Orthostatic hypotension, cognition and structural brain imaging in hemodynamically impaired patients.

BACKGROUND: Orthostatic hypotension (OH) is associated with an increased risk of dementia, potentially attributable to cerebral hypoperfusion. We investigated which patterns and characteristics of OH are related to cognition or to potentially underlying structural brain injury in hemodynamically impaired patients and healthy reference participants. METHODS: Participants with carotid occlusive disease or heart failure, and reference participants from the Heart-Brain Connection Study underwent OH measurements, neuropsychological assessment and brain MRI. We analyzed the association between OH, global cognitive functioning, white matter hyperintensity (WMH) volume and brain parenchymal fraction with linear regression. We stratified by participant group, severity and duration of OH, chronotropic incompetence and presence of orthostatic symptoms. RESULTS: Of 337 participants (mean age 67.3 ± 8.8 years, 118 (35.0%) women), 113 (33.5%) had OH. Overall, presence of OH was not associated with cognitive functioning (ß: -0.12 [-0.24-0.00]), but we did observe worse cognitive functioning in those with severe OH (≥ 30/15 mmHg; ß: -0.18 [-0.34 to -0.02]) and clinically manifest OH (ß: -0.30 [-0.52 to -0.08]). These associations did not differ significantly by OH duration or chronotropic incompetence, and were similar between patient groups and reference participants. Similarly, both severe OH and clinically manifest OH were associated with a lower brain parenchymal fraction, and severe OH also with a somewhat higher WMH volume. CONCLUSIONS: Severe OH and clinically manifest OH are associated with worse cognitive functioning. This supports the notion that specific patterns and characteristics of OH determine its impact on brain health.

Brain white matter changes and their associations with non-motor dysfunction in orthostatic hypotension in α-synucleinopathy: A NODDI study.

BACKGROUND: The specific non-motor symptoms associated with α-synucleinopathies, including orthostatic hypotension (OH), cognitive impairment, and emotional abnormalities, have been a subject of ongoing controversy over the mechanisms underlying the development of a vicious cycle among them. The distinct structural alterations in white matter (WM) in patients with α-synucleinopathies experiencing OH, alongside their association with other non-motor symptoms, remain unexplored. This study employs axial diffusivity and density imaging (NODDI) to investigate WM damage specific to α-synucleinopathies with concurrent OH, delivering fresh evidence to supplement our understanding of the pathogenic mechanisms and pathological rationales behind the occurrence of a spectrum of non-motor functional impairments in α-synucleinopathies. METHODS: This study recruited 49 individuals diagnosed with α-synucleinopathies, stratified into an α-OH group (n = 24) and an α-NOH group (without OH, n = 25). Additionally, 17 healthy controls were included for supine and standing blood pressure data collection, as well as neuropsychological assessments. Magnetic resonance imaging (MRI) was utilized for the calculation of NODDI parameters, and tract-based spatial statistics (TBSS) were employed to explore differential clusters. The fibers covered by these clusters were defined as regions of interest (ROI) for the extraction of NODDI parameter values and the analysis of their correlation with neuropsychological scores. RESULTS: The TBSS analysis unveiled specific cerebral regions exhibiting disparities within the α-OH group as compared to both the α-NOH group and the healthy controls. These differences were evident in clusters that indicated a decrease in the acquisition of the neurite density index (NDI), a reduction in the orientation dispersion index (ODI), and an increase in the isotropic volume fraction (FISO) (p < 0.05). The extracted values from these ROIs demonstrated significant correlations with clinically assessed differences in supine and standing blood pressure, overall cognitive scores, and anxiety-depression ratings (p < 0.05). CONCLUSION: Patients with α-synucleinopathies experiencing OH exhibit distinctive patterns of microstructural damage in the WM as revealed by the NODDI model, and there is a correlation with the onset and progression of non-motor functional impairments.

Aberrant microstructural integrity of white matter in mild and severe orthostatic hypotension: A NODDI study.

