110 Journal ofNeurology, Neurosurgery, and Psychiatry 1991;54:110-115 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.54.2.110 on 1 February 1991. Downloaded from SPECT, MRI and cognitive functions in

Carlo Pozzilli, Domenico Passafiume, Silvia Bemardi, Patrizia Pantano, Chiara Incoccia, Stefano Bastianello, Luigi Bozzao, Gian Luigi Lenzi, Cesare Fieschi

Abstract in the study of cognitive deficit associated Seventeen patients with relapsing remit- with Alzheimer's .2"22 ting multiple sclerosis (MS) and mild The aim of this study was to examine the physical disability had neuropsycho- regional distribution of 99mTc HMPAO in logical testing, magnetic resonance the brain, the extent of cerebral lesions by imaging (MRI) and single photon MRI and their relationship to neuropsycho- emission computerised tomography logical findings in MS. Our study specifically (SPECT) using technetium 99m (99mTc) addresses the relapsing-remitting MS type hexamethyl-propyleneamine oxime with relatively mild physical and cognitive (HMPAO). Performance in verbal disturbance. fluency, naming and memory testing appeared to be impaired in MS patients compared with 17 age-sex and education Materials and methods matched normal controls. Patients Weighted periventricular and con- Seventeen right handed MS patients (12 fluent lesion scores and the width of the women and five men), mean (SD) age 31 (10) third ventricle, proved to be the most years and educational level 14 (3 5) years were sensitive MRI measures in differentiat- selected from those admitted to our MS out- ing more cognitively impaired patients patient clinic. The patients were evaluated from those who were relatively unim- according to the Schumacher criteria as paired. having clinically definite MS.23 The diagnosis Ratios of regional to whole brain was further supported by evoked potentials activity, measured by SPECT, showed and CSF studies. All patients had a relapsing- significant reduction in the frontal lobes remitting form of MS24 and they were studied and in the left temporal lobe of MS during a stationary phase. At least three patients. A relationship was found be- months elapsed between the occurrence of an tween left temporal abnormality in exacerbation or the termination of therapy 99mTc-HMPAO uptake and deficit in (steroids/corticotropin) and testing.

verbal fluency and verbal memory. Excluded from the study were any patients http://jnnp.bmj.com/ Finally, asymmetrical lobar activity who did not meet the criteria of definite MS University of Rome, or Department of indicated a predominant left rather than whose disease course was chronic-progres- Neurological Science right temporo-parietal involvement. sive. Patients with EDSS score >4 or those C Pozzilli with Mini Mental State Examination S Bernardi P Pantano (MMSE) lower than 23 were also excluded. S Bastianello A substantial proportion of patients with mul- Mean (SD) clinical disease duration was L Bozzao tiple sclerosis (MS) show disturbance of eight (five) years, mean degree of impairment G Lenzi higher cognitive functions.'` Cognitive as estimated by the Kurtzke Expanded Dis- on September 29, 2021 by guest. Protected copyright. C Fieschi decline is more frequent at the more advanced ability Status Scale (EDSS)2" was 1-7 (1 0) Department of stage of the disease6 and in Psychology chronic progres- and mean MMSE was 28-5 (1-7). C Incoccia sive MS.7 It may, however, also be present in University of the early phase89 and in patients with mild Neuropsychological assessment L'Aquila, Rome, Italy physical disability.'°0 The extent of cognitive The neuropsychological test battery26 consis- Department of impairment is related to cerebral ventricular ted of measures Environmental of general intelligence, lan- Science size"2 corpus callosum atrophy'3 14 and degree guage, memory, attention and visuospatial D Passafiume of cerebral lesions quantified by magnetic abilities lasting approximately two hours. The Presented as an abstract at resonance imaging (MRI).1'58 battery was composed of the following tests: the 14th International Previous work using positron emission General intelligence Coloured Symposium on Cerebral Progressive Blood Flow and Metabolism, tomography (PET) has demonstrated a Matrices. This test was administered follow- "Brain 89", Bologna, 28th generalised coupled reduction in both cerebral ing the standard procedure to provide an May-Ist June 1989 oxygen utilisation and blood flow in MS estimate of non verbal general Correspondence to: intelligence. Dr Pozzilli, Department of patients. The reduction was found in both Abstract/conceptual reasoning Wisconsin Neurological Science, white and grey matter and correlated with University of Rome, Viale Sorting Card Test. This was administered dell'Universita 30, 00185 cognitive impairment, rather than with following the standard procedure. The Rome, Italy. locomotor disability or clinical disease number of perseverative errors were recorded Received 11 December 1989 duration.'9 Recently, single photon emission as a and in revised form measure of abstracting ability. 18 April 1990. computed tomography (SPECT) has given Language Boston Naming Test.27 In this test Accepted 15 May 1990 information similar to that provided by PET of confrontational naming ability, subjects SPECT, MRI and cognitivefunctions in multiple sclerosis illl

