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develop earlier, be more severe and be associated with more marked dysphagia compared to PD.

Non-motor red flags

Non-motor red flags

Severe dysautonomia As defined by the Consensus diagnostic criteria(12)

Abnormal respiration Nocturnal (harsh or strained, high pitched inspiratory sounds) or diurnal inspiratory stridor, involuntary deep inspiratory sighs/gasps, sleep apnea (arrest of breathing for >10secs), and excessive snoring (increase from premorbid level, or newly arising).

REM sleep behavior disorder Intermittent loss of muscle atonia and appearance of elaborate motor activity (striking out with arms in sleep often with talking/shouting) associated with dream mentation.

Cold hands/feet Coldness and color change (purple/blue) of extremities not due to drugs with blanching on pressure and poor circulatory return.

Raynaud's phenomenon Painful "white finger," which may be provoked by ergot drugs.

Emotional incontinence Crying inappropriately without sadness or laughing inappropriately without mirth.

H&Y, Hoehn and Yahr Staging. (Reprinted with permission from Elsevier; The Lancet Neurology 2004. 3:93-103).

(1994) have shown marked involvement of brainstem pontomedullary reticular formation with GCIs, providing a supraspinal histological counterpart for impaired visceral function. Autonomic neuronal degeneration also affects the locus coeruleus (Wenning et al., 1997b). Degeneration of sympathetic preganglionic neurones in the intermediolateral column of the thoracolumbar spinal cord is considered contributory to orthostatic hypotension (Daniel, 1999). It is noteworthy that there is not always a strong correlation between nerve cell depletion or gliosis and the clinical degree of autonomic failure. It is estimated that more than 50% of cells within the intermediolateral column need to decay before symptoms become evident (Oppenheimer, 1980).

Disordered bladder, rectal, and sexual function in SND and OPCA have been associated with cell loss in parasym-pathetic preganglionic nuclei of the spinal cord. These neurons are localized rostrally in Onuf's nucleus between sacral segments S2 and S3, and more caudally in the inferior intermediolateral nucleus, chiefly in the S3 to S4 segments (Konno et al., 1986).

In the peripheral component of the autonomic nervous system, Bannister and Oppenheimer (1972) have described atrophy of the glossopharyngeal and vagus nerves. No pathology has been reported in the visceral enteric plexuses or in the innervation of glands, blood vessels, or smooth muscles. Sympathetic ganglia have not often been examined in pathological studies of autonomic failure, and have seldom been described quantitatively. In a few cases there were either no obvious or mild abnormalities in sympathetic ganglia. Any morphological changes reported in sympathetic ganglionic neurons in MSA have tended to be nonspecific (Spokes et al., 1979), falling within the normal age-related range of appearances (Matthews, 1999).

5. Additional Sites of Pathology

A variety of other neuronal populations are noted to show cell depletion and gliosis with considerable differences in vulnerability from case to case. Various degrees of abnormality in the cerebral hemisphere, including Betz cell loss, were detected in pathologically proven MSA cases (Tsuchiya et al., 2000; Wakabayashi et al., 1998b; Konagaya et al., 1999; Konagaya et al., 2002). Fujita et al. (1993) demonstrated a distinct laminar astrocytosis of the motor cortices in the fifth layer in four of six sporadic OPCA cases and in none of five control cases by immunohistochemistry for glial fibrillary acidic protein. In three autopsy cases of MSA, cerebellar cortical lesions were more conspicuous in the vermis than in the hemisphere (Tsuchiya et al., 1998). These neuropathological findings differ from the established theory that cerebellar lesions of MSA are more pronounced in the hemisphere than in the vermis. The degree of cere-bellar cortical lesions in these cases increased in relation to the duration of the disease. Furthermore, anterior horn cells may show some depletion but rarely to the same extent as that occurring in motor neuron disease (Konno et al., 1986; Sima et al., 1993). Laryngeal stridor is a common feature of MSA and may occur as a presenting sign (Wu et al., 1996) or, more often, in later stages of the disease. Depletion of large myelinated nerve fibers in the recurrent laryngeal nerve which innervates intrinsic laryngeal muscles has been demonstrated in MSA patients with vocal cord palsy (Hayashi et al., 1997).

6. Differential Diagnosis

From a neuropathological viewpoint, there is little cause for confusion of MSA with other neurodegenerative conditions. The GCI is the hallmark that accompanies signs of degeneration involving striatonigral and olivopontocerebel-lar systems. Similar inclusions have been described in several other diseases, including progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) (Daniel et al., 1995), and familial OPCA (Berciano and Ferrer, 1996); however, they are infrequent and require careful search. GCI are distinctly different from filamentous oligodendroglial inclusions, called coiled bodies, found in other neurodegen-erative diseases, including PSP, CBD, and argyrophilic grain disease (Braak and Braak, 1989; Yamada and McGeer, 1990; Chin and Goldman, 1996).

Rarely MSA may be combined with additional pathologies. Lewy bodies (LBs) have been reported in 8-10 percent of MSA cases and show a distribution comparable with that of PD (Wenning and Quinn, 1994). This frequency is similar to that of controls and suggests an incidental finding related to aging and/or presymptomatic PD. Isolated reports of unusual clinicopathological cases occur and include overlap of MSA with PSP and CBD (Ansorge et al., 1997a,

Takanashi et al., 2002), MSA with Alzheimer disease and PD (Ansorge et al., 1997b), and MSA with atypical Pick disease (Horoupian and Dickson, 1991).

