Effects of long-term Donepezil therapy on rCBF of Alzheimer's patients.

BACKGROUND: The recent introduction of acetylcholinesterase inhibitors (AChEIs) therapy for Alzheimer's Disease (AD) has led to the need to assess the brain's response to the therapy on an objective, neurophysiological basis. Brain perfusion single photon emission computed tomography (SPECT) was used in an open-label study to evaluate the effect of chronic Donepezil administration to a group of patients affected by mild to moderate AD, compared to a group of AD patients not receiving AChEIs and kept under observation for a similar period. METHODS: Twenty-five consecutive patients with probable AD (National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria) (19 women, 6 men; mean age: 74.2+/-7.2; mean Mini-Mental State Examination score, MMSE: 19.8+/-3.5) underwent (t0) brain SPECT with 99mTc-hexamethylpropylene-amine-oxime by a brain-dedicated, high-resolution camera and were re-evaluated (t1) after 11+/-2.6 months of chronic Donepezil administration (5mg/day) (treated group). Thirteen AD patients (9 women, 4 men, mean age: 71.4+/-5.7, MMSE score: 20.6+/-3.5) were not treated with AChEIs and served as controls (untreated group). They were subjected to the same evaluation after 13+/-1.4 months as the treated group. Statistical parametric mapping (SPM) was employed to analyse SPECT findings. RESULTS: The MMSE score declined significantly (P<0.01) from t0 to t1 both in untreated (from 20.6+/-3.5 to 17.8+/-4.4) and in treated (from 19.8+/-3.5 to 17.8+/-4.1) group. At t(0), the untreated group showed higher regional cerebral blood flow (rCBF) than the treated group in a frontal and a frontal-parietal region of the left hemisphere. Between t0 and t1, significant rCBF reduction was observed in the temporal lobe and occipital-temporal cortex of the left hemisphere in the untreated group, whereas no significant change was observed in the treated group. The rCBF of the two groups did not significantly differ at t1. By covariate SPM analysis between t0 and t1 in treated patients, MMSE score changes correlated significantly with rCBF changes in a large left frontal-temporal region. CONCLUSIONS: Brain perfusion is preserved in AD patients undergoing chronic Donepezil therapy while it is reduced in untreated patients. SPECT is a promising tool with which to assess the impact of AChEI therapy on brain functioning of AD patients.     

Resting SPECT-neuropsychology correlation in very mild Alzheimer's disease.

OBJECTIVE: To investigate the relationships between brain function and some of the most frequently impaired cognitive domains in the first stages of Alzheimer's disease (AD), we searched for correlation between the scores on 3 neuropsychological tests and brain perfusion, assessed by single photon emission computed tomography (SPECT) in patients with very mild AD. METHODS: Twenty-nine consecutive outpatients (mean age 78.2+/-5.5) affected by probable AD in the very mild phase (i.e. with a score > or =20 on the mini-mental state examination, MMSE) underwent brain SPECT with (99m)Tc-ethylcisteinate dimer. For correlative purposes, word list learning (by the selective reminding test, SRT), constructional praxis test (CPT) and visual search test (VST) were chosen a priori out of an extended battery employed to diagnose AD at first patient evaluation. Voxel-based correlation analysis was achieved by statistical parametric mapping (SPM99) with a height threshold of P=0.005. Age, years of education and the MMSE score were inserted in the correlative analysis as confounding variables. RESULTS: The SRT score showed correlation with brain perfusion in 3 clusters of the left hemisphere, including the post-central gyrus, the parietal precuneus, the inferior parietal lobule and the middle temporal gyrus, and in one cluster in the right hemisphere including the middle temporal gyrus and the middle occipital gyrus. The CPT score was significantly correlated with brain perfusion in the parietal precuneus and the posterior cingulate gyrus in the left hemisphere, whereas the VST score gave a significant correlation with brain perfusion in a left cluster including the parietal precuneus and the superior temporal gyrus. CONCLUSIONS: Cognitive impairment in very mild AD is reflected by brain dysfunction in posterior associative areas, with peculiar topographical differences proper of each domain. The parietal precuneus was a common site of correlation of all 3 neuropsychological tests. This region, together with the posterior cingulate and the superficial posterior temporal-parietal cortex, is thought to be affected by disconnection from the mesial temporal lobe, besides being directly affected by increased oxidative stress and by atrophy as well. The impairment of these areas is thought to contribute to cognitive decline in verbal memory, constructional praxis and visual sustained attention which are indeed among the earliest signs of cognitive impairment in AD. SIGNIFICANCE: Assessing the relationships between neuropsychology and brain functional imaging is a key approach to clarify the pathophysiology of cognitive failure in AD; the specificity of these findings in AD remains to be proven through comparison with correlation achieved in matched controls.     

