Putative neuropathological interactions in MSA: focus in the rostral ventrolateral medulla.

We used double immunocytochemistry for α-synuclein and markers of sympathoexcitatory neurons, oligodendrocytes, iron metabolism, and autophagy to study putative neuropathological interactions in multiple system atrophy. We focused in the rostral ventrolateral medulla as a prototype vulnerable region. We found that loss of C1 neurons and oligodendrocytes related to glial cytoplasmic inclusion accumulation, downregulation of iron transport, and upregulation of autophagy and ferritin expression in these area.

Parabrachial nucleus involvement in multiple system atrophy.

UNLABELLED: Multiple system atrophy (MSA) is associated with respiratory dysfunction, including sleep apnea, respiratory dysrhythmia, and laryngeal stridor. Neurons of the parabrachial nucleus (PBN) control respiratory rhythmogenesis and airway resistance. OBJECTIVES: The objective of this study is to determine whether there was involvement of putative respiratory regions of the PBN in MSA. METHODS: We examined the pons at autopsy in 10 cases with neuropathologically confirmed MSA and 8 age-matched controls. Sections obtained throughout the pons were processed for calcitonin-gene related peptide (CGRP) and Nissl staining to identify the lateral crescent of the lateral PBN (LPB) and the Kölliker-Fuse nucleus (K-F), which are involved in respiratory control. Cell counts were performed using stereology. RESULTS: There was loss of CGRP neurons in the PBN in MSA (total estimated cell counts for the external LPB cluster was 12,584 ± 1146 in controls and 5917 ± 389 in MSA, p<0.0001); for the external medial PBN (MPB) cluster it was 15,081 ± 1758 in controls and 7842 ± 466 in MSA, p<0.001. There was also neuronal loss in putative respiratory regions of the PBN, including the lateral crescent of the LPB (13,039 ± 1326 in controls and 4164 ± 872 in MSA, p<0.0001); and K-F (5120 ± 495 in controls and 999 ± 308 in MSA, p<0.0001). CONCLUSIONS: There is involvement of both CGRP and putative respiratory cell groups in the PBN in MSA. Whereas the clinical implications of CGRP cell loss are still undetermined, involvement of the LPB and K-F may contribute to respiratory dysfunction in this disorder.

Clinicopathologic correlations in 172 cases of rapid eye movement sleep behavior disorder with or without a coexisting neurologic disorder.

OBJECTIVE: To determine the pathologic substrates in patients with rapid eye movement (REM) sleep behavior disorder (RBD) with or without a coexisting neurologic disorder. METHODS: The clinical and neuropathologic findings were analyzed on all autopsied cases from one of the collaborating sites in North America and Europe, were evaluated from January 1990 to March 2012, and were diagnosed with polysomnogram (PSG)-proven or probable RBD with or without a coexisting neurologic disorder. The clinical and neuropathologic diagnoses were based on published criteria. RESULTS: 172 cases were identified, of whom 143 (83%) were men. The mean±SD age of onset in years for the core features were as follows - RBD, 62±14 (range, 20-93), cognitive impairment (n=147); 69±10 (range, 22-90), parkinsonism (n=151); 68±9 (range, 20-92), and autonomic dysfunction (n=42); 62±12 (range, 23-81). Death age was 75±9 years (range, 24-96). Eighty-two (48%) had RBD confirmed by PSG, 64 (37%) had a classic history of recurrent dream enactment behavior, and 26 (15%) screened positive for RBD by questionnaire. RBD preceded the onset of cognitive impairment, parkinsonism, or autonomic dysfunction in 87 (51%) patients by 10±12 (range, 1-61) years. The primary clinical diagnoses among those with a coexisting neurologic disorder were dementia with Lewy bodies (n=97), Parkinson's disease with or without mild cognitive impairment or dementia (n=32), multiple system atrophy (MSA) (n=19), Alzheimer's disease (AD)(n=9) and other various disorders including secondary narcolepsy (n=2) and neurodegeneration with brain iron accumulation-type 1 (NBAI-1) (n=1). The neuropathologic diagnoses were Lewy body disease (LBD)(n=77, including 1 case with a duplication in the gene encoding α-synuclein), combined LBD and AD (n=59), MSA (n=19), AD (n=6), progressive supranulear palsy (PSP) (n=2), other mixed neurodegenerative pathologies (n=6), NBIA-1/LBD/tauopathy (n=1), and hypothalamic structural lesions (n=2). Among the neurodegenerative disorders associated with RBD (n=170), 160 (94%) were synucleinopathies. The RBD-synucleinopathy association was particularly high when RBD preceded the onset of other neurodegenerative syndrome features. CONCLUSIONS: In this large series of PSG-confirmed and probable RBD cases that underwent autopsy, the strong association of RBD with the synucleinopathies was further substantiated and a wider spectrum of disorders which can underlie RBD now are more apparent.

