Background Multiple system atrophy (MSA) is a rare, fatal neurodegenerative disorder exhibiting a combination of parkinsonism and/or cerebellar ataxia with autonomic failure. We report the first North American prospective natural history study of MSA, and the effects of phenotype and autonomic failure on prognosis. Methods 175 subjects with probable MSA, both MSA-P and MSA-C, were recruited and prospectively followed for 5 years with evaluations every 6 months in 12 centers. Natural history was evaluated by Kaplan-Meier survival analysis. We compared MSA-P with MSA-C and evaluated predictors of outcome. These subjects were evaluated with UMSARS I (a functional score of symptoms and ability to undertake activities of daily living), UMSARS II (neurological motor evaluation), and the Composite Autonomic Symptoms Scale (COMPASS)-select (a measure of autonomic symptoms and autonomic functional status. Findings Mean age of symptom onset was 63.4 (SD 8.57) years. Median survival from symptom onset by Kaplan-Meier analysis was 9.8 years (95% CI 8.8-10.7). Subjects with severe symptomatic autonomic failure (symptomatic orthostatic hypotension, urinary incontinence) at diagnosis had a worse prognosis, surviving 8.0 years (95% CI, 6.5-9.5, n=62) while remaining subjects survived a median of 10.3 years (95% CI, 9.3-11.4, n=113). At baseline MSA-P (n=126) and MSA-C (n=49) were not different in symptoms and function, UMSARS I, 25.2 (8.08) vs 24.6 (8.34), p=0.835; UMSARS II, 26.4 (8.77) vs 25.4 (10.51), p=0.7635; COMPASS_select), 43.5 (18.66) vs 42.8 (19.56), p=0.835. Progression, evaluated by change in UMSARS I, UMSARS II, COMPASS_select over the next 5 years, was not significantly different between MSA-P and MSA-C. Median time to death from enrollment baseline was 1.8 (95% CI, 0.9-2.7) years. Interpretation Probable MSA represents late-stage disease with short survival. Natural history of MSA-P and MSA-C are similar. Severe symptomatic autonomic failure at diagnosis is associated with worse prognosis. Funding National Institutes of Health (P01 NS044233), Mayo CTSA (UL1 TR000135), the Kathy Shih Memorial Foundation, and Mayo funds.

Background and Purpose-Orthostatic and other stresses trigger tachycardia associated with symptoms of tremulousness, shortness of breath, dizziness, blurred vision, and, often, syncope. It has been suggested that paradoxical cerebral vasoconstriction during head-up tilt might be present in patients with orthostatic intolerance. We chose to study middle cerebral artery (MCA) blood flow velocity (BFV) and cerebral vasoregulation during tilt in patients with orthostatic intolerance (OI). Methods-Beat-to-beat BFV from the MCA, heart rate, CO 2 , blood pressure (BP), and respiration were measured in 30 patients with OI (25 women and 5 men; age range, 21 to 44 years; mean age, 31.3Ϯ1.2 years) and 17 control subjects (13 women and 4 men; age range, 20 to 41 years; mean age, 30Ϯ1.6 years); ages were not statistically different. These indices were monitored during supine rest and head-up tilt (HUT). We compared spontaneous breathing and hyperventilation and evaluated the effect of CO 2 rebreathing in these 2 positions. Results-The OI group had higher supine heart rates (PϽ0.001) and cardiac outputs (PϽ0.01) than the control group. In response to HUT, OI patients underwent a greater heart rate increment (PϽ0.001) and greater reductions in pulse pressure (PϽ0.01) and CO 2 (PϽ0.001), but total systemic resistance failed to show an increment. Among the cerebrovascular indices, all BFVs (systolic, diastolic, and mean) decreased significantly more, and cerebrovascular resistance (CVR) was increased in OI patients (PϽ0.01) compared with control subjects. In both groups, hyperventilation induced mild tachycardia (PϽ0.001), a significant reduction of BFV, and a significant increase of CVR associated with a fall in CO 2 . Hyperventilation during HUT reproduced hypocapnia, BFV reduction, and tachycardia and worsened symptoms of OI; these symptoms and indices were improved within 2 minutes of CO 2 rebreathing. The relationships between CO 2 and BFV and heart rate were well described by linear regressions, and the slope was not different between control subjects and patients with OI. Conclusions-Cerebral vasoconstriction occurs in OI during orthostasis, which is primarily due to hyperventilation, causing significant hypocapnia. Hypocapnia and symptoms of orthostatic hypertension are reversible by CO 2

