Sick sinus syndrome and orthostatic hypotension in Parkinson’s disease

We present a case of Parkinson's disease patient whose initial symptoms were sick sinus syndrome and orthostatic hypotension. Our case illustrates difficulties in distinguishing syncope of primary cardiac or neurological origin and highlights the importance of a diagnostic workup including neurological examination.     

Clinical and neuroendocrinological characteristics of delayed orthostatic hypotension in Parkinson’s disease

Clinical Autonomic Research - Delayed orthostatic hypotension (DOH), a fall in blood pressure after a 3-min cutoff, is clinically meaningful. The aim of this study was to elucidate the clinical and...     

Cognitive correlates of cortical cholinergic denervation in Parkinson’s disease and parkinsonian dementia

We recently reported findings that loss of cortical acetylcholinesterase (AChE) activity is greater in parkinsonian dementia than in Alzheimer’s disease (AD). In this study we determined cognitive correlates of in vivo cortical AChE activity in patients with parkinsonian dementia (PDem, n = 11), Parkinson’s disease without dementia (PD, n = 13), and in normal controls (NC, n = 14) using N–[¹¹C]methyl–piperidin–4–yl propionate ([¹¹C]PMP) AChE positron emission tomography (PET). Cortical AChE activity was significantly reduced in the PDem (–20.9%) and PD (–12.7 %) subjects (P < 0.001) when compared with the control subjects. Analysis of the cognitive data within the patient groups demonstrated that scores on the WAIS-III Digit Span, a test of working memory and attention, had most robust correlation with cortical AChE activity (R = 0.61, p < 0.005). There were also significant correlations between cortical AChE activity and other tests of attentional and executive functions, such as the Trail Making and Stroop Color Word tests. There was no significant correlation between cortical AChE activity and duration of motor disease (R = –0.01, ns) or severity of parkinsonian motor symptoms (R = 0.14, ns). We conclude that cortical cholinergic denervation in PD and parkinsonian dementia is associated with decreased performance on tests of attentional and executive functioning. Supported by grants from the Department of Veterans Affairs, National Institute of Aging (Alzheimer Disease Research Center, AG05133), and The Scaife Family Foundation, Pittsburgh, PA, USA.     

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.     

Independent effect of neurogenic orthostatic hypotension on mild cognitive impairment in Parkinson’s disease

Clinical Autonomic Research - Orthostatic hypotension (OH) is an associative or causative factor of cognitive impairment in Parkinson’s disease (PD). However, the association between mild...     

Clinical and demographic correlates of apathy in Parkinson’s disease

Journal of Neurology - To better understand the demographic, neuropsychiatric, cognitive, and motor predictors of apathy in Parkinson’s disease (PD). 112 participants (Mage = 68.53 years;...     

Cognitive dysfunction and dementia in Parkinson’s disease

Parkinson's disease (PD) is a slowly progressive neurodegenerative disorder mainly characterized by degeneration of dopaminergic neurons in the substantia nigra and the ventral tegmental area, in combination with a varying loss of central noradrenergic (locus coeruleus), cholinergic (nucleus basalis of Meynert) and serotonergic (dorsal raphe nuclei) integrity, leading to a multitude of motor and non-motor behavioral disturbances. Apart from the clinical motor hallmarks, in the early stages of disease, subtle cognitive dysfunction might be seen comprising mainly executive dysfunction, with secondary visuospatial and mnemonic disturbances. In about 20-40% of patients, these problems may eventually proceed to dementia, which constitutes an important risk factor for caregiver distress, decreased quality of life and nursing home placement. Dementia in PD is typically characterized by a progressive dysexecutive syndrome with attentional deficits and fluctuating cognition, often accompanied by psychotic symptoms. It is thought to be the result of a combination of both subcortical and cortical changes. PD-related dopaminergic deficiency in the nucleus caudatus and mesocortical areas (due to degeneration of projections from the substantia nigra and ventral tegmental area) and cholinergic deficiency in the cortex (due to degeneration of ascending projections from the nucleus basalis of Meynert), combined with additional Alzheimer-pathology and cortical Lewy bodies, may greatly contribute to dementia.Current treatment of dementia in PD is based on compensation of the profound cholinergic deficiency. Recent studies with the cholinesterase inhibitors galantamine, donepezil and rivastigmine show promising results in improving cognition and ameliorating psychotic symptoms, which must further be confirmed in randomized controlled trials.     