Ocular Motor Dysfunction due to Multiple Sclerosis.

Ocular motor disorders are common in patients afflicted by multiple sclerosis. We present a particularly complex case of multifaceted ocular motor dysfunction as it illustrates the arcane associated neuroanatomy and the interplay between ocular motor systems in the brainstem, midbrain, and cerebellum.

Neuropathological analysis of brainstem cholinergic and catecholaminergic nuclei in relation to rapid eye movement (REM) sleep behaviour disorder.

AIMS: Rapid eye movement sleep behaviour disorder (RBD) is characterized by loss of muscle atonia during rapid eye movement sleep and is associated with dream enactment behaviour. RBD is often associated with α-synuclein pathology, and we examined if there is a relationship of RBD with cholinergic neuronal loss in the pedunculopontine/laterodorsal tegmental nucleus (PPN/LDT), compared to catecholaminergic neurones in a neighbouring nucleus, the locus coeruleus (LC). METHODS: This retrospective study utilized human brain banked tissues of 11 Lewy body disease (LBD) cases with RBD, 10 LBD without RBD, 19 Alzheimer's disease (AD) and 10 neurologically normal controls. Tissues were stained with choline acetyl transferase immunohistochemistry to label neurones of PPN/LDT and tyrosine hydroxylase for the LC. The burden of tau and α-synuclein pathology was measured in the same regions with immunohistochemistry. RESULTS: Both the LC and PPN/LDT were vulnerable to α-synuclein pathology in LBD and tau pathology in AD, but significant neuronal loss was only detected in these nuclei in LBD. Greater cholinergic depletion was found in both LBD groups, regardless of RBD status, when compared with normals and AD. There were no differences in either degree of neuronal loss or burden of α-synuclein pathology in LBD with and without RBD. CONCLUSIONS: Whether decreases in brainstem cholinergic neurones in LBD contribute to RBD is uncertain, but our findings indicate these neurones are highly vulnerable to α-synuclein pathology in LBD and tau pathology in AD. The mechanism of selective α-synuclein-mediated neuronal loss in these nuclei remains to be determined.

Dopamine cell loss in the periaqueductal gray in multiple system atrophy and Lewy body dementia.

BACKGROUND: Experimental studies indicate that dopaminergic neurons in the ventral periaqueductal gray matter (PAG) are involved in maintenance of wakefulness. Excessive daytime sleepiness (EDS) is a common manifestation of multiple system atrophy (MSA) and dementia with Lewy bodies (DLB) but involvement of these neurons has not yet been explored. METHODS: We sought to determine whether there is loss of dopaminergic neurons in the ventral PAG in MSA and DLB. We studied the midbrain obtained at autopsy from 12 patients (9 male, 3 female, age 61 +/- 3) with neuropathologically confirmed MSA, 12 patients (11 male, 1 female, age 79 +/- 4) with diagnosis of DLB and limbic or neocortical Lewy body disease, and 12 controls (7 male, 5 female, ages 67 +/- 4). Fifty-micron sections were immunostained for tyrosine hydroxylase (TH) or alpha-synuclein and costained with thionin. Cell counts were performed every 400 mum throughout the ventral PAG using stereologic techniques. RESULTS: Compared to the total estimated cell numbers in controls (21,488 +/- 8,324 cells), there was marked loss of TH neurons in the ventral PAG in both MSA (11,727 +/- 5,984; p < 0.01) and DLB (5,163 +/- 1,926; p < 0.001) cases. Cell loss was more marked in DLB than in MSA. There were characteristic alpha-synuclein inclusions in the ventral PAG in both MSA and DLB. CONCLUSIONS: There is loss of putative wake-active ventral periaqueductal gray matter dopaminergic neurons in both multiple system atrophy and dementia with Lewy bodies, which may contribute to excessive daytime sleepiness in these conditions.