were shown line drawings, one at a time, of 60 radiologist (LB) blind to the clinical and J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.54.2.110 on 1 February 1991. Downloaded from objects that varied in familiarity. The total neuropsychological findings. number of correct responses serves as the Lesions were divided into two categories: score. single lesions and confluent lesions. Single Set test. This is a verbal fluency test, based lesions were defined as rounded areas of on the number of components in a given abnormal high signal intensity. Confluent category that the subject can denominate in lesions have an appearance of more than one 120s. We adopted the categories "furniture" rounded single lesion having come together to and "birds". Scoring is the mean of names form an irregularly shaped "lump" or thick produced in the two categories. (> 5 mm) linear area abnormality.28 Visuospatial abilities Street Completion Weighted lesion scores were developed Test. This is a test of "speed of closure". We based on the number and size of lesions. We adopted the 11 items version. Each item is assigned the following weights according to composed by an incomplete black figure of lesion size: 1 = < 8 mm; 2 = 8-20 mm; a common object that has to be identified. 3 = >20 mm. Scoring is on pass/fail basis. Lesions which were periventricular in part Elithorn's Perceptual Maze Test. This is and extended out into the brain parenchyma composed of an 18 lattice type maze and the were considered "periventricular", while subject has to trace a line from bottom to top lesions which were apparently separate from of the maze, through the maximum number of the ventricles were designated "discrete" black points randomly placed on the net cerebral lesions.29 This latter group included figure. The scoring is on time and number of both "pure" white matter lesions and those black point basis. located just beneath the cortical surface (grey- Verbal memory Digit Span. We administered white matter junctions). and scored this subtest of WAIS following The evaluation of the corpus callosum (CC) standard instructions. was carried out on sagittal TI weighted Rey Auditory Verbal Learning. A list of 15 images. To obtain area measurements of CC stimulus-name of common objects is read five and cerebral hemisphere, the outlines of these times by the examiner to the subject. After structures were traced on a monitor screen each presentation the subject has to repeat as with a cursor and their areas were then cal- many words as he/she can recall. We assigned culated by a means of a computerised graphic two different scores. Short term memory table. The CC/brain area ratio was calculated scores: number of words recalled after the and then analysed."' first presentation; Long term memory scores: Finally, linear measurements were recorded the words correctly reported after a 15 min- including: (1) Frontal Horn Index, the ratio utes delay. of the maximal distance between the lateral Visuospatial memory Corsi Tapping Test. border of the frontal horns and the maximal The subject is presented with nine blocks width of the outer skull table at the same level; impartially arranged on a board. The exam- (2) Cella Media Index, the ratio of the mini- iner taps the blocks, and the subject is mal width of the lateral ventricles at the cella required to tap the same blocks in exactly the media level to outer skull table at the same same pattern. Scoring is the longest sequence level; (3) Third Ventricular Index, the ratio of of blocks correctly tapped. the maximal width of the third ventricle and http://jnnp.bmj.com/ Rey Osterreith Complex Figure. The width of outer skull at the same level. subject is presented with a complex geo- metrical drawing that he/she has to reproduce SPECT first by copying and after 15 minutes from SPECT brain imaging was performed with a memory. Scores are the number of element rotating gamma camera (GE 400 T) connected correctly reproduced and placed. to a dedicated computer (HP 1000, Eurobit).

