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Normalization of rCBF pattern in senile dementia of the Alzheimer's type
Psvehiairv Research. 29 : 303 -306
303
Elsevier
Normalization of rCBF Pattern in Senile Dementia of the Alzheimer's Type Z . Mubrin, S . Knezevic, G . Spilich, J . Risberg, N . Gubarev, W . Wannenmacher, and G . Vucinic
Since no established treatment for any form of Alzheimer's disease presently exists, even partial improvement of the primary symptoms is a challenge . Our aim in this study was to assess the effect of a drug, pyritinol, on cognitive disturbance, and on regional cerebral blood flow (rCBF) in patients with senile dementia of the Alzheimer's type (SDAT) . Drug effects were tested by randomized double-blind crossover trial of pyritinol versus placebo with a treatment period of 10 weeks each for drug and placebo . Before treatment began, there was a 2-week washout phase for all patients during which they received one coated tablet of placebo containing 10 mg pyritinol, a dose that is known to be devoid of pharmacological effects . During treatment, the patients received either a dose of three 200-mg coated pyritinol tablets or three 10-mg coated placebo tablets which were identical in taste and appearance . At the beginning of the trial, 31 patients were included, 26 (6 men, 20 women) of whom finished the study, with a mean age of 76 .2 years (SD = 8 .0) . At the beginning . the patients were screened using DSM-III criteria, and those suffering from dementing disorders other than Alzheimer's disease were excluded by means of a detailed case history, ECG, and routine laboratory tests . Furthermore, CT scans were performed to exclude those in whom dementia might have developed as a result of another intracranial process . Additionally, patients suffering from the following conditions did not enter the trial : those with severe speech disorders, hearing defects, alcohol or drug abuse, schizophrenia or severe endogenous depression, seizure disorders, and stroke during the last 3 months . Beyond that, only patients with a Cognitive Disturbance Score of 9-24 in the SCAG and a score of 9-24 in the SKT were included . Thus, patients with a dementia of mild to moderate degree were investigated in whom the differential diagnosis of SDAT, multi-infarct dementia, and mixed cases was done using the modified Hachinski score of Rosen et al . (1980) . All patients were examined three times : after the 2 week washout phase, and after each of the two 10-week treatment periods . At these time points, psychiatric and neurological examinations as well as psychometric testing and rCBF measurements at rest and after mental activation were performed . For the rCBF measurements, standard 32-detector equipment (Inhalation Cerebrograph 32B, Novo Diagnostic Systems A/ S, Denmark) was used . For the first measurement, the patient rested for about 15 min, lying in the same supine position . The activation measurement was then performed as described by Mubrin et al . (1985) . For mental activation, a
Reprint requests to : Zdenko Mubrin, M .D ., Memory Center of the University Hospital Center, Y41000 Zagreb, Yugoslavia. 0165-1781/89/$0350 ® 1989
Elsevier Scientific Publishers Ireland Ltd .
304 slightly modified version of Word Pair Learning and Recall (WPLR), a subtest of the Wechsler Memory Scale, was used . Six highly related and six unrelated word pairs were presented three times by tape recorder during the second rCBF measurement . After each presentation, the word pairs were recalled aloud by the patient while rCBF was measured . Responding required no special effort since a microphone was built into the face mask assembly . Initial Slope Index (ISI), which is considered to be the most reliable parameter representing cortical blood flow, and originally defined by Risberg et al . (1975), was used for the analysis of the data . Arterial pCO2 was estimated from end-tidal recordings of expiratory CO, . Before treatment, no significant differences between patients and age-matched elderly normal controls were seen regarding pCO 2 . Resting cortical blood flow pattern showed the typical rCBF pathology of Alzheimer's disease : a focal decrease of flow mainly in the parietal and parietotemporal regions bilaterally . Mental activation revealed a significant increase in mean hemispheric values for both controls and SDAT patients (8-9%) with close to identical values for the two groups . However, a profound difference between patients and controls was found in the cortical pattern during mental activation (Fig . IA, Fig . IB) : SDAT patients showed a significant increase in 28 of 32 regions (14 R + 14 L) while the increase in the controls was only in 13 areas (5 R + 8 L) . Very important in this respect was the fact that the much larger area of flow increase in the SDAT group was associated with a significantly poorer WPLR performance . After treatment with placebo, the mean hemispheric blood flow at rest remained unchanged when compared to pretreatment, and the amplitude of the increase during activation diminished slightly . Furthermore, a diminished number of activated areas (23 ; 12 R + I I L) was found in the placebo group (Fig . IC) which was associated with a significant increase in WPLR performance compared to pretreatment conditions . After treatment with pyritinol, the resting blood flow level and pattern were unchanged . However, during mental activation much more pronounced changes were seen after the treatment with pyritinol than after placebo : The size of the area of significantly higher blood flow during activation diminished again (Fig . ID). In other words, a significantly smaller number (17 ; 9 R + 8 L) of activated regions was found in comparison to placebo, which again was accompanied by a significantly better WPLR performance when compared to the placebo group . This change to a more focal activation is considered to be a normalization since the controls showed the most pronounced focal pattern involving temporal and left central regions . The interpretation of the focalized activation during pyritinol treatment as a normalization is also supported by the significantly improved performance on the activation test . A coupling between poorer performance and more diffuse flow increase has been reported earlier and has been discussed recently (Maximilian and Brawanski, 1988) . Poorly performing patients struggle and try hard-and this effort is reflected as a large and global flow increase . On the other hand, when performance of the patients improves, the task becomes easier, less effort is needed for the solution, and this results in higher neuronal activity in fewer areas . In conclusion, these results clearly demonstrate the effect of pyritinol on disturbed cognitive functions, and on rCBF in SDAT patients .
