Anatomical and functional correlates of cognitive deficit in multiple sclerosis

Journal of the Neurological Sciences, 115 (Suppl.) (1993) S55--$58

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© 1993 ElsevierSciencePublishers B.V. All rights reserved0022-510X/93/$06.00 JNS 04017

Anatomical and functional correlates of cognitive deficit in multiple sclerosis C. Pozzilli, C. Gasperini, A. Anzini, M.G. Grasso, G. Ristori and C. Fieschi Department of Neurological Science, University of Rome "'La Sapienza "', Rome, Italy

Key words: Multiple sclerosis; Cognitive deficit; Magnetic resonance imaging (MRI); Positron emission tomography (PET); Single photon

emission tomography (SPET)

Summary This brief article reviews the present state of knowledge concerning the relationship between structural and functional cerebral abnormalities and the cognitive deficits associated with multiple sclerosis. Currently available neuroimaging techniques have substantially contributed to a better understanding of the latter, suggesting that cortical-subcortical disconnection is the most likely cause of the cognitive disturbance. Longitudinal studies are needed to determine the natural history of the cognitive deficit and its relationship to the cerebral changes detected by neuroimaging techniques.

Introduction Neuropsychological studies document that a high percentage of patients with multiple sclerosis (MS) suffer cognitive dysfunction. The majority or recent neuropsychological studies estimate the prevalence of impaired cognition to range from 43 to 65% (Staples and Lincoln 1979; Peyser et al. 1980; Eaton et al. 1985; Lyon-Caen et al. 1986; Rao 1986; Rao et al. 1991). Cognitive decline is more frequent at the more advanced stage of the disease (Staples and Lincoln 1979), and in chronic progressive MS (Eaton et al 1985): however, it may also be present in the early phase (Lyon-Caen et al. 1986) and in patients with mild physical disability (Van den Burg et al. 1987). The pathophysiology of the cognitive disturbance has not been fully elucidated although the recent advent of neuroimaging procedures such as computed tomography (CT), magnetic resonance imaging (MRI), single photon emission tomography (SPET) and positron emission tomography (PET) has made more accurate clinicopathological correlations possible. In this article, we present an overview of present knowledge concerning the neuropathological correlates of cognitive dysfunction in MS.

CT studies Rao et al. (1985) first attempted to relate psychometric Correspondence to: CarloPozzilli,MD, Phi), DepartmentofNeurological Science, Universityof Rome "La Sapienza", Viale dell'Universitg30, 1-00185 Rome,Italy.Tel.: 06-49914716; Fax: 06-4440790.

measures of cognitive dysfunction with morphological changes in brain structure, as reflected in CT measures of atrophy. They demonstrated that the size of ventricular spaces is a gross indicator of cognitive deficit in patients with chronic progressive MS. Ventricular enlargement was associated with poor'performance on the verbal rather than the spatial memory tasks; however, the authors discarded the hypothesis of a greater impairment in linguistic memory as a result of greater left hemisphere involvement since cerebral plaques were evenly distributed in both hemispheres. Rabins et al. (1986) studied 37 MS plaques with CT, psychiatric interview and Mini Mental State (MMS) examinations. Enlarged ventricles were found more frequently in patients with "euphoria" and in those with lower MMS scores.

MRIstudies MRI, which has proved to be extremely sensitive in detecting lesions of MS, has been widely used to determine whether a particular pattern of anatomic involvement is related to cognitive dysfunction. Of several MRI measures, the total lesion score (Franklin et al. 1988; Callanan et al. 1989), total lesion area (TLA) (Rao et al. 1989a), periventricular damage (Medaer et al. 1987; Reischies et al. 1988; Anzola et al. 1990; Pozzilli et al. 1991a), third ventricle index (Bone et al., 1990; Pozzilli et al. 1991a), and corpus callosum (CC) atrophy (Huber et al. 1987; Rao et al. 1989a) proved to be the most sensitive indicators of cognitive deficit.

$56 Few studies investigated the relation between specific cognitive processes and brain pathology. Bilateral demyelination in the hyppocampal regions has been correlated with the extent of anterograde memory impairment (Brainin et al. 1988). Rao et al. (1989a) demonstrated that TLA was a strong predictor of performance on measures of recent memory and abstract/conceptual reasoning, while CC size was a better predictor of information processing speed, rapid problem solving and mental arithmetic. Various tests of linguistic processes and visuospatial problem-solving skills were also predicted by both TLA and CC size. Moreover, MS patients with CC atrophy exhibit a reduced performance on laterality tasks such as verbal dichotic listening and tachistoscopic object-naming latency which supports the hypothesis that the efficiency of crosscallosal information flow is reduced (Rao et al. 1989b). To determine whether different portions of the CC are responsible for transfering the informations of specific cognitive functions, we have recently (Pozzilli et al. 1991b) examined 18 females with relapsing-remitting MS in the early phase of the disease, using neuropsychological procedures and MRI. Measures of both anterior and posterior CC areas were obtained in patients with MS as well as in 18 age- and sex-matched healthy controls. The extent of demyelinating lesions in both periventricular and subcortical areas was also assessed. We were interested in establishing whether CC atrophy itself could be related to cognitive dysfunction or if it were simply another marker of the extent of total cerebral involvement. In spite of their short disease duration, patients with MS exhibited a statistically significant decrease in both anterior CC and posterior CC areas as well as in CC areas controlled for sagittal brain size. Therefore the CC atrophy area may not be simply considered as an element of diffuse brain atrophy but as an early sign of disease process. The results of statistical analysis showed that, even when the effect of demyelinating lesions was taken into account within a regression equation, the atrophy of the anterior CC area strongly affected the performance on verbal fluency tasks. These results support the assumptions that fibers of different portions of the CC transfer particular kinds of information and suggest that a normal interhemispheric transfer between the frontal cortex of the two hemispheres is a necessary requirement for an adequate performance in verbal fluency tasks. PET and SPET studies