Quantitative EEG and perfusional single photon emission computed tomography correlation during long-term donepezil therapy in Alzheimer's disease.

OBJECTIVE: There is an increasing interest in the effects of the acetylcholinesterase inhibitors (AChEIs) in Alzheimer's disease (AD), as investigated by means of objective, neurophysiological tools. In an open-label study, we evaluated the neurophysiological effects of chronic administration of donepezil to AD patients, by means of a correlative approach between quantitative EEG (qEEG) and perfusional brain single photon emission computed tomography (SPECT). METHODS: Sixteen patients (mean age: 74.8+/-7.9 years) with mild to moderate AD (MMSE score >13, mean: 20.7+/-4.6) underwent qEEG and SPECT examinations at the time of diagnosis (t0) and after approximately 1 year of donepezil therapy (t1). The brain SPECT (99mTc-hexamethylpropyleneamine oxime) was performed by means of a high-resolution SPECT camera; the qEEG was recorded from 19 scalp electrodes by average reference and digitized at 512 Hz. The mean frequency (MF) value of the mean power spectrum (fast Fourier transform) from 4 brain regions (one frontal and one temporal-parietal in each hemisphere) was chosen for statistical analysis. Changes in MMSE score and qEEG-MF values between t0 and t1 were assessed by analysis of variance. SPECT differences between t0 and t1, as well as the relationships between SPECT and qEEG changes, were assessed by statistical parametric mapping (SPM 99; height threshold: P=0.001 at cluster level). RESULTS: Between t0 and t1, the MMSE score significantly (P<0.05) decreased (from 20.7+/-4.64 to 19.1+/-5.09; 95% confidence interval: 1.14) and qEEG was unchanged. There was no regional perfusion decrease; a small area of relative perfusion increase was observed, including the right occipital cuneus and the left lingual gyrus. A positive correlation was found between the right frontal MF and brain perfusion in the left superior parietal lobule. A post hoc SPM analysis (height threshold: P=0.01) showed a positive correlation between brain perfusion and each of the 4 qEEG MF values in the left parietal lobe, including the precuneus, the superior parietal lobule, and the post-central gyrus. CONCLUSIONS: The posterior parietal region, which is involved in memory and attention, is often affected by hypoperfusion in AD, as a likely consequence of disconnection from the atrophic mesial temporal cortex. Metabolic activation induced by AChEIs may especially influence this disconnected but still not grossly impaired area, which could be one of the pathophysiological substrates of the cognitive effects of AChEIs. The modest topographical sensitivity of qEEG, reflecting the rather diffuse changes in AD, is further confirmed.     

Hippocampal perfusion and pituitary-adrenal axis in Alzheimer's disease

The hippocampus is involved in Alzheimer's disease (AD) and regulates the hypothalamus-pituitary-adrenal axis (HPAA). Enhanced cortisol secretion has been reported in AD. Increased cortisol levels affect hippocampal neuron survival and potentiate beta-amyloid toxicity. Conversely, dehydroepiandrosterone (DHEA) and its sulfate (DHEAS) are believed to antagonize noxious glucocorticoid effects and exert a neuroprotective activity. The present study was aimed at investigating possible correlations between hippocampus perfusion - evaluated by SPECT - and HPAA function in AD. Fourteen patients with AD and 12 healthy age-matched controls were studied by (99m)Tc-HMPAO high-resolution brain SPECT. Plasma adrenocorticotropin, cortisol, and DHEAS levels were determined at 2.00, 8.00, 14.00, 20.00 h in all subjects and their mean values were computed. Cortisol/DHEAS ratios (C/Dr) were also calculated. Bilateral impairment of SPECT hippocampal perfusion was observed in AD patients as compared to controls. Mean cortisol levels were significantly increased and DHEAS titers were lowered in patients with AD, as compared with controls. C/Dr was also significantly higher in patients. Using a stepwise procedure for dependent SPECT variables, the variance of hippocampal perfusional data was accounted for by mean basal DHEAS levels. Moreover, hippocampal SPECT data correlated directly with mean DHEAS levels, and inversely with C/Dr. These data show a relationship between hippocampal perfusion and HPAA function in AD. Decreased DHEAS, rather than enhanced cortisol levels, appears to be correlated with changes of hippocampal perfusion in dementia.     