305 Fig . 1 . Cerebral blood flow in controls and patients treated with pyritinol ACTIVATION PATTERN WPLR CONTROLS
SDAT
A
B
ACTIVATION PATTERN WPLR PLACEBO
C
PYRITINOL
D
Hatched areas are the regions where the flow was significantly higher during the activation
306 References Maximilian, V .A ., and Brawanski, A . Functional and vascular challenge procedures during noninvasive rCBF measurements . In : Knezevic, S . ; Maximilian, V .A . ; Mubrin, Z . ; Prohovnik, I . ; and Wade, J ., eds . Handbook of Regional Cerebral Blood Flow . Hillsdale, NJ-London : Lawrence Erlbaum Associates, 1988 . P . 79 . Mubrin, Z. ; Knezevic, S . ; Barac, B . ; Gubarev, N . ; Lazic, M . ; Liscic, R . ; and Vidosic, S . Distinct rCBF pattern during different types of short-term memory activation . In : Hartmann, A ., and Hoyer, S ., eds . Cerebral Blood Flow and Metabolism Measurement . Berlin : Springer Verlag, 1985. p. 81 . Risbcrg, J . ; Ali, Z . ; Wilson, E .M . ; Wills, E .L. ; and Halscy, J .H ., Jr . Regional cerebral blood flow by '»xenon inhalation : Preliminary evaluation of an initial slope index in patients with unstable flow compartments . Stroke, 6:142, 1975 . Rosen, W .G . ; Terry, R .D . ; Fuld, P .A . ; et al . Pathological verification of ischemic score in differentiation of dementias . Annals of Neurology, 7 :486, 1980 .
303
Elsevier
Normalization of rCBF Pattern in Senile Dementia of the Alzheimer's Type Z . Mubrin, S . Knezevic, G . Spilich, J . Risberg, N . Gubarev, W . Wannenmacher, and G . Vucinic
Since no established treatment for any form of Alzheimer's disease presently exists, even partial improvement of the primary symptoms is a challenge . Our aim in this study was to assess the effect of a drug, pyritinol, on cognitive disturbance, and on regional cerebral blood flow (rCBF) in patients with senile dementia of the Alzheimer's type (SDAT) . Drug effects were tested by randomized double-blind crossover trial of pyritinol versus placebo with a treatment period of 10 weeks each for drug and placebo . Before treatment began, there was a 2-week washout phase for all patients during which they received one coated tablet of placebo containing 10 mg pyritinol, a dose that is known to be devoid of pharmacological effects . During treatment, the patients received either a dose of three 200-mg coated pyritinol tablets or three 10-mg coated placebo tablets which were identical in taste and appearance . At the beginning of the trial, 31 patients were included, 26 (6 men, 20 women) of whom finished the study, with a mean age of 76 .2 years (SD = 8 .0) . At the beginning . the patients were screened using DSM-III criteria, and those suffering from dementing disorders other than Alzheimer's disease were excluded by means of a detailed case history, ECG, and routine laboratory tests . Furthermore, CT scans were performed to exclude those in whom dementia might have developed as a result of another intracranial process . Additionally, patients suffering from the following conditions did not enter the trial : those with severe speech disorders, hearing defects, alcohol or drug abuse, schizophrenia or severe endogenous depression, seizure disorders, and stroke during the last 3 months . Beyond that, only patients with a Cognitive Disturbance Score of 9-24 in the SCAG and a score of 9-24 in the SKT were included . Thus, patients with a dementia of mild to moderate degree were investigated in whom the differential diagnosis of SDAT, multi-infarct dementia, and mixed cases was done using the modified Hachinski score of Rosen et al . (1980) . All patients were examined three times : after the 2 week washout phase, and after each of the two 10-week treatment periods . At these time points, psychiatric and neurological examinations as well as psychometric testing and rCBF measurements at rest and after mental activation were performed . For the rCBF measurements, standard 32-detector equipment (Inhalation Cerebrograph 32B, Novo Diagnostic Systems A/ S, Denmark) was used . For the first measurement, the patient rested for about 15 min, lying in the same supine position . The activation measurement was then performed as described by Mubrin et al . (1985) . For mental activation, a
Reprint requests to : Zdenko Mubrin, M .D ., Memory Center of the University Hospital Center, Y41000 Zagreb, Yugoslavia. 0165-1781/89/$0350 ® 1989
Elsevier Scientific Publishers Ireland Ltd .