Patterns of cerebral metabolism and cerebral blood flow have been analyzed in vivo by imaging studies using PET and SPET tecniques. In a study using PET, Brooks et al. (1984) demonstrated a generalized coupled reduction in both cerebral oxigen utilization and blood flow in MS pa-

tients. The reduction was found in both white and gray matter and correlated with cognitive impairment but not with locomotor disability or clinical disease duration. The observation of a metabolic reduction in the gray matter which could reflect cortical suppression or deactivation, secondary to disconnection from subcortical structures, was particularly interesting. Further evidence of disconnection from well documented MS plaques was also reported (Herscovitch et al. 1984; Pozzilli et al 1987). More specific information on the relationships between anatomic, neuropsychological and metabolic functions has been obtained using a high spatial resolution PET scanning which allows a more accurate assessment of regional metabolism in cortical and subcortical structures. Regional metabolic reduction of the thalami, mesial temporal areas and anterior cingulate cortex bilaterally has been reported in MS patients with memory deficits (Perani et al 1990). To determine the relationship between CC atrophy and cortical brain metabolism, we have recently compared the cerebral metabolic rates for glucose (CMRglc) measured by PET of 8 MS patients with evidence of CC atrophy on midsagittal MRI, 8 MS patients without CC atrophy and 10 healthy controls (Pozzilli et al. 1992). We found that presence of CC atrophy was not associated with absolute lower cerebral metabolism. Whereas, only patients with CC atrophy showed greater directional metabolic asymmetry than controls, the left frontal, temporal and parietal association cortices being significantly lower than the right. Predominant left hemispheric metabolic reduction were not accompanied by a corresponding left-sided predominance in the extent of demyelinating lesions detected by MRI. These data implied that CC atrophy affects more left than right cortical metabolic function. Parallel studies in other neurological diseases such as dementia, where both left hemisphere hypometabolism and CC atrophy have been observed, give support to this hypothesis, although further research is required (Lowenstein et al. 1989; Tanaka et al. 1989). Because PET has shown that regional cerebral blood flow and metabolism are coupled in MS, we have measured regional cerebral blood flow using SPET in 17 patients with relapsing-remitting MS and mild physical disability (Pozzilli et al. 1991a). Normalized blood flow values obtained by means of technetium-99m (99mTc) hexamethylpropyleneamine oxime (HMPAO) showed significant reduction in the frontal lobes and in the left temporal lobes of MS patients compared with age-matched normal controls. A decrease of frontal blood flow was also observed in patients with short disease duration despite normal findings on neuropsychological tests measuring "frontal" functions (i.e., Wisconsin Card Sorting). An example of a selective bilateral reduction of frontal flow is shown in Fig. 1. This pattern is different from that associated with Alzheimer's disease, where parieto-temporal cortex is early corn-

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Fig. 1. MRI and SPET images of a 31-year-old MS female patient with a EDSS score of 1 and only a mild attentional deficit. MRI scan shows both periventricular and non periventricular white matter damage. SPET image of 99mTc-HMPAO, obtained from the same level as MRI, shows a reduced uptake of the tracer in the frontal lobe bilaterally. (Courtesy of Patrizia Pantano, M.D., Dept. Neurol. Sci., Univ. of Rome "La Sapienza", Rome.)

promized and frontal involvement is seen in more advanced stages (Frackowiak et al. 1981). Early frontal cortex hypometabolism was reported as a characteristic feature of "subcortical dementias" including progressive supranuclear palsy (D'Antona et al. 1985; Goffinet et al. 1989) and Huntington's disease (Hasselbach et al. 1989; Pantano et al. 1989). MS has not often been named as one of the causes of subcortical dementia (Cummings and Benson 1984) although the nature of the cognitive impairment is compatible with the concept of subcortical dementia as recently suggested (Rao 1986). The decrease of blood flow in the supero-temporal lobe which was prevalent on the left side of our MS patients correlated with a poor performance in fluency and verbal memory tasks. A similar correlation between verbal memory deficits and left temporal lobe hypoperfusion has recently been reported also in Alzheimer's disease (Burns et al. 1989). Conclusions

Neuroimaging tecniques have provided new insight into the pathogenesis of the cognitive deficits associated with MS. Although the contribution of cortical damage (i.e., cortical atrophy or small cortical plaques) to the genesis of

cognitive disturbance cannot be completely ruled out, cortical suppression or deactivation, secondary to disconnection from subcortical structures, is the best current explanation for the cognitive deficits in MS. Initial PET and SPET studies have shown that metabolic and flow abnormalities extend to brain regions far from the site of damage. Some of these abnormalities have been suggested as characteristic. They range from an early frontal lobe depression to a predominant left hemisphere hypometabolism and to the specific involvement of brain structures related to memory functions. Cognitive deficit often correlates with metabolic or flow abnormalities, although the apparently early presence of frontal hypofunction before the appearance of "frontal" cognitive deficits suggests that PET or SPET may provide an earlier measure of dysfunction than neuropsychological testing. Longitudinal studies are therefore needed to determine whether PET or SPET could be useful in predicting cognitive impairment in MS. Future research should also include research into the relationships between behavioral disturbances and brain metabolic function as well as the study of the effects of cerebral activation tasks. Acknowledgements Research developed within the targeted FATMA project (prevention and control of risk factors), sub-project community

$58 medicine, of the CNR (Italian National Research Council), 1990-1995.

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