Background and Purpose-We sought to evaluate cerebral autoregulation in patients with orthostatic hypotension (OH). Methods-We studied 21 patients (aged 52 to 78 years) with neurogenic OH during 80°head-up tilt. Blood flow velocities (BFV) from the middle cerebral artery were continuously monitored with transcranial Doppler sonography, as were heart rate, blood pressure (BP), cardiac output, stroke volume, CO 2 , total peripheral resistance, and cerebrovascular resistance. Results-All OH patients had lower BP (PϽ.0001), BFV_diastolic (PϽ.05), CVR (PϽ.007), and TPR (PϽ.02) during head-up tilt than control subjects. In control subjects, no correlations between BFV and BP were found during head-up tilt, suggesting normal autoregulation. OH patients could be separated into those with normal or expanded autoregulation (OH_NA; nϭ16) and those with autoregulatory failure (OH_AF; nϭ5). The OH_NA group showed either no correlation between BFV and BP (nϭ8) or had a positive BFV/BP correlation (R 2 Ͼ.75) but with a flat slope. An expansion of the "autoregulated" range was seen in some patients. The OH_AF group was characterized by a profound fall in BFV in response to a small reduction in BP (mean ⌬BP Ͻ40 mm Hg; R 2 Ͼ.75). Conclusions-The

The dynamics of the respiratory and cardiovascular systems were studied by continuously slowing respiration from 0.46 to 0.05 Hz. The time-frequency distribution and global spectral analysis were used to assess the R-R interval (R-R) and the systolic and diastolic blood pressure fluctuations in 16 healthy subjects. During rest, the nonrespiratory-to-respiratory frequency ratios were not affected by occasional slow breathing, whereas the low- (0.01-0.15 Hz) to high- (0.15-0.3 Hz) frequency indexes for blood pressure were increased (P < 0.05). The respiratory fluctuations in R-R and the systolic and diastolic pressures were paced over the 0.46- to 0.05-Hz range. As respiration slowed to 0.07-0.09 Hz, the frequency content of the respiration and cardiovascular variables increased sharply and nonlinearly to a maximum that exceeded values at higher frequencies (P < 0.001). The nonrespiratory frequency content remained stable in the 0.01- to 0.05-Hz range and did not significantly differ from that at rest. In contrast, the nonstable 0.05- to 0.1-Hz component was suppressed. A slow 0.012- to 0.017-Hz rhythm modulated respiration and hemodynamic fluctuations at both respiratory and nonrespiratory frequencies. The study indicated that respiration input should be considered in the interpretation of global spectra. Furthermore the time-frequency distributions demonstrated that a close nonlinear coupling exists between the respiratory and cardiovascular systems.

OBJECTIVETo determine acute effects of intranasal insulin on regional cerebral perfusion and cognition in older adults with type 2 diabetes mellitus (DM).RESEARCH DESIGN AND METHODSThis was a proof-of-concept, randomized, double-blind, placebo-controlled intervention evaluating the effects of a single 40-IU dose of insulin or saline on vasoreactivity and cognition in 15 DM and 14 control subjects. Measurements included regional perfusion, vasodilatation to hypercapnia with 3-Tesla MRI, and neuropsychological evaluation.RESULTSIntranasal insulin administration was well tolerated and did not affect systemic glucose levels. No serious adverse events were reported. Across all subjects, intranasal insulin improved visuospatial memory (P ≤ 0.05). In the DM group, an increase of perfusion after insulin administration was greater in the insular cortex compared with the control group (P = 0.0003). Cognitive performance after insulin administration was related to regional vasoreactivity. Improvements of visuospatial memory after insulin administration in the DM group (R2adjusted = 0.44, P = 0.0098) and in the verbal fluency test in the control group (R2adjusted = 0.64, P = 0.0087) were correlated with vasodilatation in the middle cerebral artery territory.CONCLUSIONSIntranasal insulin administration appears safe, does not affect systemic glucose control, and may provide acute improvements of cognitive function in patients with type 2 DM, potentially through vasoreactivity mechanisms. Intranasal insulin-induced changes in cognitive function may be related to vasodilatation in the anterior brain regions, such as insular cortex that regulates attention-related task performance. Larger studies are warranted to identify long-term effects and predictors of positive cognitive response to intranasal insulin therapy.

