Anne Pavy-Le Traon

Dynamics of cerebral blood flow autoregulation in hypertensive patients

In hypertensive patients, the upper and lower limits of cerebral autoregulation are shifted to higher levels. However, the dynamics of cerebral autoregulation in hypertensive patients are less well known. We compared the dynamics of cerebral autoregulation in 21 treated hypertensive patients (13 men and 8 women; mean age: 48.9+/-13.6 years) and in 21 normotensive subjects (13 men and 8 women; mean age: 51+/-14.5 years) by transcranial Doppler (TCD) of the middle cerebral artery (MCA) during the acute decrease in blood pressure induced by standing up after 2 min in squatting position. MCA maximal outline blood flow velocity (FV), blood pressure (Finapres) and end-tidal PCO2 were continuously monitored and computerised. A cerebral vascular resistance index (CR) was calculated as follows: mean arterial BP/MCA mean FV with normalised changes in CR per second during the blood pressure decrease (CR slope). The CR slope reflecting the rate of cerebral autoregulation did not differ between the two groups and within the hypertensive patients [well controlled (8 patients) and not controlled (13 patients)]. The time to maximum decrease of CR (T1) and the time to full recovery of CR after the initial drop (T2) were also similar in the two groups (controls T1: 11.3+/-3.1 s, T2: 12+/-5.9 s; hypertensive T1: 11.7+/-2.5 s, T2: 10.7+/-4.5 s) and within hypertensive patients. These findings suggest that the dynamics of cerebral autoregulation are well preserved in hypertensive patients, with no difference according to the efficiency of treatment of hypertension.

Comparison of a 4-day confinement and head-down tilt on endocrine response and cardiovascular variability in humans

The aim of this study was to determine the effects of a 4-day head-down tilt (HDT; − 6°) and 4-day confinement on several indicators that might reflect a state of cardiovascular deconditioning on eight male subjects. Measurements were made of endocrine responses, heart rate variability and spontaneous baroreflex response (SBR) slope before, during and after each intervention. Plasma volume decreased by 10% after the 4-day HDT. The concentration of active renin was increased and that of urinary atrial natriuretic peptide decreased during the 4-day experiment in both groups. Plasma arginine vasopressin concentration decreased significantly only after 4-day confinement. After the 4-day HDT, one of the spectrum analysis parameters was statistically changed: the parasympathetic indicator decreased significantly (P < 0.05) whereas the sympathetic indicator and the total power spectrum were unaltered. After 4-day confinement spectrum analysis parameters were not statistically altered. A significant decrease of SBR (P < 0.05) was noticed only after the 4-day HDT. These data would suggest that exposure to a 4-day HDT was sufficient to induce a cardiovascular deconditioning which may have been induced by confinement and inactivity.

The Movement Disorders task force review of dysautonomia rating scales in Parkinson's disease with regard to symptoms of orthostatic hypotension†‡

Orthostatic hypotension is defined as a blood pressure fall of > 20 mm Hg systolic and/or 10 mm Hg diastolic within 3 minutes of an upright position. The Movement Disorders Society commissioned a task force to assess existing clinical rating scales addressing symptoms of orthostatic hypotension in Parkinsons disease. Seven neurologists and a clinimetrician assessed each scales previous use and critiqued its clinimetric properties. A scale was “recommended” if it had been applied to populations of patients with Parkinsons disease, with data on its use in studies beyond the group that developed the scale, and was found to be clinimetrically valid. A scale was considered “suggested” if it had been applied to Parkinsons disease, but only 1 of the other criteria was applied. A scale was “listed” if it met only 1 criterion. Symptoms of orthostatic hypotension are generally assessed in scales on wider autonomic or nonmotor symptoms. Some scales designed to detect orthostatic hypotension–related symptoms provide information on their severity: the AUTonomic SCale for Outcomes in PArkinsons Disease and the COMPosite Autonomic Symptom Scale met criteria for recommended with some limitations; the Novel Non‐Motor Symptoms Scale and the Orthostatic Grading Scale were classified as suggested. The Self‐completed Non‐Motor Symptoms Questionnaire for Parkinsons Disease was classified as suggested as a tool for screening orthostatic symptoms. However, these and the listed scales need further validation and application before they can be recommended for clinical use in patients with Parkinsons disease.

Factors related to orthostatic hypotension in Parkinson's disease.

