Alpha-synuclein pathology of the spinal and peripheral autonomic nervous system in neurologically unimpaired elderly subjects

Studies on cases with incidental Lewy body disease (ILBD) suggest that alpha-synuclein (alphaSN) pathology of Parkinson's disease (PD) starts in lower brainstem nuclei and in the olfactory bulb. However, medullary structures as the induction site of alphaSN pathology have been questioned as large parts of the nervous system, including the spinal cord and the peripheral autonomic nervous system (PANS), have not been examined in ILBD. Thus, the time course of PD lesions in the spinal cord or PANS in relation to medullary lesions remains unknown. We collected 98 post mortem cases with no reference to PD-associated symptoms on clinical records. alphaSN pathology was found in the central nervous system, including the spinal cord, and in the PANS in 17 (17.3%) cases. alphaSN pathology was encountered in autonomic nuclei of the thoracic spinal cord, brainstem and olfactory nerves in 17/17, in sacral parasympathetic nuclei in 15/16, in the myenteric plexus of oesophagus in 14/17, in sympathetic ganglia in 14/17, and in the vagus nerve in 12/16 cases. In addition to the thoracic lateral horns, a high number of alphaSN lesions was also found in non-autonomic spinal cord nuclei. Considering supraspinal structures our cases corresponded roughly to the recently described sequential order of alphaSN involvement in PD. Our study indicates, however, that the autonomic nuclei of the spinal cord and the PANS belong to the most constantly and earliest affected regions next to medullary structures and the olfactory nerves. A larger cohort of ILBD cases will be needed to pinpoint the precise induction site of alphaSN pathology among these structures.     

Ultrastructural pathology of the peripheral nervous system

Summary The present paper gives an introduction to fundamental pathologic features of various diseases of the peripheral nervous system, such as Wallerian degeneration, axonal degeneration, segmental degeneration, primary impairment of the endoneural interstitium. It is based on electron-microscope analysis. The range of reactions available to the peripheral nervous system is limited; thus noxious influences of various etiologies will act via largely common pathogenic mechanisms to produce similar morphologic changes.Supported by the Swiss National Fund (3. 747. 72).     

Parkinson's disease: the distribution of Lewy bodies in the peripheral autonomic nervous system

The distribution of Lewy bodies (LBs) in the peripheral autonomic nervous system was examined in the following 3 groups: group A, 10 patients with Parkinson's disease (age range, 56-82 years); group B, 5 nonparkinsonian patients with many LBs in the central nervous system (CNS) (range, 26-79 years); group C, 176 nonparkinsonian patients without LBs in the CNS (range, 7-107 years). In group A, LBs were found in the paravertebral and/or celiac sympathetic ganglia in 9 cases, enteric nervous system in all cases, cardiac and pelvic plexuses in 4 cases each, and adrenal medullae in 3 cases. They were almost exclusively intraneural . LBs were also found in group B: sympathetic ganglia in 4 cases, enteric nervous system in 5 cases, and pelvic plexus and adrenal medullae in one case each. Interestingly, both the distribution and the number of LBs in a patient with diffuse Lewy body disease were similar to those in group A. LBs, although definitely fewer in number, were also found in group C: sympathetic ganglia in 5 out of 136 cases; enteric nervous system in 8 out of 40 cases; and cardiac plexus in 2 out of 25 cases. All of these positive cases were over age 60. The wide occurrence of LBs in the peripheral autonomic nervous system in patients with Parkinson's disease may play an important role in causing a variety of autonomic symptoms in the disease. On the other hand, LBs have been occasionally found in nonparkinsonian patients over age 60.(ABSTRACT TRUNCATED AT 250 WORDS)     

Predicting lewy body pathology in a community-based sample with clinical diagnosis of Alzheimer's disease

Accurate antemortem prediction of Lewy body pathology in patients with dementia is problematic. This study generates a model that better predicts Lewy body pathology in community-based patients with clinical Alzheimer's disease. Lewy body pathology was detected in 80 of 152 participants (52.6%) with an initial diagnosis of probable Alzheimer's disease. In a stepwise logistic regression model, female gender, lower education, being married, bradykinesia, hallucinations, and absence of irritability predicted the greatest likelihood of Lewy body pathology. The predictive model correctly diagnosed Lewy body pathology with an estimated sensitivity of 75%, specificity of 68%, and accuracy of 72%; the area under the receiver operating characteristic curve was 0.75. In a community-based autopsy sample, this predictive model confirmed parkinsonism and hallucinations as important predictors of Lewy body pathology in patients with clinical Alzheimer's disease. The model also identified other demographic and clinical characteristics that might enhance the prediction of Lewy body pathology.     