OBJECTIVE: Scarce evidence is available to elucidate the association between the abnormal microstructure of white matter (WM) and cognitive performance in patients with orthostatic hypotension (OH). This study investigated the microstructural integrity of WM in patients with mild OH (MOH) and severe OH (SOH) and evaluated the association of abnormal WM microstructure with the broad cognitive domains and cognition-related plasma biomarkers. METHODS: Our study included 72 non-OH (NOH), 17 MOH, and 11 SOH participants. Across the groups, the WM integrity was analyzed by neurite orientation dispersion and density imaging (NODDI), and differences in WM microstructure were evaluated by nonparametric tests and post hoc models. The correlations between WM microstructure and broad cognitive domains and cognition-related plasma biomarkers were assessed by Spearman's correlation analysis. RESULTS: The abnormal WM microstructure was localized to the WM fiber bundles in MOH patients but distributed widely in SOH cohorts (p < 0.05). Further analysis showed that the neurite density index of the left cingulate gyrus was negatively associated with amyloid ß-40, glial fibrillary acidic protein, neurofilament light chain, phospho-tau181 (p < 0.05) but positively with global cognitive function (MOCA, MMSE, AER-III), memory, attention, language, language fluency, visuospatial function and amyloid ß-40 / amyloid ß-42 (p < 0.05). Additionally, other abnormal WM microstructures of OH were associated with broad cognitive domains and cognition-related plasma biomarkers to varying degrees. CONCLUSION: The findings evidence that abnormal WM microstructures may present themselves as early as in the MOH phase and that these structural abnormalities are associated with cognitive functions and cognition-related plasma biomarkers.

In vivo cerebral metabolic and dopaminergic characteristics in multiple system atrophy with orthostatic hypotension.

PURPOSE: Multiple system atrophy (MSA) is a rare neurodegenerative disease, often presented with orthostatic hypotension (OH), which is a disabling symptom but has not been very explored. Here, we investigated MSA patients with OH by using positron emission tomography (PET) with 18F-fluorodeoxyglucose (18F-FDG) and 11C-N-2-carbomethoxy-3-(4-fluorophenyl)-tropane (11C-CFT) for in vivo evaluation of the glucose metabolism and dopaminergic function of the brain. METHODS: Totally, 51 patients with MSA and 20 healthy controls (HC) who underwent 18F-FDG PET/CT were retrospectively enrolled, among which 24 patients also underwent 11C-CFT PET/CT. All patients were divided into MSA-OH(+) and MSA-OH(-) groups. Then, statistical parametric mapping (SPM) method was used to reveal the regional metabolic and dopaminergic characteristics of MSA-OH(+) compared with MSA-OH(-). Moreover, the metabolic networks of MSA-OH(+), MSA-OH(-) and HC groups were also constructed and analyzed based on graph theory to find possible network-level changes in MSA patients with OH. RESULTS: The SPM results showed significant hypometabolism in the pons and right cerebellar tonsil, as well as hypermetabolism in the left parahippocampal gyrus and left superior temporal gyrus in MSA-OH(+) compared with MSA-OH(-). A reduced 11C-CFT uptake in the left caudate was also shown in MSA-OH(+) compared with MSA-OH(-). In the network analysis, significantly reduced local efficiency and clustering coefficient were shown in MSA-OH(+) compared with HC, and decreased nodal centrality in the frontal gyrus was found in MSA-OH(+) compared with MSA-OH(-). CONCLUSION: In this study, the changes in glucose metabolism in the pons, right cerebellar tonsil, left parahippocampal gyrus and left superior temporal gyrus were found closely related to OH in MSA patients. And the decreased presynaptic dopaminergic function in the left caudate may contribute to OH in MSA. Taken together, this study provided in vivo pathophysiologic information on MSA with OH from neuroimaging approach, which is essential for a better understanding of MSA with OH.

Neurogenic orthostatic hypotension in Parkinson's disease: is there a role for locus coeruleus magnetic resonance imaging?