Effect of strength training on orthostatic hypotension in Parkinson’s disease—a pilot study

Clinical Autonomic Research -     

Orthostatic hypotension and attention in Parkinson’s disease with and without dementia

Summary. To compare frequency and degree of orthostatic hypotension (OH) in Parkinson’s disease (PD) and Parkinson’s disease with dementia (PDD) and its effect on attention and word fluency, blood pressure (BP) and heart rate changes during tilt were determined in 10 PD and 8 PDD patients. Attention and word fluency were evaluated in supine and tilted position using standard neuropsychological tests. OH defined as systolic BP (SBP) drop of ≥20 mmHg and/or diastolic BP (DBP) drop of ≥10 mmHg was present in 5 PDD patients and in 2 PD patients. SBP drop was significantly greater in PDD than in PD patients (P < 0.05). Whereas word fluency was unaffected by tilt in both patient groups, attention as assessed with the Test of Everyday Attention (TEA) deteriorated significantly in the PDD group, correlating with blood pressure response (ΔSBP and TEA-2, r = 0.828, P < 0.05; ΔDBP and TEA-2, r = 0.828, P < 0.05). We conclude that OH is frequent in PDD and should be addressed therapeutically since it may exacerbate attentional dysfunction.     

Cognitive and neuropsychiatric effects of subthalamotomy for Parkinson’s disease

Since the advent of deep brain stimulation (DBS) for the treatment of Parkinson’s disease (PD), subsequent cognitive and neuropsychiatric effects of this procedure have become well-chronicled. Yet, thermolitic lesion of the subthalamic nucleus (STN) is still a valid option when DBS cannot be applied, and little has been published regarding its impact on cognition and mood. We examined the cognitive and neuropsychiatric functions of 10 consecutive patients with advanced PD undergoing simultaneous bilateral subthalamotomies. With 24 months of follow-up, the patients, three of whom were on anticholinergics prior to surgery, showed no deterioration in cognitive assessments including verbal fluency. Hypoactive behaviors (depression and apathy) showed lasting improvement, while hyperactive behaviors (euphoria and disinhibition) transiently increased after surgery. Improvement in hypoactive behaviors correlated with improvement in hypokinetic movements, and enhanced hyperactive behaviors followed the course of post-operative hyperkinetic movements. Such correlations may support the role of the STN in modulating limbic connections between the basal ganglia and frontal cortex. The results of this proof-of-concept pilot study suggest the need for larger, long-term, randomized controlled studies to assess motor, neuropsychiatric, behavioral and radiologic correlations after subthalamotomies.     

Progression of small vessel disease correlates with cortical thinning in Parkinson’s disease

ObjectiveCerebral small-vessel disease (SVD) is a risk factor for dementia in Parkinson’s disease (PD), however the pathophysiological role of SVD in PD-dementia is unclear. We investigated the impact of baseline and progression of SVD on cortical thickness and the correlation to cognition.MethodsSeventy-three mild PD patients with baseline and follow-up structural MRI scans, serial clinical and neuropsychological assessments were studied. SVD included the load of white matter hyperintensities (WMH), lacunes and perivascular spaces (PVS). WMH progression was assessed using the modified Rotterdam Progression scale, while for lacunes and PVS, development of new lesions was considered as lesion progression. Patients were classified as having SVD-progression and SVD-no-progression based on the longitudinal changes in their SVD measures. Freesurfer was used to measure baseline and follow-up regional cortical thickness and subcortical volumes and correlated to cognitive performance.ResultsFourteen patients were classified as SVD-progression and 59 as SVD-no-progression. Over 18 months, PD SVD-progression demonstrated significant cortical thinning in the left frontal and bilateral parietal regions with associated decline in memory, executive function, and motor functions. PD SVD-progression also had reduced volumes in the nucleus accumbens and amygdala at baseline and greater atrophy in the caudate nucleus over 18 months.DiscussionThe extent and progression of SVD is associated with focal cerebral atrophy and domain-specific cognitive dysfunction. Measures to retard SVD may be potentially useful in preventing dementia in PD.     