Guidance cues involved in the development of the peripheral autonomic nervous system

All peripheral autonomic neurons arise from neural crest cells that migrate away from the neural tube and navigate to the location where ganglia will form. After differentiating into neurons, their axons then navigate to a variety of targets. During the development of the enteric nervous system, GDNF appears to play a role in inducing vagal neural crest cells to enter the gut, in retaining neural crest cells within the gut and in promoting the migration of neural crest cells along the gut. Sema3A regulates the entry of extrinsic axons into the distal hindgut, netrin-DCC signaling is responsible for the centripetal migration of cells to form the submucosal ganglia within the gut, Slit-Robo signaling prevents trunk level neural crest cells from entering the gut, and neurturin plays a role in the innervation of the circular muscle layer. During the development of the sympathetic nervous system, the migration of trunk neural crest cells through the somites is influenced by ephrin-Bs, Sema3A and F-spondin. The migration of neural crest cells ventrally beyond the somites requires neuregulin signaling and the clumping of cells into columns adjacent to the dorsal aorta is regulated by Sema3A. The rostral migration of cells to form the superior cervical ganglion (SCG) and the extension of axons along blood vessels involves artemin signaling through Ret and GFRalpha3, and the entry of sympathetic axons into target tissues involves neurotrophins and GDNF. Relatively little is known about the development of parasympathetic ganglia, but GDNF appears to play a role in the migration of some cranial ganglion precursors to their correct location, and both GDNF and neurturin are involved in the growth of parasympathetic axons into particular targets.     

New insights into the pathology of Parkinson's disease: does the peripheral autonomic system become central?

Recent studies in aged, neurologically unimpaired subjects have pointed to a specific induction site of the pathological process of Parkinson's disease (PD) in the region of the dorsal glossopharyngeus–vagus complex as well as in the anterior olfactory nucleus. From the lower brainstem, the disease process would then pursue an ascending course and involve more rostral brainstem areas, limbic structures, and eventually the cerebral cortex. One barrier to the acceptance of the caudal medullary structures as the induction site of PD pathology is that not all parts of the nervous system have been investigated for the presence of PD-associated lesions in cases of early asymptomatic PD. Using alpha-synuclein immunostaining, we investigated the brain, the sacral, and thoracic autonomic nuclei of the spinal cord as well as several components of the peripheral autonomic nervous system in a autopsy cohort of 98 neurologically unimpaired subjects aged 64 or more. Our data indicate that the autonomic nuclei of the spinal cord and the peripheral autonomic nervous system belong to the most constantly and earliest affected regions next to medullary structures and the olfactory nerves in neurologically unimpaired older individuals, thus providing a pathological basis for early premotor autonomic dysfunctions at a prodromal stage of PD.     

Accumulation of NACP/alpha-synuclein in lewy body disease and multiple system atrophy

OBJECTIVES: NACP/alpha-synuclein is an aetiological gene product in familial Parkinson's disease. To clarify the pathological role of NACP/alpha-synuclein in sporadic Parkinson's disease and other related disorders including diffuse Lewy body disease (DLBD) and multiple system atrophy (MSA), paraffin sections were examined immunocytochemically using anti-NACP/alpha-synuclein antibodies. METHODS: A total of 58 necropsied brains, from seven patients with Parkinson's disease, five with DLBD, six with MSA, 12 with Alzheimer's disease, one with Down's syndrome, one with amyotrophic lateral sclerosis (ALS), three with ALS and dementia, one with Huntington's disease, two with progressive supranuclear palsy (PSP), one with Pick's disease, one with myotonic dystrophy, and three with late cerebellar cortical atrophy (LCCA), and 15 elderly normal controls were examined. RESULTS: In addition to immunoreactive Lewy bodies, widespread accumulation of NACP/alpha-synuclein was found in neurons and astrocytes from the brainstem and basal ganglia to the cerebral cortices in Parkinson's disease/DLBD. NACP/alpha-synuclein accumulates in oligodendrocytes from the spinal cord, the brain stem to the cerebellar white matter, and inferior olivary neurons in MSA. These widespread accumulations were not seen in other types of dementia or spinocerebellar ataxia. CONCLUSION: Completely different types of NACP/alpha-synuclein accumulation in Parkinson's disease/DLBD and MSA suggest that accumulation is a major step in the pathological cascade of both diseases and provides novel strategies for the development of therapies.     

