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Type 2 diabetes mellitus (T2DM) increases the risk of dementia. Intranasal insulin (INI) has emerged as treatment for T2DM-related cognitive impairment. This randomized, doubled blind trial consisted of 24-week treatment with 40 IU of intranasal insulin (Novolin® R) or placebo (sterile saline) once daily and 24-week follow-up period. T2DM and control participants > 50 years old and able to walk for 6 minutes, were enrolled. The primary outcomes were INI effect on cognition and normal and dual task walking. A total of 244 participants (122 women; 65.8 ± 9.1 years old) were randomized in the four groups (57 DM-INI, 58 DM-Placebo, 65 Control-INI, 64 Control-Placebo). Of 223 at baseline, 174 completed treatment (84 DM [70% of planned enrollment] and 90 controls [100%]), and 156 (69 DM) completed the follow-up. In T2DM, INI did not improve cognitive outcomes or depression as compared to placebo. In controls, INI improved verbal learning during on-treatment (p=0.03) and post-treatment (p=0.03) periods (Mixed Models). DM-INI group had faster normal walking at baseline and on-treatment (p Disclosure V. Novak: Advisory Panel; Spouse/Partner; Endonovo Therapeutics, Inc., Consultant; Spouse/Partner; Dysimmune Foundtation, Other Relationship; Spouse/Partner; Oxford University Press. L. Aponte becerra: None. L. H. Ngo: Consultant; Self; Five Islands Consulting, Other Relationship; Self; Radiological Society of America. C. Mantzoros: Advisory Panel; Self; Amgen Inc., GENFIT, Intercept Pharmaceuticals, Inc., Novo Nordisk, Regeneron Pharmaceuticals Inc. P. Novak: Other Relationship; Self; Dysimmune Foundation, Endonovo Therapeutics, Oxford Press. R. Mcglinchey: None. W. Dai: None. V. Lioutas: Consultant; Self; QMetis. S. Buss: Consultant; Self; Kinto Care. C. B. Fortier: None. F. Khan: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (1R01DK103902); U.S. Food and Drug Administration (IND107690); Novo Nordisk (ISS-001063), Medtronic (NERP15-0310); World Health Organization (UTN-U111-1175-1588)

Effective recruitment and retention strategies in clinical trials are essential to achieve the enrollment goals. We aimed to identify baseline characteristics predicting dropouts and analyze the effect of retention strategies within the MemAID elderly cohort. The trial consisted of 12 visits during 24 weeks of INI/placebo treatment and 24 weeks of follow-up. Retention strategies were implemented 2 years after the beginning of the study and included incentives (meals, stipend, transportation), revised eligibility criteria, and flexibility in scheduling. A total of 244 participants (122 female; 65.8 ± 9.1 years old, 115 diabetes (DM)) were randomized, and completed baseline (223), treatment (174), and follow-up (156). After randomization, 65 participants (27%, 30 DM [46%]) dropped out. Dropouts occurred earlier in the study (19.6% cumulative failure at 100 days) as compared to later (25.3% cumulative failure at 300 days). Cox models showed no risk of dropout with DM diagnosis, but increased risk (p Disclosure F. Khan: None. D. F. Isaza-pierotti: None. P. Novak: Other Relationship; Self; Dysimmune Foundation, Endonovo Therapeutics, Oxford Press. C. Mantzoros: Advisory Panel; Self; Amgen Inc., GENFIT, Intercept Pharmaceuticals, Inc., Novo Nordisk, Regeneron Pharmaceuticals Inc. L. H. Ngo: Consultant; Self; Five Islands Consulting, Other Relationship; Self; Radiological Society of America. V. Novak: Advisory Panel; Spouse/Partner; Endonovo Therapeutics, Inc., Consultant; Spouse/Partner; Dysimmune Foundtation, Other Relationship; Spouse/Partner; Oxford University Press. Funding National Institute of Diabetes and Digestive and Kidney Diseases (1R01DK103902); U.S. Food and Drug Administration (IND107690); Novo Nordisk (ISS-001063), Medtronic (NERP15-0310); World Health Organization (UTN-U111-1175-1588)

INI has emerged as a potential treatment for T2DM-related functional decline and is safe in adults without T2DM. However, INI safety in T2DM-IDDM is unknown. We aimed to demonstrate safety of long-term INI use in T2DM-IDDM MemAID participants. We screened 86 participants with T2DM-IDDM, 14 were randomized (9 INI/5 Placebo), 9 started treatment (5 INI [60±14 years, 2 Female]; 4 Placebo [68±2 years, 1 Female]). Of those, 2-INI and 3-Placebo participants completed 24 weeks of treatment and 24 weeks of follow-up. Participants underwent one week of continuous glucose monitoring (CGM)(Medtronic IPro2) at baseline and after INI (Novolin® R ) or placebo initiation. HbA1c, fasting plasma and capillary glucose, and insulin were measured throughout the study. Insulin levels were unchanged across the study. In 2 INI-treated participants, HbA1c, fasting plasma and capillary glucose declined from baseline, but the average values were similar during treatment and follow up, and comparable to 3 placebo-treated participants. Both INI-treated participants had adjustments of IDDM regimens. Capillary glucose did not decline 2 hours after INI administration, and there were no interactions between INI and subcutaneous insulin. There were no INI-related serious adverse events. Of 13 hypoglycemia (HG) episodes across the study, 2 asymptomatic level-1 HG (15.4%) occurred in INI group and 7 (53.8%) in placebo group. There were 2 asymptomatic level-2 HG (15.4%) in both INI and placebo groups. INI therapy was not associated with serious adverse events or HG in older participants with T2DM-IDDM. This study may pave the way towards future larger studies evaluating the safety of concomitant administration of INI and subcutaneous insulin (NCT02415556). Disclosure L. Aponte becerra: None. B. Galindo mendez: None. F. Khan: None. C. Mantzoros: Advisory Panel; Self; Amgen Inc., GENFIT, Intercept Pharmaceuticals, Inc., Novo Nordisk, Regeneron Pharmaceuticals Inc. P. Novak: Other Relationship; Self; Dysimmune Foundation, Endonovo Therapeutics, Oxford Press. V. Lioutas: Consultant; Self; QMetis. L. H. Ngo: Consultant; Self; Five Islands Consulting, Other Relationship; Self; Radiological Society of America. Memaid investigators (j. trevino): n/a. V. Novak: Advisory Panel; Spouse/Partner; Endonovo Therapeutics, Inc., Consultant; Spouse/Partner; Dysimmune Foundtation, Other Relationship; Spouse/Partner; Oxford University Press. Funding National Institute of Diabetes and Digestive and Kidney Diseases (1R01DK103902); U.S. Food and Drug Administration (IND107690); Novo Nordisk (ISS-001063), Medtronic (NERP15-0310); World Health Organization (UTN-U111-1175-1588)

