Primary lateral sclerosis

We examined regional cerebral blood flow (rCBF) and oxygen metabolism (CMRO^sub 2^) in 10 patients with progressive dementia and amyotrophic lateral sclerosis (DALS), in 21 patients with classical amyotrophic lateral sclerosis without dementia (ALS), and in 17 controls. The mean rCBF and rCMRO^sub 2^, especially in the anterior cerebral hemispheres, decreased significantly in patients with DALS. Patients with only ALS showed very mild changes in rCBF and rCMRO^sub 2^ which were not significant except for the reductions in the sensorimotor area. Some rCBF and rCMRO^sub 2^ values in ALS showed a significant correlation with some neurological signs indicating upper motor neuron involvement. These data suggest that hypoperfusion and oxygen hypometabolism in the anterior cerebral hemispheres have an etiological relationship with the deterioration of intellect in patients with progressive dementia and ALS. The metabolic and perfusional changes in the cerebral cortex of ALS patients are likely to depend on upper motor neuron involvement, but they are not confined to the neurons of the corticospinal tract. [Neurol Res 2003; 25: 351-356]

Keywords: Positron emission tomography; progressive dementia; amyotrophic lateral sclerosis; motor neuron disease; cerebral oxygen metabolism; cerebral blood flow

INTRODUCTION

The symptoms of classical amyotrophic lateral sclerosis (ALS), which are confined to the voluntary motor system with varying degrees of upper and lower motor neuron involvement, do not include memory or intellectual derangement. Dementia associated with ALS and usually with parkinsonism is known in small populations in the Western Pacific1. Reports of another type of dementia with ALS (DALS) have come from the Japanese population2-4, and led to the recognition of patients in Western countries5,6 bearing a close resemblance to the Japanese patients. In such patients, disordered frontal brain regions are thought to have a pathogenetical relationship with dementia6. This is mainly supported by psychological and rarely by pathological assessments. Neurodiagnostic imaging with single photon emission computed tomography (SPECT) appears informative for cerebral blood flow changes7. However, no quantitative evaluation could be made with SPECT.

Using quantitative positron emission tomography (PET) with oxygen-15 gas and oxygen-15 labeled carbon dioxide, we previously examined cerebral blood flow and oxygen metabolism in four patients with DALS closely resembling previously reported Japanese patients. We reported hypoperfusion and oxygen hypometabolism in the anterior cerebral hemispheres in DALS8. The patient population of the study, however, might be too small to draw a definite conclusion. Thereafter, we accumulated the data of 10 DALS patients and evaluated 21 patients with ALS and normal intellectual function to see whether decreased cerebral blood flow and oxygen metabolism would be found in DALS cerebral cortices outside of the primary motor areas, and such changes would not be found in ALS without dementia, hoping that these would demonstrate an etiological relationship with the intellectual deterioration in DALS.

PATIENTS AND METHODS

Patients

Cerebral blood flow and oxygen metabolism in 10 patients with ALS and progressive dementia (DALS) including four patients reported previously6 were studied using PET. Diagnosis was based on the clinical criteria of Mitsuyama2: progressive dementia with slowly progressive onset in the pre-senile period; neurogenic muscular wasting during the course of illness; the absence of extrapyramidal symptoms and clear sensory deficits; no characteristic abnormalities in cerebrospinal fluid or electroencephalography; and no parental consanguinity or familial occurrence. Eight DALS patients showed some personality or emotional change as described previously2,8. The patients also met the criteria of the revised third edition of the American Psychiatric Association Diagnostic and Statistical Manual for degenerative dementia9. The summary of the patients' clinical data is given in Table 1. WAIS was used as an index of mental deterioration for patients 1-4; and WAIS-R for patients 5-10. ALS presented by 21 patients without dementia (Table 2) was classified into classical amyotrophic lateral sclerosis showing neurologic and electrophysiologic evidence of both upper and lower motor neuron involvement. Familial ALS was not included in the present series. No patients in this report had had any previous medical or psychiatric history. There had been no occupational exposure to chemicals or metals. They had not suffered major head injury and had no history of alcohol abuse. Seventeen healthy volunteers were subjected to a PET study as control subjects.