Lyme disease and the peripheral nervous system

Lyme disease, the multisystem infectious disease caused by the tick-borne spirochete Borrelia burgdorferi, causes a broad variety of peripheral nerve disorders, including single or multiple cranial neuropathies, painful radiculopathies, and diffuse polyneuropathies. Virtually all appear to be varying manifestations of a mononeuropathy multiplex. Diagnosis requires that the patient should have had possible exposure to the only known vectors, Ixodes ticks, and also have either other pathognomonic clinical manifestations or laboratory evidence of exposure. Treatment with antimicrobial regimens is highly effective. The mechanism underlying these neuropathies remains unclear, although interactions between anti-Borrelia antibodies and several peripheral nerve constituent molecules raise intriguing possibilities.     

Impairment of the peripheral nervous system in Creutzfeldt-Jakob disease

BACKGROUND: The clinical manifestations of Creutzfeldt-Jakob disease (CJD) primarily reflect involvement of the central nervous system. The coexistence of CJD with peripheral nervous system involvement has also been reported. OBJECTIVE: To analyze peripheral neuron electrophysiologic changes and to compare these data with neuropathologic features of spinal motor neurons in patients with definite CJD. DESIGN AND PATIENTS: Electrophysiologic examinations were performed on 16 patients with sporadic CJD. The diagnosis was confirmed by neuropathologic examinations (15 patients) or by intravital detection of the 14-3-3 protein in the cerebrospinal fluid (1 patient). The spinal cord was neuropathologically examined in 8 patients. SETTING: Department of Clinical Neurophysiology, I Neurological Department, Institute of Psychiatry and Neurology, Warsaw, Poland. MAIN OUTCOME MEASURES: Electromyography, compound muscle and sensory nerve action potentials, distal latencies, F waves, peripheral motor and sensory conduction velocity, and spinal motor neuron numbers and morphologic characteristics. RESULTS: All patients had signs of central nervous system damage typical of sporadic CJD. Only 3 patients had clinical signs of peripheral nervous system involvement. Electrophysiologic examinations confirmed peripheral nervous system damage in these patients and revealed preclinical peripheral nervous system impairment in 11 more patients. In 1 patient, electrophysiologic examination revealed features of motor neuron disease; in 9, axonal disease; and in 4, axonal-demyelinating neuropathy. Neuropathologic examination results confirmed severe loss of spinal motor neurons in 1 patient with motor neuron disease and revealed the features of motor neuron chronic disease in 4. In 2 of them, electrophysiologic data were normal. CONCLUSION: In sporadic cases of CJD, peripheral nervous system impairment should be considered to be an integral component of disease.     

What is the clinical prevalence of lewy body dementia?

The reported prevalence of Lewy body dementia (LBD) has varied from 12% to 20% in postmortem series. Such series may not be representative of the dementia population as a whole. We have attempted to determine the prevalence of LBD in patients referred to a district general hospital with a diagnosis of dementia. The case notes of a consecutive series of patients with a clinical diagnosis referred to the care of two consultants in old age psychiatry over a period of 1 year (N= 114) were analysed using a checklist incorporating the items of the criteria proposed by McKeith and by Byrne for the in vivo diagnosis of LBD. The analysis was repeated for the subgroup (N = 76) fulfilling ICD 10 criteria for Alzheimer's disease. The prevalence of LBD was 26.3% according to McKeith criteria, 7% according to Byrne probable and 16.6% according to Byrne possible criteria. There were, however, considerable disagreements between different criteria. The frequencies of individual clinical features within subjects fulfilling and not fulfilling LBD were reviewed. Logistic regression analysis revealed the main clinical features capable of differentiation between LBD and other dementias were: presence of visual or auditory hallucinations; extrapyramidal features or neuroleptic sensitivity syndrome; fluctuating pattern of clinical features over a long period of time (McKeith criteria); and presence of classical Parkinsonism with simulataneous or earlier onset of dementia (Byrne criteria). The results were essentially similar in the Alzheimer's disease subsample. A significant proportion of patients with dementia referred to an old age psychiatry service thus fulfil in vivo criteria for LBD. The variation in frequency of diagnosis of LBD by the different criteria suggests that these clinical criteria may need revising.     