III. BIOCHEMICAL/ NEUROPHARMACOLOGICAL FINDINGS

A. Biochemical Findings

Neurochemical studies have shown alterations consistent with sites of major pathology. Calcineurin, a marker for medium-sized spiny neurons, is decreased in striosomes of the putamen and in the efferent pathway of the globus pal-lidus and substantia nigra (Goto et al., 1989b). Ito et al. (1996) also reported that regardless of clinical presentation, there is reduced immunoreactivity for additional markers of the striatal efferent system, including metenkephalin, substance P, and calbindin. In the SNC, tyrosine hydroxylase (TH) containing dopaminergic neurons are depleted. Similar neurones in the C1 and A2 regions of the medulla also showed reduced TH activity, which has been associated with orthostatic hypotension (Kato et al., 1995).

Biochemical analyses have found only minor differences in reduced striatal and nigral dopamine content in MSA when compared with PD (Brucke et al., 1997). However, unlike PD, mitochondrial respiratory chain function in the substantia nigra is normal in MSA (Gu et al., 1997). An increase in total iron content appears to reflect sites of primary damage and occurs in both PD and MSA substan-tia nigra, as well as in MSA striatum (Dexter et al., 1991). Decreased noradrenaline levels are reported in septal nuclei, nucleus accumbens, hypothalamus, and locus ceruleus, while a consistent deficit of choline acetyltransferase is found in red nucleus, dentate, pontine, and inferior olivary nuclei, with variable involvement of the striatum and additional areas (Spokes et al., 1979). Cerebellar and, in particular, Purkinje cell damage has been indicated by reduced levels of glutamate dehydrogenase (Plaitakis et al., 1993), amino acid binding sites (Price et al., 1993), and cerebrospinal fluid (CSF) calbindin-D (Kiyosawa et al., 1993). Holmberg et al. (1998) showed that the content of neurofilament (NFL) in CSF was significantly higher in both PSP and MSA compared to PD patients, reflecting the degree of ongoing neuronal degeneration affecting mainly the axonal compartment.

Several studies have measured CSF content of biogenic amine metabolites/derivates, thiamine, neuropeptide Y, substance P, or corticotropin-releasing hormone in MSA patients (Gonzalez-Quevedo et al., 1993; Botez et al., 2001; Orozco et al., 1989; Martignoni et al., 1992; Nutt et al., 1980; Suemaru et al., 1995). Botez et al. (2001) measured levels of the dopamine metabolite homovanillic acid (HVA), the serotonin metabolite 5-hydroxindoleacetic acid (5HIAA)

and precursor tryptophan, as well as the noradrenaline metabolite 3-methoxy-4-hydroxyphenylethylene glycol (MHPG), and thiamine in the CSF of patients with OPCA (among others), as compared with sex- and age-matched control subjects. CSF HVA, MHPG, and thiamine values were markedly lower than those in control patients, whereas CSF 5HIAA values showed only a trend towards lower levels than control subjects.

B. Neuropharmacological Findings

The combination of nigral and striatal degeneration is the core pathology underlying parkinsonism in MSA. The degenerative process affects nigrostriatal dopaminergic transmission at both pre- and post-synaptic sites (Fearnley and Lees, 1991; Kume et al., 1993). Pathologically, the loss of dopaminergic neurons in MSA-P is comparable to that found in PD (Tison et al., 1995a). Only a few patients with MSA exhibit a presynaptic pattern with minimal putaminal changes (Tison et al., 1995a; Wenning et al., 1994c; Berciano et al., 2002). There is a close anatomical relationship between nigral and striatal degeneration in MSA-P. Degeneration of pigmented dopaminergic neurons begins and predominantly involves the ventrolateral tier of SNC, which in turn projects to the dorsolateral posterior putamen. The latter is the predominant site of striatal degeneration in MSA. Several post-mortem immunohistochemical and autoradiographical, as well as in vivo neuroimaging studies, suggest that both striatal outflow pathways are affected: encephalin-containing striatal neurons projecting to the external globus pallidus that carry dopamine D2 receptors (indirect pathway) and substance P (SP)-containing cells projecting to internal globus pallidus and substantia nigra pars reticulata (SNR) that carry Di receptors (direct pathway) (Quik et al., 1979; Cortes et al., 1989; Brooks et al., 1992; Churchyard et al., 1993; Vogels et al., 2000; Goto et al., 1989a; Goto et al., 1989c; Goto et al., 1990; Goto et al., 1996; Schelosky et al., 1993; van Royen et al., 1993; Ito et al., 1996).

In accordance with the topographical projection of the putamen onto pallidal segments, the posterolateral portions of the external and internal globus pallidus, and the ventrolateral portion of the substantia nigra are deafferented from striatal projections (Brooks et al., 1992).

Progressive loss of striatal dopamine receptors and stri-atal output systems might explain levodopa unresponsive-ness in most MSA-P patients (Tison et al., 1995a; Ito et al., 1996; Parati et al., 1993; Rajput et al., 1990). Those patients with a good initial response to levodopa would thus have less striatal damage than those with absent or poor initial response. However, there is evidence suggesting that the response to levodopa does not always depend solely on the degree of striatal cell loss (Wenning et al., 1994c). In vivo PET studies by Brooks et al. (1992) have also failed to clearly correlate therapeutic response with striatal D2 receptor status. Additional loss of Di and opiate receptors could also be an important factor underlying dopaminergic unresponsiveness in MSA-P (Burn et al., 1995), as well as other changes downstream of striatum itself.

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