Behavioral and psychological symptoms in Alzheimer's disease. Relation between apathy and regional cerebral perfusion

Fundamental and therapeutic research in Alzheimer's disease (AD) focused for a long time exclusively on cognitive aspects. However, AD also frequently involves complex disorders of affect and behavior, which are currently grouped under the heading 'behavioral and psychological signs and symptoms of dementia' (BPSSD). Several rating tools have been developed over the years on the basis of a variety of source data. Some are derived from psychiatric practise or have specifically been developed for dementia, such as the Neuropsychiatric Inventory (NPI). In this study we prospectively used the NPI to examine BPSSD. Sixty-three French patients (mean age 74.7 years, SD 7.9) with a Mini-Mental State Examination (MMSE) score higher than 10 were examined. BPPSD were detected by NPI in 95. 2% of the patients. Anxiety was the most common abnormality (65.1%), followed by apathy and dysphoria (58.7%). The highest frequency x severity NPI score was observed for apathy. In order to identify the relationship between regional cerebral perfusion and apathy, 20 of these AD patients underwent a technetium-99m-bicisate SPECT protocol within the same week as the NPI evaluation. The mean age of this population was 74.4 years (SD 5.3) and the mean MMSE score was 21 (SD 4.1). The apathy NPI score was correlated with right cingulate deficit whereas the highest correlation for the MMSE was with the left temporoparietal area. This stresses the interest to focus on SPECT imaging of AD patients not only in the posterior areas. CopyrightCopyright 1999S.KargerAG,Basel     

Predictive utility of apolipoprotein E genotype for Alzheimer disease in outpatients with mild cognitive impairment

BACKGROUND: In cognitively impaired patients without dementia, the utility of apolipoprotein E (APOE) genotyping is unclear. OBJECTIVE: To evaluate the predictive utility of the APOE epsilon4 genotype for conversion to probable Alzheimer disease (AD). DESIGN: Naturalistic, longitudinal study. SETTING: Memory disorders outpatient clinic. PATIENTS: A total of 136 patients with memory complaints were determined to have mild cognitive impairment and were evaluated every 6 months. Fifty-seven age- and sex-matched healthy controls were evaluated annually. MAIN OUTCOME MEASURES: Primary outcome measures included conversion to AD. Secondary outcome measures included change over time in Mini-Mental State Examination (MMSE) score and Selective Reminding Test (SRT) delayed recall score. RESULTS: The APOE epsilon4 allele was present in 25% of patients and 21% of healthy controls. During a mean +/- SD follow-up of 35.2 +/- 24.3 months, 35 of 136 patients converted to AD. APOE epsilon4 carrier status did not differ between converters (31%) and nonconverters to AD (23%, P = .3) and did not affect the time trend in MMSE or SRT scores in the entire sample. Four of 5 APOE epsilon4 homozygotes converted to AD compared with 7 of 29 heterozygotes (P = .02). In a Cox proportional hazards model stratified by age quartiles, after controlling for sex, education, MMSE score, and SRT delayed recall score, APOE epsilon4 increased the risk of AD in patients 70 to 85 years old (n = 57; risk ratio, 2.77; 95% confidence interval, 1.1-7.3; P = .03) but not in patients 55 to 69 years old (n = 79; P = .7). CONCLUSIONS: APOE epsilon4 carrier status was associated with conversion to AD in older outpatients after controlling for known demographic and clinical risk factors, and APOE epsilon4 homozygosity was associated with increased risk of conversion to AD. However, APOE epsilon4 carrier status by itself did not predict cognitive decline or conversion to AD, indicating that APOE genotyping in patients with mild cognitive impairment may have limited clinical applicability for prediction of outcome.     

Negative symptoms, depression and Alzheimer's disease

OBJECTIVES: To apply the negative symptoms (NS) concept used in schizophrenia to patients with AD, to compare the results with the frontal lobe perfusion in ethyl cysteinate dimmer (ECD) single-photon emission computed tomography (SPECT) and with the apolipoprotein E genotype. METHOD: 32 patients with a diagnosis of probable AD were assessed by the Positive and Negative Symptoms Scale (PANSS-N), the Montgomery and Asberg Depression Scale (MADRS), the NeuroPsychiatric Inventory (NPI), and the Mini-Mental Status Examination (MMSE). Each patient underwent ECD SPECT and APO E genotyping. PANSS-N, MADRS, NPI, and MMSE were administered to 19 normal elderly control subjects. RESULTS: The mean PANSS-N score for AD patients (20.56, SD: 8, range: 7-40) was significantly higher (p < 0.001) than that of controls (7, SD: 0). MADRS scores were not significantly different (p = 0.75) between AD patients (9.03, SD: 6.14, range: 0-25) and controls (6.2, SD: 3.61, range: 1-15). The NPI apathy score (0-12) was correlated with PANSS-N (p < 0.001). Correlation between prominent frontal hypoperfusion (six cases) and NS was at the limit of significance. No relation was found between epsilon E4 and NS. CONCLUSION: This consideration is important in distinguishing between depression and AD.     