Structural and functional correlates of subthalamic deep brain stimulation-induced apathy in Parkinson’s disease

BackgroundNotwithstanding the large improvement in motor function in Parkinson’s disease (PD) patients treated with deep brain stimulation (DBS), apathy may increase. Postoperative apathy cannot always be related to a dose reduction of dopaminergic medication and stimulation itself may play a role.ObjectiveWe studied whether apathy in DBS-treated PD patients could be a stimulation effect.MethodsIn 26 PD patients we acquired apathy scores before and >6 months after DBS of the subthalamic nucleus (STN). Magnetoencephalography recordings (ON and OFF stimulation) were performed ≥6 months after DBS placement. Change in apathy severity was correlated with (i) improvement in motor function and dose reduction of dopaminergic medication, (ii) stimulation location (merged MRI and CT-scans) and (iii) stimulation-related changes in functional connectivity of brain regions that have an alleged role in apathy.ResultsAverage apathy severity significantly increased after DBS (p < 0.001) and the number of patients considered apathetic increased from two to nine. Change in apathy severity did not correlate with improvement in motor function or dose reduction of dopaminergic medication. For the left hemisphere, increase in apathy was associated with a more dorsolateral stimulation location (p = 0.010). The increase in apathy severity correlated with a decrease in alpha1 functional connectivity of the dorsolateral prefrontal cortex (p = 0.006), but not with changes of the medial orbitofrontal or the anterior cingulate cortex.ConclusionsThe present observations suggest that apathy after STN-DBS is not necessarily related to dose reductions of dopaminergic medication, but may be an effect of the stimulation itself. This highlights the importance of determining optimal DBS settings based on both motor and non-motor symptoms.     

Orthostatic hypotension acutely impairs executive functions in Parkinson’s disease

Orthostatic hypotension is a frequent non-motor symptom of Parkinson’s disease, with negative prognostic role on cognitive functions. Here we measured the acute effects of orthostatic hypotension on executive functions in Parkinson’s disease patients devoid of hypertension, carotid artery stenosis, and significant chronic cerebrovascular pathology. Measurements were carried out during regular visits in outpatient setting. Twenty-eight Parkinson’s disease patients were recruited and studied along scheduled outpatient visits. They were divided into two groups (n?=?14 each) based on the presence or lack of orthostatic hypotension. This was diagnosed according to international guidelines. All patients were submitted to the Stroop’s test and to the phonological and semantic verbal fluency test after 10-min resting in supine position and immediately upon standing in upright position. Testing lasted less than 5 min in either position. In upright position, subjects with orthostatic hypotension displayed significantly worse performances at the Stroop’s test word reading time (22.1?±?4.1 vs. 14.9?±?4.0 s), interference time (56.1?±?12.3 vs. 41.4?±?11.8 s), and number of errors at the interference section (5.8?±?3.2 vs. 1.3?±?2.1) as compared to those without orthostatic hypotension. These results demonstrate that worsening of attentive function upon standing can be measured in Parkinson’s disease patients with orthostatic hypotension during routine outpatient visits. These findings suggest that clinically asymptomatic orthostatic hypotension in Parkinson’s disease patients may acutely worsen neuropsychological performances with possible negative impact on daily functioning.     

Cognitive and SPECT characteristics predict progression of Parkinson’s disease in newly diagnosed patients

OBJECTIVE: To identify features in cognitive functioning and regional cerebral blood flow (rCBF) in newly diagnosed Parkinson's disease (PD) patients and to determine whether these factors are able to predict the progression of the disease in general and the development of cognitive decline in particular. METHODS: 50 previously treatment-naive PD patients participated in the study. Cognitive assessment and SPECT were performed twice: at the time of diagnosis and then 3 years later. Six patients died or refused to continue. The Mattis dementia rating scale, the WAIS-R digit span test, a word list learning/recall test, a word fluency task and the Stroop word-colour test were used to assess cognitive function. rCBF was measured in 10 pairs of regions of interest. Principal component analysis of the data from the final examination was used to determine which variables allowed the formation of patient subgroups. Thereafter, factorial discriminant analysis (FDA) was performed in order to obtain a predictive model of these final classes. RESULTS: A stepwise procedure enabled the identification of 3 clusters (26, 16 and 2 patients). As the patients in the smallest cluster met the criteria for dementia at the final examination, they were discarded from further analyses. All the cognitive variables contributed to the constitution of the two other clusters. Age, educational level and all the rCBF parameters also contributed but to a lesser extent. Comparison of these groups showed reduced overall cognitive efficiency and an exacerbated subcorticofrontal syndrome in the 16-patient cluster. FDA showed that the best predictive model for the final classes was based on 7 variables: educational level, semantic and alternating word fluency, Stroop interference index and the right medial frontal, left parietal and left lenticular nucleus rCBF findings. CONCLUSION: Even though both cognitive and rCBF parameters help predict the progression of newly diagnosed PD patients and bearing in mind the limitations of the SPECT method used here, it appears that the contribution of cognitive assessment is greater than that of rCBF measurement.     