Mast cells (MCs) are important in intestinal homeostasis and pathogen defense but are also implicated in many of the clinical manifestations in disorders such as irritable bowel syndrome. The utility of specifically staining for MCs in order to quantify and phenotype them in intestinal biopsies in patients with gastrointestinal (GI) symptoms is controversial and is not a widely adopted practice. Whether or not intestinal MCs are increased or have a unique phenotype in individuals with hereditary alpha-tryptasemia (HαT), who have extra copies of the mast cell tryptase gene TPSAB1 and typically elevated baseline serum tryptase levels >8ng/mL is not known. We examined the duodenal biopsies of 17 patients with HαT and compared them to 15 patients with mast cell activation syndrome who had baseline serum tryptases

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., Highlights • Post COVID-19 syndrome is associated with fatigue, brain fog and pain. • Orthostatic cerebral hypoperfusion syndrome (OCHOS) can be responsible for fatigue and brain fog in post COVID-19 syndrome. • Small fiber neuropathy (SFN) can be responsible for pain in post COVID-19 syndrome. • OCHOS and SFN in post COVID-19 syndrome may have autoimmune basis and early immunotherapy with intravenous immunoglobulins may be effective.

ObjectiveTo evaluate the safety and efficacy of l-serine in humans with hereditary sensory autonomic neuropathy type I (HSAN1).MethodsIn this randomized, placebo-controlled, parallel-group trial with open-label extension, patients aged 18–70 years with symptomatic HSAN1 were randomized to l-serine (400 mg/kg/day) or placebo for 1 year. All participants received l-serine during the second year. The primary outcome measure was the Charcot-Marie-Tooth Neuropathy Score version 2 (CMTNS). Secondary outcomes included plasma sphingolipid levels, epidermal nerve fiber density, electrophysiologic measurements, patient-reported measures, and adverse events.ResultsBetween August 2013 and April 2014, we enrolled and randomized 18 participants, 16 of whom completed the study. After 1 year, the l-serine group experienced improvement in CMTNS relative to the placebo group (−1.5 units, 95% CI −2.8 to −0.1, p = 0.03), with evidence of continued improvement in the second year of treatment (−0.77, 95% CI −1.67 to 0.13, p = 0.09). Concomitantly, deoxysphinganine levels dropped in l-serine-treated but not placebo-treated participants (59% decrease vs 11% increase; p < 0.001). There were no serious adverse effects related to l-serine.ConclusionHigh-dose oral l-serine supplementation appears safe in patients with HSAN1 and is potentially effective at slowing disease progression.Clinicaltrials.gov identifierNCT01733407.Classification of evidenceThis study provides Class I evidence that high-dose oral l-serine supplementation significantly slows disease progression in patients with HSAN1.

Background: Small fiber neuropathy (SFN) is a common health problem. SFN is associated with loss of small fibers, either sensory, autonomic or both. Reduced autonomic sudomotor sweat gland nerve fiber density (SGNFD) and sensory epidermal nerve fiber density (ENFD) can be seen in SFN. Electrochemical skin conductance (ESC) is a non-invasive test for measurement of sudomotor function. This study evaluated the diagnostic accuracy of ESC to detect abnormal SGNFD and ENFD.Methods: This was a retrospective blinded study of participants referred for evaluation of SFN. The primary outcome measure was the specificity and sensitivity of ESC to diagnose loss of small fibers using SGNFD and ENFD as reference tests. The secondary outcome measures were the correlation between ESC and neuropathy severity, pain, and autonomic clinical scales.Results: Two hundred ten patients were enrolled in the study, age (mean ± sd) 45.5 ± 16.1 years, men/women = 52/158. ESC adjusted for weight (ESC/kg) was reduced in subjects with abnormally low SGNFD (normal/abnormal, ESC/kg = 1.19 ± 0.31/0.94 ± 0.37 μS/kg, p < 0.0001) and abnormally low ENFD (normal/abnormal ESC/kg 1.20 ± 0.37/1.04 ± 0.33 μS/kg, p < 0.0011). ESC/kg correlated with SGNFD (ρ = 0.39, p < 0.0001) and ENFD (ρ = 0.47, p < 0.0001). ESC/kg did not correlate with symptom scales. ESC/kg had 64% sensitivity and 77% specificity (ROC 0.73, p = 0.0001) to predict abnormal SGNFD and 69% sensitivity and 55% specificity (ROC 0.63, p = 0.0017) to predict abnormal ENFD. In comparison, SGNFD had 50.1% sensitivity and 85.1% specificity to predict abnormal ENFD (ROC 0.69, p = 0.0001).Conclusion: ESC/kg has modest accuracy to detect SGNFD loss. ESC may be a useful test in characterization of small fiber neuropathy.

