Lewy bodies in the lower sacral parasympathetic neurons of a patient with Parkinson's disease

Summary Lewy bodies were observed incidentally in the neurons of the dorsal group of nucleus intermediolateralis of the 3rd sacral segment of the spinal cord in a 74-year-old male with Parkinson's disease. The findings indicate the degeneration of the preganglionic parasympathetic neurons innervating the internal anal sphincter. The correlation between the findings and the mechanism of constipation in this disease are discussed.Supported in part by a Grant-in-Aid for Co-operative Research (A) No. 62304040 from the Ministry of Education, Science and Culture, Japan     

Parkinson's Disease: Distribution of Lewy Bodies in the Peripheral Autonomic Nervous System

This report concerns the presence and distribution of Lewy bodies in the peripheral nervous system of three patients with Parkinson's disease and ten age-matched nonparkinsonian individuals. We examined the paravertebral and celiac ganglia as representatives of the sympathetic system; the submandibular ganglion as representative of the parasympathetic system; the esophagus, stomach, duodenum, jejunum, ileum and colon as representatives of the enteric system, and the trigeminal and dorsal spinal ganglia as representatives of the somatic sensory system. Lewy bodies were observed in the peripheral sympathetic and enteric systems of two of the three patients with Parkinson's disease. These two patients had numerous Lewy bodies in the submandibular ganglia. The third patient did not have Lewy bodies in the peripheral autonomic nervous system, nor did the ten control individuals studied. Lewy bodies were not detected in the somatic sensory system of any of the three parkinsonian patients. Our findings indicate that the peripheral autonomic system, including the parasympathetic system is affected in Parkinson's disease.     

Amygdala pathology in Parkinson's disease

The amygdala undergoes severe pathological changes during the course of Parkinson's disease (PD). Lewy bodies and Lewy neurites are distributed in a specific manner throughout the nuclear complex. The lesional pattern displays only minor interindividual variation. The most prominent changes occur in the accessory cortical and central nuclei. The cortical, accessory basal and granular nuclei show less severe alterations, while the basal and lateral nuclei, as well as the intercalated cell masses, generally remain uninvolved. The amygdala receives a broad range of afferents, allowing integration of exteroceptive information with interoceptive data. It generates major projections to the isocortex (the prefrontal cortex in particular), limbic system (hippocampus and entorhinal region) and centers regulating endocrine and autonomic functions. The specific lesional pattern seen in PD destroys part of the nuclear gray matter and its connections and, thus, may likely contribute to the development of behavioral changes and autonomic dysfunction.     

Evaluation of sympathetic skin response in Parkinson's disease

There is no clear definition on the role of sympathetic skin response (SSR) in the evaluation of patients with Parkinson's disease (PD). We recorded the SSR of the palms of 64 controls and 46 patients with PD to electrical stimulation of the median nerve at the wrist. We analyzed onset latency and peak-to-peak amplitude. A study of parasympathetic function (R–R interval analysis) was also undertaken. We found that patients with PD had more absent SSRs than controls. The mean amplitude of the SSR was significantly reduced in both lower and upper limbs of PD patients in comparison with control subjects (p<0.001). The onset latency was longer in the lower limbs of these patients in respect to the control group (p<0.003). There was a significant inverse correlation between SSR amplitudes and age, severity and late onset of the disease. There was no association of these parameters with dysautonomic symptoms or R–R interval variation. In conclusion, there is a significant association between altered SSR and PD and an inverse correlation in this group of patients between SSR values and older age, greater severity and later onset of disease. Therefore, the study of SSR may provide valuable information on cholinergic sympathetic function in patients with PD.     

Parkinson's disease: an immunohistochemical study of Lewy body-containing neurons in the enteric nervous system

Summary We performed immunohistochemical analysis of specimens from three autopsied patients with Parkinson's disease, using antibodies to tyrosine hydroxylase (TH), vasoactive intestinal polypeptide (VIP), somatostatin, met-enkephalin, leu-enkephalin and substance P in an attempt to reveal the types of neurons that contain Lewy bodies (LBs) in the paravertebral and celiac sympathetic ganglia and in the enteric nervous system of the alimentary tract. In the sympathetic ganglia, almost all LB-containing neuronal cell bodies and processes were immunoreactive for TH. In the alimentary tract, however, most LBs were found in the VIP-immunoreactive (VIP-IR) neuronal cell bodies and processes. In spite of the significant presence of TH-IR neuronal cell bodies and processes in the alimentary tract, LB-containing TH-IR neuronal elements were rarely encountered. These findings indicate that in the alimentary tract, the VIP neuron system is mainly involved in the disease process of Parkinson's disease.Supported in part by a research grant for CNS degenerative diseases from the Ministry of Health and Welfare, Japan     