Hyposialorrhea as an early manifestation of Parkinson disease.

We sought to determine whether hyposialorrhea is an early manifestation of Parkinson disease (PD). We measured basal and citric acid stimulated secretion of whole saliva in 20 patients with early stage (Hoehn-Yahr I-II) PD who had motor symptoms for less than 1 year and were on no medication and 11 age matched controls. Compared to controls, PD patients had significant reduction of both basal (0.0964+/-0.08 vs 0.293+/-0.112 ml/min, p<0.001) and reflex (0.263+/-0.213 vs 0.537+/-0.313 ml/min, p<0.001) salivary secretion. Our findings confirm that hyposialorrhea is an early autonomic manifestation of PD.

Mesopontine cholinergic neuron involvement in Lewy body dementia and multiple system atrophy.

BACKGROUND: The pedunculopontine (PPT) and laterodorsal (LDT) tegmental nuclei are involved in control of REM sleep and thalamocortical arousal. REM sleep behavior disorder (RBD) is a feature of multiple system atrophy (MSA) and dementia with Lewy bodies (DLB), which is also associated with visual hallucinations and cognitive fluctuations. We sought to determine the degree of PPT/LDT involvement in DLB compared to MSA. METHODS: We counted the cholinergic neurons in the PPT and LDT in 13 patients with neuropathologically confirmed DLB, 11 patients with MSA, and 11 control cases. Five patients with DLB and eight patients with MSA had history or polysomnographic evidence of RBD. Ten patients with DLB and no patient with MSA had history of visual hallucinations or cognitive fluctuations. RESULTS: There was a significant loss of PPT and LDT neurons in both DLB and MSA. Cell loss in both the PPT and LDT was more severe in MSA than in DLB. The number of cells/section for the PPT were 148 +/- 21 in controls, 54 +/- 10 in DLB (p < 0.001), and 20 +/- 3 in MSA (p < 0.001), and for the LDT, 112 +/- 16 in controls, 49 +/- 8 in DLB (p < 0.01), and 16 +/- 2 in MSA (p < 0.001). Severity of neuronal loss in MSA or DLB did not relate to the presence or absence of history of RBD. CONCLUSIONS: Loss of cholinergic pedunculopontine tegmental nuclei/laterodorsal tegmental nuclei neurons occurs in both dementia with Lewy bodies and multiple system atrophy but is probably not the primary mechanism of REM sleep behavior disorder in these disorders.

[Imagination: its definition, purposes and neurobiology]. / Imaginacion: definicion, utilidad y neurobiologia.

Imagination, distinct from imagery, memory, and cognition, is a poorly understood but fascinating cognitive ability of human beings. Herein, imagination is defined as 'the cognitive process which enables the individual to manipulate intrinsically generated phenomenal information in order to create a representation perceived by the mind's senses.' This definition is expanded within the context of the neurobiology of the brain and the possible purposes the imagination fulfills in daily living, human development, and normal behavior.

Imaginación: definición, utilidad y neurobiología / Imagination: Its definition, purposes and neurobiology

La imaginación, a diferencia de la generación de imágenes y la memoria, es una fascinante capacidad cognitiva del ser humano que no está bien estudiada. Definimos la imaginación como ‘el proceso cognitivo que permite al individuo manipular información generada intrínsecamente con el fin de crear una representación que se percibe a través de los sentidos de lamente’. Esta definición se amplía dentro del contexto de la neurobiología del cerebro y el posible propósito que la imaginación satisface en la vida diaria, en el desarrollo humano y en el comportamiento normal

Imagination, distinct from imagery, memory, and cognition, is a poorly understood but fascinating cognitive ability of human beings. Herein, imagination is defined as ‘the cognitive process which enables the individual to manipulate intrinsically generated phenomenal information in order to create a representation perceived by the mind’s senses.’ This definition is expanded within the context of the neurobiology of the brain and the possible purposes the imagination fulfills in daily living, human development, and normal behavior

Rostral raphe involvement in Lewy body dementia and multiple system atrophy.