Background Type 2 diabetes mellitus (T2DM) accelerates brain aging and increases the risk for dementia. Insulin is a key neurotrophic factor in the brain, where it modulates energy metabolism, neurovascular coupling, and regeneration. Impaired insulin-mediated brain signaling and central insulin resistance may contribute to cognitive and functional decline in T2DM. Intranasal insulin (INI) has emerged as a potential therapy for treating T2DM-related cognitive impairment. Methods/design Ongoing from 2015, a prospective, two-center, randomized, double-blind, placebo-controlled trial of 210 subjects (120 T2DM and 90 non-diabetic older adults) randomized into four treatment arms (60 T2DM-INI, 60 T2DM-Placebo, 45 Control-INI, and 45 Control-Placebo) evaluating the long-term effects of daily intranasal administration of 40 International Units (IU) of human insulin, as compared to placebo (sterile saline) over 24 weeks and 24 weeks of post-treatment follow-up. Study outcomes are: 1) long-term INI effects on cognition, daily functionality, and gait speed; 2) identifying a clinically relevant phenotype that predicts response to INI therapy; 3) long-term safety. Conclusion This study addresses an important knowledge gap about the long-term effects of intranasal insulin on memory and cognition in older people with T2DM and non-diabetic controls, and may provide a novel therapeutic target for prevention and treatment of cognitive and functional decline and dementia. Trial Registration NCT02415556

ObjectivesTo examine whether post-treatment Lyme disease syndrome (PTLDS) defined by fatigue, cognitive complaints and widespread pain following the treatment of Lyme disease is associated with small fiber neuropathy (SFN) manifesting as autonomic and sensory dysfunction.MethodsThis single center, retrospective study evaluated subjects with PTLDS. Skin biopsies for assessment of epidermal nerve fiber density (ENFD), sweat gland nerve fiber density (SGNFD) and functional autonomic testing (deep breathing, Valsalva maneuver and tilt test) were performed to assess SFN, severity of dysautonomia and cerebral blood flow abnormalities. Heart rate, end tidal CO2, blood pressure, and cerebral blood flow velocity (CBFv) from middle cerebral artery using transcranial Doppler were monitored.Results10 participants, 5/5 women/men, age 51.3 ± 14.7 years, BMI 27.6 ± 7.3 were analyzed. All participants were positive for Lyme infection by CDC criteria. At least one skin biopsy was abnormal in all ten participants. Abnormal ENFD was found in 9 participants, abnormal SGNFD in 5 participants, and both abnormal ENFD and SGNFD were detected in 4 participants. Parasympathetic failure was found in 7 participants and mild or moderate sympathetic adrenergic failure in all participants. Abnormal total CBFv score was found in all ten participants. Low orthostatic CBFv was found in 7 participants, three additional participants had abnormally reduced supine CBFv.ConclusionsSFN appears to be associated with PTLDS and may be responsible for certain sensory symptoms. In addition, dysautonomia related to SFN and abnormal CBFv also seem to be linked to PTLDS. Reduced orthostatic CBFv can be associated with cerebral hypoperfusion and may lead to cognitive dysfunction. Autonomic failure detected in PTLDS is mild to moderate. SFN evaluation may be useful in PTLDS.

The objective of the study was to identify markers of hypocapnic cerebral hypoperfusion (HYCH) in patients with orthostatic intolerance (OI) without tachycardia and without orthostatic hypotension. This single center, retrospective study included OI patients referred for autonomic evaluation with the 10 min tilt test. Heart rate, end-tidal CO2 (ET-CO2), blood pressure, and cerebral blood flow velocity (CBFv) from middle cerebral artery were monitored. HYCH was defined by: (1) Symptoms of OI; (2) Orthostatic hypocapnia (low ET-CO2); (3) Abnormal decline in orthostatic CBFv due to hypocapnia; 4) Absence of tachycardia, orthostatic hypotension, or other causes of low CBFv or hypocapnia. Sixteen subjects met HYCH criteria (15/1 women/men, age 38.5±8.0 years) and were matched by age and gender to postural tachycardia patients (POTS, n = 16) and healthy controls (n = 16). During the tilt, CBFv decreased more in HYCH (-22.4±7.7%, p

Introduction: Hereditary sensory and autonomic neuropathy type 1 (HSAN1) is most commonly caused by missense mutations in SPTLC1. In this study we mapped symptom progression and compared the utility of outcomes. Methods: We administered retrospective surveys of symptoms and analyzed results of nerve conduction, autonomic function testing (AFT), and PGP9.5-immunolabeled skin biopsies. Results: The first symptoms were universally sensory and occurred at a median age of 20 years (range 14–54 years). The onset of weakness, ulcers, pain, and balance problems followed sequentially. Skin biopsies revealed universally absent epidermal innervation at the distal leg with relative preservation in the thigh. Neurite density was highly correlated with total Charcot-Marie-Tooth Examination Score (CMTES; r2 = −0.8) and median motor amplitude (r2 = −0.75). Conclusions: These results confirm sensory loss as the initial symptom of HSAN1 and suggest that skin biopsy may be the most promising biomarker for future clinical trials. Muscle Nerve, 2015 Muscle Nerve 51: 489–495, 2015

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.

