Impaired novelty P3 potentials in multiple system atrophy—correlation with orthostatic hypotension

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Abstract

Although neuropsychological tests demonstrate frontal lobe dysfunction in multiple system atrophy (MSA), assessment of frontal function using event-related brain potentials (ERPs) has not been sufficiently performed in MSA. The correlation between frontal lobe dysfunction and orthostatic hypotension (OH), which is known to cause frontal hypoperfusion, remains unclear. Our objectives were to assess frontal lobe dysfunction in MSA patients using ERPs and to elucidate the relevance of OH to changes in ERPs. Nine consecutive patients with MSA and nine age- and gender-matched healthy controls were compared by performance in the Wisconsin Card Sorting Test (WCST) and somatosensory ERPs to target and novel stimuli, namely, parietal maximal P3 (target P3) and fronto-central P3 (novelty P3), respectively. The correlation between novelty P3 and OH was evaluated in the MSA group. The MSA group showed a poorer performance in categories achieved (CA), total errors (TE) and perseverative errors by Nelson's (PEN) method in the WCST compared with the control group (CA and PEN: p<0.01; TE: p<0.02). Novelty and target P3s in the MSA group showed significantly prolonged latency (novelty: p<0.05; target: p<0.01) and reduced amplitude (novelty: p<0.02; target: p<0.01) compared with the control group. There was a significant negative correlation between novelty P3 latency and a drop in systolic blood pressure (r=0.76; p<0.02). Abnormalities of novelty P3 in the MSA group might reflect frontal lobe dysfunction, namely failure of attentional set-shifting, that was identified by the WCST. OH may play a role in the development of frontal lobe dysfunction in MSA.

Introduction

Multiple system atrophy (MSA) is a neurodegenerative disorder characterized by autonomic failure/urinary dysfunction, Parkinsonism, cerebellar ataxia, and corticospinal dysfunction [1]. Although generalized dementia has not been observed in MSA, previous reports indicate impairment of executive functions as shown by performance on neuropsychological tests sensitive to frontal lobe function [2], [3], [4], [5], [6], [7], [8]. It was also discovered that deficits in visuospacial organization and visuomotor ability were similar to those seen in Parkinson's disease (PD) [3], [4], [8]. In contrast to these studies, few reports have investigated cognitive function in MSA patients, particularly in frontal lobe function, by a neurophysiological method [9], [10].

The endogenous components of event-related potentials (ERP) with auditory, visual, and somatosensory modalities have been established as physiological indices of cognitive function. Of these components, a parietal maximal P3 response (target P3) is generated by task-relevant, correctly detected stimuli. The latency and amplitude of target P3 waves are regarded as reflecting cognitive processing time and central processing resources, respectively [11], [12]. On the other hand, a fronto-central P3 response (novelty P3), which is generated by unexpected and deviant stimuli in the environment, is considered to reflect a central nervous system index of the orienting response [13], [14]. Lesion studies in humans and depth electrode studies suggest that the frontolimbic circuits, which involve the prefrontal cortex, posterior hippocampus and anterior cingulate gyrus, are crucial for development of the novelty P3 response [14], [15], [16], [17], [18], [19], [20]. A single photon emission tomography (SPECT) study showed a correlation between novelty P3 amplitude and blood flow in the anterior cingulate cortex, suggesting that novelty processing is conducted in the prefrontal cortex [21]. A second investigation combining novelty P3 and functional magnetic resonance imaging (fMRI) revealed the involvement of two generators of novelty processing, namely the superior temporal gyrus and the prefrontal cortex [22]. Therefore, novelty P3 could be a useful neurophysiological and quantitative index of attentional and cognitive deficits related to frontal lobe dysfunction.

Frontal lobe dysfunction in MSA has often been compared to that in PD and progressive supranuclear palsy (PSP), as patterns of abnormality may be useful in differentiating these akinetic-rigid syndromes [23]. It is not surprising that PSP shows the most impaired frontal function among these basal ganglia disorders [3], [4], [6], [7], as massive neuronal loss occurs in this illness, extending from the midbrain tegmentum to premotor and prefrontal areas, which play an important role in cognitive function [24]. On the other hand, conflicting evidence on frontal lobe dysfunction in MSA and PD have been reported. Some reports suggest a similar degree of impairment in these disorders, while others show a higher incidence of impairment in MSA [2], [3], [4], [6], [7], [8]. Although frontal dysfunction most likely depends on nigral and caudate dysfunction, which induces deafferentation of projections to the premotor and prefrontal areas [3], [4], [7], the precise mechanism remains unclear. However, orthostatic hypotension (OH), which induces frontal hypoperfusion [25], [26], [27], is more common and severe in MSA compared with PD [28]. Therefore, the condition may constitute one factor accelerating frontal dysfunction through chronic frontal ischemia.

This study is aimed at assessing ERPs, namely target and novelty P3 responses, in patients with MSA. In addition, we investigated whether or not a drop in blood pressure during head-up tilt (HUT) is correlated with changes in the novelty P3 wave.

Section snippets

Subjects

Nine patients with MSA (seven males and two females; mean age, 52±6 years; age range, 42–66 years), who were diagnosed according to the consensus statement on the diagnosis of MSA [1], participated in the present study. All patients were categorized as probable MSA. Of these, five had features of sympathetic neurocirculatory failure (persistent orthostatic hypotension), and the remaining four showed parasympathetic dysautonomia (urinary symptoms, accompanied by impotence in men). The duration

Neuropsychological tests

Table 1 shows the results of the modified WCST. In the first step, the MSA group had significantly poorer performances in CA, TE and PEN compared with the control group (CA and PEN: p<0.01; TE: p<0.02). On the other hand, the DMS did not show a significant difference between both groups. Five patients with MSA and one healthy control performed the second step due to their poor performance of CA in the first step. In the second step, the MSA patients did not show a significant improvement in CA,

Discussion

The principal findings of this study are (1) the MSA group had a poor performance in the WCST, (2) the MSA group showed a significant prolonged latency and reduced amplitude of target and novelty P3 responses, and (3) a relationship was shown to exist between novelty P3 latency and a drop in systolic BP during HUT.

The MSA group did not have an obvious intellectual impairment as assessed by their HDS-R score, which is a useful screening test for dementia. However, poor performance on the WCST,

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