Locus coeruleus (LC) is the main noradrenergic nucleus of the brain, and degenerates early in Parkinson's disease (PD). The objective of this study is to test whether degeneration of the LC is associated with orthostatic hypotension (OH) in PD. A total of 22 cognitively intact PD patients and 52 age-matched healthy volunteers underwent 3 T magnetic resonance (MRI) with neuromelanin-sensitive T1-weighted sequences (LC-MRI). For each subject, a template space-based LC-MRI was used to calculate LC signal intensity (LC contrast ratio-LCCR) and the estimated number of voxels (LCVOX) belonging to LC. Then, we compared the LC-MRI parameters in PD patients with OH (PDOH+) versus without OH (PDOH-) (matched for sex, age, and disease duration) using one-way analysis of variance followed by multiple comparison tests. We also tested for correlations between subject's LC-MRI features and orthostatic drop in systolic blood pressure (SBP). PDOH- and PDOH+ did not differ significantly (p > 0.05) based on demographics and clinical characteristics, except for blood pressure measurements and SCOPA-AUT cardiovascular domain (p < 0.05). LCCR and LCVOX measures were significantly lower in PD compared to HC, while no differences were observed between PDOH- and PDOH+. Additionally, no correlation was found between the LC-MRI parameters and the orthostatic drop in SBP or the clinical severity of autonomic symptoms (p > 0.05). Conversely, RBD symptom severity negatively correlated with several LC-MRI parameters. Our results failed to indicate a link between the LC-MRI features and the presence of OH in PD but confirmed a marked alteration of LC signal in PD patients.

Interactive effect of orthostatic hypotension on gray matter atrophy associated with hyposmia and RBD in de novo Parkinson's disease.

BACKGROUND: Orthostatic hypotension (OH) is a potential modifiable risk factor for cognitive impairment in patients with Parkinson's disease (PD). Although other risk factors for dementia, hyposmia and REM sleep behavior disorder (RBD), are closely associated with autonomic dysfunction in PD, little is known about how these risk factors influence cognitive function and cerebral pathology. OBJECTIVE: We investigated how these three factors contribute to gray matter atrophy by considering the interaction of OH with hyposmia and RBD. METHODS: We analyzed cortical thickness, subcortical gray matter volume, and cognitive measures from 78 patients with de novo PD who underwent the head-up tilt test for the diagnosis of OH. RESULTS: Whole-brain analyses with Monte Carlo corrections revealed that hyposmia was associated with decreased cortical thickness in a marginal branch of the cingulate sulcus among patients with OH, and cortical thickness in this area correlated with cognitive functioning only in patients with OH. Subcortical gray matter volume analysis indicated that severe RBD was associated with decreased volume in the left hippocampus and bilateral amygdala among patients with OH. CONCLUSION: Even in early PD, OH exerts effects on gray matter atrophy and cognitive dysfunction by interacting with RBD and hyposmia. OH might exacerbate cerebral pathology induced by hyposmia or RBD.

Caudate-anchored cognitive connectivity pursuant to orthostatic hypotension in early Parkinson's disease.

18F-Florbetaben is a tracer used to evaluate the metabolic activity of and amyloid accumulation in the brain when measured in early- and late-phase, respectively. The metabolism of neural substrates could be viewed as a network and might be an important factor in cognition. Orthostatic hypotension (OH) might play an indirect moderating role in cognition, and its latent influence could modify the inherent cognitive network. This study aimed to identify changes of cognitive connectivity according to orthostatic stress in patients with early Parkinson's disease (PD). This study included 104 early PD patients who were evaluated with a head-up tilt-test and18F-Florbetaben positron emission tomography (PET). Cognition was assessed with a comprehensive neuropsychological battery that gauged attention/working memory, language, visuospatial, memory, and executive functions. PET images were analyzed visually for amyloid deposits, and early-phase images were normalized to obtain standardized uptake ratios (SUVRs) of pre-specified subregions relevant to specific cognitive domains. The caudate nucleus was referenced and paired to these pre-specified regions. The correlations between SUVRs of these regions were assessed and stratified according to presence of orthostatic hypotension. Among the patients studied, 22 (21.2%) participants had orthostatic hypotension. Nineteen patients (18.3%) were positive for amyloid-ß accumulation upon visual analysis. Moderate correlations between the caudate and pre-specified subregions were observed (Spearman's rho, range [0.331-0.545]). Cognition did not differ, but the patterns of correlation were altered when the disease was stratified by presence of orthostatic stress. In conclusion, cognition in early PD responds to hemodynamic stress by adapting its neural connections between regions relevant to cognitive functions.