Parkinson disease (PD) is associated with cognitive impairment. We aimed to determine the effects of intranasal insulin (INI) on cognition and motor performance in PD. This was a proof of concept, randomized, double-blinded, placebo-controlled trial evaluating the effects of 40 international units (IU) of insulin or saline once daily for four weeks on cognitive and functional performance. Of 16 subjects enrolled, eight in the INI group and six in the placebo group completed verbal fluency (FAS), Unified Parkinson Disease Scale (UPDRS), and modified Hoehn and Yahr scale (HY, PD severity) at baseline and post-treatment and were included in the analyses. After treatment, the INI group had a better total FAS score (p = 0.02) (41 ± 8.2 vs. 30.8 ± 7.1, mean ±SD, p = 0.02) compared to the placebo group. The INI group also had improved HY (p = 0.04) and UPDRS-Motor (Part III) (p = 0.02) scores when compared to baseline. One INI treated patient with multiple system atrophy (MSA) remained stable and did not show disease progression. The placebo group had no change. INI administration was well tolerated and there were no hypoglycemic episodes or serious study related adverse events or medications interactions. INI is safe in PD and MSA patients and may provide clinically relevant functional improvement. Larger studies are warranted to determine the INI effect in treatment of cognitive and motor impairment in Parkinson disease. Trial Registration: ClinicalTrial.gov NCT02064166.

Purpose: Electrochemical skin conductance (ESC) using reverse iontophoresis and chronoamperometry has been used to evaluate abnormal function of small fibers. How ESC correlates with loss of small fibers in skin is unclear. Methods: This was a prospective, blinded study. The primary outcome measure was the correlation between ESC at the feet and results of skin biopsies including epidermal nerve fiber density (ENFD) and sweat gland nerve fiber density (SGNFD) at the distal leg. ESC, ENFD, and SGNFD data were normalized by adjusting for weight. The secondary outcome measures were the correlation between ESC and the following variables: quantitative sudomotor axon reflex test (QSART) and symptom scales (neuropathy, pain and autonomic). Results: Eighty-one patients (mean ± sd): age = 53.3 ± 17.3, men/women = 25/56 were enrolled in the study. ESC was reduced in subjects with abnormally low ENFD (ENFD normal/abnormal, ESC = 1.17 ± 0.27/0.87 ± 0.34 μSiemens/kg, p < 0.0008) and abnormally low SGNFD (SGNFD normal/abnormal ESC = 1.09 ± 0.34/0.78 ± 0.3 μSiemens/kg, p < 0.0003). ESC correlated with ENFD (ρ = 0.73, p = 0.0001) and SGNFD (ρ = 0.64, p = 0.0001). ESC did not correlate with symptom scales. Conclusion: ESC is diminished in subjects who have a reduced number of small fibers in the skin and the ESC reduction is proportional to ENFD and SGNFD. ESC can be useful in detecting loss of small nerve fibers.

OBJECTIVE To investigate the effects of inflammation on perfusion regulation and brain volumes in type 2 diabetes. RESEARCH DESIGN AND METHODS A total of 147 subjects (71 diabetic and 76 nondiabetic, aged 65.2 ± 8 years) were studied using 3T anatomical and continuous arterial spin labeling magnetic resonance imaging. Analysis focused on the relationship between serum soluble vascular and intercellular adhesion molecules (sVCAM and sICAM, respectively, both markers of endothelial integrity), regional vasoreactivity, and tissue volumes. RESULTS Diabetic subjects had greater vasoconstriction reactivity, more atrophy, depression, and slower walking. Adhesion molecules were specifically related to gray matter atrophy (P = 0.04) and altered vasoreactivity (P = 0.03) in the diabetic and control groups. Regionally, sVCAM and sICAM were linked to exaggerated vasoconstriction, blunted vasodilatation, and increased cortical atrophy in the frontal, temporal, and parietal lobes (P = 0.04–0.003). sICAM correlated with worse functionality. CONCLUSIONS Diabetes is associated with cortical atrophy, vasoconstriction, and worse performance. Adhesion molecules, as markers of vascular health, have been indicated to contribute to altered vasoregulation and atrophy.

Dysosmia in PD (Parkinson’s Disease) may result from changes in the olfactory apparatus or in structures involved in olfactory perception. Previous work 1,2 has suggested that deep brain stimulation (DBS) patients have improved odor discrimination in stimulation-on/medicationoff state in comparison to their own scores in a stimulation-off/ medication-off state. What remains unclear is whether it is the ON state itself or an effect of stimulation that leads to improved olfaction. In this study we evaluate dysosmia in two PD cohorts in the ON state, those treated with medication alone and those treated with medication and DBS. A prospective study geared at improving predictive value of olfactory testing with a battery of psychological tests enrolled 45 PD patients and 44 controls. Of the PD patients, 9 had bilateral STN (subthalamic nucleus) DBS and 36 were medically treated. Subset analysis of PD patients with and without DBS placement revealed no difference in apathy or depression. DBS patients had better olfaction on UPSIT (Univ of Pennsylvania Smell Identification Test) (p