Juvenile Parkinson's disease with widespread Lewy bodies in the brain

Summary A clinico-pathological case report on a case of juvenile Parkinson's disease (JPD) with widespread Lewy bodies (LBs) in the brain is presented with comparative morphological studies on two demented cases of classical Parkinson's disease (CPD) with disease onset at an older age. The clinical and histological pictures of this JPD case were typical of Parkinson's disease, excepting numerous Lewy bodies in the cerebrum. There were no neurofibrillary change nor senile plaques throughout the CNS. The distribution and histochemical and ultrastructural characters of the histological lesions (i.e., LBs) in the JPD and the two CPD cases were investigated and compared. The comparison showed no qualitative but only quantitative differences between the two types of Parkinson's disease. The present study also revealed that in CPD cases significant numbers of LBs could be present in the cerebral cortex, amygdaloid and claustrum. These lesions can be in part responsible for dementia in CPD.     

The second brain and Parkinson's disease

Parkinson's disease is the second most common neurodegenerative disease after Alzheimer's disease. It has been classically considered that the pathological hallmarks of Parkinson's disease, namely Lewy bodies and Lewy neurites, affect primarily the substantia nigra. Nevertheless, it has become increasingly evident in recent years that Parkinson's disease is a multicentric neurodegenerative process that affects several neuronal structures outside the substantia nigra, among which is the enteric nervous system. Remarkably, recent reports have shown that the lesions in the enteric nervous system occurred at a very early stage of the disease, even before the involvement of the central nervous system. This led to the postulate that the enteric nervous system could be critical in the pathophysiology of Parkinson's disease, as it could represent a route of entry for a putative environmental factor to initiate the pathological process (Braak's hypothesis). Besides their putative role in the spreading of the pathological process, it has also been suggested that the pathological alterations within the enteric nervous system could be involved in the gastrointestinal dysfunction frequently encountered by parkinsonian patients. The scope of the present article is to review the available studies on the enteric nervous system in Parkinson's disease patients and in animal models of the disease. We further discuss the strategies that will help in our understanding of the roles of the enteric nervous system, both in the pathophysiology of the disease and in the pathophysiology of the gastrointestinal symptoms.     

Prevalence of tremor and Parkinson's disease

To determine the prevalence of essential tremor (ET) and Parkinson's disease (PD) in a retirement community, all residents of Carefree, Arizona, aged over 65 years were contacted. All participants completed validated questionnaires for PD and ET, and were examined using the Unified Parkinson's Disease Rating Scale. Of 356 individuals evaluated, 155 (43.5%) had tremor; 73 (20.5%) had ET; 26 (7.3%) had PD; and 56 (15.7%) had postural tremor (PT). Thus, a large percentage of individuals were found to have tremor, in the plurality of whom it could be classified as ET. The number of individuals with Parkinson's disease exceeded our expectations.     

The influence of the type,duration, severity and levodopa treatment of Parkinson's disease on cardiovascular autonomic responses

The influence of the type, duration, severity and levodopa treatment of Parkinson's disease on autonomic involvement has been assessed. The Valsalva manoeuvre, deep breathing, handgrip and orthostatic tests were performed in 50 patients with Parkinson's disease and in a control group of 30 healthy subjects. No attempt was made to classify further patients with parkinsonian features into groups such as the Shy—Drager syndrome or multiple system atrophy. All test results were significantly smaller in patients than in healthy subjects. The diastolic pressure increase during handgrip was significantly smaller in akinetic-rigid than in tremor-akinetic-rigid type patients. The Valsalva ratio and orthostatic test results were significantly smaller in patients with longer duration than in those with shorter duration of disease. All test results except those of the orthostatic test were significantly smaller in patients with the more severe form than in those with the less severe form of disease. Comparing test results of levodopa-treated and -untreated patients no significant differences were found. Our studies in parkinsonian patients suggest that (1) sympathetic impairment is more pronounced in akinetic-rigid than in tremor-akinetic-rigid type patients; (2) sympathetic impairment occurs early, whereas parasympathetic impairment develops later; (3) sympathetic and parasympathetic impairment parallels the severity of disease; (4) orthostatic parameters are more duration-sensitive than severity-sensitive; (5) chronic levodopa treatment does not markedly influence cardiovascular autonomic responses.     

Parkinson's disease: the presence of Lewy bodies in Auerbach's and Meissner's plexuses

Summary We systematically studied the enteric nervous system of the alimentary tract in seven patients with Parkinson's disease. In all patients, characteristic inclusions histologically and ultrastructurally identical to Lewy bodies were found in Auerbach's and Meissner's plexuses. They were most frequent in the Auerbach's plexus of the lower esophagus. Lewy bodies were found in 8 out of 24 age-matched nonparkinsonian patients. However, they were obviously small in number. These findings clearly indicate that the plexuses are also involved in Parkinson's disease.     