Correlation of the cognitive function and the duration of the illness with the regional cerebral blood flow in the patients with Parkinson's disease: objective evaluation using stereotactic extraction estimation analysis in 123I-IMP SPECT]

OBJECTIVE: To investigate the correlation of the cognitive function and the duration of the illness with the regional cerebral blood flow (rCBF) in patients with Parkinson's disease (PD), by means of an objective diagnostic index of brain imaging, stereotactic extraction estimation (SEE) of 123I-IMP SPECT. PATIENTS AND METHODS: We examined 123I-IMP SPECT in 24 patients with PD (age = 71.79 +/- 5.18 years; the Mini-Mental State Examination: MMSE score = 21.46 +/- 7.62 points; the duration of the illness = 6.63 +/- 3.91 years; Yahr scale = 3.29 +/- 0.74). A contrast database was created by averaging extracted database sets of the contrast group (numbers = 14 cases; age = 74.64 +/- 5.99 years, the MMSE score > or = 29 points). We applied SEE for Z-score images of three-dimensional stereotactic surface projection analysis (3D-SSP) for 123I-IMP SPECT, and calculated Z*extent ratio by taking advantage of severity of Z-score (the mean value) with extent ratio (%) in the frontal, occipital, temporal, parietal and posterior cingulate cortices, and precuneus, respectively. We investigated the correlation coefficient between the MMSE score and Z*extent ratio, and between the duration of the illness and Z*extent ratio in the six regions. In addition, we compared Z*extent ratio in the six regions between the non-demented group (numbers = 12 patients; MMSE > or = 24 points) and the demented group (numbers =12 patients; E score < or = 23 points). RESULTS: There were negative correlations between the MMSE score and Z*extent ratio in the temporal (p < 0.05) and posterior cingulate cortices (p < 0.05), and positive correlations between the duration of the illness and Z*extent ratio in the frontal (p < 0.01), temporal (p < 0.01), parietal (p < 0.05) and posterior cingulate cortices (p < 0.01). Z*extent ratio was significantly high only in the posterior cingulate cortex(p < 0.05) in the demented group. CONCLUSIONS: SEE for Z-score images of 3D-SSP revealed a close relationship between the decline of the MMSE score and the duration of the illness, and the perfusion reduction of the posterior cingulate cortex in patients with PD. These findings suggest that the perfusion reduction of the posterior cingulate cortex reflects the decline of cognitive impairment of patients with PD.     

Quantitative EEG changes in Alzheimer patients during long-term donepezil therapy

Twenty patients affected with probable mild-to-moderate Alzheimer's disease (AD; NINCDS-ADRDA criteria; 14 women and 6 men, mean age 75.2 +/- 7.1 years) who regularly received an oral acetylcholinesterase inhibitor (AChEI; donepezil 5 mg/day; Dz group) were compared with a control group of 11 AD patients (6 women and 5 men, mean age 73.5 +/- 6.0 years) diagnosed and followed up in the pre-AChEIs era (C group). At basal evaluation (t(0)), the 2 groups were comparable for age, education, and severity of disease (Global Deterioration Scale). All patients underwent quantitative EEG (qEEG, average reference, 10-20 International System), and were reexamined about 1 year later (t(1); i.e., after 12.3 +/- 3.6 months the Dz group, and after 13.7 +/- 3.9 months the C group). Log-transformed values of two qEEG bands, i.e. 2-6 and 6.5-12 Hz, were averaged between adjacent channels (frontal F3 and F7, F4 and F8; parietotemporal P3 and T7, P4 and T8) to obtain a qEEG ratio (6.5-12/2-6 Hz.) from one frontal and one temporoparietal region in each hemisphere. Neuropsychological impairment was summarized by the Mini-Mental Status Examination (MMSE). At t(0), both the MMSE score and the qEEG ratio values were somewhat higher in the C than in the Dz group, although nonsignificantly. Between t(0) and t(1), the MMSE score decreased significantly (p < 0.01) more in the C group (-4.36 +/- 2.25) than in the Dz group (-1.45 +/- 2.16), as did the qEEG ratio in the right frontal region (p < 0.01), whereas in the left frontal region the significance level was not reached (p = 0.02). Between t(0) and t(1), the qEEG ratio difference in both frontal regions and in the right temporoparietal region significantly correlated with the MMSE difference (p < 0.01), but neither with time between examinations nor with the difference on the Visual Search Test score. Long-term treatment with Dz led to a lesser deterioration of qEEG, paralleling a milder neuropsychological decline. The effect was significant in frontal regions, possibly because they are relatively spared during the mild-to-moderate phases of the disease.     