Targeting of the subthalamic nucleus (STN) during deep brain stimulation (DBS) surgery using standard atlas coordinates is used in some centers. Such coordinates are accurate for only a subgroup of patients, and subgroup size depends on the extent of inter-individual variation in STN position/size and degree to which atlas represents average anatomical relations. Few studies have addressed this issue.Sixty-two axial T(2)-weighted magnetic resonance (MR) images of the brain (1.5 T) were obtained before STN-DBS in 62 patients (37 males) with Parkinson's disease using a protocol optimized for STN visualization. Image distortion was within sub-millimeter range. Midcommissural point (MCP)-derived coordinates of STN borders, STN center, and other brain landmarks were obtained using stereotactic software. MR-derived measurements were compared to Schaltenbrand and Wahren Atlas.We evaluated 117 best-visualized STNs. STN dimensions and coordinates of its center were highly variable. STN lateral coordinate ranged 8.7 mm-14.5 mm from MCP, A-P coordinate 3.5 mm posterior to 0.5 mm anterior to MCP, and vertical coordinate 1.3 mm-6 mm below MCP. The antero-posterior nucleus dimension varied by 8 mm and lateral-medial dimension by 5.8 mm. Differences between mean values of MR-derived data sets and Atlas values were statistically significant but moderate, excluding AC-PC length, for which the Atlas value was below the 1st percentile of the MR data set. The STN lateral coordinate strongly correlated with the width of the third ventricle (r = 0.73, p0.001).It is now possible to directly evaluate STNs at 1.5 T with minimal image distortion, which reveals variation in STN position and dimensions in the range of nucleus size. This puts under question the rationale of use of standard STN coordinates during DBS surgery.

Objective Orthostatic dizziness without orthostatic hypotension is common but underlying pathophysiology is poorly understood. This study describes orthostatic cerebral hypoperfusion syndrome (OCHOs). OCHOs is defined by (1) abnormal orthostatic drop of cerebral blood flow velocity (CBFv) during the tilt test and (2) absence of orthostatic hypotension, arrhythmia, vascular abnormalities, or other causes of abnormal orthostatic CBFv. Methods This retrospective study included patients referred for evaluation of unexplained orthostatic dizziness. Patients underwent standardized autonomic testing, including 10 min of tilt test. The following signals were monitored: heart rate, end tidal CO2, blood pressure, and CBFv from the middle cerebral artery using transcranial Doppler. Patients were screened for OCHOs. Patients who fulfilled the OCHOs criteria were compared to age- and gender-matched controls. Results From 1279 screened patients, 102 patients (60/42 women/men, age 51.1 ± 14.9, range 19–84 years) fulfilled criteria of OCHOs. There was no difference in baseline supine hemodynamic variables between OCHOs and the control group. During the tilt, mean CBFv decreased 24.1 ± 8.2% in OCHOs versus 4.2 ± 5.6% in controls (p

Objective. The head-up tilt test is widely used for evaluation of orthostatic intolerance. Although orthostatic symptoms usually reflect cerebral hypoperfusion, the cerebral blood flow velocity (CBFv) profile in orthostatic syndromes is not well described. This study evaluated CBFv and cardiovascular patterns associated with the tilt test in common orthostatic syndromes. Methods. This retrospective study analyzed the tilt test of patients with history of orthostatic intolerance. The following signals were recorded: ECG, blood pressure, CBFv using transcranial Doppler, respiratory signals, and end tidal CO2. Results. Data from 744 patients were analyzed. Characteristic pattern associated with a particular orthostatic syndrome can be grouped into abnormalities predominantly affecting blood pressure (orthostatic hypotension, orthostatic hypertension syndrome, vasomotor oscillations, and neurally mediated syncope—cardioinhibitory, vasodepressor, and mixed), cerebral blood flow (orthostatic hypoperfusion syndrome, primary cerebral autoregulatory failure), and heart rate (tachycardia syndromes: postural tachycardia syndrome, paroxysmal sinus tachycardia, and inappropriate sinus tachycardia). Psychogenic pseudosyncope is associated with stable CBFv. Conclusions. The tilt test is useful add-on in diagnosis of several orthostatic syndromes. However diagnostic criteria for several syndromes had to be modified to allow unambiguous pattern classification. CBFv monitoring in addition to blood pressure and heart rate may increase diagnostic yield of the tilt test.

Multiple system atrophy (MSA) is characterized clinically by Parkinsonism, cerebellar dysfunction, and autonomic impairment. Multiple mutations in the LRRK2 gene are associated with parkinsonian disorders, and the most common one, the G2019S mutation, has been found in approximately 1% of sporadic cases of Parkinsonism. In a well-characterized cohort of 136 subjects with probable MSA and 110 neurologically evaluated control subjects, none carried the G2019S mutation. We conclude that the G2019S mutation in the LRRK2 gene is unlikely to be associated with MSA.

Identifying measures that are associated with the cytosine-adenine-guanine (CAG) expansion in individuals before diagnosis of Huntington disease (HD) has implications for designing clinical trials.To identify the earliest features associated with the motor diagnosis of HD in the Prospective Huntington at Risk Observational Study (PHAROS).A prospective, multicenter, longitudinal cohort study was conducted at 43 US and Canadian Huntington Study Group research sites from July 9, 1999, through December 17, 2009. Participants included 983 unaffected adults at risk for HD who had chosen to remain unaware of their mutation status. Baseline comparability between CAG expansion (≥37 repeats) and nonexpansion (37 repeats) groups was assessed. All participants and investigators were blinded to individual CAG analysis. A repeated-measures analysis adjusting for age and sex was used to assess the divergence of the linear trend between the expanded and nonexpanded groups. Data were analyzed from April 27, 2010, to September 3, 2013.Huntington disease mutation status in individuals with CAG expansion vs without CAG expansion.Unified Huntington's Disease Rating Scale motor (score range, 0-124; higher scores indicate greater impairment), cognitive (symbol digits modality is the total number of correct responses in 90 seconds; lower scores indicate greater impairment), behavioral (score range, 0-176; higher scores indicate greater behavioral symptoms), and functional (Total Functional Capacity score range, 0-13; lower scores indicate reduced functional ability) domains were assessed at baseline and every 9 months up to a maximum of 10 years.Among the 983 research participants at risk for HD in the longitudinal cohort, 345 (35.1%) carried the CAG expansion and 638 (64.9%) did not. The mean (SD) duration of follow-up was 5.8 (3.0) years. At baseline, participants with expansions had more impaired motor (3.0 [4.2] vs 1.9 [2.8]; P .001), cognitive (P .05 for all measures except Verbal Fluency, P = .52), and behavioral domain scores (9.4 [11.4] vs 6.5 [8.5]; P .001) but not significantly different measures of functional capacity (12.9 [0.3] vs 13.0 [0.2]; P = .23). With findings reported as mean slope (95% CI), in the longitudinal analyses, participants with CAG expansions showed significant worsening in motor (0.84 [0.73 to 0.95] vs 0.03 [-0.05 to 0.11]), cognitive (-0.54 [-0.67 to -0.40] vs 0.22 [0.12 to 0.32]), and functional (-0.08 [-0.09 to -0.06] vs -0.01 [-0.02 to 0]) measures compared with those without expansion (P .001 for all); behavioral domain scores did not diverge significantly between groups.Using these prospectively accrued clinical data, relatively large treatment effects would be required to mount a randomized, placebo-controlled clinical trial involving premanifest HD individuals who carry the CAG expansion.