Methods for the PET study

PET was performed by a PCT-H1 (Hitachi, Tokyo, Japan) using four rings with 128 bismuth germanate oxide detectors providing seven views per scan cycle10. The best spatial resolution was 7.4 mm full width at half maximum (FWHM) at the center of the scan field, and axial resolution at the center was 16 mm (slice thickness). Prior to the PET study, X-ray CT (CT-HSF, Hitachi) images were obtained to identify anatomical structures in the PET views. PET and X-ray CT scanners were located side by side and joined by rails on which the bed moved with the patient's position fixed, thus providing identical tomographic planes. The patient's head was fixed to the headrest to obtain a tomographic plane parallel to the orbitomeatal line. The initial positioning and the absence of head tilt during the scan were ensured by crossed beams projected on ink marks drawn on the patient's face. A transmission scan using germanium-68 and gallium-68 was performed for 10 min for attenuation correction. Calibration factors between the PET scanner and the well counter were obtained in each study. The oxygen-15 steady state technique was employed to measure the regional cerebral blood flow (rCBF), and regional cerebral oxygen metabolic rate (rCMRO^sub 2^). Oxygen-15 gas (750-1,100 MBq per min) then oxygen-15 labeled carbon dioxide (350-550 MBq per minute) were inhaled continuously. Scan data was collected for 5-8 min. The blood was sampled three times during each scan process from the cannulated radial artery and was subjected to determinations of oxygen-15 radioactivity in whole blood and plasma as well as blood cell counts and blood gas analyses. No correction was performed for intravascular oxygen-15 labeled oxyhemoglobin, because the patients with dementia did not fully cooperate with bolus inhalation of oxygen-15 labeled carbon monoxide.

Image data was processed with a Hitachi image processing computer using system subroutines to re-construct functional images comprising 128x128 pixels. The regions of interest (ROls) were determined on bilateral cerebral cortices (frontal, temporal, parietal and occipital lobes, and sensorimotor areas) and cerebellar hemispheres of the X-ray CT image. Cortical ribbons and the outlines of cerebellar hemispheres were traced by a track ball, carefully avoiding the sinuses and cerebrospinal fluid spaces. The same ROIs were super-imposed on rCBF and rCMRO^sub 2^ tomographic planes identical to the X-ray CT plane8,10. The mean values of cerebrocortical rCBF and rCMRO^sub 2^, global cortical blood flow and oxygen metabolism, were also calculated and expressed as mCBF and mCMRO^sub ^, respectively.

Statistical procedures

The mean age, rCBF and rCMRO^sub 2^ values of patients with DALS or patients with ALS alone were compared with those of the controls. Statistical differences were determined by one-factorial analysis of variance (ANOVA) with Scheffe's F-test as a post hoc test. The illness durations in each diagnostic category were also compared using Student's f-test. To examine the relationship between PET data and clinical manifestations, we used Mann-Whitney U- test for the presence of bulbar palsy or extensor plantar response, and Spearman's rank correlation coefficient for the degree of muscle atrophy or tendon reflex.

RESULTS

There were no significant differences in the mean age of the patient groups (56.2 + or - 10.8 years old for DALS and 59.1 + or -9.4 years old for ALS) and controls (57.0 + or -13.6 years old). The illness duration, time interval from onset to the PET study, in the two groups (14.1 + or -9.1 months for DALS and 22.8 + or - 19.7 months for ALS) was also not significantly different.

Functional images of rCBF and rCMRO^sub 2^ in DALS indicated that cerebral and cerebellar blood flow and oxygen metabolism decreased in all brain regions, especially in frontal regions. Absolute values for rCBF and rCMRO^sub 2^ in DALS were reduced in all brain regions examined (Tables 3 and 4). A significant reduction of rCBF in DALS was found in all brain regions except for the cerebellar hemispheres. The rCBF and p values compared with controls indicated a frontal dominant deterioration of brain perfusion. The rCMRO^sub 2^ in DALS also decreased significantly in all cerebral cortices examined except for the right occipital cortex. No significant reduction in rCMRO^sub 2^ was found in the bilateral cerebellar hemispheres. The frontal areas also seemed the most severely damaged from the viewpoint of rCMRO^sub 2^. There was no significant relationship between other neurological signs and symptoms and PET data in DALS.

rCBF and rCMRO^sub 2^ values in ALS were much higher than those in patients with DALS. Compared with the controls, a significant difference was found only in bilateral sensorimotor cortices in rCBF and rCMRO^sub 2^. On visual inspection, there were no distinctive findings in functional images of rCBF and rCMRO^sub 2^ for this patient group besides the sensorimotor areas.

