Diagnosing Alzheimer's disease in elderly,mildly demented patients: the impact of routine single photon emission computed tomography

Based on the observation of bilateral temporoparietal hypoperfusion in Alzheimer's disease (AD), single photon emission computed tomography (SPECT) is advocated by some as a powerful diagnostic tool in the evaluation of demented patients. We studied whether routine brain SPECT in elderly, mildly demented outpatients increases the a priori diagnostic sensitivity and specificity of a careful clinical examination.^99mTc-HMPAO SPECT imaging was performed in 110 patients for a first evaluation for dementia. A semiquantitative measure of temporoparietal (TP) perfusion was calculated as the ratio of the activity in the temporoparietal cortex to activity in the cerebellum. A diagnosis of probable AD according to the McKhann criteria was made in 68 patients (mean age of 79.3 years) based on the results of a clinical examination, ancillary investigations and a 6-month follow-up. TP perfusion was significantly lower in AD patients than in 18 age-matched, non-demented controls. However, at a specificity of 89%, sensitivity was only 43% for detecting probable AD. The clinicians judged that SPECT had contributed to the final diagnosis in only 8% of the demented patients investigated. Routine brain SPECT in elderly, mildly demented outpatients does not contribute substantially to diagnostic accuracy after a careful clinical examination using current diagnostic criteria. Clinical guidelines have to be developed for the use of SPECT in patients with (suspected) dementia.     

Usefulness of a blood flow analyzing program 3DSRT to detect occipital hypoperfusion in dementia with Lewy bodies

In the latest criteria for the clinical diagnosis of dementia with Lewy bodies (DLB), supportive features include generalized low uptake on SPECT/PET perfusion scan with reduced occipital activity. In this study, we investigated the usefulness of a cerebral blood flow (CBF) quantification program '3DSRT' in detecting occipital hypoperfusion in DLB. Twenty two patients with probable DLB, 38 patients with probable Alzheimer's disease (AD) and 16 normal controls underwent brain perfusion SPECT. Compared with AD, DLB patients had a bilateral lower CBF in the posterior cerebral segments. The correlation of clinical symptoms and brain blood perfusion was examined by dividing the subjects into subgroups. DLB patients with Parkinsonism, when compared to non-Parkinsonism subgroup, had a lower CBF throughout the cerebrum with statistical significance in the posterior cerebral segments. The quantitative analysis of brain perfusion SPECT by 3DSRT could be a useful supportive measurement in the diagnosis of DLB.     

Subjective memory complaints: objective neural markers in patients with Alzheimer's disease and major depressive disorder

Patients with probable Alzheimer's disease and depressive patients frequently present with subjective memory complaints. Objective distinction of underlying neuronal substrate malfunction and early cross-sectional differential diagnosis have been elusive thus far. We used repetitive learning and free recall of abstract geometric patterns during functional magnetic resonance imaging to assess episodic memory in older subjects (ages 56-64 years) who sought first-time medical attention with subjective memory complaints and were diagnosed with probable Alzheimer's disease (NINCDS-ADRDA criteria; ages 51-67 years) or major depressive disorder (DSM-IV; ages 50-65 years). Contrasting healthy seniors or depressive patients with Alzheimer's disease patients revealed superiority of hippocampal activation. Contrasting Alzheimer's disease patients with seniors showed bilateral prefrontal activity as a correlate of futile compensation of episodic memory failure. Contrasting patients who had major depressive disorder with seniors or patients who had Alzheimer's disease showed bilateral activation of the orbitofrontal cortex and the anterior cingulate. Subjective memory complaints may be classified objectively and very early with functional magnetic resonance imaging of episodic memory in groups of patients with Alzheimer's disease and depressive syndrome. This may facilitate drug trials with evaluation of specific treatments, but further studies will be needed to establish the differential diagnosis for the individual patient.     

The diagnosis of dementia with single photon emission computed tomography

Single photon emission computed tomography is a practical modality for the study of physiologic cerebral activity in vivo. We utilized single photon emission computed tomography and N-isopropyl-p-iodoamphetamine iodine 123 to evaluate regional cerebral blood flow in nine patients with Alzheimer's disease (AD), five healthy elderly control subjects, and two patients with multi-infarct dementia. We found that all subjects with AD demonstrated flow deficits in temporoparietal cortex bilaterally, and that the ratio of activity in bilateral temporoparietal cortex to activity in the whole slice allowed the differentiation of all patients with AD from both the controls and from the patients with multi-infarct dementia. Furthermore, this ratio showed a strong correlation with disease severity in the AD group. Single photon emission computed tomography appears to be useful in the differential diagnosis of dementia and reflects clinical features of the disease.     

Specificity of changes in cerebral blood flow in patients with frontal lobe dementia.