Objective To examine if statins have an effect on small nerve fibers. Methods This retrospective study evaluated the effect of statins in pure small-fiber neuropathy (SFN). Outcome measures were symptom scales (numbness, tingling, and autonomic symptoms), skin biopsies assessing epidermal nerve fiber density (ENFD), sweat gland nerve fiber density (SGNFD), and quantitative autonomic testing. Results One hundred and sixty participants with pure SFN were identified. Eighty participants (women/men, age ± SD 33/47, 68.1 ± 11.6 years old) were on statins for 53.5 ± 28.7 months to treat dyslipidemia and they were age and gender matched with 80 participants (33/47, 68.1 ± 9.5) that were off statins. ANOVA showed reduced ENFD/SGNFD at the proximal leg in the statin group [(count/mm) 8.3 ± 3.6/51.3 ± 14.2] compared to the off statin group (10.4 ± 3.8, p = 0.0008/56.4 ± 12.7, p = 0.018). There was no difference in ENFD/SGNFD at the distal leg in the statin group (4.9 ± 3.2/39.8 ± 15.7) compared to the off statin group (5.9 ± 3.4, p = 0.067/41.8 ± 15.9, p = 0.426). Statins did not affect symptom scales and the outcome of autonomic testing. Conclusion Statin use is associated with degeneration of sensory and autonomic fibers. The pattern of abnormalities, e.g., degeneration of proximal while sparing of distal fibers, is consistent with a non-length-dependent process with lesions in the dorsal root and the autonomic ganglia. The statin-associated sensory and autonomic ganglionopathy is mild.

Non-infarct zone white matter wallerian degeneration is well-documented in large volume territorial infarctions. However to what extent these abnormalities exist in small volume infarction is not known, particularly since routine T2/FLAIR MR images show minimal changes in such cases. We therefore utilized DTI based quantitative 3D tractography for quantitative assessment of white matter integrity in chronic phase of small volume anterior circulation infarcts.Eleven chronic stroke subjects with small anterior circulation large vessel infarcts (≤10cm(3) volume of primary infarct) were compared with 8 age matched controls. These infarcts had negligible to mild gliosis and encephalomalacia in the primary infarct territory without obvious wallerian degeneration on conventional MRI. Quantitative Diffusion Tensor 3-D tractography was performed for CST, genu and splenium of corpus callosum. Tract based Trace and fractional anisotropy (FA) were compared with age matched controls.On univariate analysis, Chronic stroke subjects had significant elevation in Trace measurement in genu of corpus callosum (GCC), ipsilesional and contralesional CST, (p0.05), compared to controls. After adjusting for smoking, hypertension (HTN) and non-specific white matter hyperintensities, (WMHs), there was significant elevation in trace within the ipsilesional CST (p=0.05). Contralesional CST FA correlated significantly with walking speed, r=0.67, p=0.03.Stroke subjects with small volume infarcts demonstrate significant quantitative microstructural white matter abnormalities in chronic phase, which are otherwise subthreshold for detection on routine imaging. Ability to quantify these changes provides an important marker for assessing non-infarct zone neuroaxonal integrity in the chronic phase even in the setting of small infarction.

Background: Orthostatic intolerance including dizziness and syncope is common and may reflect autonomic dysfunction. Cardiovascular reflex tests (deep breathing, Valsalva maneuver and tilt test) are established diagnostic methods for evaluation of orthostatic and autonomic symptoms. Small fiber neuropathy, a frequent underlying mechanism, is evaluated by the quantitative sudomotor axonal reflex test (QSART) and skin biopsies. The comprehensive quantitative scale to grade abnormalities in these tests is lacking. Methods: This study defines the QASAT - Quantitative scale for grading of cardiovascular reflex tests using heart rate, blood pressure, n transcranial Doppler, QSART and small fibers (intrapidermal sensory and sweat gland) densities from skin biopsies. The QASAT has three main categories: cardiovascular, cerebral blood flow (includes cerebral autoregulation/vasoreactivity score) and small fiber neuropathy. QASAT was validated in 612 participants with diabetes mellitus (92), Parkinson’s disease (88), multiple system atrophy (23) and other diagnoses (409). The QASAT was compared with the Composite Autonomic Severity Score using ANOVA, correlations and sensitivity/specificity analysis. Results: Scores of heart rate variability from deep breathing, orthostatic hypotension, orthostatic cerebral blood flow, sensory and sweat gland small fiber densities were disease specific (p

