Orthostatic hypotension in Parkinson's disease: association with cognitive decline?

BACKGROUND: Orthostatic hypotension is common in Lewy body disorders and may be related to disease progression and the spread of Lewy body pathology. We therefore hypothesize that PD patients with orthostatic hypotension (OH) have a different cognitive profile compared to PD patients without OH. METHODS: This cross-sectional study included 175 PD patients. Blood pressure (BP) was measured with a validated digital blood pressure monitor and patients with a systolic BP drop of > or =20 mmHg or a systolic pressure of <90 mm Hg after standing were considered to have OH. Cognition was assessed using MMSE extended by a selection of computerized cognitive tests focusing on reaction time, sustained attention, working memory and episodic verbal and visual memory. RESULTS: Eighty-seven (49.7%) of the PD patients had OH. These patients were significantly more impaired in sustained attention and visual episodic memory compared to PD patients without OH. CONCLUSION: We conclude that there are differences in the neuropsychological performance of patients with PD and OH, supporting the hypothesis that OH might be a marker for disease progression and cognitive decline in PD.     

Is cerebral vasomotor reactivity impaired in Parkinson disease?

Purpose

The ability of a blood vessel to change diameter in response to a change in carbon dioxide concentration is often referred to as vasomotor reactivity. This study aimed to determine whether vasomotor reactivity is impaired in patients with idiopathic Parkinson's Disease in comparison to healthy controls.

Methods

Transcranial Doppler was used to measure cerebral blood flow velocity in the middle cerebral arteries at baseline and under hypocapnic conditions in 40 patients with idiopathic Parkinson's disease and 50 healthy controls.

Results/Conclusions

Vasomotor reactivity, assessed under hypocapnic conditions, is not impaired in patients with idiopathic Parkinson's Disease in comparison to healthy controls.

     

Neurogenic orthostatic hypotension of Parkinson's disease: What exploration for what treatment?

The aim of this short review is to illustrate, using orthostatic hypotension as an example, the clinical problems related to autonomic features in Parkinson's disease. Orthostatic hypotension is frequently encountered in Parkinson's disease and its diagnosis remains manometric (a fall of at least 20 and/or 10 mmHg in standing blood pressure). It is often associated with supine hypertension to be taken into account before prescribing. To distinguish between the role of disease and of drugs (not only antiparkinsonian drugs), a simple clinical test of autonomic nervous system activity (deep breathing test and standing test with measurement of 30/15 ratio) can be used. When diagnosis with multisystem atrophy is discussed, cardiac [¹²³I]-metaiodobenzylguanidine (MIBG) scintigraphy is of value showing in Parkinson's disease a decreased uptake of the radiopharmaceutical indicating postganglionic sympathetic denervation. Concerning treatment, nonpharmacological methods have to be systematically used since no drug has been specifically evaluated for the treatment of orthostatic hypotension of Parkinson's disease.     

Are current recommendations to diagnose orthostatic hypotension in Parkinson's disease satisfactory?

We interviewed 50 Parkinson's disease (PD) patients using a questionnaire to verify the reliability of orthostatic symptoms in warning the presence of orthostatic hypotension (OH). OH is defined as 20 mm Hg systolic or 10 mm Hg diastolic BP fall within 3 min of tilting or standing but if this fall occurs after 3 min we called it ‘late OH’ (L‐OH). We compared if OH in Parkinson's disease (PD) was more frequent after head‐up tilt or on standing and if the period of postural challenge matters in detecting OH. Twenty‐one (42%) patients had OH that occurred twice more often after tilting (n = 20) than on standing (n = 10). OH occurred within 3 min of tilting in 9 patients (18%) and appeared beyond the currently recommended 3 min in 11 patients (55%) (L‐OH). Ten of the 20 patients developing OH on tilting were symptomatic. The 10 patients who had OH on standing were asymptomatic. Reporting of symptoms was independent of age or severity of BP fall. Most (90%) patients reporting orthostatic symptoms on standing had OH on tilting for 3 min. Orthostatic symptoms in PD have a high specificity but low sensitivity in predicting OH. In Parkinson's disease OH occurs often after tilting than on standing and is delayed (after 3 min). As OH in PD is often asymptomatic and delayed it could contribute to falls and increase morbidity. We suggest routine evaluation of OH in PD by tilting them longer than the recommended 3 minutes to detect delayed OH. © 2009 Movement Disorder Society     

Orthostatic hypotension and cognitive impairment in Parkinson's disease: Causation or association?