A SPECT study of wandering behavior in Alzheimer's disease

BACKGROUND: Among behavior disturbance during Alzheimer's disease (AD), wandering is one of the most common. Different psychological processes have been suggested to explain the wandering behavior. The aim of this study was to examine whether wandering during AD was associated with cerebral perfusion patterns measured by (99 m)Tc-labeled bicisate (ECD) brain SPECT. METHODS: We compared SPECT scans of 13 AD subjects with wandering behavior (sex ratio M/F, 4/9; age, 73.1 years, SD 7.4; Mini Mental Status Examination score, median 20 interquartile range [16-23]), 13 AD subjects without wandering behavior (matched for age [ +/- 2 years], sex and MMSE score [ +/- 2 points]) and 13 healthy controls (matched for age [ +/- 2 years] and sex) without cognitive impairment. Wandering was defined on the Neuro-Psychiatric Inventory. Score of leukoaraiosis, assessed with the scale of Blennow and number of lacuna infarction were compared on CT scan. SPECT imaging was compared using statistical parametric mapping (SPM 2). RESULTS: There were no significant differences between the groups in term of educational level and CT scan analysis. SPECT imaging was consistent with the diagnosis of AD in both wanderers and AD subjects without wandering behavior. Despite similar clinical dementia severity, wanderers had more severely reduced regional cerebral blood flow (rCBF) in the left parietal-temporal lobe than AD subjects without wandering behavior. CONCLUSION: Wandering behavior could be facilitated by a specific patterns of cerebral blood flow. Wandering, as a physical activity, could also enhance the recruitment of the cortical network.     

A SPECT study of apathy in Alzheimer's disease

BACKGROUND/AIMS: To assess the association between regional cerebral blood flow (rCBF) and apathy in Alzheimer's Disease (AD). METHODS: SPECT and MRI scans were obtained from 51 nondepressed outpatients meeting criteria for probable AD (age 77.6 +/- 6.6 years; MMSE 22.3 +/- 5.1; 23 apathetic, 28 nonapathetic) and 23 healthy elderly (75.6 +/- 3.8 years) controls. The following regions of interest (ROIs) were compared between apathetic and nonapathetic AD patients and then referenced against aged controls: anterior cingulate, orbitofrontal cortex, middle medial temporal cortex, hippocampus, medial superior temporal cortex, thalamus/hypothalamus and pons. RESULTS: Apathetic and nonapathetic patients had significant differences in rCBF. Relative to nonapathetic AD patients, apathetic AD patients had lower perfusion in 2 ROIs (right orbitofrontal cortex and left anterior cingulate) and higher perfusion in 5 ROIs (right and left hippocampi, left medial superior temporal gyrus, and right and left middle medial temporal cortex). Comparison of rCBF in these 7 ROIs to healthy elderly controls confirmed hypoperfusion in the left anterior cingulate and right orbitofrontal cortex and suggested a relative sparing of perfusion among apathetic AD patients in the remaining 5 ROIs. CONCLUSIONS: In this group of nondepressed patients with AD, apathetic subjects displayed significant perfusion differences compared to nonapathetic subjects.     