Cognition and transcranial sonography in Parkinson's disease patients with or without orthostatic hypotension.

BACKGROUND: Orthostatic hypotension (OH) is a common nonmotor symptom in patients with Parkinson's disease (PD), with an incidence ranging from 14% to 54%. AIMS: This study explored changes in cognition and transcranial sonography (TCS) findings in patients with PD and OH. METHODS: We enrolled PD patients who visited the outpatient or inpatient department from 2017 to 2020. Blood pressure was measured in different positions, and demographic data were collected. Motor and nonmotor symptoms were evaluated using standard scales. A subset of 107 patients underwent TCS. RESULTS: We enrolled 66 PD-OH patients and 92 PD-no orthostatic hypotension (NOH) patients. There were no significant differences in gender, age, disease duration, or Hoehn and Yahr stage between groups. Binary logistic regression revealed age as an independent risk factor for OH in PD patients. There were statistically significant group differences in visuospatial and executive function and Unified Parkinson's Disease Rating Scale (UPDRS) I and II scores (p < .05). Among PD-OH patients, there was a statistically significant difference in UPDRS II and III scores between patients with or without clinical symptoms (p < .05). The substantia nigra (SN) area was significantly larger in PD-NOH patients (0.45 ± 0.18 cm2 ) than PD-OH patients (0.34 ± 0.16 cm2 ) (p < .05). CONCLUSIONS: PD-OH patients had poorer visuospatial and executive function and lower UPDRS I and II scores compared with PD-NOH patients. Within the PD-OH group, there was no significant difference in cognition between patients with or without clinical symptoms. The difference in the SN area may indicate different subtypes of PD or a tendency to develop parkinsonism syndrome.

Paradoxical Cerebral Perfusion in Parkinson's Disease Patients with Orthostatic Hypotension: A Dual-Phase 18F-Florbetaben Positron Emission Tomography Study.

BACKGROUND: Orthostatic hypotension (OH) may antedate Parkinson's disease (PD) or be found in early stages of the disease. OH may induce a PD brain to chronic hypotensive insults. 18F-Florbetaben (18F-FBB) tracer has a high first-pass influx rate and can be used with positron emission tomography (PET) as a surrogate marker for early- and late-phase evaluation of cerebral perfusion and cerebral amyloidosis, respectively. OBJECTIVE: In this study, we evaluated whether 18F-FBB uptake in the early- and late-phases of PD was related to OH. This study manipulated the imaging modality to illustrate the physiology of cerebral flow with OH in PD (PD + OH). METHODS: A group of 73 early-stage PD patients was evaluated with a head-up tilt-test and 18F-FBB PET imaging. The cognitive status was assessed by a comprehensive battery of neuropsychological tests. PET images were normalized, and both early- and late-phase standardized uptake value ratios (SUVRs) of pre-specified regions were obtained. The associations between regional SUVRs and OH and cognitive status were analyzed. RESULTS: Twenty (27.4%) participants had OH. Thirteen (17.8%) patients were interpreted as having amyloid pathology based on regional 18F-FBB uptake. Early-phase SUVRs were higher in specific brain regions of PD + OH patients than those without OH. However, late-phase SUVRs did not differ between the groups. The early-phase SUVRs were not influenced by amyloid burden or by interaction between amyloid and orthostatic hypotension. Cognitive functions were not disparate when PD + OH patients were contrasted with non-OH patients in this study. CONCLUSION: Cerebral blood flow was elevated in patients with early PD + OH. This finding suggests augmented cerebral perfusion in PD + OH might be a compensatory regulation in response to chronic OH.