A comparison of cerebral glucose metabolism in Parkinson's disease, Parkinson's disease dementia and dementia with Lewy bodies

Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB) share many similar aspects, and making a clinical diagnosis of one disorder over the other relies heavily on an arbitrary criterion, so-called 1-year rule. This study was designed to search for any difference of metabolic patterns in these two disorders using F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) images.
We enrolled 16 patients with PD, 13 patients with PDD, and seven patients with DLB. FDG PET was performed, and images were reconstructed by iterative reconstruction using the computed tomography (CT) images, and were normalized to a standard template. Statistical comparison between groups were performed on a voxel-by-voxel basis using t -statistics (two-sample t -test).
Compared with the patients with PD, both PDD and DLB patients showed similar patterns of decreased metabolism in bilateral inferior and medial frontal lobes, and right parietal lobe ( P _uncorrected < 0.001). In a direct comparison, DLB patients had significant metabolic decrease ( p _uncorrected < 0.005) in the anterior cingulate compared with those with PDD. These findings support the concept that PDD and DLB have similar underlying neurobiological characteristics, and that they can be regarded as a spectrum of Lewy body disorders.     

Levodopa, bromocriptine and selegiline modify cardiovascular responses in Parkinson's disease

Autonomic nervous system (ANS) involvement is frequently found in Parkinson's disease (PD), but its causal relationship to the disease itself and its medication is unclear. We evaluated the effects of PD medications on cardiovascular ANS functions. Heart rate (HR) responses to normal and deep breathing, the Valsalva manoeuvre and tilting, and blood pressure (BP) responses to tilting and isometric work were measured prospectively in 60 untreated PD patients randomised to receive either levodopa (n=20), bromocriptine (n=20) or selegiline (n=20) as their initial treatment. The results were compared with those of 28 healthy controls. The responses were recorded at baseline, after 6 months on medication and following a 6-week washout period. At baseline HR responses to normal breathing, deep breathing and tilting were already lower and the fall in the systolic BP immediately and at 5 min after tilting was more pronounced in the PD patients than in the controls. Six months' levodopa treatment diminished the systolic BP fall after tilting when compared to baseline, whereas bromocriptine and selegiline increased the fall in systolic BP after tilting and selegiline diminished the BP responses to isometric work. The BP responses returned to the baseline values during the washout period. The drugs induced no change in the HR responses. Thus PD itself causes autonomic dysfunction leading to abnormalities in HR and BP regulation and the PD medications seem to modify ANS responses further. Bromocriptine and selegiline, in contrast to levodopa, increase the orthostatic BP fall and supress the BP response to isometric exercise reflecting mainly impairment of the sympathetic regulation. Received: 17 February 2000 / Received in revised form: 25 May 2000 / Accepted: 15 June 2000     

The rostral mesencephalon in Parkinson's disease and Alzheimer's disease

Summary The rostal mesencephalon at the level of the posterior commissure was studied by light microscopy in two patients with idiopathic Parkinson's disease, one patient with Alzheimer's disease, and one patient with senile dementia of Alzheimer's type. In the Parkinsonian cases, the rostral part of the nucleus of Edinger Westphal disclosed Lewy bodies in 3% of the neurons, neurofibrillary degeneration in 2% of the neurons, and a 54% neuronal loss. In Alzheimer's disease, 2% of Edinger Westphal neurons contained neurofibrillary degeneration, whereas in senile dementia of Alzheimer's type only rare neurofibrillary degeneration was evident in this nucleus. Neuronal loss was not apparent in the nucleus of Edinger Westphal in either of the Alzheimer's cases. The pathologic changes observed in this presumably cholinergic nucleus resemble in some respects changes reported in the cholinergic centers of the basal forebrain in these diseases.In addition, the central gray matter and pretectal region in Parkinson's disease contained a patchy increase in astroglia, some with scant reactive cell bodies; however, Lewy bodies were limited to that part of the central gray matter corresponding to the nucleus of Darkschewitsch. A few neurofibrillary tangles were present in the nucleus of Darkschewitsch in both diseases.     