Background Multiple system atrophy (MSA) is a progressive neurodegenerative disorder of unknown etiology, manifesting as combination of parkinsonism, cerebellar syndrome and dysautonomia. Disease-modifying therapies are unavailable. Activation of microglia and production of toxic cytokines suggest a role of neuroinflammation in MSA pathogenesis. This pilot clinical trial evaluated safety and tolerability of intravenous immunoglobulin (IVIG) in MSA. Methods This was a single-arm interventional, single-center, open-label pilot study. Interventions included monthly infusions of the IVIG preparation Privigen®, dose 0.4 gram/kg, for 6 months. Primary outcome measures evaluated safety and secondary outcome measures evaluated preliminary efficacy of IVIG. Unified MSA Rating Scale (UMSARS) was measured monthly. Quantitative brain imaging using 3T MRI was performed before and after treatment. Results Nine subjects were enrolled, and seven (2 women and 5 men, age range 55–64 years) completed the protocol. There were no serious adverse events. Systolic blood pressure increased during IVIG infusions (p Conclusions Treatment with IVIG appears to be safe, feasible and well tolerated and may improve functionality in MSA. A larger, placebo-controlled study is needed.

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.

Balance impairment is common following cerebral infarction. However, the effects of lesion hemisphere on postural control are largely unknown. We examined dependence upon vision and noninfarcted regional brain tissue volumes for postural control in individuals with right and left hemisphere middle cerebral artery (MCA) infarcts.Subjects with right MCA infarct (n = 17, age = 65 +/- 8 years, 7 +/- 6 years poststroke), left MCA infarct (n = 20, age = 65 +/- 8 years, 7 +/- 6 years poststroke), and controls (n = 55, age = 65 +/- 8 years) were studied. Postural control was defined by average velocity and the range and variability of mediolateral (ML) and anteroposterior (AP) sway during eyes-open and eyes-closed standing. Regional brain volumes were quantified using anatomic MRI at 3 Tesla.Right and left hemisphere stroke groups had similar infarct volumes and outcomes. Subjects with right hemisphere infarcts demonstrated greater sway velocity, ML range, and ML variability with eyes closed compared to eyes open. In this group, smaller occipital lobe volumes were associated with greater eyes-open sway velocity (R = -0.64, p = 0.012) and ML range (R = -0.82, p = 0.001). Smaller cerebellar volumes were associated with greater eyes-closed sway velocity (R = -0.60, p = 0.015), ML range (R = -0.70, p = 0.007), and ML variability (R = -0.85, p0.001). These associations were not observed in left hemisphere infarct subjects or controls. AP sway was unaffected by infarct hemisphere or visual condition and did not correlate with regional brain volumes.Right hemisphere middle cerebral artery infarcts are associated with increased dependence on vision and noninfarcted brain regions (i.e., occipital lobes, cerebellum) to control postural sway. Strategies emphasizing postural tasks under reduced visual conditions may enhance functional recovery in these individuals.

Objective: It is unknown if impaired cerebral vasoreactivity recovers after ischemic stroke, and whether it compromises perfusion in regions surrounding infarct and other vascular territories. We investigated the regional differences in CO 2 vasoreactivity (CO 2 VR) and their relationships to peri-infarct T2 hyperintensities (PIHs), chronic infarct volumes, and clinical outcomes. Methods: We studied 39 subjects with chronic large middle cerebral artery territory infarcts and 48 matched controls. Anatomic and three-dimensional continuous arterial spin labeling imaging at 3-Tesla MRI were used to measure regional cerebral blood flow (CBF) and CO 2 VR during normocapnia, hypercapnia, and hypocapnia in main arteries distributions. Results: Stroke patients showed a significantly lower augmentation of blood flow at increased CO 2 but greater reduction of blood flow with decreased CO 2 than the control group. This altered vasoregulatory response was observed both ipsilateral and contralateral to the stroke. Lower CO 2 VR on the stroke side was associated with PIHs, greater infarct volume, and worse outcomes. The cases with PIHs (n = 27) had lower CBF during all conditions bilaterally ( p Conclusions: Perfusion augmentation is inadequate in multiple vascular territories in patients with large artery ischemic infarcts, but vasoconstriction is preserved. Peri-infarct T2 hyperintensities are associated with lower blood flow. Strategies aimed to preserve vasoreactivity after an ischemic stroke should be tested for their effect on long-term outcomes.

Background: White matter hyperintensities (WMHs) on MRI have been associated with age, cardiovascular risk factors and falls in the elderly. This study evaluated the relationship between WMHs and dynamics of postural control in older adults without history of falls. Methods: We studied 76 community-living subjects without history of falls (age 64.5±7.3 years). Brain and WMH volume calculations and clinical rating were done on fluid-attenuation inversion recovery (FLAIR) and MP-RAGE MR images on 3 T. Balance was assessed from the center of pressure displacement using the force platform during 3 min of quiet standing using traditional and dynamic measures (using stabilogram-diffusion analysis). Gait speed was measured from 12-min walk. Results: Age-adjusted periventricular and focal WMHs were associated with changes in certain dynamic balance measures, including reduced range of postural sway in anteroposterior direction (fronto-temporal WMHs, P=.045; parieto-occipital WMHs, P=.009) and more irregular long-term mediolateral fluctuations (P=.046). Normal walking speed was not affected by WMHs. Conclusions: Periventricular and focal WMHs affect long-term dynamics of postural control, which requires engagement of feedback mechanisms, and may contribute to mobility decline in the elderly.