Seventeen normal controls (NC) matched Twenty mCi of 99mTc HMPAO was injec- on September 29, 2021 by guest. Protected copyright. one to one with the patients in terms of age, ted into an antecubital vein with the patient sex and education level, were recruited from sitting quietly in a softly lit room. After 10 the community. Normal controls were people minutes, patients were placed supine using a from the hospital staff without a history of head holder to minimise motion. Acquisitions central disease or alcohol were made recording 64 angular views using a abuse. Normal controls were evaluated using 64 x 64 matrix format. In 30 minutes four the same neuropsychological procedures as million total counts were collected. After those used for patients. reconstruction, a complete set of axial tomographic slices from the posterior fossa up to the vertex was obtained. The slice thickness MRI was 1-2 cm and the spatial resolution was MRI studies were performed with a 1 5 Tesla 21 cm full width half maximum (FWHM). superconductive unit (Philips, Gyroscan S- SPECT scans were evaluated by an investi- 15). Ti weighted spin-echo sequences (TR gator (PP) blind to the clinical and neuro- 350, TE 30) on sagittal plane and both axial psychological data. and coronal T2 weighted spin-echo sequences The following axial tomographic slices were (TR 2300, TE 30-120) were obtained from considered; one slice corresponding to the each patient. Hyperintense demyelinating plane defined by the cerebellum (OM + areas, easily seen on proton density and T2 2-1 cm) and three supratentorial cerebral weighted images, were quantified by a neuro- slices corresponding to the level of the basal 112 Pozzilli, Passafiume, Bernardi, Pantano, Incoccia, Bastianello, Bozzao, Lenzi, Fieschi J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.54.2.110 on 1 February 1991. Downloaded from Table 1 Mean (SD) row scores and significancefor group comparison on the Results neuropsychological battery Neuropsychological testing Table 1 compares neuropsychological per- Tests Normal controls (n= 17) MS patients (n= 17) p* formance of MS patients with that of controls. General intelligence: The data were analysed by Student's t tests to Progressive matrices 332 (28) 31-6 (32) NS detect specific group differences in each of the Abstract/conceptual reasoning: neuropsychological measures. Five tests Wisconsin card sorting 6-9 (10 4) 11 5 (14 7) NS showed significant group differences: patients Language: with MS were significantly impaired in terms Boston naming 52 7 (5 4) 46-8 (6-8) 0 014 Set 29 4 (7 1) 24-4 (6-2) 0024 ofverbal fluency, naming and memory deficits. The patient sample was then divided into Visuospatial abilities: Street completion 9 0 (2-1) 8 2 (2-1) NS two groups: (1) patients who were relatively Elithorn's perceptual maze 28-4 (3 4) 27 4 (3 4) NS "cognitively impaired" with 2 SD below Verbal memory: normal control performance on at least two or Digit span 10 5 (2 6) 10 4 (2 4) NS more neuropsychological tests; (2) patients Rey auditory verbal learning: Short term 7 2 (1 3) 6 1 (1-5) 0015 who were relatively "cognitively intact" with Long term 131 (15) 11 1 (22) 0009 an impairment on one or less of the neuro- Visuospatial memory: psychological measures. Corsi tapping 5 6 (0 9) 5-5 (1-3) NS Out of the eight patients classified as "cog- Rey-Osterreith Complex figure memory 21 6 (7-5) 16-4 (8 1) 0 040 nitively impaired", three patients failed on 2 neuropsychological measures, two patients on *Derived from paired Student's t test (two tailed). 3 measures and the remaining three patients on 4, 6 and 8 measures respectively. Table 2 describes demographic, clinical and MRI characteristics of the two MS groups. As ganglia, the corona radiata and centrum shown in table 2, patients with cognitive im- semiovale (OM + 4 5 cm, 5-7 cm, 6-9 cm) pairment were significantly more likely to show respectively. abnormalities in the Mini Mental State test, Scans were analysed semiquantitatively by measuring tracer uptake in 16 regions of interest (ROIs), 4 x 4 pixels, (24 x 24 mm). Right The ROIs were placed in the right and left supero-frontal, infero-frontal, antero-supero- 1.1 - temporal, postero-infero-temporal, supero- parietal, infero-parietal, occipital lobes and cerebellum. Normalised regional activity rates (Q -g 1-0- values) were expressed as a ratio of activity per pixel in the ROIs to the activity per pixel in the whole brain. Normalised lobar activity rates were also calculated, reflecting the mean 09 value for the ROIs contained in the frontal,