Eight patients with a clinical diagnosis of probable Alzheimer's disease, eight patients with the clinical diagnosis of frontal lobe dementia, and eight controls were examined with single photon emission tomography (SPECT) using 99Tc-HMPAO. Patients with Alzheimer's disease and those with frontal lobe dementia met DSM-III-R criteria for mild dementia and were in the early stages of the illness. Compared with patients with Alzheimer's disease, the group with frontal lobe dementia had significantly lower blood flow in the frontal lobes (dorsolateral and orbital), the anterior temporal cortex, and the basal ganglia. Within the frontal lobe dementia group, blood flow was significantly lower in the orbital than in the dorsal frontal cortex, and in the anterior temporal than in the dorsal temporal cortex. The present study shows the specificity of changes in regional cerebral blood flow in the diagnosis of different types of dementia, and supports the importance of orbitofrontal, anterior temporal, and basal ganglia dysfunction in the production of the psychiatric syndrome of frontal lobe dementia.     

Combined Analysis of CSF Tau Levels and [(123)I]Iodoamphetamine SPECT in Mild Cognitive Impairment: Implications for a Novel Predictor of Alzheimer's Disease

OBJECTIVE: The aim of this study was to establish an objective and reliable index to predict the development of Alzheimer's disease in a large pool of elderly patients with mild cognitive impairment. METHOD: Twenty-three patients with probable Alzheimer's disease, 22 patients with mild cognitive impairment who eventually developed Alzheimer's disease, eight patients with mild cognitive impairment who did not develop dementia, and 19 cognitively normal subjects were included in the study. The authors constructed a new diagnostic index, the CSF-CBF index, based on CSF tau levels divided by regional cerebral blood flow (CBF) in the posterior cingulate cortex. RESULTS: Receiver operating characteristic analysis showed that applying a cutoff value for the CSF-CBF index of 296.0 achieved a sensitivity of 88.5% and a specificity of 90.0% in discriminating mild cognitive impairment that progressed to Alzheimer's disease from mild cognitive impairment that did not progress to Alzheimer's disease. CONCLUSIONS: The CSF-CBF index is useful in predicting Alzheimer's disease in subjects with mild cognitive impairment.     

Determination of cerebral blood flow by SPECT: a valuable tool in the investigation of dementia?

Positron emission tomography (PET) studies have demonstrated distinctive abnormalities in Alzheimer's disease (AD), multi-infarct-dementia (MID) and Pick's disease. Since PET is a complicated and expensive technique, its clinical application will be limited in the near future. An important finding in these PET studies is persistent coupling of brain metabolism and regional cerebral blood flow (rCBF). Therefore it should be possible to demonstrate bilateral temporoparietal hypometabolism as seen in patients with clinically diagnosed AD indirectly by measuring cerebral blood flow by Single Photon Emission Computer Tomography (SPECT). We report our first experiences with SPECT in the differential diagnosis of dementia with four case histories. We demonstrated temporoparietal hypoperfusion in AD and frontal hypoperfusion in Pick's disease as shown previously by PET. We could not demonstrate a typical SPECT in MID. The main purpose of SPECT in MID could be exclusion of coexisting AD. Based on current knowledge the possibilities and the limitation of this new technique are discussed. It is concluded that rCBF-SPECT may be of value in the diagnosis of AD and Pick's disease. Before this method can be used in daily clinical routine, its diagnostic value should be established according to principles of clinical decision making.     

Assessment of cerebral blood flow in Alzheimer's disease by spin-labeled magnetic resonance imaging

To evaluate the utility of arterial spin-labeled blood flow magnetic resonance imaging for the detection of cerebral blood flow abnormalities in Alzheimer's disease, arterial spin-labeled blood flow images in 16 contiguous 5-mm axial sections were acquired in 18 patients diagnosed with probable Alzheimer's disease and 11 age-matched controls. Blood flow images from all subjects were transformed to a standard anatomical space for voxel-by-voxel statistical analysis. High quality blood flow images were obtained from all but 1 subject. Statistical analysis demonstrated significant flow decreases relative to control subjects in temporal, parietal, frontal, and posterior cingulate cortices. Increased severity of disease, as measured by Mini-Mental State Examination, correlated with posterior parietal and posterior cingulate decreases but not temporal decreases. Arterial spin-labeled magnetic resonance imaging was found to be an effective tool for characterizing flow decreases accompanying Alzheimer's disease. The absence of ionizing radiation or injection and the ability to obtain high quality anatomical images within the same scanning session make arterial spin labeling an attractive technique for the study of Alzheimer's disease, for the evaluation of pharmacological therapies, and, possibly, for early diagnosis.     