Correlation of neuropsychological evaluation and SPECT imaging in patients with Alzheimer's disease

BACKGROUND: Mini-Mental State Examination (MMSE) is a very useful tool for diagnosing changes in cognitive functions by the general practitioner or other medical staff who is not familiar with neuropsychological tests. On the other hand, HMPAO brain SPECT has been shown to have a high sensitivity to detect neurodegenerative processes, which lead to dementia. The correlation between both methods is unknown. We compared both methods in order to find a rational evaluation tool for the practitioner to obtain a higher efficacy and cost effective way of using both methods. PATIENTS AND METHODS: Fifty-one patients diagnosed as having Alzheimer's disease (AD) were examined. Each patient underwent MMSE analysis, as well as HMPAO brain SPECT. The severity of SPECT abnormalities was categorized into mild, moderate and severe. Statistical analysis was performed in order to evaluate the correlation between imaging findings and neuropsychological testing. RESULTS: Marginal inverse correlation was found between global MMSE SPECT imaging on right and left side (p = 0.05) and the left temporal region (p = 0.05). MMSE subgroup component of orientation was highly significantly inversely associated with SPECT imaging of right and left frontal region (p > 0.0001). The MMSE subgroup of immediate memory was significantly correlated to left and right temporal regions (p = 0.001 and p = 0.002 respectively). Age was not significantly correlated to global MMSE or any of its subtest components. CONCLUSION: MMSE score has no linear correlation to SPECT perfusion findings. In cases of abnormal orientation score subgroup SPECT imaging is not recommended. In most instances, a combination of both methods should be employed by the general practitioner for further evaluation of dementia.     

Absence of cerebrospinal fluid oligoclonal bands is associated with delayed disability progression in relapsing-remitting MS patients treated with interferon-beta

To determine whether combined studies of Mini-Mental State Examination (MMSE) and brain single photon emission CT (SPECT) would provide more useful means of differentiating between dementia with Lewy bodies (DLB) and Alzheimer's disease (AD), we studied 36 patients with probable DLB and 96 patients with probable AD. DLB patients had significantly better performance on word recall, but more impaired attention and copying than AD patients. We confirmed that a weighted score derived by Ala et al. [Ala, T.A., Hughes, L.F., Kyrouac, G.A., Ghobrial, M.W., Elble, R.J. The Mini-Mental State exam may help in the differentiation of dementia with Lewy bodies and Alzheimer' disease. Int J Geriatr Psychiatry 2002;17:503–9]: (Attention − 5/3 · Memory + 5 · Construction), was helpful in discriminating between DLB and AD. SPECT study revealed that medial occipital perfusion significantly decreased in DLB patients than AD patients. Combined studies of MMSE and brain SPECT achieved a high discrimination between DLB and AD with a sensitivity of 81% and a specificity of 85%, suggesting that there is a useful and practical approach to differentiate DLB from AD. Our findings will need to be substantiated in an independent and prospective study sample.     

Utility of (99m)Tc-HM-PAO SPECT hippocampal image to diagnose early stages of Alzheimer's disease using semiquantitative analysis

OBJECTIVE: Examination of the utility of (99m)Tc-hexamethylpropylene amine oxide ((99m)Tc-HM-PAO) SPECT hippocampal image to diagnose early stages of Alzheimer's disease (AD) using semiquantitative analysis. SUBJECTS: 10 early-stage AD patients and 8 normal sex-matched elderly controls. SETTING: Outpatient division of the Ehime University Hospital. METHOD: We performed (99m)Tc-HM-PAO SPECT perfusion imaging in each subject. A semiquantitative method of assessing regional variation was used. The regions of interest for temporal regions were set at images parallel to the long axis of the hippocampal formation which were reconstructed at 30 degrees negative to the orbitomeatal line and those for other regions were set on ordinary transaxial images. RESULTS: The regional cerebral blood flow ratio of the bilateral medial temporal lobe at the hippocampal image was significantly lower in the AD subjects than in the normally aged controls without any other differences in ordinary transaxial images. CONCLUSION: This study suggests that (99m)Tc-HM-PAO SPECT hippocampal images might be a helpful tool for the diagnosis of very-early-stage AD.     

Cerebral perfusional effects of cholinesterase inhibitors in Alzheimer disease

Cholinesterase (ChE) inhibitors improve or stabilize cognitive impairment in patients with Alzheimer disease (AD). However, the regional metabolic and perfusion correlates of treatment with ChE inhibitors are not fully known. Twenty-four patients with mild to moderate AD were evaluated with Tc-ethyl cysteinate dimer (ECD) single-photon-emission CT scanning (SPECT), before and after 4.3 +/- 1.1 months of treatment with ChE inhibitors (donepezil, rivastigmine). Clinical evaluations included the Mini-Mental State Examination (MMSE) as well as the Neuropsychiatric Inventory (NPI). Inclusion criterion was a clear favorable response to therapy with ChE inhibitors (MMSE improvement of at least 2 points; total NPI improvement of at least 4 points). SPECT data were analyzed by Statistical Parametric Mapping (SPM 99, Wellcome, Department of Cognitive Neurology, London, UK). SPM analysis showed a significant increase (P < 0.01) of regional cerebral perfusion (rCBF) after short-term ChE inhibitor therapy with respect to baseline in the right anterior cingulate, the dorsolateral prefrontal, and the temporoparietal areas bilaterally. These data suggest that cognitive or behavioral benefits after ChE inhibitor therapy are related to a clear increase of rCBF in crucial areas specifically involved in the attentional and limbic networks.     