克-亚二氏病的周围神经损害

目的 探讨克-亚二氏病(CJD)肌电罔与临床的关系。方法 分析5例CJD患者，2例为病理诊断，3例为临床诊断，对5例患者进行肌电图检查，其中1例病人在病程的不同阶段进行肌电图观察，并将肌电图改变与临床症状和体征进行分析总结。结果 5例病人中，1例出现束颤电位，1例出现神经性受损，其余3例为阴性。结论 在散发的CJD中，周围神经系统的损害应看作是疾病的一部分。     

Focus on the role of Glutamate in the pathology of the peripheral nervous system

The role of Glutamate (Glu), one of the major excitatory neurotransmitters in the central nervous system, has been thoroughly investigated in animal models and in humans in several physiologic events, such as brain development and synaptic plasticity, but also in acute and chronic neurologic diseases and psychiatric disorders. Recently, it has been demonstrated that Glu is important for sensory input transduction, particularly along the nociceptive pathway. Glu involvement in peripheral neuropathies has also been suggested on the basis of experimental studies in animals, thus widening the spectrum of possible sites of action of this neurotransmitter from the central to the peripheral nervous system. This rather unexpected observation may have important therapeutic implications, provided that a complete characterization of the glutamatergic system in the peripheral nervous system is achieved and its changes under the different pathological conditions are investigated. This review will focus on the most recent advances in the research into the role of Glu and the glutamatergic system in the pathology of the peripheral nervous system.     

Cardiovascular autonomic nervous system evaluation in Parkinson disease and multiple system atrophy

BackgroundAutonomic nervous system dysfunction (ANSd) heralds or follows motor symptoms (MS) in Parkinson disease (PD), but may precede years and progress more rapidly in multiple system atrophy (MSA). Cardiac dysautonomia severity correlates with disabling symptoms thus a Cardiac Autonomic Nervous System Evaluation protocol (CANSEp) is useful to assess ANSd in PD and MSA patients.Methods and resultsConsecutive patients with PD or MSA were studied. The severity of MS was quantified with UPDR III and Hoehn/Yahr scales. CANSEp consisted of the 5-test Ewing protocol (EP) and Heart Rate Variability analysis (HRVa), in time-domain (TD) and frequency-domain (FD).36 patients with parkinsonian symptoms (23 PD, 13 MSA) and 40 healthy controls were studied. Parkinsonism was more severe in MSA, comparing UPDR III and Hoehn/Yahr scales (p < 0.0001). Higher EP's scores were found in MSA (mean 5.1 ± 1.98) compared to PD (mean 3.5 ± 2) and controls (score 0.25 ± 0.1). TD and FD-HRVa were abnormal in PD and MSA, compared to controls. In PD depression of vagal tone was predominant during sleep, whereas in MSA depression of sympathetic tone prevailed during daily activity.ConclusionsWhereas its specificity is very high, the sensitivity of the EP was only 43.5% in PD and 76.9% in MSA. HRVa improved diagnosis accuracy in 10 patients, unidentified by the EP alone, with overall sensitivity of 65.2% in PD and 92.3% in MSA. Thus CANSEp provides a better assessment of cardiovascular dysautonomia in parkinsonian syndromes, useful to differentiate PD from MSA and to address clinical and pharmacological management.     

Involvement of peripheral nervous system in juvenile Parkinson''s disease

We evaluated, by using electrophysiological techniques, 29 patients with juvenile Parkinson's disease (JP), who had no known causes or clinical signs of neuropathy. Electromyographic evidence of chronic partial denervation with reinnervation was observed in nine patients (34.6%). Abnormalities of motor conduction in the common peroneal nerve were present in four (13.8%), Sural sensory conduction in nine (31.9%) and sympathetic skin response (SSR) in eleven (37.9%) patients. The symptoms of dysautonomia correlated poorly with changes in SSR. These abnormalities were independent of age at onset, duration or severity of the disease and antiparkinsonian drugs used. This study suggests that the peripheral nervous system is involved in JP in more than 50% of patients. The commonly observed symptoms of dysautonomia in Parkinson's disease may have a peripheral origin.