parietal, temporal and occipital lobes. http://jnnp.bmj.com/ Asymmetry indices for each lobe were ex- pressed as left to right count ratio according to the formula (R - L)/(R + L) x 200. Left The ratios for MS patients were compared 1.1 - with those obtained fron nine age-matched healthy controls with no known neurological disorders. a> 1-0- on September 29, 2021 by guest. Protected copyright. Table 2 Clinical and MRI characteristic of MS patients with and without cognitive impairment 0.9 - "Cognitively" intact "Cognitively" impaired Mean (SD) (n = 9) (n = 8) P* Age, years 30 4 (8 7) 32 9 (10-9) NS Education, years 14 7 (2 1) 12 1 (4-1) NS I I I I I I I 1I Disease duration, years 7-1 (4-2) 64 (6-8) NS SF IF AST PIT SP IP OC CB EDSS 16 (12) 18 (10) NS Cerebral regions Mini Mental State 29 4 (0 5) 27-5 (2 0) 0-012 MRI measures: Figure I Mean (SE) regional Q values (single ROI Total lesion score 354 (16-3) 400 (13-8) NS count/whole brain counts) for right (top) and left L/R total lesion score* 1-0 (0 2) 1 2 (0 4) NS (bottom) (white circle) and nine normal controls (black Total periventricular score 11-6 (54) 20-9 (76) 0-010 circle). L/R periventricular score 1 1 (0 3) 0 9 (0-2) NS SF indicates Supero-frontal; IF, Infero-frontal; AST, Discrete lesion score 23-9 (14 4) 18-8 (10-8) NS PIT, Postero-infero-temporal; Confluent lesion score 1-7 (2-6) 7-1 (4 5) 0-008 Antero-supero-temporal; Callosal-brain ratio 7-0 (1-5) 7 8 (1-2) NS SP, Supero-parietal; IP, Infero-parietal; OC, Frontal horn index 318 (2 6) 31-1 (3 0) NS Occipital; CB, Cerebellum. Significant reductions in MS Third ventricle index 44 (08) 5-3 (1-0) 0049 group werefound on right supero-frontal lobe, both right Cella media index 21 7 (3 0) 22-7 (3 9) NS and left infero-frontal lobe and left antero-supero- temporal lobe. Pairs of comparisons were made using the Derived from unpaired Student's t test (two tailed). Mann Whitney U statistic. * = p < 0 05; *Left/right ratio. **= p <0.01. SPECT, MRI and cognitivefunctions in multiple sclerosis 113 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.54.2.110 on 1 February 1991. Downloaded from Table 3 Lobar 99mTc HMPAO asymmetry indicesfor MS patients and normal impaired" group (n = 8) shows a significant controls (NC)* decrease in the left temporal and bilateral frontal lobe. Brain region NC (n = 9) MS (n = 17) P value Supratentorial hemisphere 0-8 (0 8) 2-2 (1-0) NS Frontal lobe 0 5 (1-8) -0-8 (1-8) NS Discussion Temporal lobe 0-1 (1-8) 4-7 (1 9) <0-05 includ- Parietal lobe 0-6 (0-9) 2-7 (1-8) <0-01 An impairment of cognitive functions Occipital lobe 2-0 (2 5) 0-6 (2 3) NS ing naming, verbal fluency, short and long term memory was detected in our MS sample al- *Asymmetry indexes are presented as mean (SE). Positive asymmetry values correspond to relatively left sided hypoactivity, while negative values correspond to relatively left sided though only relapsing-remitting patients and hyperactivity. those with minimal physical disability (mean Pairs of comparison were made using the Mann Whitney U statistic. EDSS score of 1'7) were studied. These find- ings are consistent with the view that decline of cognition is not limited to the chronic-progres- total periventricular score, confluent lesion sive patients or those with severe motor impair- score and third ventricle index. ment. 47 10 11 The Rey Auditory Verbal Learning test in SPECT evaluation both the modalities (Short Term and Long In fig 1 are shown regional SPECT rates Term) was the most sensitive test to elicit normalised to the mean cerebral activity rate (Q memory deficit, while Digit Span was not values) for different brain regions in both MS shown to be significantly impaired. Several patients and healthy normal controls. Pairs of studies have shown that short term memory comparison for each region were made using capacity (that is, span memory) appears