Orthostatic hypotension and cognitive impairment are common in Parkinson's disease (PD) and significantly impair quality of life. Orthostatic hypotension and cognitive impairment appear to be interrelated. Whether the relationship is causative or associative remains unclear. The vascular hypothesis proposes that recurrent episodic hypotension results in cerebral hypoperfusion, in turn causing anoxic damage to vulnerable areas of the brain and impaired cognitive function. Support for this hypothesis has come from brain MRI studies showing an association between white matter hyperintensities and a postural drop in blood pressure among PD patients. Alternatively, the association between orthostatic hypotension and cognitive decline in PD may reflect shared underlying synuclein‐related pathology affecting common neuroanatomical and neurochemical substrates. Cardiac imaging studies demonstrate noradrenergic denervation early in PD, and cardiac denervation has been associated with poorer cognition. Neurogenic orthostatic hypotension occurs as a result of defective norepinephrine release from sympathetic terminals upon standing. Neuropathological studies have also demonstrated Lewy body pathology in the locus coeruleus; the main source of noradrenaline in the brain. Locus coeruleus norepinephrine levels are reduced in PD patients with dementia when compared with PD patients without. In this review, we examine the evidence for an association between orthostatic hypotension and cognitive impairment in PD. We evaluate the literature supporting the hypothesis that progressive noradrenergic denervation underlies both orthostatic hypotension and cognitive impairment, and we examine studies suggesting that recurrent cerebral hypoperfusion results in cognitive decline in PD. Finally, we explore how modulation of blood pressure and the noradrenergic nervous system may improve cognition in PD. © 2016 International Parkinson and Movement Disorder Society     

Parkinson's disease in diphenyl-exposed workers--a causal association?

We report a cluster of five cases of Parkinson's disease (PD) among paper mill workers exposed to a fungicide, diphenyl. The cause of PD is still unknown, but epidemiological studies have indicated an elevated risk of developing PD after exposure to pesticides. The five cases of PD were found in a group of 255 diphenyl-exposed workers, and the number of expected cases in the exposed group was estimated to be 0.9, resulting in a relative risk of 5.6 (95% CI 1.8-13). Exposure to diphenyl may have contributed to this PD cluster, but chance is an alternative explanation.     

Orthostatic hypotension in Parkinson's disease: Does it matter if asymptomatic?

IntroductionOrthostatic hypotension (OH) may frequently be asymptomatic in patients with Parkinson's disease (PD). However, the relationship between symptomatic/asymptomatic status and functional disability remains unclear.MethodsUsing orthostatic blood pressure (BP) measurements and the Orthostatic Hypotension Symptom Assessment (OHSA) questionnaire, 121 consecutive PD patients without history of chronic hypertension and not taking alpha-adrenergic antagonists for bladder disorders were classified according to (1) OH symptomatic status, based on presence/absence of orthostatic symptoms (symptomatic OH: OHSA item 1 ≥ 1), and (2) OH severity, based on the magnitude of BP fall on the lying-to-standing test: OH- (<20/10 mmHg); moderate OH+ (≥20/10 mmHg but < 30/15 mmHg); and severe OH+ (≥30/15 mmHg). The primary endpoints were the activities of daily living/instrumental activities of daily living (ADL/iADL) and the Ambulatory Capacity Measure (ACM). Secondary endpoints included PD quality of life (PDQ-8) and prevalence of falls.ResultsThe overall prevalence of OH+ was 30.6% (37/121 patients), with 62.2% symptomatic (23/37) and 37.8% asymptomatic (14/37). Symptomatic and asymptomatic OH + patients had similar impairments in ADL/iADL and ACM, significantly worse than OH- (p ≤ 0.035). There was a trend for worse ADL/iADL and ACM scores in severe OH + compared to moderate OH+, but both were worse than OH- (p ≤ 0.048). Symptomatic and asymptomatic OH + showed similar impairment in PDQ-8 and higher prevalence of falls compared to OH-.ConclusionsAsymptomatic OH+ was associated with similar impairments in ADL/iADL and ACM than symptomatic OH+. These findings support screening for OH in PD patients regardless of postural lightheadedness.     