Depression is a feature of both Lewy body disorders and multiple system atrophy (MSA). Since serotonergic neurons of the rostral raphe have been implicated in depression, we sought to determine whether there is a differential involvement of these neurons in cases with clinically diagnosed dementia with Lewy bodies (DLB) or MSA. We studied the brainstem obtained at autopsy from fourteen patients with diagnosis of DLB and pathological limbic or neocortical stage Lewy body disease, 13 patients with clinical and neuropathological diagnosis of MSA, and 12 controls with no history of neurologic disease. The clinical features of these patients were analyzed retrospectively by reviewing their medical records. Serial sections were immunostained for tryptophan hydroxylase (TrOH) and alpha-synuclein and cell counts were performed in the dorsal raphe (DR), median raphe (MR) and medullary raphe nuclei. There was loss of serotonergic cells in both the DR and MR in DLB compared to control cases: For the DR, the number of cells/section were 53 +/- 6 in DLB versus 159 +/- 13 (P < 0.001) respectively, and for the MR 70 +/- 11 in DLB versus 173 +/- 23 (P < 0.001) respectively. In contrast, these cells were relatively preserved in MSA. The caudal raphe groups were affected both in MSA and in DLB. There is a differential involvement of raphe neurons in DLB and MSA. Although loss of rostral raphe neurons may contribute to depression in DLB, this appears to be less likely in MSA. Factors other than the neurochemical phenotype determine neuronal vulnerability in MSA.

Pathophysiology of REM sleep behaviour disorder and relevance to neurodegenerative disease.

REM sleep behaviour disorder (RBD) is a parasomnia characterized by the loss of normal skeletal muscle atonia during REM sleep with prominent motor activity accompanying dreaming. The terminology relating to RBD, and mechanisms underlying REM sleep without atonia and RBD based on data in cat and rat are presented. Neuroimaging data from the few published human cases with RBD associated with structural lesions in the brainstem are presented, in which the dorsal midbrain and pons are implicated. Pharmacological manipulations which alter RBD frequency and severity are reviewed, and the data from human neuropathological studies are presented. An anatomic framework and new schema for the pathophysiology of RBD are proposed based on recent data in rat regarding the putative flip-flop switch for REM sleep control. The structure in man analogous to the subcoeruleus region in cat and sublaterodorsal nucleus in rat is proposed as the nucleus (and its associated efferent and afferent pathways) crucial to RBD pathophysiology. The association of RBD with neurological disease ('secondary RBD') is presented, with emphasis on RBD associated with neurodegenerative disease, particularly the synucleinopathies. The hypothesized pathophysiology of RBD is presented in relation to the Braak staging system for Parkinson's disease, in which the topography and temporal sequence of synuclein pathology in the brain could explain the evolution of parkinsonism and/or dementia well after the onset of RBD. These data suggest that many patients with 'idiopathic' RBD are actually exhibiting an early clinical manifestation of an evolving neurodegenerative disorder. Such patients may be appropriate for future drug therapies that affect synuclein pathophysiology, in which the development of parkinsonism and/or dementia could be delayed or prevented. We suggest that additional clinicopathological studies be performed in patients with dementia or parkinsonism, with and without RBD, as well as in patients with idiopathic RBD, to further elucidate the pathophysiology and also characterize the clinical and pathophysiological relevance of RBD in neurodegenerative disease. Furthermore, longitudinal studies in patients with idiopathic RBD are warranted to characterize the natural history of such patients and prepare for future therapeutic trials.

Insights into REM sleep behavior disorder pathophysiology in brainstem-predominant Lewy body disease.

BACKGROUND AND PURPOSE: Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia reflecting changes in the brain, but which specific neuronal networks are involved in human RBD pathogenesis has not yet been determined. To date, only one case of idiopathic RBD has undergone autopsy, in which "incidental Lewy body disease" was found. Due to the severe neuronal loss and gliosis in the substantia nigra (SN) and locus ceruleus (LC) in this case, degeneration of brainstem monoaminergic neurons was postulated as the underlying substrate for RBD. Additional cases of idiopathic RBD with neuropathologic examination may help clarify which key brainstem structures are involved. PATIENT AND METHODS: Case report with neuropathologic analysis. RESULTS: A man with polysomnographically proven RBD (onset age 57 years), but no other neurologic signs or symptoms, underwent neuropathologic examination upon his death at age 72. Histopathologic analysis showed Lewy body disease, but no significant neuronal loss or gliosis was present in the SN or LC. CONCLUSIONS: This case represents another example of Lewy body disease associated with RBD. The minimal degenerative changes in the SN and LC call into question the role of these nuclei in RBD, at least in our case. We suggest additional cases of idiopathic RBD undergo neuropathologic analyses to better delineate the neurologic substrate of this intriguing parasomnia.