to be the Mann Whitney U statistic. unaffected in MS' 5' suggesting a specific The regions that showed a significant reduc- memory problem in the learning ability rather tion in the MS group were right supero-frontal than in retention.5103 Furthermore, in ac- lobe, both right and left infero-frontal lobe, and cordance with a number ofprevious studies,3 5 9 left antero-supero-temporal lobe. memory deficit was noted with both verbal and When the mean lobar asymmetry values visuospatial material. were specifically examined (Mann Whitney U We found a significant impairment in the statistic), MS patients showed significant left performances of verbal fluency and confronta- side hypoactivity in the temporal and parietal tional naming tests. While an impairment in lobes compared with controls (table 3). verbal fluency has been widely described in MS,71031 there are only few reports suggesting Relationship between neuropsychological and naming difficulties in MS patients.'32 SPECT variables Some authors found that major naming Intercorrelations were then examined between deficit is rare in relapsing remitting MS neuropsychological test scores and regional patients being limited to patients with chronic- SPECT rates by using the Kendall tau test. progressive disease.73' This discrepancy with Only variables which were significantly dif- our data may probably be due to variability ferent from the control group were considered. among patient samples. Two out of 20 intercorrelations were signi- CT and more recently MRI have been used ficant. Left temporal side hypoactivity sig- to determine whether a particular pattern of http://jnnp.bmj.com/ nificantly correlated with the Set test anatomic involvement correlated with cogni- (p < 0-01) and verbal memory measured by the tive and psychological disturbance in MS.'2-'8 Rey Auditory short term memory (p < 0-01). Of several CT or MRI measures, the width of Figure 2 shows mean lobar Q values for both the third ventricle,12 periventricular lesion MS subgroups as compared with normal con- burden,'1'7 total weighted lesion score418 and trols (n = 9) by Dunnett's test. In the "cog- corpus callosum atrophy13 14 proved to be the nitively intact" group (n = 9), a significant

most sensitive indicators of cognitive dysfunc- on September 29, 2021 by guest. Protected copyright. depression was seen only in the right frontal tion. lobe. On the other hand, the "cognitively In keeping with previous data we detected greater increase in the width of the third ventricle and higher "periventricular lesion Figure 2 Mean (SE) "Cognitively impaired" score" in patients with mild cognitive disability lobar Q values (lobar compared with those with good overall per- ROIs counts/whole brain Right O "Cognitively intact" are shown formance. Moreover, a striking difference in counts) for .W * T Controls "cognitively impaired" "confluent lesion score" was noted between the 1'0 ((n = 8) and two groups. This was not surprising, however, "cognitively intact" lesions were (n = 9) MS patients since confluent mainly peri- compared with controls ventricular. The two MS groups did not (n = 9). Significant exhibit statistically significant differences in reductions in mean Q Huber et found values as compared with the callosal-brain ratio. al'3 o Left controls are found in the that callosal atrophy was only evident in rightfrontal lobes of both - T, patients with dementia and there was no dis- MS groups and in left 1.0 frontal and temporal lobes tinction between patients with moderate and of "cognitively impaired" those with minimal intellectual impairment. group. * = p < 0 05; SPECT findings must be interpreted with **= p < 0-01; Tc99m HMPAO is a new radio- (Dunnett's test). I caution. Frontal Temporal Parietal Occipital pharmaceutical which passes the blood-brain 114 Pozzilli, Passafiume, Bernardi, Pantano, Incoccia, Bastianello, Bozzao, Lenzi, Fieschi