Obesity is a risk factor for cerebrovascular disease. We aimed to determine the effects of high body mass index (BMI) on cerebral blood flow regulation in patients with type-2 diabetes mellitus, hypertension, and stroke.We analyzed data from 90 controls, 30 diabetics, 45 hypertensives, and 32 ischemic stroke patients who underwent transcranial Doppler for evaluation of blood flow velocities (BFV) in the middle cerebral arteries (MCA) and cerebrovascular resistance (CVR) during supine rest and head-up tilt. This study was a cross-sectional analysis. We used a structural equation multiple indicators modeling to determine the effects of BMI and other background variables (age, sex, race, smoking, alcohol use, and systolic blood pressure) on cerebral BFV.Higher BMI (P = 0.02) and age (P = 0.004) were associated with lower mean BFV during baseline, independent of diagnosis of diabetes mellitus, hypertension or stroke, and after adjusting for all background variables and vessel diameters. Men, especially those with stroke, had a lower mean BFV than women (P = 0.01). CVR increased with BMI (P = 0.001) at baseline and during head-up tilt (P = 0.02), and was elevated in obese subjects (P = 0.004) compared to normal weight subjects across all groups.High BMI is associated with a reduction in cerebral BFV and increased CVR. These findings indicate that obesity can adversely affect cerebral blood flow and resistance in the cerebrovascular bed, independent of diagnosis of type-2 diabetes, hypertension or stroke. Obesity may contribute to cerebromicrovascular disease, and affect clinical functional outcomes of the older population.

Multiple system atrophy (MSA) is a neurodegenerative disorder exhibiting a combination of parkinsonism, cerebellar ataxia, and autonomic failure. A disease-specific scale, the Unified Multiple System Atrophy Rating Scale (UMSARS), has been developed and validated to measure progression of MSA, but its use as an outcome measure for therapeutic trials has not been evaluated. On the basis of twelve months of follow-up from an observational study of 67 patients with probable MSA, we evaluated three disease-specific scores: Activities of Daily Living, Motor Examination, and a combined score from the UMSARS and two general health scores, the Physical Health and Mental Health scores of the SF-36 health survey, for their use as outcome measures in a therapeutic trial. We discuss related design issues and provide sample size estimates. Scores based on the disease-specific UMSARS seemed to be equal or superior to scores based on the SF-36 health survey. They appeared to capture disease progression, were well correlated and required the smallest sample size. The UMSARS Motor Examination score exhibited the most favorable characteristics as an outcome measure for a therapeutic trial in MSA with 1 year of follow-up.

Background Previous studies have suggested that impaired proprioceptive processing in the striatum may contribute to abnormal gait in Parkinson's disease (PD). Methods This pilot study assessed the effects of enhanced proprioceptive feedback using step-synchronized vibration stimulation of the soles (S-VS) on gait in PD. S-VS was used in 8 PD subjects (3 women and 5 men, age range 44–79 years, on medication) and 8 age-matched healthy subjects (5 women and 3 men). PD subjects had mild or moderate gait impairment associated with abnormal balance, but they did not have gait freezing. Three vibratory devices (VDs) were embedded in elastic insoles (one below the heel and two below the forefoot areas) inserted into the shoes. Each VD operates independently and has a pressure switch that activates the underlying vibratory actuator. The VD delivered the 70-Hz suprathreshold vibration pulse upon touch by the heel or forefoot, and the vibration pulse was deactivated upon respective push-offs. Six-minute hallway walking was studied with and without S-VS. Gait characteristics were measured using the force-sensitive foot switches. The primary outcome was the stride variability expressed as a coefficient of variation (CV), a measure of gait steadiness. Secondary outcome measures were walking distance and speed, stride length and duration, cadence, stance, swing and double support duration, and respective CVs (if applicable). Results The walking speed (p < 0.04) and the CV of the stride interval (p < 0.02) differed between the groups and S-VS conditions. In the PD group, S-VS decreased stride variability (p < 0.002), increased walking speed (p < 0.0001), stride duration (p < 0.01), stride length (p < 0.0002), and cadence (p < 0.03). In the control group, S-VS decreased stride variability (p < 0.006) and increased gait speed (p < 0.03), but other locomotion parameters were not significantly altered. Conclusion Augmented sensory feedback improves parkinsonian gait steadiness in the short-term setting. Because the suprathreshold stimulation prevented blinding of subjects, the learning effect and increased attention can be a confounding factor underlying results. Long-term studies are needed to establish the clinical value of the S-VS.

Objective To identify clinical and laboratory indices that improve the diagnosis of the postural tachycardia syndrome (POTS). Design We assessed associations of orthostatic intolerance by using multivariate regression analysis. Material and Methods We evaluated autonomic symptoms and autonomic function in 30 patients with POTS, 30 patients with mild orthostatic intolerance, and 19 age- and gender-matched control subjects. Indices of parasympathetic and sympathetic functions were analyzed on the basis of (1) autonomic function tests (head-up tilt), (2) oscillations at respiratory and nonrespiratory frequencies (0.01 to 0.09 Hz) in R-R interval and blood pressure (Wigner distribution), and (3) deterministic component (rescaled range analysis). Results The four clinical and laboratory indices that independently supported the diagnosis of POTS are as follows: (1) orthostatic heart rate during the first minute of head-up tilt, (2) autonomic deficit (adrenergic autonomic score), (3) loss of spectral powers in R-R interval during head-up tilt at the fifth minute, and (4) severity of orthostatic dizziness, fatigue, palpitations, and shortness of breath. Conclusion Enhancing the sensitivity and specificity of the diagnosis of POTS should be possible by using these four indices. A hyperadrenergic state and distal neuropathy, affecting adrenergic sympathetic cardiovagal fibers, seem to be involved in the pathophysiology of POTS. Certain features suggest brain-stem dysregulation.