Cognitive and behavioral dysfunction in Parkinson’s disease: neurochemical and clinicopathological contributions

The cognitive and behavioral sequelae (i.e., nonmotor profile) of Parkinson's disease (PD), with executive dysfunction and depression being most prominent, have typically been overshadowed due to an emphasis on motor symptomatology. The apparent categorization of PD as a disorder isolated to the dopaminergic system may be a generalization of the disease pathology. Dopamine therapy, used for the treatment of motor symptoms, has not consistently been shown to resolve nonmotor impairments. Research evidence indicates that nondopaminergic neurotransmitter systems (i.e., serotonergic, noradrenergic, & cholinergic) are disrupted in PD and may contribute to cognitive and behavioral dysfunction. Furthermore, Lewy bodies within cortical and subcortical structures can add to the nonmotor profile in PD. Pharmacological interventions for the treatment of cognitive and behavioral impairments associated with PD are few, especially for nondemented patients. The current review of the literature highlights evidence that associates nonmotor dysfunctions with neurochemical and clinicopathological correlates of PD.     

Parkinson’s disease in patients and obligate carriers of Gaucher disease

BackgroundGaucher disease is an autosomal recessive disorder caused by glucocerebrosidase gene mutations. Accumulating evidence from several Parkinson’s disease cohorts of varying ethnicities suggests that glucocerebrosidase mutations even in the heterozygous state (carriers) may be a susceptibility factor for Parkinson’s. Very few studies have analyzed the frequency of Parkinson’s in carriers and individuals with Gaucher disease.ObjectiveTo determine frequency of Parkinson’s in patients with Gaucher disease and obligate carriers of glucocerebrosidase mutations and compare it with a control group.MethodsA questionnaire was completed by 100 Ashkenazi Jewish Gaucher patients followed at our center and 109 ethnicity-matched controls with no personal or family history of Gaucher disease.ResultsFrequency of Parkinson’s was higher in Gaucher patients (8/100) than in controls (0/109; P = 0.0024). Frequency of Parkinson’s in obligate carriers (11/200) was higher than controls (6/218), but the difference was not statistically significant (P = 0.215). Average age of onset of Parkinson’s was earlier in Gaucher patients (57.2) than the general population and in obligate carriers (60) when compared with controls (76.8; P = 0.01). The L444P genotype was more frequent in Gaucher patients who reported a parent with Parkinson’s (36.40%) than those who did not (4.50%).ConclusionOur study suggests that the risk for developing Parkinson’s may be higher in affected versus carriers of glucocerebrosidase mutations and suggests that L444P may pose a higher risk of developing Parkinson’s than other mutations. It also confirms previous findings that the age of onset of Parkinson’s associated with glucocerebrosidase mutations is earlier than in the general population.     

Depression and apathy in Parkinson’s disease

This article provides an update on depression and apathy in Parkinson’s disease (PD), both of which are common but often misunderstood. The diagnosis of depression in PD can be challenging and we still do not have solid evidence on which to base our treatment decisions. Apathy is most commonly seen in the setting of dementia or depression but emerging evidence suggests that it may be a core feature of PD. There are conflicting reports about the effects of deep brain stimulation (DBS) on mood and apathy, but studies suggest that at least some patients may develop depression and apathy after the procedure. Although we are making strides toward a better understanding of depression and apathy in PD, it is clear that more research is needed about these non-motor features.