barrier and is trapped inside functioning cells." The prevalent left supero-temporal hypo- J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.54.2.110 on 1 February 1991. Downloaded from Kinetic studies have shown that cerebral activity seen in our MS patients was related to uptake of radioisotope is largely determined by the poor performance on fluency and verbal regional blood flow,34 but at present quanti- memory tasks. Similar correlation between tative data cannot be retrieved from SPECT memory deficit and left temporal lobe has been studies. However, normalisation by the local/ recently reported using SPECT in Alzheimer's global activity ratios may reduce within-group disease.22 intersubject variability providing an index of Reduced activity in the frontal and left regional brain perfusion. temporal lobes may reflect cortical suppression The relationship between HMPAO uptake or deactivation, secondary to disconnection and cerebral perfusion is complicated in clini- from subcortical structures. Sporadic evidence cal situations, such as MS, by other factors of disconnection from well documented MS including changes in tissue PH, blood-brain subcortical lesions has been recently re- barrier (BBB) alteration and presence of in- ported."47 Some authors have speculated that flammatory cells able to take up the tracer.35 periventricular MS lesions may disrupt white Pathological data have suggested that a com- matter fibre tracts interconnecting prefrontal- mon feature of active MS plaques is a local limbic structures resulting in a deficit of breakdown of the BBB associated with pre- memory and "frontal" functions.5 dominant lymphocitic infiltration.6 Although The predominant left hemisphere dysfunc- our patients have been examined during a tion observed in this study seems not to be stationary phase of the disease, the presence of peculiar to MS since it has been recently recent active MS lesions could not be com- demonstrated using SPECT and PET in pletely ruled out as recently documented using Alzheimer's disease and multi-infarct demen- gadolinium enhanced MRI.3738 It should, tia despite a lack of consistent asymmetrical however, be emphasised that MS lesions are pathological involvement in these diseases.2048 mainly confined to subcortical regions. On the other hand, symmetrical weighted Therefore, cortical hypoactivity observed in lesions scores were also observed in our MS our patients is unlikely to be due to artefactual sample (see table 2). A series ofhypotheses has tracer uptake. been formulated to explain this lateralised In this study, the regional 99mTc HMPAO brain dysfunction. The most likely explana- uptake pattern indicates a predominant frontal tion, however, was that the greater complexity abnormality and a greater left than right tem- of the left hemisphere organisation could lead poroparietal deficit in MS patients compared to greater functional and behavioural deficit with normal subjects. In addition, lower when both hemispheres are equally involved.'8 activity in the left temporal lobe was found only This study underlines the potential utility of in patients with cognitive impairment and SPECT in the investigation of cognitive dys- correlated with a disorder in fluency and in function in MS. More specific information on verbal memory. the interrelationship between anatomic, The pattern of a reduced activity affecting neuropsychological and metabolic functions the frontal lobes observed in our patients is could be obtained using current PET scanning different from that associated with Alzheimer's with higher resolution and sensitivity. disease where parieto-temporal cortex is com- promised early and a frontal involvement is Research developed within the targeted project FATMA http://jnnp.bmj.com/ seen in the more advanced (prevention and control ofrisks factors), sub-project community stages.39 Early medicine, of the CNR (Italian National Research Council), frontal cortex hypometabolism was reported as 1990-1995. a characteristic feature of "subcortical demen- The authors are indebted to Dr V Di Piero for helpful tias" including progressive supranuclear suggestions, and to C Mattei for technical assistance. We are also palsy4"' and Huntington's disease."243 MS has grateful to all the patients and their consultants for participating not been commonly mentioned among the in this study. causes of subcortical dementia44 the although on September 29, 2021 by guest. Protected copyright. nature of cognitive impairment is 1 Jambor KL. Cognitive functioning in multiple sclerosis. Br compatible J Psychiatry 1969;11:765-75. with the concept of subcortical dementia as 2 Peyser JM, Edwards KR, Poser CM, et al. Cognitive recently function in patients with multiple sclerosis. Arch Neurol suggested." 