Relevance of functional neuroimaging in the progression of mild cognitive impairment

AIM: To assess whether combining neuropsychological tests and cerebral blood flow markers improves progression accuracy from mild cognitive impairment (MCI) to Alzheimer's disease (AD) than each of them on its own. METHODS: Forty-two patients were investigated prospectively, undergoing baseline and 3-year follow-up neuropsychological tests and neuroimaging with Tc-ECD-SPECT. Twenty-one patients had developed AD while 21 retained their initial diagnosis. The relative blood flow and cognitive differences were studied. Validity parameters, multivariant analysis and logistic regression model were calculated. RESULTS: Patients who deteriorated showed lower scoring than stable subjects in some neuropsychological tests (p = 0.03-0.001) and in relative blood flow in selected regions (8-10%). Low cognitive test scoring and low relative blood flow in some regions showed sensibilities and specificities from 70% to 86% for the diagnosis of early Alzheimer's disease. The relative risk of progression to AD was up to 4.7 times higher for these patients (p = 0.0001). The left frontal relative blood flow, the CAMCOG and orientation scoring were the best data to predict the risk of progression to AD. CONCLUSIONS: The combination of functional imaging and neuropsychological tests can diagnose with high sensitivity and specificity if a patient is suffering cognitive impairment in its early stages, and may aid in predicting the risk of developing dementia.     

Clinical diagnosis of Binswanger''s disease.

To aid in the prospective study of Binswanger's disease, a poorly understood form of vascular dementia, a standardised criteria for its antemortem diagnosis was proposed. These criteria include dementia, bilateral radiological abnormalities on computed tomography (CT) or magnetic resonance imaging (MRI), and at least two of the following three clinical findings: A) a vascular risk factor or evidence of systemic vascular disease; B) evidence of focal cerebrovascular disease; and C) evidence of "subcortical" cerebral dysfunction. These criteria were validated in two ways. First, by retrospectively applying them to a series of 30 demented patients with various pathological diagnoses. Second, by prospectively applying them to a series of 184 patients with clinically typical Alzheimer's disease. The sensitivity and specificity of the criteria appear adequate for use in clinical research.     

SPECT and MRI analysis in Alzheimer''s disease: relation to apolipoprotein E epsilon 4 allele.

OBJECTIVES--The epsilon 4 allele of apolipoprotein E (ApoE) is a risk factor for late onset Alzheimer's disease. ApoE is present in senile plaques, neurofibrillary tangles, and cerebrovascular amyloid, and it is implicated in synaptogenesis. The effect of ApoE polymorphism on the volumes of hippocampus, amygdala, and frontal lobe was studied. The hypothesis was that the patients with Alzheimer's disease carrying the epsilon 4 allele have more pronounced atrophy. The relation of ApoE and cerebral blood flow on cortical areas was also assessed. METHODS--Fifty eight patients with Alzheimer's disease at the early stage of the disease and 34 control subjects were studied. Patients with Alzheimer's disease were divided into subgroups according to the number of the epsilon 4 alleles. Volumes were measured by MRI and regional cerebral blood flow ratios referred to the cerebellum were examined by 99mTc-HMPAO SPECT. ApoE genotypes were determined by digestion of ApoE polymerase chain reaction products with the restriction enzyme Hha1. RESULTS--patients with Alzheimer's disease had smaller volumes of hippocampi and amygdala compared with control subjects, and the patients with Alzheimer's disease homozygous for the epsilon 4 allele had the most prominent volume loss in the medial temporal lobe structures. The frontal lobe volumes did not differ significantly. All patients with Alzheimer's disease had bilateral temporoparietal hypoperfusion and the subgroups with one or no epsilon 4 alleles also had frontal hypoperfusion compared with control subjects. The occipital perfusion ratios tended to decrease with increasing number of epsilon 4 alleles. CONCLUSIONS--Patients with Alzheimer's disease homozygous for the epsilon 4 allele seem to have severe damage in the medial temporal lobe structures early in the disease process and differ from the patients with Alzheimer's disease with one or no epsilon 4 alleles.     