Pain-autonomic interactions.

There are extensive interactions between the neural structures involved in pain sensation and autonomic control. The insular and anterior cingulate cortices, amygdala, hypothalamus, periaqueductal grey, parabrachial nucleus, nucleus of the solitary tract, ventrolateral medulla and raphe nuclei receive converging nociceptive and visceral inputs from the spinal and trigeminal dorsal horns and initiate arousal, affective, autonomic, motor and pain modulatory responses to painful stimuli. This review will focus on some central pain-autonomic interactions potentially relevant for the pathophysiology of primary headache.

Involvement of vagal autonomic nuclei in multiple system atrophy and Lewy body disease.

BACKGROUND: Multiple system atrophy (MSA) and Lewy body disorders (LBDs) are associated with impaired control of gastrointestinal and cardiac functions. The dorsal vagal nucleus (DMV) innervates enteric neurons, whereas the ventrolateral nucleus ambiguus (NAmb) innervates the heart. The relationship between DMV and NAmb involvement and the gastrointestinal or cardiovagal manifestations in MSA and LBD is unclear. METHODS: The authors counted the cholinergic neurons in the DMV and NAmb in 15 cases of neuropathologically confirmed MSA, 14 of LBD (4 brainstem, 3 limbic, and 7 neocortical), and 12 control cases. All MSA and 8 of the 14 LBD cases had gastrointestinal symptoms; 8 of 12 MSA and 1 of 4 LBD cases had laboratory evidence of cardiovagal failure; 5 of the MSA and no LBD cases had laryngeal stridor. RESULTS: There was loss of cholinergic DMV neurons in all MSA and LBD cases. The degree of DMV cell loss was similar in LBD patient with or without gastrointestinal symptoms. In MSA but not in LBD cases, there was neuronal loss in the ventrolateral NAmb, with lower counts in patients with cardiovagal failure. CONCLUSIONS: There is comparable involvement of the dorsal vagal nucleus (DMV) in multiple system atrophy (MSA) and different stages of Lewy body disorders (LBDs). The relationship of DMV involvement and gastrointestinal symptoms is uncertain. Loss of neurons in the ventrolateral nucleus ambiguus may explain the more consistent cardiovagal failure in MSA than in LBD.

A randomized controlled crossover trial of aspirin for fatigue in multiple sclerosis.

Pharmacotherapeutic options for multiple sclerosis (MS)-related fatigue are limited. Thirty patients were randomly assigned to aspirin (ASA) 1,300 mg/day or placebo in a double-blind crossover study. Results favored ASA for the main clinical outcomes: Modified Fatigue Impact Scale scores (p = 0.043) and treatment preference (p = 0.012). There were no significant adverse effects. The results warrant further study and support a role for ASA-influenced mechanisms, perhaps immunologic, in the generation of MS-related chronic fatigue.

Autonomic dysfunction in dementia with Lewy bodies.