Parkinson's disease: Distribution of Lewy bodies and monoamine neuron system

Summary A systematic study of the central and peripheral nervous systems in 3 cases of Parkinson's disease has demonstrated that Lewy bodies are present in 27 nuclei. Of these 20 nuclei (12 pigmented and 8 unpigmented) are involved in 2 or all 3 cases.It is noticed that the distribution of Lewy bodies in Parkinson's disease described here corresponds surprisingly well to that of monoamine (dopamine, noradrenaline and serotonin) cell bodies demonstrated in rats by the histochemical fluorescence method. This correlation is similar to that of Alzheimer's neurofibrillary changes in postencephalitic Parkinsonism as described by Ishii. Inasmuch as these viewpoints are also in agreement with previously reported biochemical data on Parkinsonism, it is suggested that Parkinsonism (idiopathic and postencephalitic) should represent a system degeneration of monoamine neuron systems.This work was supported in part by grant from the Japanese Ministries of Education and Health and Welfare.     

Resting parasympathetic nervous system activity is associated with greater antiviral gene expression

Parasympathetic nervous system activity can downregulate inflammation, but it remains unclear how parasympathetic nervous system activity relates to antiviral activity. The present study examined associations between parasympathetic nervous system activity and cellular antiviral gene regulation in 90 adolescents (M_age = 16.28, SD = 0.73; 51.1% female) who provided blood samples and measures of cardiac respiratory sinus arrhythmia (RSA), twice, five weeks apart. Using a multilevel analytic framework, we found that higher RSA (an indicator of higher parasympathetic nervous system activity)—both at rest and during paced breathing—was associated with higher expression of Type I interferon (IFN) response genes in circulating leukocytes, even after adjusting for demographic and biological covariates. RSA was not associated with a parallel measure of inflammatory gene expression. These results identify a previously unrecognized immunoregulatory aspect of autonomic nervous system function and highlight a potential biological pathway by which parasympathetic nervous system activity may relate to health.     

Sympathetic and parasympathetic pupillary dysfunction in familial dysautonomia

Objective assessment of autonomic dysfunction in familial dysautonomia (FD) is largely based on the analysis of cardiovascular responses to challenge maneuvers such as orthostatic stress. Infrared pupillometry (IPM) provides an additional reliable method for cranial autonomic evaluation and has the advantage of requiring minimal cooperation.This study was performed to determine whether IPM contributes to the assessment of autonomic function in FD patients.In 14 FD patients and 14 healthy controls, we studied absolute and relative light reflex amplitude, pupillary constriction velocity (v(constr)), pupillary diameter, early and late pupillary re-dilatation velocity (v(dil 1), v(dil 2)) after dark adaptation. Prior to IPM, all patients had an ophthamological examination to evaluate refraction and corneal integrity.In comparison to controls, patients had a significant reduction of the parameters reflecting parasympathetic pupillary function (absolute light reflex amplitude 1.34 +/- 0.21 vs. l.86 +/- 0.14 mm, relative light reflex amplitude 22.74 +/- 7.11% vs. 30.76 +/- 3.57%, v(constr) 3.75 +/- 1.09 vs. 5.80 +/- 0.59 mm/s) and of the parameters reflecting sympathetic pupillary function (diameter 5.69 +/- 0.66 vs. 6.35 +/- 0.60 mm, v(dil 1) 1.29 +/- 0.23 vs. 1.95 +/- 0.23 mm/s, v(dil 2) 0.64 +/- 0.13 vs. 0.72 +/- 0.l2 mm/s; Mann-Whitney U-test: p<0.05).The non-invasive technique of IPM demonstrates dysfunction not only of the cranial parasympathetic, but also of the cranial sympathetic nervous system and, thus, further characterizes autonomic dysfunction in FD.     

Microtubule-associated protein 5 is a component of Lewy bodies and Lewy neurites in the brainstem and forebrain regions affected in Parkinson's disease

Ubiquitin-positive Lewy neurites and Lewy bodies are found in idiopathic Parkinson's disease (PD) and diffuse Lewy body disease (DLBD). We found that, in three patients with PD and one with DLBD, microtubule-associated protein 5 (MAP5) immunostaining was consistently present in both Lewy neurites and Lewy bodies throughout the brainstem and forebrain regions affected in the disease. In contrast, other cytoskeletal markers (neurofilaments and MAP2) could be demonstrated in only a small fraction of Lewy bodies and neurites. Confocal microscopy demonstrated that MAP5 immunolabeling was located around the perimeter of the ubiquitin-positive labeling which occupied the central region of the neurite and Lewy body, with some overlap between MAP5 and ubiquitin staining. In contrast, in those Lewy bodies and neurites immunopositive for phosphorylated and non-phosphorylated neurofilament proteins, the neurofilament labeling was quite peripheral to the ubiquitin staining, with little or no overlap. Our results suggest MAP5 is more closely associated with the ubiquitinated proteins of Lewy bodies and neurites than other cytoskeletal proteins. Received: 3 July 1995 / Revised, accepted: 8 September 1995