Test-retest variability and reliability of 123I-IBZM SPECT measurement of striatal dopamine D2 receptor availability in healthy volunteers and influence of iterative reconstruction algorithms

OBJECTIVE: 123I-IBZM single photon emission computed tomography (SPECT) is a widely used method to measure D(2) receptor availability. However, test-retest variability and reliability have not been reported yet. This study aimed to further characterize 123I-IBZM SPECT in healthy volunteers (HVs), by assessing (1) pseudoequilibrium interval after bolus injection; (2) normal specific uptake ratio (SUR) values using filtered-backprojection (FBP); and the iterative reconstruction algorithm ordered-subsets expectation maximization (OSEM); (3) test-retest variability and reliability (intraclass correlation coefficient); and (4) influence of OSEM on test-retest variability and reliability. METHODS: Ten HVs (Group A) were scanned twice 48 h apart for test-retest variability and reliability measurements, and n = 4 of them were sequentially scanned over time. Eighteen HVs (Group B) were scanned once at pseudoequilibrium. For reconstruction FBP was used. Test-retest scans were reconstructed in addition using OSEM. SPECT-MRI coregistration was used for region of interest drawing. RESULTS: Pseudoequilibrium was achieved at 90 min postinjection (p.i.) and maintained until the end of the SPECT session (n = 4), and mean SUR at this time point was 0.96 +/- 0.14 (Groups A + B, n = 28). Mean SUR at test was 0.96 +/- 0.19 and at retest 0.94 +/- 0.19 (Group A, n = 10). Using FBP, test-retest variability was (12.7 +/- 9.6)% and reliability was 0.74. Using OSEM with 18 equivalent iterations, test-retest variability and reliability were improved to (6.5 +/- 5.2)% and 0.84, respectively. CONCLUSIONS: 123I-IBZM SPECT imaging using the bolus injection and a single scan at 90 min p.i. is a reproducible method showing acceptable test-retest variability and reliability. Test-retest variability and reliability can be substantially improved using OSEM with 12-36 equivalent iterations.     

Effects of carotid endarterectomy on cerebral blood flow and neuropsychological test performance in patients with high-grade carotid stenosis

We examined the changes in cognitive function following carotid endarterectomy (CEA) in relation to the cerebral blood flow (CBF) in patients with high-grade carotid stenosis. The subjects consisted of 23 patients who underwent CEA and 17 controls matched by age and education. Single photon emission computed tomography (SPECT) and neuropsychological tests were performed 2 weeks before and 4 weeks after CEA in all patients. The preoperative CBF tests revealed a decreased vasodilatory reserve in the ipsilateral cerebral hemisphere in nine patients, which was increased after CEA. In these patients, the grade of carotid stenosis was significantly higher than in those with a normal perfusion reserve (90.2+/-8.1% vs. 78.6+/-11.3%, respectively, p<0.05). In the patient group, the postoperative scores (27.2+/-2.9) of the mini-mental state examination (MMSE) improved significantly over the preoperative ones (26.1+/-3.2, p<0.05). Moreover, the scores in the block-design test after CEA (86.8+/-19.8) were significantly higher than those before the operation (81.8+/-22.3, p<0.01). The error score in immediate retention improved from 9.0+/-3.1 to 7.7+/-4.0 following CEA (p<0.05). In the control group, none of the test scores showed significant improvement between the first and second tests. In the patients with an impaired vasodilatory reserve, the mean score of the block-design test significantly improved from 65.6+/-22.1 to 74.0+/-19.2 after CEA compared with those in patients without impairment (p<0.05). High-grade carotid stenosis was thus concluded to cause cognitive impairment due to cerebral hemodynamic failure, which is presumably reversed by CEA.     