Correlation of orthostatic hypotension with extracranial carotid and intracranial cerebral arteries atherosclerosis in patients with acute ischemic stroke under cerebral angiography.

OBJECTIVE: The clinical management of patients with acute ischemic stroke (AIS) is complicated by orthostatic hypotension, which might have close relationship with the atherosclerosis of cerebral arteries. The primary objectives were to evaluate the relationship of orthostatic hypotension with extracranial carotid arteries atherosclerosis (ECAS) and intracranial atherosclerosis (ICAS) in AIS patients. METHODS: This study was a prospective cohort analysis of consecutive AIS patients under cerebrovascular angiography. A total of 289 patients were included. orthostatic hypotension was defined as a systolic BP decline ≥20 mmHg or a diastolic BP decline ≥10 mmHg within 3 min of standing. Univariate and multivariate analysis were performed to investigate the association of the clinical variables with orthostatic hypotension. RESULTS: Orthostatic hypotension was identified in 80 (27.7%) of all patients. ECAS (≥70%) and ICAS (≥50%) was found in 39 (13.5%) and 71 (24.6%) respectively. In multivariate analysis, only diabetes mellitus (odds ratio = 2.00, 95% confidence interval, 1.12-3.58, P = 0.019) and ECAS (odds ratio = 1.97, 95% confidence interval, 1.54-2.51, P < 0.001) were independent risk factors for orthostatic hypotension. CONCLUSIONS: Orthostatic hypotension is a relatively common finding among patients with AIS. AIS patients should be screened for orthostatic hypotension, especially combined with severe ECAS and diabetes mellitus.

Dopaminergic Correlates of Orthostatic Hypotension in de novo Parkinson's Disease.

BACKGROUND: Orthostatic hypotension (OH) at an early stage of Parkinson's disease (PD) predicts poor prognosis, which may suggest degeneration of dopaminergic neurons affects sympathetic function, causing OH. OBJECTIVE: We tested the hypothesis that striatal dopaminergic depletion is associated with OH in PD. METHODS: Out of 99 patients with newly diagnosed untreated PD, 81 patients were enrolled according to our selection criteria. All patients underwent head-up tilt-table testing and striatal 123I-2ß-carbomethoxy-3ß-(4-iodophenyl)-N-(3-fluoropropyl) nortropane (123I-FP-CIT) dopamine transporter single photon emission computed tomography (DAT-SPECT). DaTQUANT software (GE Healthcare) was used as a semi-quantitative tool to analyze DAT-SPECT data. The association between hemodynamic changes and 123I-FP-CIT uptake was examined. RESULTS: 123I-FP-CIT uptake in the putamen, especially the anterior part and left side, was related not only to motor severity but also to OH. Change in systolic blood pressure correlated negatively with 123I-FP-CIT uptake in bilateral anterior putamen (left: p < 0.01, right: p < 0.05) and left posterior putamen (p < 0.05). Patients with OH had more severe dopamine depletion in left anterior (p = 0.008) and posterior (p = 0.007) putamen at a similar motor severity than did patients without OH even though both groups have similar baseline characteristics. An analysis of asymmetry index showed patients with OH had symmetrically decreased dopamine levels in anterior putamen when compared to those without OH (p = 0.024). CONCLUSION: OH is closely related to striatal dopamine depletion in PD. This relation may help to account for the prognostic value of OH.

A Longitudinal Skin Biopsy Study of Phosphorylated Alpha-Synuclein in a Patient With Parkinson Disease and Orthostatic Hypotension.

The aim of our study was to assess the distribution of phosphorylated α-synuclein (p-syn) deposits in a patient affected by early stage Parkinson disease and orthostatic hypotension through a longitudinal skin biopsy study. We found widespread p-syn spatial diffusion from deep autonomic dermis nerve bundles to autonomic terminals, suggesting a centrifugal spread of p-syn from ganglia to the innervation target structures. Furthermore, the case suggests the possibility of discriminating synucleinopathies at an early stage of disease by means of skin biopsy. If confirmed, these data support skin biopsy as a useful and promising tool for the diagnosis, longitudinal evaluation, and pathological understanding of Parkinson disease.