1980;37:577-9. Our data show a significant frontal SPECT 3 Grant I, McDonald WI, Trimble MR, et al. Deficit learning abnormality despite certain neuropsycho- and memory in early and middle phases of multiple sclerosis. J Neurol Neurosurg Psychiatry 1984;47:250-5. logical tests measuring "frontal" functions 4 Rao SM, Hammeke TA, McQuillen MP,. et al. Memory (that is, Wisconsin Card sorting) which disturbance in chronic/progressive multiple sclerosis. Arch Neurol 1984;41:625-31. appeared to be relatively unaffected. 5 Rao SM. Neuropsychology of multiple sclerosis: a critical It has been suggested that patients with mild review. J Clin Exp Neuropsychol 1986;8:503-42. 6 Staples D, Lincoln NB. Intellectual impairment in multiple dementia caused by progressive supranuclear sclerosis and its relation to functional abilities. Rheumatol palsy may show metabolic reductions before Rehab 1979;18:153-60. 7 Heaton RK, Nelson LM, Thompson DS, et al. Neuro- neuropsychological changes occur.' Further- psychological findings in relapsing/remitting and chronic/ more, one may speculate that other neuro- progressive multiple sclerosis. J Consult Clin Psychol 1985;53:103-10. logical or behavioural patterns, which have not 8 Young AC, Saunders J, Ponsford JR. Mental change as an been tested in this study, could reveal an early early feature of multiple sclerosis. J Neurol Neurosurg Psychiatry 1976;39:1008-13. frontal abnormality. 9 Lyon-Caen 0, Jouvent R, Hauser S, et al. Cognitive Recent evidence was found of prominent function in recent onset . Arch Neurol 1986;43:1138-41. frontal release signs" early attentional distur- 10 Van den Burg W, Van Zomeren AH, Minderhoud JM, et al. bance,'8 and emotional symptoms'6 in MS Cognitive impairment in patients with multiple sclerosis and mild physical disability. Arch Neurol 1987;44: patients with mild physical disability. 494-501. SPECT, MRI and cognitivefunctions in multiple sclerosis 115 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.54.2.110 on 1 February 1991. Downloaded from

11 Franklin GM, Nelson LM, Filley CM, et al. Cognitive loss 31 Beatty WW, Goodkin DE, Monson N, et al. Cognitive in multiple sclerosis: Case reports and review of the disturbances in patients with relapsing remitting multiple literature. Arch Neurol 1989;46:162-7. sclerosis. Arch Neurol 1989;46:1113-9. 12 Rao SM, Glatt S, Hammeke TA, et al. Chronic progressive 32 Caine ED, Bamford KA, Schiffer RB, et al. A controlled multiple sclerosis: Relationship between cerebral veii- neuropsychological comparison of Huntington's disease tricular size and neuropsychological impairment. Arch and multiple sclerosis. Arch Neurol 1986;43:249-54. Neurol 1985;42:678-82. 33 Leonard JP, Nowotnik DP, Neirincks RD, et al. Tech- 13 Huber SJ, Paulson GW, Shuttleworth EC, et al. Magnetic netium-99m-d, 1-HM-PAO: a new radiopharmaceutical resonance imaging correlates of dementia in multiple for imaging regional brain perfusion using SPECT. A sclerosis. Arch Neurol 1987;44:732-6. comparison with iodine-123 HIPDM. J Nuci Med 1986; 14 Rao SM, Leo GJ, Haughton VM, et al. Correlation of 27:1819-23. magnetic resonance imaging with neuropsychological 34 Lucignani G, Perani D, Rossetti C, et al. Biodistribution and testing in multiple sclerosis. Neurology 1989;39:161-6. clinical evaluation of99m Tc HM-PAO: A tracer for CBF 15 Medaer R, Nelissen E, Appel B, et al. Magnetic resonance assessment by SPECT. J Cereb Blood Flow Metab 1987;7: imaging and cognitive functioning in multiple sclerosis. S538. J Neurol 1987;235:86-9. 35 Peters AM, Dampure HJ, Osman S, et al. Clinical 16 Reischies FM, Baum K, Brau H, et al. Cerebral magnetic experience with 99m Tc hexamethylpropyleneamine- resonance imaging findings in multiple sclerosis: Relation oxime for labelling leucocytes and imaging . to disturbance ofaffect, drive, and cognition. Arch Neurol Lancet 1986;ii:946-9. 1988;45:1114-6. 