An observational clinical study of the efficacy and tolerability of donepezil in the treatment of Alzheimer's disease

An open-label, observational Post-Marketing Surveillance (PMS) study was undertaken in Germany to examine the efficacy and tolerability of donepezil in routine clinical practice. Alzheimer's disease (AD) patients were treated with donepezil (5 or 10 mg once daily) and observed for a period of approximately 3 months. Study assessments included the Mini-Mental State Examination (MMSE), the Nurses' Observation Scale for Geriatric Patients (NOSGER), and adverse events (AEs). A total of 2,092 patients (mean age 73.0 years; mean +/- SD MMSE score 17.8 +/- 5.8) were included in the efficacy assessments. MMSE and NOSGER scores showed statistically significant improvements in the total patient population and in the subpopulations with severe AD or AD with concomitant Parkinsonian symptoms (ADPS cohort). AEs were reported in a total of 12% of patients and were mostly due to peripheral cholinergic effects. In this observational PMS study, donepezil was shown to be an effective and well-tolerated therapy in the overall patient population, in patients with severe AD, and in the ADPS cohort.     

Presenilin-1-associated abnormalities in regional cerebral perfusion

OBJECTIVE: To investigate the influence of the presenilin-1 gene (PS-1) mutation on regional cerebral perfusion, SPECT was evaluated in 57 individuals. The subjects were members of a large pedigree from Colombia, South America, many of whom carry a PS-1 mutation for early-onset AD. METHODS: Members of this large kindred who were cognitively normal and did not carry the PS-1 mutation (n = 23) were compared with subjects who were carriers of the mutation but were asymptomatic (n = 18) and with individuals with the mutation and a clinical diagnosis of AD (n = 16). Cerebral perfusion was measured in each subject using hexamethylpropyleneamine oxime SPECT. The data were analyzed in two ways: 1) Mean cerebral perfusion in each of 4320 voxels in the brain was compared among the groups using t-tests (t-maps); and 2) each individual received a weighted score on 20 vectors (factors), based on a large normative sample (n = 200), using a method known as singular value decomposition (SVD). RESULTS: Based on t-maps, subjects with the PS-1 mutation who were asymptomatic demonstrated reduced perfusion in comparison with the normal control subjects in the hippocampal complex, anterior and posterior cingulate, posterior parietal lobe, and anterior frontal lobe. The AD patients demonstrated decreased perfusion in the posterior parietal and superior frontal cortex in comparison with the normal control subjects. Discriminant function analysis of the vector scores derived from SVD (adjusted for age and gender) accurately discriminated 86% of the subjects in the three groups (p < 0.0005). CONCLUSION: Regional cerebral perfusion abnormalities based on SPECT are detectable before development of the clinical symptoms of AD in carriers of the PS-1 mutation.     

SPECT Follow-Up Study of Cerebral Blood Flow Changes During Donepezil Therapy in Patients with Alzheimer''s Disease

BACKGROUND AND PURPOSE: Treatment with acetylcholinesterase inhibitors (AchEIs) is beneficial for patients with Alzheimer's disease (AD). But the clinical response varies. Functional neuroimaging techniques might allow objective evaluation of the topographic correlates of the effect of therapy on brain functioning. We attempted to evaluate the possible correlation between regional cerebral blood flow (rCBF) differences in patients with AD and response to donepezil hydrochloride (Donepezil) therapy. METHODS: The subjects of this study were 51 consecutive patients with AD receiving Donepezil who underwent SPECT at baseline and 10-14 months later. We divided the patients into stabilized (n = 19) and nonstabilized (n = 32) subgroups based on changes in the Mini Mental State Examination (MMSE) score. Analysis of single-photon emission computed tomography (SPECT) data was done using 3-dimensional stereotactic surface projections (3D-SSP) and the stereotactic extraction estimation (SEE) method. We compared differences in rCBF between the two subgroups at baseline and follow-up, and between the baseline and follow-up in each subgroup. RESULTS: Significant correlation was recognized between the mean Z score changes of the left frontal lobe, left limbic lobe, and MMSE change. There were no significant baseline differences in rCBF in any region of the brain between the two subgroups. At the study endpoint, the nonstabilized subgroup showed lower rCBF in the lateral and medial frontal lobes, limbic lobe, lower lateral temporal lobe, and cingulate gyrus compared to the stabilized subgroup. Both patient groups showed a significant post-treatment increase over baseline values in the frontal lobe, and the stabilized group had more extensive and intense increases in the lateral and medial frontal lobes and orbital surface. CONCLUSIONS: Our study suggests that the diversity of clinical responses to Donepezil therapy in patients with AD is associated with rCBF changes, mainly in the frontal lobe. SPECT may be a promising tool to assess the impact of AchEI therapy on the brain function of patients with AD.