In ALS patients, an exaggeration of some deep tendon reflexes showed a negative correlation with rCBF or rCMRO^sub 2^ values. Deep tendon reflexes in the left lower extremity correlated with mCMRO^sub 2^ (p

DISCUSSION

DALS in the present report is regarded as ALS with coincidental frontotemporal dementia. The diagnosis is based on the criteria proposed by Mitsuyama2 that includes a large group of DALS patients having been reported in Japan2-4,8. The present PET study using oxygen-15 labeled O^sub 2^ and CO^sub 2^ demonstrated that cerebral blood perfusion and oxygen metabolism in DALS deteriorated, particularly in frontal brain regions, while those in ALS without dementia were not changed significantly. Although our previous study8 has already suggested these findings, the number of patients might be too small to reach definite conclusions. The outstanding clinical difference between the two disease groups is intellectual function. Patients with DALS showed moderate to severe dementia accompanied by some personal or emotional change which were well described previously2,3,8, while patients with ALS were intellectually normal. There was no distinctive neurological difference in ALS with or without dementia. Therefore, reduced cerebral blood flow and oxygen metabolism, especially in frontal regions, in progressive dementia with ALS could have an etiological relationship with intellectual deterioration. It is unlikely that the observed reductions in rCBF and rCMRO^sub 2^ are explained by the degeneration of corticospinal tract neurons. The alterations in rCBF and rCMRO^sub 2^ may represent principally a decline in metabolic demand by dysfunctional or missing neurons which could be linked to intellectual deterioration, and partially by a diaschisis due to primary loss of neurons distant from the site with declined rCBF and rCMRO^sub 2^. Such a decline in frontotemporal perfusion and metabolism detected by PET will serve as an objective diagnostic marker.

We have previously discussed cerebral hypoperfusion and hypometabolism in relation to clinical patterns of dementia as well as mood or affect changes^sup 8^. These are true of the patients in the present study. Briefly, changes in personality and a breakdown in social conduct predominated, with disinhibition, apathy, unconcern and lack of mental effort being notable symptoms. Language disorders were characterized by progressive diminution in speech output and responses to questions becoming brief and stereotyped, leading finally to mutism. Spatial cognitive function was relatively spared. These psychological profiles in DALS implicated the disordered function of the anterior cerebral hemispheres, with the relative preservation of the function of posterior association cortices. This was also supported by some previous studies using SPECT, which demonstrated a pattern of relative reduction in radioactivities in frontal regions^sup 7^. Frontal lobe atrophy was sometimes demonstrated pathologically or by X-ray CT^sup 2,5^. Mood or affect changes can produce frontal hypoperfusion and hypometabolism. Phelps et al.11 reported glucose hypometabolism in the frontal lobe and part of the temporal lobe in depressed patients. However, the reductions observed in the affective disorders seem to be much less than those in progressive dementia with ALS as shown in our patients^sup 4,12^. Metabolic asymmetry restricted to the frontotemporal lobe cortex rather than frontal hypometabolism was accentuated in unipolar depressed patients^sup 11^. Therefore, mood or affect changes, even if concurring, could not fully account for the marked frontal hypoperfusion and oxygen metabolism usually accompanied by brain atrophy^sup 8^ . It is also likely that the decreased rCBF and rCMRO^sub 2^ were caused for the most part by frontal lobe pathology.

The cerebellar perfusion and oxygen metabolism in our previous study^sup 8^ seemed to be decreased, although there were neither neurological signs nor morphological changes in MRI indicating cerebellar involvement in our patients. In the present study with the increased number of patients, however, ANOVA showed only significant group differences in the cerebellar rCBF, while the post hoc test failed to demonstrate significant p values over the area. One of the possible explanations was functional deactivation as a result of bilateral or diffuse supratentorial damage, bilateral crossed cerebellar diaschisis^sup 8,10^. Similar findings are demonstrated in the occipital blood flow in the present study. Although the occipital lobes show a mild but significant reduction in rCBF, pathological studies have not found consistent abnormality in the occipital lobes of DALS. Moreover, there has been no study, to our knowledge, reporting any cognitive dysfunction responsible for the occipital lobe pathology. In this case, the functional deactivation as a result of frontotemporal pathology could also explain such rCBF changes.

In the present study, we have found that some neurological manifestations of ALS correlated with cerebral perfusion and oxygen metabolism. Deep tendon reflexes in the left lower extremity negatively correlated with mCMRO^sub 2^ and rCBF in the right frontal cortex. Deep tendon reflexes in the right lower extremity negatively correlated with rCMRO^sub 2^ in the left sensorimotor cortex and mCMRO^sub 2^. Extensor plantar responses on both sides depended on the decrease in mCBF. All these findings indicate a close relationship between the involvement of the corticospinal tract and cerebral blood flow and metabolism. However, the areas were not confined to the cerebral cortex corresponding to the corticospinal tract. Dalakas ef al.^sup 13^ reported that the regional cerebral metabolic rate for glucose (rCMRGIc) evaluated by PET with fluorine-18 labeled 2-fluoro-2-deoxy-D-giucose (FDG) was lowered in cerebral cortices in ALS with upper motor neuron signs. Furthermore, that degree of hypometabolism correlated with the duration of clinical signs and extended throughout the cortex and basal ganglia, but not to the cerebellum. In contrast, ALS patients with disease confined to the lower motor neurons had normal or near normal rCMRGIc throughout the brain. These findings, including our own, suggest that metabolic and perfusional changes in the cerebral cortex of ALS patients depend on upper motor neuron involvement, but they are not confined to the neurons of the corticospinal tract. Dalakas et al.^sup 13^ postulated that the functional deafferentiation in ALS could explain the reduction in rCMRGIc at sites remote from the primary motor cortex, the area to be the primary pathologic target. This effect could depend on the duration of illness which seemed to be longer in their cases than in ours (22.8 months). Moreover, the PET study using FDG could be sensitive to subtle cortical metabolic changes, though it can not evaluate the cerebral blood flow simultaneously. These are possible explanations for the difference between the PET findings of Dalakas et al.^sup 13^ and our's.