INTRODUCTION Orthostatic hypotension (OH), a frequent feature of Parkinsons disease (PD) can contribute to falls and is usually related to the disease itself and/or to drugs. OBJECTIVES To explore factors related to OH and to assess the concordance between abnormal blood pressure (BP) fall after standing and the presence of orthostatic symptoms. METHODS Non-demented, non-operated idiopathic PD out-patients were questioned about the presence of orthostatic symptoms. Afterward, BP was measured 5-min after lying down and for 3-min after standing up. OH was defined as systolic and/or diastolic BP fall ≥ 20 and/or 10 mmHg after standing. Patients were further evaluated by the Unified PD Rating Scale (UPDRS) and their medications were recorded. RESULTS 103 patients were included in this study (mean age = 66 ± 1 years, mean disease duration = 9 ± 1 years; mean UPDRS II+III in ON-state = 37 ± 2 points). Forty-one subjects (40%) reported the presence of orthostatic symptoms during the previous week and 38 (37%) had OH according to manometric definition. Independent factors related to OH, as assessed by logistic regression were age >68 years (OR, 95% CI=3.61, 1.31-9.95), polypharmacy (defined as intake of >5 medications, OR = 3.59, 1.33-9.69), amantadine (7.45, 1.91-29.07) or diuretics (5.48, 1.10-54.76), whereas the consumption of entacapone was protective (0.20, 0.05-0.76). The agreement between abnormal BP fall and presence of orthostatic symptoms was poor (kappa = 0.12 ± 0.1, p = 0.23). CONCLUSION OH was significantly related to older age, polypharmacy and amantadine or diuretics intake, while entacapone exposure appeared to reduce the risk of OH. Low concordance between OH and orthostatic symptoms was observed.

Multimodal MRI assessment of nigro‐striatal pathway in multiple system atrophy and Parkinson disease

Parkinsons disease (PD) and multiple system atrophy (MSA) are two neurodegenerative alpha‐synucleinopathies characterized by severe impairment of the nigro‐striatal pathway. Based on T1‐, T2*‐, and diffusion‐weighted magnetic resonance imaging (MRI), macro‐structural and micro‐structural abnormalities in these diseases can be detected.

Multiple system atrophy: A prototypical synucleinopathy for disease-modifying therapeutic strategies

Despite active fundamental, translational and clinical research, no therapeutic intervention has yet shown convincing effects on disease progression in Parkinsons disease (PD) patients. Indeed, several disease-modification trials failed or proved to be inconclusive due to lack of consistency between clinical rating scales and putative surrogate markers of disease progression, or confounding symptomatic effects of the tested compound. Multiple system atrophy (MSA) is a rapidly progressing orphan disorder leading to severe motor disability within a few years. Together with PD and dementia with Lewy bodies (DLB), MSA belongs to the synucleinopathies, a group of neurodegenerative disorders characterized by the abnormal accumulation of alpha-synuclein. Crucial milestones have been reached for successfully conducting clinical intervention trials in a large number of patients with MSA. In this personal view, we will review evidence, and discuss why MSA could prove the most relevant clinical model for assessing treatments that target mechanisms operating in all synucleinopathies.

Changes in kinetics of cerebral auto-regulation with head-down bed rest.

Thoraco‐cephalic fluid shift induced by weightlessness may influence cerebral autoregulation. Our objective was to assess effects of simulated weightlessness by a 7‐day head‐down bed rest (HDBR) on the kinetics of cerebral blood flow (CBF) autoregulation in eight healthy women (27·9 ± 0·9 years). This was studied by transcranial Doppler (TCD) of the middle cerebral artery (MCA) during the sudden decrease in blood pressure (BP) induced by quickly deflating thigh cuff after a 4‐min arterial occlusion before (D – 3), during (D2, D5) and after the HDBR (D + 1). BP (Finapres) and MCA maximal blood flow velocity were continuously recorded. Cerebrovascular resistance (CR) was expressed as the ratio of mean BP to mean MCA velocity. The CR slope was defined as changes in CR per second during the BP decrease. The magnitude of the relative decrease in mean BP and MCA velocity as well as the CR slope did not differ significantly before, during and after the HDBR, showing no major impairment of cerebral autoregulation during short‐term HDBR. The time to maximum decrease in CR (T1 in s), corresponding to the maximum vasodilation was reduced on D2 (7·2 ± 0·6) versus D – 3 (9·9 ± 1·3), D5 (9·6 ± 0·8) and R + 1 (11·7 ± 1·1) probably as a result of the fluid shift. We also looked if the responses during the thigh cuff release differed in women according to their tolerance to the 10 min stand test performed after the HDBR: T1 was larger in the five women who presented orthostatic intolerance suggesting that some differences in cerebral autoregulatory responses may be related to orthostatic intolerance.

