) and other forms of autonomic dysfunction. Methods: An author-designed, US-based survey was conducted by Harris Poll. Eligible participants were aged ≥18 years with PD, multiple system atrophy (MSA), or pure autonomic failure and ≥1 of the following: orthostatic hypotension, nOH, low BP, OH/nOH symptoms, or were caregivers of eligible patients. Results: Most patients (90%) had a diagnosis of PD, and most caregivers (88%) cared for a patient with PD (Table 1) . Patients (34%) and caregivers (49%) reported experiencing nOH symptoms before PD or MSA motor symptoms and &gt;40% indicated that nOH symptoms were more troublesome than motor manifestations of PD or MSA. Less than a quarter (22%) of respondents suggested symptoms were most severe in the morning; more (30%) reported a consistent severity throughout the day. Patients (40%) and caregivers (63%) reported trouble managing symptoms during the day. In the past 12 months, a fall due to nOH symptoms was reported by 57% of patients and 80% of caregivers. Conclusions: These findings suggest that nOH symptoms may predate the onset of motor symptoms in neurodegenerative conditions linked to alpha-synuclein pathology. Many respondents report nOH symptoms are the same severity through the day. Patients with nOH may have trouble managing symptoms and note an increased risk for falls.

Abstract P393: Orthostatic Heart Rate-Blood Pressure Relationship Identifies Neurogenic Orthostatic Hypotension

Background: Neurogenic orthostatic hypotension (nOH) is a chronic disabling condition associated with significant morbidity and mortality. Currently, the diagnosis of nOH relies on impaired autonomic reflexes as determined by testing available only in specialized centers. Our objective was to test the hypothesis that a blunted heart rate (HR) increase in response to a given systolic blood pressure (SBP) fall will correctly diagnose nOH. Methods: We performed a retrospective study of nOH patients (studied in an inpatient environment off medications that can interfere with autonomic function) and control subjects. nOH was diagnosed on the basis of SBP fall ≥20 mmHg on standing associated with a decrease in SBP≥ 20 mmHg during phase 2 of the Valsalva maneuver and absence of phase 4 SBP overshoot. Controls had any SBP fall on standing but intact autonomic reflexes. Receiver operator characteristic curve (ROC) analysis was performed on the ratio of the changes from supine to 3 min standing in HR and SBP (ΔHR/ΔSBP). Results: We studied 171 nOH patients (66±1 years, males 61%, multiple system atrophy 42%, Parkinson disease 14%, pure autonomic failure 32% and undetermined 12%) and 53 controls (51±3 years, males 28%). nOH patients had a greater drop in standing SBP (-63±2 vs. -16±4 mmHg in controls; p&lt;0.01) but a smaller increase in HR (13±1 vs. 18±1 bpm in controls; p&lt;0.01). The ROC analysis at 95% Confidence Interval showed that a ΔHR/ΔSBP ratio &lt;0.445 had a 81% specificity and 79% sensitivity in identifying nOH (AUC=0.86, p&lt;0.01. Figure). Conclusions: Our study suggests that a simple ratio of ΔSBP/ΔHR &lt;0.445 during a posture test in clinic can reliably identify patients with nOH.

Pure autonomic failure.

Pure autonomic failure is a degenerative disorder of the peripheral autonomic nervous system. Patients experience symptomatic hypotension that requires them to sit, squat or lie down to prevent syncope. It is associated with characteristic histopathological findings, resulting in neuronal cytoplasmic inclusions in the peripheral autonomic nerves. These lesions are responsible for defects in the synthesis and release of norepinephrine from sympathetic nerve terminals, resulting in significant hypotension. Patients with autonomic failure also have exaggerated blood pressure responses to common stimuli such as food or fluid intake, heat, exercise and medications. Tilt table (head-up) testing is probably the test most commonly used to establish the diagnosis. However, simple office testing is also useful, such as having the patient stand after lying supine with blood pressure monitoring. Treatment options range from simply increasing fluid and salt intake, and using compressive garments, to medications administered orally, subcutaneously or intravenously in more severe cases.

REM Sleep Behavior Disorder in Parkinson's Disease and Other Synucleinopathies.

Rapid eye movement sleep behavior disorder is characterized by dream enactment and complex motor behaviors during rapid eye movement sleep and rapid eye movement sleep atonia loss (rapid eye movement sleep without atonia) during polysomnography. Rapid eye movement sleep behavior disorder may be idiopathic or symptomatic and in both settings is highly associated with synucleinopathy neurodegeneration, especially Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, and pure autonomic failure. Rapid eye movement sleep behavior disorder frequently manifests years to decades prior to overt motor, cognitive, or autonomic impairments as the presenting manifestation of synucleinopathy, along with other subtler prodromal "soft" signs of hyposmia, constipation, and orthostatic hypotension. Between 35% and 91.9% of patients initially diagnosed with idiopathic rapid eye movement sleep behavior disorder at a sleep center later develop a defined neurodegenerative disease. Less is known about the long-term prognosis of community-dwelling younger patients, especially women, and rapid eye movement sleep behavior disorder associated with antidepressant medications. Patients with rapid eye movement sleep behavior disorder are frequently prone to sleep-related injuries and should be treated to prevent injury with either melatonin 3-12 mg or clonazepam 0.5-2.0 mg to limit injury potential. Further evidence-based studies about rapid eye movement sleep behavior disorder are greatly needed, both to enable accurate prognostic prediction of end synucleinopathy phenotypes for individual patients and to support the application of symptomatic and neuroprotective therapies. Rapid eye movement sleep behavior disorder as a prodromal synucleinopathy represents a defined time point at which neuroprotective therapies could potentially be applied for the prevention of Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, and pure autonomic failure. © 2017 International Parkinson and Movement Disorder Society.