Disorders associated with dysfunction of autonomic nervous system are quite common yet frequently unrecognized. Quantitative autonomic testing can be invaluable tool for evaluation of these disorders, both in clinic and research. There are number of autonomic tests, however, only few were validated clinically or are quantitative. Here, fully quantitative and clinically validated protocol for testing of autonomic functions is presented. As a bare minimum the clinical autonomic laboratory should have a tilt table, ECG monitor, continuous noninvasive blood pressure monitor, respiratory monitor and a mean for evaluation of sudomotor domain. The software for recording and evaluation of autonomic tests is critical for correct evaluation of data. The presented protocol evaluates 3 major autonomic domains: cardiovagal, adrenergic and sudomotor. The tests include deep breathing, Valsalva maneuver, head-up tilt, and quantitative sudomotor axon test (QSART). The severity and distribution of dysautonomia is quantitated using Composite Autonomic Severity Scores (CASS). Detailed protocol is provided highlighting essential aspects of testing with emphasis on proper data acquisition, obtaining the relevant parameters and unbiased evaluation of autonomic signals. The normative data and CASS algorithm for interpretation of results are provided as well. Video LinkThe video component of this article can be found at https://www.jove.com/video/2502/ Protocol Equipment, data acquisition and processing of autonomic signalsAs a bare minimum, the clinical autonomic laboratory has to have motorized tilt table, ECG, noninvasive beat-to-beat blood pressure monitor, respiratory monitor and a mean to evaluate sudomotor functions. Recommended equipment is listed at Table 9. The data acquisition and analyzing software is a critical to be able to run the lab effectively. Unfortunately, the commercially suitable software has some restrictions and most of the autonomic laboratories wrote their own acquisition or analyzing software in house. Robust R wave detection and detection of corresponding systolic/diastolic values in blood pressure, eventually in blood flow, is of paramount importance. At University of Massachusetts we use ADInstrument-based recording system (Figures 1-4, Table 9) that is easy to program and provides many mathematical functions in real time.The protocol use in the paper is based on methodology developed primary by Dr. P. Low and his team (1). This paper assumes that the reader knows how to correctly place ECG electrodes, setup of the continuous blood pressure monitor and how to record the data. Details of the electrode/sensor placement and recommended standards for data acquisition are at reference 4. Deep breathingDeep breathing tests cardiac parasympathetic functions. Because the heart responses to deep breathing are mediated by the vagal nerve, the test is also referred to as cardiovagal testing. Deep breathing evaluates changes in the instant heart rate that is provoked by "deep" breathing at 6 breaths/min. The t...

Type 2 diabetes mellitus (T2DM) alters brain function and manifests as brain atrophy. Intranasal insulin has emerged as a promising intervention for treatment of cognitive impairment. We evaluated the acute effects of intranasal insulin on resting-state brain functional connectivity in older adults with T2DM. This proof-of-concept, randomized, double-blind, placebo-controlled study evaluated the effects of a single 40 IU dose of insulin or saline in 14 diabetic and 14 control subjects. Resting-state functional connectivity between the hippocampal region and default mode network (DMN) was quantified using functional MRI (fMRI) at 3Tesla. Following insulin administration, diabetic patients demonstrated increased resting-state connectivity between the hippocampal regions and the medial frontal cortex (MFC) as compared with placebo (cluster size: right, P = 0.03) and other DMN regions. On placebo, the diabetes group had lower connectivity between the hippocampal region and the MFC as compared with control subjects (cluster size: right, P = 0.02), but on insulin, MFC connectivity was similar to control subjects. Resting-state connectivity correlated with cognitive performance. A single dose of intranasal insulin increases resting-state functional connectivity between the hippocampal regions and multiple DMN regions in older adults with T2DM. Intranasal insulin administration may modify functional connectivity among brain regions regulating memory and complex cognitive behaviors.

Coronavirus disease (COVID-19) is a novel highly contagious infectious disease caused by the coronavirus SARS-CoV2. The virus affects the human respiratory and other systems, and presents mostly as acute respiratory syndrome with fever, fatigue, dry cough, myalgia and dyspnea. The clinical manifestations vary from no symptoms to multiple organ failure. Majority of patients fully recover. Several postinfectious presumably autoimmune complications of COVID-19 affecting the brain or peripheral large nerve fibers have been reported. This report describes a post COVID-19 patient who developed chronic fatigue, orthostatic dizziness and brain fog consistent with orthostatic hypoperfusion syndrome (OCHOS), a form of orthostatic intolerance, and painful small fiber neuropathy (SFN). Initially, the patient was diagnosed with. OCHOS (detected by the tilt test with transcranial Doppler monitoring) and SFN (confirmed by skin biopsy), and both OCHOS/SFN were attributed to Post Treatment Lyme Disease Syndrome of presumed autoimmune etiology. Patient recovered on symptomatic therapy. COVID-19 triggered exacerbation of OCHOS/SFN responded to immunotherapy with intravenous immunoglobulins. This case suggests that post COVID-19 syndrome may present as an autoimmune OCHOS/SFN and that early immunotherapy may be effective. Further studies are necessary to confirm the link between OCHOS/SFN and COVID-19 disease as well as to confirm the benefit of immunotherapy.