36 Broman T. Blood-brain barrier damage in multiple sclerosis: 17 Franklin GM, Heaton RK, Nelson LM, et al. Correlation of supravital test-observations. Acta Neurol Scand 1964;40 neuropsychological and MRI findings in chronic/progres- (Suppl 10):21-4. sive multiple sclerosis. Neurology 1988;38:1826-9. 37 Miller DH, Rudge P, Johnson G, et al. Serial gadolinium 18 Callananan MM, Logsdail SJ, Ron MA, et al. Cognitive enhanced magnetic resonance imaging in multiple impairment in patients with clinically isolated lesions of sclerosis. Brain 1988;111:927-39. the type seen in multiple sclerosis: A psychometric and 38 Bastianello S, Pozzilli C, Bernardi S, et al. Serial study of MRI study. Brain 1989;112:361-74. Gadolinium-DTPA MRI enhancement in multiple 19 Brooks DJ, Leenders KL, Head G, et al. Studies on regional sclerosis. Neurology 1990;40:591-5. cerebral oxygen utilization and cognitive function in 39 Frackowiak RSJ, Pozzilli C, Legg NJ, et al. Regional multiple sclerosis. JNeurol Neurosurg Psychiatry 1984;47: cerebral oxygen supply and utilization in dementia: A 1182-91. clinical and physiological study with oxygen-15 and 20 Bonte FJ, Ross ED, Chehabi HH, et al. SPECT study of positron tomography. Brain 1981;104:753-78. regional cerebral blood flow in Alzheimer's disease. 40 D'Antona R, Baron JC, Samson Y, et al. Subcortical J Comp Assist Tomogr 1986;10:579-83. dementia: Frontal cortex hypometabolism detected by 21 Perani D, Di Piero V, Vallar G, et al. Technetium-99m positron tomography in patients with progressive supra- HMPAO-SPECT study of regional cerebral perfusion in nuclear palsy. Brain 1985;108:785-99. early Alzheimer's disease. J Nucl Med 1988j29:1507-14. 41 Gofflinet AM, De Volder AG, Gillain C, et al. Positron 22 Burns A, Philpot MP, Costa DC, et al. The investigation of tomography demonstrates frontal lobe hypometabolism in Alzheimer's disease with single photon emission tomo- progressive supranuclear palsy. Ann Neurol 1989;25: graphy. J Neurol Neurosurg Psychiatry 1989;52:248-53. 131-9. 23 Schumacher GA, Beebe G, Kibler RF, et al. Problems of 42 Pantano P, Lenzi GL, Berardelli A, et al. Regional CBF experimental trials in therapy in multiple sclerosis. Ann pattern in patients with Huntington's disease. J Cereb NY Acad Sci 1965;122:552-68. Blood Flow Metab 1989;9:S22. 24 Poser CM, Paty DW, Scheinberg L, et al. New diagnostic 43 Hasselbach S, Andersen A, Sorensen S, et al. Regional criteria for multiple sclerosis: guidelines for research cerebral blood flow in Huntington's disease using SPECT protocols. Ann Neurol 1983;13:227-31. and 99m Tc-HMPAO. J Cereb Blood Flow Metab 1989;9: 25 Kurtzke JF. Rating neurologic impairment in multiple S350. sclerosis: an expanded disability status scale (EDSS). 44 Cummings JL, Benson DF. Subcortical dementia: review of Neurology 1983;33:1444-52. an emerging concept. Arch Neurol 1984;41:874-9. 26 Lezak MD. Neuropsychological assessment. New York: 45 Filley CF, Heaton RK, Nelson LM, et al. A comparison of Oxford University Press, 1987. dementia in Alzheimer's disease and multiple sclerosis. 27 Kaplan ED, Goodglass H, Weintraub S. Boston naming test. Arch Neurol 1989;46:157-61. Philadelphia: Lea and Febiger, 1983. 46 Herscovitch P, Trotter JL, Lemann W, et al. Positron 28 Koopmans RA, Li P, Grochowski E, et al. Benign versus emission tomography (PET) in active MS: Demonstration chronic progressive multiple sclerosis: Magnetic reso- of demyelination and diachisis. Neurology 1984;34 nance features. Ann Neurol 1989;25:74-81. (Suppl):78. 29 Ormerod IEC, Miller DH, McDonald WI, et al. The role of 47 Pozzilli C, Pantano P, Bozzao L, et al. Sequential computed NMR imaging in the assessment ofmultiple sclerosis and tomography and 123 I-HIPDM scans in multiple sclerosis isolated neurological lesions: a quantitative study. Brain with large plaque: A case report. Eur Neurol 1987;27: 1987;110:1579-616. 88-91. 30 Reinars SJ, Coffman CE, Smoker WRK, et al. MR imaging 48 Loewenstein DA, Barker WW, Chang JY, et al. Pre- of the corpus callosum: Normal and pathologic findings dominant left hemisphere metabolic dysfunction in and correlation with CT. AJNR 1988;9:649-56. dementia. Arch Neurol 1989;46:146-52. http://jnnp.bmj.com/ on September 29, 2021 by guest. Protected copyright.