Assessment of the Scopa-Aut questionnaire in multiple system atrophy: Relation to UMSARS scores and progression over time

Autonomic failure is a key feature of multiple system atrophy (MSA). Moreover, early autonomic failure is an independent predictive factor for rapid disease progression and shorter survival. The assessment of autonomic failure is therefore important for both, the diagnosis and prognosis of MSA. Here, we evaluate autonomic dysfunction in MSA patients by the Scopa-Aut questionnaire. Potential associations between the Scopa-Aut questionnaire and established markers of disease progression - that is the Unified MSA Rating Scale (UMSARS) - were further assessed. The results confirm early and prominent autonomic failure in MSA patients. Relative scores were highest for the sexual and urinary subdomains. Surprisingly, relative scores in the cardiovascular subdomain were lowest suggesting that the Scopa-Aut questionnaire is suboptimal for the screening and evaluation of cardiovascular symptoms in MSA. A multivariate regression showed an association between total Scopa-Aut and UMSARS I scores. No significant changes in Scopa-Aut scores were observed during follow-up except for the urinary subdomain, while UMSARS I, II and IV scores significantly increased over time. In conclusion, Scopa-Aut can be used as a simple auto-questionnaire for the screening of autonomic symptoms in multiple system atrophy. It seems not useful as endpoint for disease-modification or neuroprotection trials.

Clinical effects of thigh cuffs during a 7-day 6° head-down bed rest

Thigh cuffs are used by Russian cosmonauts to limit the fluid shift induced by space flight. A ground simulation using the head-down bed rest (HDBR) model was performed to assess the effects of thigh cuffs on clinical tolerance and orthostatic adaptation. 8 male healthy volunteers (32.4 +/- 1.9 years) participated twice in a 7-day HDBR--one time with thigh cuffs (worn daily from 9 am to 7 pm) (TC) and one time without (WTC). Orthostatic tolerance was assessed by a 10 minute stand test and by a LBNP test (5 min at -15, -30, -45 mmHg) before (BDC-1) and at the end of the HDBR period (R+1). Plasma volume was measured before and at the end of HDBR by the Evans blue dye dilution technique. Thigh cuffs limits headache due to fluid shift, as well as the loss in plasma volume (TC: -5.85 +/- 0.95%; WTC: -9.09 +/- 0.82%, p<0.05). The mean duration of the stand test (R+1) did not differ in the two group (TC 7.1 +/- 1.3 min; WTC 7.0 +/- 1.0 min). The increase in HR and decrease in diastolic blood pressure were slightly but significantly larger without thigh cuffs. Duration of the LBNP tests did not differ with thigh cuffs. Thigh cuffs limit the symptoms due to fluid shift and the loss in plasma volume. They partly reduced the increase in HR during orthostatic stress but had no effect on duration of orthostatic stress tests.

Cerebral autoregulation is preserved in multiple system atrophy: A transcranial Doppler study

Patients with multiple system atrophy (MSA) present large changes in blood pressure (BP) due to autonomic disturbances. We analyzed how this change may influence dynamic cerebral autoregulation (DCA). Simultaneous recordings of arterial BP (Finapres) and middle cerebral artery (MCA) blood flow velocity (BFV) (transcranial Doppler) were performed in 10 patients with MSA (61 ± 12 yr of age) and 12 healthy volunteers (61 ± 11 yr of age): cerebral BFV response to oscillations in mean BP was studied in the supine position by cross‐spectral analysis of mean BP and mean MCA BFV. The DCA was also studied during the decrease in BP the first seconds when standing up from a sitting position by the assessment of the cerebrovascular resistance index (CR; mean BP/mean MCA BFV ratio). The MCA BFV/BP cross‐spectral analysis showed a phase for the mid‐frequency band (0.07–0.2 Hz) significantly larger in MSA, suggesting more active autoregulation in response to larger changes in BP. Changes in CR reflecting the rate of autoregulation, when standing did not differ between the two groups. These data suggest that dynamic cerebral autoregulation is preserved in MSA.