Evidence of Impaired Cerebellar Connectivity at Rest and During Autonomic Maneuvers in Patients with Autonomic Failure.

The objective of the current study was to investigate whether patients with neurogenic orthostatic hypotension (NOH) secondary to autonomic failure have impaired functional connectivity between the cerebellum and central autonomic structures during autonomic challenges. Fifteen healthy controls (61 ± 14 years) and 15 NOH patients (67 ± 6 years; p = 0.12) completed the following tasks during a functional brain MRI: (1) 5 min of rest, (2) 5 min of lower-body negative pressure (LBNP) performed at - 35 mmHg, and (3) Three, 15-s Valsalva maneuvers (VM) at 40 mmHg. Functional connectivity (Conn Toolbox V18) between central autonomic structures and discrete cerebellar regions involved in cardiovascular autonomic control, including the vermis and posterior cerebellum, was assessed using a regions-of-interest approach during rest, LBNP and VM. Functional connectivity was contrasted between controls and patients with autonomic failure. At rest, controls had significantly more intra-cerebellar connectivity and more connectivity between cerebellar lobule 9 and key central autonomic structures, including: bilateral anterior insula (TR-value: 4.84; TL-value: 4.51), anterior cingulate cortex (T-value: 3.41) and bilateral thalamus (TR-value: 3.95; TL-value: 4.51). During autonomic maneuvers, controls showed significantly more connectivity between cardiovascular cerebellar regions (lobule 9 and anterior vermis) and important autonomic regulatory sites, including the brainstem, hippocampus and cingulate: vermis-brainstem (T-value: 4.31), lobule 9-brainstem (TR-value, 5.29; TL-value, 4.53), vermis-hippocampus (T-value, 4.63), and vermis-cingulate (T-value, 4.18). Anatomical and functional studies in animals and humans substantiate a significant role for the cerebellum in cardiovascular autonomic control during postural adjustments. In the current study, patients with NOH related to autonomic failure showed evidence of reduced connectivity between cardiovascular cerebellar regions and several important central autonomic structures, including the brainstem. The cerebellum is an established structure in cardiovascular autonomic control; therefore, evidence of impaired cerebellar connectivity to other autonomic structures may further contribute to the inability to properly regulate blood pressure during postural changes in NOH patients.

Orthostatic hypotension as a risk factor for longitudinal deterioration of cognitive function in the elderly.

BACKGROUND AND PURPOSE: Orthostatic hypotension is frequent with aging with a prevalence of 20%-30% in people aged 65 or older and is considered to increase the risk for coronary events, strokes and dementia. Our objective was to characterize the association of orthostatic hypotension and cognitive function longitudinally over 6 years in a large cohort of the elderly aged over 50 years. METHODS: In all, 495 participants were assessed longitudinally with the Schellong test and comprehensive cognitive testing using the extended CERAD neuropsychological test battery at baseline and after 6 years. In a subgroup of 92 participants, cerebral magnetic resonance imaging was evaluated for white matter changes using a modified version of the Fazekas score. RESULTS: The prevalence of orthostatic hypotension increases with aging reaching up to 30% in participants aged >70 years. Participants with orthostatic hypotension presented with a higher vascular burden index (1.03 vs. 0.69, P ≤ 0.001), tended to have a higher prevalence of cerebral white matter hyperintensities (91.7% vs. 68.8%, P = 0.091) and showed a faster deterioration in executive and memory function (Trail Making Test B 95 vs. 87 s, P ≤ 0.001; word list learning sum -0.53 vs. 0.38, P = 0.002) compared to participants without orthostatic hypotension. CONCLUSION: Orthostatic hypotension seems to be associated with cognitive decline longitudinally.

Hemodynamic changes in women with symptoms of supine hypotensive syndrome.