Oxidative stress and inflammation in Parkinson's disease: is there a causal link?

Parkinson's disease (PD) is a neurodegenerative disorder characterized by a dramatic loss of dopaminergic neurons in the substantia nigra (SN). Among the many pathogenic mechanisms thought to contribute to the demise of these cells, dopamine-dependent oxidative stress has classically taken center stage due to extensive experimental evidence showing that dopamine-derived reactive oxygen species and oxidized dopamine metabolites are toxic to nigral neurons. In recent years, however, the involvement of neuro-inflammatory processes in nigral degeneration has gained increasing attention. Not only have activated microglia and increased levels of inflammatory mediators been detected in the striatum of deceased PD patients, but a large body of animal studies points to a contributory role of inflammation in dopaminergic cell loss. Recently, postmortem examination of human subjects exposed to the parkinsonism-inducing toxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), revealed the presence of activated microglia decades after drug exposure, suggesting that even a brief pathogenic insult can induce an ongoing inflammatory response. Perhaps not surprisingly, non-steroidal anti-inflammatory drugs (NSAIDs) have been shown to reduce the risk of developing PD. In the past few years, various pathways have come to light that could link dopamine-dependent oxidative stress and microglial activation, finally ascribing a pathogenic trigger to the chronic inflammatory response characteristic of PD.     

Parkinson’s disease with orthostatic hypotension: analyses of clinical characteristics and influencing factors

ABSTRACT

Objectives: This study was designed to investigate clinical symptoms and blood pressure (BP) characteristics in Parkinson’s disease (PD) with orthostatic hypotension (OH), and to figure out the influencing factors of PD with OH (PD-OH).

Methods: Total 150 PD patients were divided into PD-OH and PD with no OH (PD-NOH) groups based on BP value. Series of scales were used to evaluate clinical symptoms. Twenty-four-hour ambulatory BP monitoring was adopted.

Results: Total 49 PD patients (32.67%) were with OH. PD-OH group had significantly older age, longer disease duration, more diabetes cases, higher levels of fasting blood glucose, higher levels of hemoglobin A1c (HbA1c) and higher levodopa-equivalent daily doses (P < 0.05). Motor symptoms and non-motor symptoms, including autonomic dysfunction, fatigue and cognitive impairment indicated by significantly changed scores of related scales were found in PD-OH group (P < 0.05). PD-OH group had increased BP variability (BPV) and a higher proportion of non-dipper BP pattern (P < 0.05). Binary logistic regression analysis showed that age (B, 0.064; 95% CI, 1.007 ~ 1.128; P < 0.05), HbA1c (B, 1.091; 95% CI, 1.158 ~ 7.648; P < 0.05), and systolic BPV (B, 0.138; 95% CI, 1.004 ~ 1.312; P < 0.05) were independent related factors for PD-OH group. The PD-OH group had significantly compromised daily activities and quality of life (P < 0.05).

Conclusion: Older age, higher levels of HbA1c and increased systolic BPV were the influencing factors of PD-OH patients. Daily activities and quality of life of PD-OH patients were fairly compromised.     

Cognitive and MRI correlates of orthostatic hypotension in Parkinson’s disease

Orthostatic hypotension (OH) is a frequent nonmotor feature of Parkinson’s disease (PD), and its occurrence has been associated with cognitive impairment. The underlying mechanism could be mediated by development of cerebrovascular disease induced by chronic or episodic hypoperfusion, but the extent of brain vascular load in PD patients with OH has never been investigated. This study aimed to assess the relationship between OH and cognitive function in PD patients and to investigate the contribution of brain vascular lesions. Forty-eight PD patients underwent a tilt table test (TT) to assess supine and orthostatic blood pressure as well as an extensive neuropsychological evaluation to evaluate cognitive function. Brain magnetic resonance imaging was acquired in 44/48 patients and analyzed by a visual semiquantitative scale. Twenty-three patients presented OH at TT (13/23 were symptomatic), and 25 did not. There were no differences in motor severity or disease duration between patients with and without OH. In patients with OH we found significantly worse cognitive performance in specific tasks, such as sustained attention, visuospatial and verbal memory, compared with patients without OH. However, there were no differences in vascular burden between the two groups. Our study confirms that there is an association between OH and selective cognitive deficits in PD, but rebuts the hypothesis that this is underlined by the development of cerebrovascular disease.     