304 slightly modified version of Word Pair Learning and Recall (WPLR), a subtest of the Wechsler Memory Scale, was used . Six highly related and six unrelated word pairs were presented three times by tape recorder during the second rCBF measurement . After each presentation, the word pairs were recalled aloud by the patient while rCBF was measured . Responding required no special effort since a microphone was built into the face mask assembly . Initial Slope Index (ISI), which is considered to be the most reliable parameter representing cortical blood flow, and originally defined by Risberg et al . (1975), was used for the analysis of the data . Arterial pCO2 was estimated from end-tidal recordings of expiratory CO, . Before treatment, no significant differences between patients and age-matched elderly normal controls were seen regarding pCO 2 . Resting cortical blood flow pattern showed the typical rCBF pathology of Alzheimer's disease : a focal decrease of flow mainly in the parietal and parietotemporal regions bilaterally . Mental activation revealed a significant increase in mean hemispheric values for both controls and SDAT patients (8-9%) with close to identical values for the two groups . However, a profound difference between patients and controls was found in the cortical pattern during mental activation (Fig . IA, Fig . IB) : SDAT patients showed a significant increase in 28 of 32 regions (14 R + 14 L) while the increase in the controls was only in 13 areas (5 R + 8 L) . Very important in this respect was the fact that the much larger area of flow increase in the SDAT group was associated with a significantly poorer WPLR performance . After treatment with placebo, the mean hemispheric blood flow at rest remained unchanged when compared to pretreatment, and the amplitude of the increase during activation diminished slightly . Furthermore, a diminished number of activated areas (23 ; 12 R + I I L) was found in the placebo group (Fig . IC) which was associated with a significant increase in WPLR performance compared to pretreatment conditions . After treatment with pyritinol, the resting blood flow level and pattern were unchanged . However, during mental activation much more pronounced changes were seen after the treatment with pyritinol than after placebo : The size of the area of significantly higher blood flow during activation diminished again (Fig . ID). In other words, a significantly smaller number (17 ; 9 R + 8 L) of activated regions was found in comparison to placebo, which again was accompanied by a significantly better WPLR performance when compared to the placebo group . This change to a more focal activation is considered to be a normalization since the controls showed the most pronounced focal pattern involving temporal and left central regions . The interpretation of the focalized activation during pyritinol treatment as a normalization is also supported by the significantly improved performance on the activation test . A coupling between poorer performance and more diffuse flow increase has been reported earlier and has been discussed recently (Maximilian and Brawanski, 1988) . Poorly performing patients struggle and try hard-and this effort is reflected as a large and global flow increase . On the other hand, when performance of the patients improves, the task becomes easier, less effort is needed for the solution, and this results in higher neuronal activity in fewer areas . In conclusion, these results clearly demonstrate the effect of pyritinol on disturbed cognitive functions, and on rCBF in SDAT patients .
305 Fig . 1 . Cerebral blood flow in controls and patients treated with pyritinol ACTIVATION PATTERN WPLR CONTROLS
SDAT
A
B
ACTIVATION PATTERN WPLR PLACEBO
C
PYRITINOL
D
Hatched areas are the regions where the flow was significantly higher during the activation
306 References Maximilian, V .A ., and Brawanski, A . Functional and vascular challenge procedures during noninvasive rCBF measurements . In : Knezevic, S . ; Maximilian, V .A . ; Mubrin, Z . ; Prohovnik, I . ; and Wade, J ., eds . Handbook of Regional Cerebral Blood Flow . Hillsdale, NJ-London : Lawrence Erlbaum Associates, 1988 . P . 79 . Mubrin, Z. ; Knezevic, S . ; Barac, B . ; Gubarev, N . ; Lazic, M . ; Liscic, R . ; and Vidosic, S . Distinct rCBF pattern during different types of short-term memory activation . In : Hartmann, A ., and Hoyer, S ., eds . Cerebral Blood Flow and Metabolism Measurement . Berlin : Springer Verlag, 1985. p. 81 . Risbcrg, J . ; Ali, Z . ; Wilson, E .M . ; Wills, E .L. ; and Halscy, J .H ., Jr . Regional cerebral blood flow by '»xenon inhalation : Preliminary evaluation of an initial slope index in patients with unstable flow compartments . Stroke, 6:142, 1975 . Rosen, W .G . ; Terry, R .D . ; Fuld, P .A . ; et al . Pathological verification of ischemic score in differentiation of dementias . Annals of Neurology, 7 :486, 1980 .