Finally, our data support previous suggestions that frontal lobe dementia is typical of the cognitive changes accompanied by ALS. The present study also suggests that quantitative PET can provide key information for diagnosing and clinically evaluating progressive dementia with ALS, supplementing neurological and psychological findings in the absence of pathologic information. However, we have not revealed specific changes in DALS compared with functional neuroimaging data on any other types of frontotemporal dementia without ALS in the literature. To find such specific changes, we need large-scale and sophisticated neuroimaging studies to compare DALS with other subgroups of frontotemporal dementia on a pathological basis.

REFERENCES

1 Gajdusek DC. A focus of high incidence amyotrophic lateral sclerosis and parkinsonism and dementia syndromes in a small population of Auyu and Jakai people of Southern West New Guinea. In: Tsubaki T, Toyokura Y, eds. Amyotrophic Lateral Sclerosis, Tokyo: Tokyo University Press, 1979: pp. 287-305

2 Mitsuyama Y. Presenile dementia with motor neuron disease in Japan: Clinico-pathological review of 26 cases. J Neurol Neurosurg Psychiatry 1984; 47: 953-959

3 Morita K, Kaiya H, lkeda T, Namba M. Presenile dementia combined with amyotrophy: A review of 34 Japanese cases. Arch Gerontol Ceriatr 1987; 6: 263-267

4 Okamoto K, Murakami N, Kusaka H, Yoshida M, Hashizume Y, Nakazato Y, Matsubara E, Hirai S. Ubiquitin-positive intraneuronal inclusions in the extramotor cortices of presenile dementia with motor neuron disease. J Neurol 1992; 239: 426-430

5 Neary D, Snowden JS, Mann DMA, Northen B, Goulding PJ, Macdermott N. Frontal lobe dementia and motor neuron disease. J Neurol Neurosurg Psychiatry 1990; 53: 23-32

6 Wikstrom J, Paetau A, Palo J, Sulkava R, Haltia M. Classic amyotrophic lateral sclerosis with dementia. Arch Neurol 1982; 39: 681-683

7 Ohnishi T, Hoshi H, Nagamachi S, Jinnouchi S, Futami S, Watanabe K, Mitsuyama Y. Regional cerebral blood flow study with ^sup 123 ^I-IMP in patients with degenerative dementia. AJNR 1991; 12: 513-520

8 Tanaka M, Kondo S, Mirai S, Sun X, Yamagishi T, and Okamoto K. Cerebral blood flow and oxygen metabolism in progressive dementia associated with amyotrophic lateral sclerosis. J Neural Sci 1993; 120: 22-28

9 American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders, 3rd Edition revised, Washington DC: APA, 1987

10 Tanaka M, Kondo S, Hirai S, lshiguro K, lshihara T, Morimatsu M. Crossed cerebellar diaschisis accompanied by hemiataxia: A PET study. J Neurol Neurosurg Psychiatry 1992; 55: 121-125

11 Phelps ME, Mazziotta JC, Baxter L, Gerner R. Positron emission tomographic study of affective disorders: Problems and strategies. Ann Neurol 1984; 15 (Suppl.): S149-S156

12 Buchsbaum MS, Cappelleti J, Ball R, Hazlett E, King AC, Johnson J, Wu J, DeLisi LE. Positron emission tomographic image measurement in schizophrenia and affective disorders. Ann Neurol 1984; 15 (Suppl.): S157-S165

13 Dalakas MC, Hatazawa J, Brooks RA, Di Chiro G. Lowered cerebral glucose utilization in amyotrophic lateral sclerosis. Ann Neural 1987; 22: 580-586

Makoto Tanaka, Taku Ichiba, Susumu Kondo, Shunsaku Hirai and Koichi Okamoto

Department of Neurology, Gunma University School of Medicine, Maebashi, Japan

Correspondence and reprint requests to: M. Tanaka, Department of Neurology, Gunma University School of Medicine, Showamachi, Maebashi, Gunma 371-8511, Japan. [tanakama@showa.gunma-u.ac.jp] Accepted for publication January 2003.

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