What is pathological with gaze shift fragmentation in Parkinson's disease?

Oculomotor dysfunction in Parkinson's disease (PD) is mainly characterized by a fragmentation of memory-guided gaze shifts (target is reached by several hypometric saccades). Since this phenomenon can also be observed in normal subjects, we scrutinized its pathophysiological significance in PD patients. We recorded horizontal eye movements in eleven mildly- or moderately-affected PD patients and eleven control subjects. A quantitative assessment of gaze shift fragmentation was made possible by increasing its incidence over a sequence of two visually- and two subsequent memory-guided gaze shifts. Basic saccade measures (latency, velocity, etc.) were similar in the two subject groups as well as in fragmented versus non-fragmented gaze shifts. Fragmentation probability is increased in the second memory-guided gaze shift, and this clearly more so in patients than in controls. The fragmentation shows a typical gain pattern (uniform increase of gain of saccadic amplitudes across correction saccades towards 1.0 with the last saccade of the gaze shift) independent of subject group, stimulus mode, and fragmentation degree. Gaze shift fragmentation represents a physiological phenomenon, which has thus far been overlooked. It reflects a robust correction mechanism, which assures that target is reached even if the pre-oculomotor drive through the basal ganglia to the superior colliculus becomes abnormally weak or under inadequately strong inhibition – as is postulated for PD. Thus, only the abnormally high incidence of fragmentation, and of the associated amplitude reduction of the primary saccades, rather than the phenomenon per se, can be used as a diagnostic criterion in early stages of PD. Received: 19 June 2001, Received in revised form: 19 October 2001, Accepted: 24 October 2001     

Levodopa-induced dyskinesias in Parkinson's disease: is sensitization reversible?

Levodopa-induced dyskinesias (LIDs) in patients with Parkinson's disease are considered to result from the severity of dopaminergic denervation in the striatum, which is an irrevocable phenomenon, and sensitization induced by long-term intermittent administration of levodopa. Taking advantage of the 64% reduction of levodopa treatment allowed in 12 Parkinson's disease patients by continuous high-frequency stimulation of the subthalamic nucleus, we evaluated the severity of parkinsonian motor disability and LIDs during two levodopa challenges performed before the surgical implantation of the stimulation electrodes and after 8.8 months of continuous bilateral subthalamic nucleus stimulation that was interrupted 2 hours before the levodopa test. Motor disability during the "off" and "on" drug periods was unchanged. The severity of LIDs during the "on" period and dystonia during the "off" period decreased by 54% and 62%, respectively. The reduced severity of LIDs in the absence of subthalamic nucleus stimulation demonstrates that the sensitization phenomenon resulting from long-term intermittent levodopa administration is partially reversible.     

Antithrombin replacement in neonates: is there any indication?

INTRODUCTION: Activation of the coagulation system and severe acquired antithrombin (AT) deficiency are common and prognostically important findings in sick and preterm neonates. It has been hypothesised that treatment of the acquired AT deficiency with AT concentrate may improve the outcome of conditions such as the neonatal respiratory distress syndrome (RDS), intracranial hemorrhage (ICH) and sepsis. MATERIALS AND METHODS: We performed a systematic review of randomised controlled trials (RCTs) of AT replacement therapy in newborn infants. RESULTS: Two full-length trial reports were found. Both were placebo-controlled. The first RCT examined the effects of AT therapy in 122 preterm infants with RDS. Administration of AT prolonged rather than shortened the duration of mechanical ventilation and oxygen therapy. The second RCT determined whether AT replacement decreased the incidence of ICH in 60 preterm infants who were born before 30 weeks of gestation. No beneficial effect on ICH was found. CONCLUSIONS: Preterm infants with RDS do not benefit from therapy with AT concentrate and may be harmed. There is also little evidence that the administration of AT reduces the risk of ICH. The role of AT replacement during neonatal sepsis remains uncertain.