INTRODUCTION: Supine positioning during late pregnancy causes the gravid uterus to compress the inferior vena cava, resulting in dramatic hemodynamic changes. The maintenance of placental perfusion requires maternal circulatory and autonomic adaptations. Women with supine hypotensive syndrome (defined as a drop in systolic blood pressure of anything between 15 and 30 mmHg or an increase in heart rate of 20 bpm, with or without symptoms) may have reduced ability to compensate for the effects of supine positioning. MATERIAL AND METHODS: Twelve women with uncomplicated pregnancies and no symptoms of supine hypotension (normal) and 10 women with uncomplicated pregnancies who reported symptoms of supine hypotension between 34 and 38 weeks' gestation underwent magnetic resonance imaging in the supine and left lateral positions. Phase contrast images were evaluated to measure blood flow through the aorta, inferior vena cava, superior vena cava and azygos vein. RESULTS: Women with symptoms of supine hypotension showed significant reductions in azygos venous flow rate compared with the normal group (-0.15 (-0.30 to -0.01) L/min). Those with symptoms showed no statistically significant compensatory changes in heart rate compared with the normal group (heart rate change 4.5 (-3.1 to 12.1) bpm). Hemodynamic changes in response to positioning were similar across both groups including: a reduction in inferior vena cava blood flow, reduction in cardiac output and an increase in azygos blood flow. CONCLUSIONS: Maternal hemodynamic adaptations were found to be consistent across groups irrespective of whether the women had symptoms of supine hypotension. In both groups a reduction in blood flow through the inferior vena cava occurred in the supine position with a subsequent reduction in cardiac output. Both groups showed a compensatory increase in blood flow through the azygos vein in order to partially compensate for this. Taking into account the effect of maternal position, women with symptoms were found to have reduced azygos flow compared with asymptomatic women. There was a significant increase in heart rate when the women were supine than when they were in the left lateral position.

Long-term trends in myocardial sympathetic innervation and function in synucleinopathies.

INTRODUCTION: Parkinson disease (PD), pure autonomic failure (PAF), and multiple system atrophy (MSA) are characterized by intra-cerebral deposition of the protein alpha-synuclein and are termed synucleinopathies. Lewy body synucleinopathies involve decreased cardiac sympathetic innervation and functional abnormalities in residual noradrenergic terminals. This observational, retrospective, cohort study describes long-term trends in indices of cardiac sympathetic innervation and function in synucleinopathies. METHODS: Patients with PD (N = 31), PAF (N = 9), or MSA (N = 9) underwent repeated 18F-dopamine positron emission tomography (median follow-up 3.5 years). Interventricular septal 18F-dopamine-derived radioactivity 8 min after tracer injection (8' Radioactivity) was used as an index of sympathetic innervation and the slope of mono-exponential decline of radioactivity between 8 and 25 min (k8'-25') as an index of intraneuronal vesicular storage. Healthy volunteers (HVs) (N = 33) and individuals at high risk of PD (N = 15) were controls. RESULTS: Upon initial evaluation the groups with PD and orthostatic hypotension (OH), PAF, or PD and no OH had low mean 8' Radioactivity compared to HVs (p < 0.0001, p = 0.0002, p = 0.006) and had elevated k8'-25' (p = 0.0007, p = 0.007, p = 0.06). There was no significant difference between MSA and HVs. In PD 8' Radioactivity decreased by a median of 4% per year and did not decrease in MSA. k8'-25' values did not change during follow-up in any group. CONCLUSIONS: Neuroimaging evidence of decreased vesicular uptake in cardiac sympathetic nerves is present upon initial evaluation of patients with Lewy body synucleinopathies and may provide a biomarker of catecholaminergic dysfunction early in the disease process.

Haemodynamic and cerebrovascular effects of intermittent lower-leg compression as countermeasure to orthostatic stress.