OBJECTIVE: To assess autonomic function in patients with dementia with Lewy bodies (DLB). METHODS: The authors compared data from 20 DLB patients evaluated from 1995 to 2000 to 20 age-matched multiple system atrophy (MSA) and Parkinson disease (PD) patients evaluated from 1999 to 2002. Analysis of variance, Fisher exact test, and Student t-test were applied to compare disease characteristics, autonomic symptoms, and function tests on the Composite Autonomic Scoring Scale (CASS) and Thermoregulatory Sweat Test (TST). RESULTS: In DLB, mean age at onset of autonomic symptoms was 70.3 +/- 8.9 years. Orthostatic symptoms were common and orthostatic hypotension occurred in 10/20 DLB, 17/20 MSA, and 1/20 PD patients (p = 0.023, 0.003). CASS-sudomotor for DLB, MSA, and PD were 1.6 +/- 1.2, 2.5 +/- 0.7, and 0.9 +/- 0.8 (p < 0.00001). CASS-cardiovagal were 1.4 +/- 0.9, 2.1 +/- 0.8, and 0.7 +/- 0.6 (p < 0.00001). CASS-adrenergic function were 2.4 +/- 1.2, 3.5 +/- 0.9, and 0.5 +/- 0.6 (p < 0.00001). Total CASS were 5.2 +/- 2.0, 8.1 +/- 1.3, and 2.2 +/- 1.2 (p < 0.00001). The most common pattern of TST in DLB was distal anhidrosis. Mean duration of follow-up was 3.0 +/- 1.8 years. Six patients needed medication to maintain blood pressure and five had good response. CONCLUSIONS: Autonomic dysfunction is frequent in dementia with Lewy bodies and the severity is intermediate between that of multiple system atrophy and Parkinson disease.

Synucleinopathy pathology and REM sleep behavior disorder plus dementia or parkinsonism.

OBJECTIVE: To determine if synucleinopathy pathology is related to REM sleep behavior disorder (RBD) plus dementia or parkinsonism. METHODS: The clinical and neuropathologic findings were analyzed on all autopsied cases evaluated at Mayo Clinic Rochester from January 1990 to April 2002 who were diagnosed with RBD and a neurodegenerative disorder. Ubiquitin and/or alpha-synuclein immunocytochemistry was used in all cases. The clinical and neuropathologic diagnoses were based on published criteria. RESULTS: Fifteen cases were identified (14 men). All had clear histories of dream enactment behavior, and 10 had RBD confirmed by polysomnography. RBD preceded dementia or parkinsonism in 10 (66.7%) patients by a median of 10 (range 2 to 29) years. The clinical diagnoses included dementia with Lewy bodies (DLB) (n = 6); multiple-system atrophy (MSA) (n = 2); combined DLB, AD, and vascular dementia (n = 1); dementia (n = 1); dementia with parkinsonism (n = 1); PD (n = 1); PD with dementia (n = 1); dementia/parkinsonism/motor neuron disease (n = 1); and AD/Binswanger's disease (n = 1). The neuropathologic diagnoses were Lewy body disease (LBD) in 12 (neocortical in 11 and limbic in 1) and MSA in 3. Three also had argyrophilic grain pathology. In the LBD cases, concomitant AD pathology was present in six (one also with Binswanger's pathology, and one also with multiple subcortical infarcts). CONCLUSION: In the setting of degenerative dementia or parkinsonism, RBD often reflects an underlying synucleinopathy.

Cardiovascular and respiratory consequences of bilateral involvement of the medullary intermediate reticular formation in syringobulbia.

We studied five patients with clinical and radiological evidence of syringobulbia (SB) to determine whether the distribution of lesions in relationship to the cardiorespiratory control networks in the medullary intermediate reticular zone (IRt) correlates with the presence of abnormalities in autonomic cardiovascular and respiratory control in these patients. All patients underwent high resolution MRI to characterize the size, volume and distribution of the SB lesions, cardiovascular autonomic function testing and polysomnography. One patient with bilateral IRt involvement at both the rostral and caudal medulla had orthostatic hypotension (OH), absent HR(DB), abnormal Valsalva ratio, exaggerated fall of BP during phase II and absent phase IV during VM, and a dramatic fall of BP during head up tilt; this patient also had severe obstructive sleep apnea (OSA) and exhibited BP drops during each respiratory effort. A second patient, with bilateral IRt involvement restricted to the caudal medulla, had less severe cardiovascular autonomic dysfunction but also exhibited severe OSA. The other three patients had small SB cavities sparing the IRt and had sleep apnea but no autonomic dysfunction. Autonomic dysfunction could not be related to the size of the syrinx or the degree of atrophy in the cervical spinal cord in any of the five patients. Bilateral involvement of the IRt by SB produces cardiovascular autonomic failure and sleep apnea. In patients with more restricted lesions, autonomic and respiratory dysfunction may be dissociated. Clinico-radiological correlations using high resolution MRI assessment of medullary lesions can provide insight into the central organization of cardiovascular and respiratory control in humans.