NEW FINDINGS: What is the central question of this study? Does smartly timed intermittent compression of the lower legs alter cerebral blood velocity and oxygenation during acute orthostatic challenges? What is the main finding and its importance? Intermittent compression timed to the local diastolic phase increased the blood flux through the legs and heart after two different orthostatic stress tests. Cerebral blood velocity improved during the first minute of recovery, and indices of cerebral tissue oxygenation remained elevated for 2 min. These results provide promise for the use of lower-leg active compression as a therapeutic tool for individuals vulnerable to initial orthostatic hypotension and orthostatic stress. ABSTRACT: Intermittent compression of the lower legs provides the possibility of improving orthostatic tolerance by actively promoting venous return and improving central haemodynamics. We tested the hypothesis that intermittent compression of 65 mmHg timed to occur only within the local diastolic phase of each cardiac cycle would attenuate the decrease in blood pressure and improve cerebral haemodynamics during the first minute of recovery from two different orthostatic stress tests. Fourteen subjects (seven female) performed four squat-to-stand transitions and four repeats of standing bilateral thigh-cuff occlusion and release (TCR), with intermittent compression of the lower legs applied in half of the trials. Blood flow in the superficial femoral artery, mean arterial pressure, Doppler ultrasound cardiac output, total peripheral resistance, middle cerebral artery blood velocity (MCAv) and cerebral tissue saturation index (TSI%) were monitored. With both orthostatic stress tests, there was a significant compression × time interaction for superficial femoral artery flow (P < 0.001). The hypotensive state was attenuated with intermittent compression despite decreased total peripheral resistance (squat-to-stand, compression × time interaction, P < 0.001; TCR, compression × time interaction, P = 0.002) as a consequence of elevated cardiac output in both tests (P < 0.001). Intermittent compression also increased MCAv (P = 0.001) and TSI% (P < 0.001) during the squat-to-stand transition and during TCR (MCAv and TSI%, compression × time interaction, P < 0.001). Intermittent compression of the lower legs during quiet standing after an active orthostatic challenge augmented local, central and cerebral haemodynamics, providing potential as a therapeutic tool for individuals vulnerable to orthostatic stress.

Reduced brainstem functional connectivity in patients with peripheral autonomic failure.

Autonomic homeostasis is dependent upon several brainstem nuclei, as well as several cortical and subcortical structures. Together, these sites make up, in part, the central autonomic network. Neurogenic orthostatic hypotension (NOH) is a cardinal feature of autonomic failure that occurs due to a failure to increase sympathetic efferent activity in response to postural changes. Therefore, the purpose of the current study was to investigate brainstem functional connectivity in NOH patients with peripheral autonomic lesions resulting in autonomic failure. Fifteen controls (63 ±â€¯13 years) and fifteen Neurogenic Orthostatic Hypotension patients (67 ±â€¯6 years; p = .2) with peripheral autonomic dysfunction completed 5-min of rest and three Valsalva maneuvers during a functional brain scan. Functional connectivity from the brainstem to cortical and subcortical structures were contrasted between patients and controls. At rest controls had significantly greater brainstem connectivity to the anterior cingulate cortex (T-value: 4.29), left anterior insula (T-value:3.31), left putamen (T-value:3.31) and bilateral thalamus (TRIGHT-value: 3.83; TLEFT-value:4.25) (p-FDR < 0.005). During Valsalva, controls showed significantly more connectivity between the brainstem and both the left anterior (cerebellum 4/5) and bilateral posterior cerebellum (cerebellar 9 and left cerebellar 6). Other cerebellar regions included brainstem-to-vermis. Other brainstem-to-cortical and subcortical regions included: bilateral putamen, posterior cingulate cortex (PCC), amygdala and medial prefrontal cortex. There was a significant negative correlation between the brainstem-cerebellar connectivity and severity of autonomic dysfunction (p < .01). During recovery phase of the Valsalva, controls had greater brainstem connectivity to the left thalamus (T-value:4.17); PCC (T-value:3.32); right putamen (T-value:3.28); right paracingulate gyrus (T-value:3.25) and left posterior cerebellum (C9) (T-value:3.21) (p-FDR < 0.05). The effect sizes for each brainstem connectivity during Valsalva and recovery ranged from moderate to strong. Patients with autonomic failure show reduced coupling between the brainstem and regions of the central autonomic network, including the cerebellum, insula, thalamus and cingulate cortices. Connectivity was associated with autonomic impairment. These findings may suggest impaired brainstem connectivity in patients with autonomic failure.