Combined magnetic resonance imaging and single-photon emission tomography scanning in the discrimination of Alzheimer's disease from age-matched controls

OBJECTIVE: To compare the utility of temporal lobe magnetic resonance imaging (MRI) and single-photon emission tomography (SPET) scanning in discriminating between subjects with Alzheimer's disease (AD) and age-matched controls. METHODS: Thirty subjects with NINCDS-ADRDA AD (23 probable AD, 5 possible AD, 2 definite AD) and 22 age- and sex-matched controls underwent T1-weighted coronal MRI scanning (0.3 T) and technetium 99m-HMPAO SPET scanning. MRI scans were analyzed using a digitizer system with volumes of hippocampus, amygdala, entorhinal cortex, parahippocampal gyrus, and whole cerebral cortex calculated. From SPET scans, regional cerebral blood flow (rCBF) was assessed in anterior and posterior frontal, parietal, occipital, and mesial temporal cortex using a region of interest analysis with the cerebellum as a reference area. RESULTS: Using MRI, the areas that best separated groups were left hippocampal and left amygdala volume, resulting in correct classification (patient vs. control) in 79% of cases (sensitivity 77%, specificity 82%). Exactly the same proportion of subjects were correctly classified by SPET, with the most discriminating rCBF changes being left parietal and right posterior frontal. Combining information from both scans improved the proportion of correctly classified subjects in a discriminant function to 90% (sensitivity 93%, specificity 86%; only 2 AD and 3 controls misclassified). All AD subjects had abnormalities on MRI and/or SPET (sensitivity for combined examinations 100%), while abnormalities on both MRI and SPET had a positive predictive value of 100% for dementia (including the detection of one control subject who later had dementia). Significant correlations between MRI and SPET measures were seen in control subjects but not in patients. CONCLUSION: Both 0.3 T MRI and single rotating gamma camera SPET were equally useful in separating AD subjects from age-matched controls, although the combination of both significantly enhanced discrimination. In particular, all AD subjects had abnormalities on either MRI or SPET and both techniques may have an important role in assisting with clinical diagnosis, though replication in other centers and examination of differentiation of AD from other causes of dementia need to be examined.     

Neuropathological findings in patients with clinical diagnoses of probable Alzheimer's disease

To assess prospectively the accuracy of standard antemortem clinical diagnostic criteria for Alzheimer's disease, post-mortem examinations were performed on 25 patients who had met DSM-III criteria for primary degenerative dementia and National Institute of Neurological and Communicative Disorders and Stroke criteria for probable Alzheimer's disease. Seventeen patients (68%) met neuropathological criteria for Alzheimer's disease. Two presenile-onset patients had diffuse neocortical senile plaques of insufficient number for definite Alzheimer's disease. Six patients had non-Alzheimer's disease diagnoses. Five of these six had presenile-onset dementia. These results suggest caution in the antemortem diagnosis of Alzheimer's disease in presenile-onset dementia.     

阿尔茨海默病~(18)F-FDG PET显像诊断的研究

目的 探讨阿尔茨海默病（AD）脑葡萄糖代谢及其18F-脱氧葡萄糖正电子发射计算机断层扫描（18F-FDG PET）显像的影像学特征和PET诊断标准。方法 静脉注射18F-FDG后行脑断层显像,检查13例 AD、13例非AD痴呆及13例正常人。获得纹状体、丘脑、黑质、顶叶、颞叶、额叶、枕叶、海马单位面积放射性计数与小脑计数的比值（Rcl/cb）,进行半定量分析,并与MR进行对照。结果AD患者PET异常率为100％,MR异常者占10/13。PET显像特征:①对称性双侧颞顶叶及海马伴额叶或枕叶代谢减低占9例（9/13）;②双侧颞叶对称性代谢减低伴海马或额叶代谢下降占3例（3/13）;③双顶叶对称性代谢降低1例（1/13）。12例（12/13）非AD痴呆表现为不对称、多发性代谢降低,降低区位于黑质、纹状体、丘脑及脑皮质区,MR异常率为11/13。结论 在除外脑内结构特异性损害基础上,PET发现对称性双颞顶叶、海马或颞叶、顶叶,伴或不伴枕叶、额叶代谢下降,可诊断AD。PET对AD早期诊断及鉴别诊断具有临床意义。     

The validity of 3 clinical diagnostic criteria for Alzheimer's disease

To examine the validity of criteria-based (clinical) diagnosis of Alzheimer's disease (AD), 4 physicians experienced in the evaluation of dementia patients applied 3 sets of diagnostic criteria to each of 62 patients based on standardized medical record information. Diagnostic outcome was validated by neuropathologic examination (completed previously) for all (43) demented patients and 4 nondemented patients and by follow-up in the remainder (15) with no dementia. Raters were blind to the composition of the study group as well as to the clinical and pathologic diagnoses. We evaluated 3 diagnostic criteria sets for AD: the American Psychiatric Association diagnostic criteria from the Diagnostic and Statistical Manual (DSM-III), the NINCDS-ADRDA Work Group criteria for the diagnosis of Alzheimer's disease (NINCDS), and the Eisdorfer and Cohen research diagnostic criteria for primary neuronal degeneration (ECRDC). ECRDC had the highest specificity (0.88) but also the greatest odds of false-negative diagnosis (LRneg = 0.61, sensitivity = 0.46). NINCDS had the best sensitivity (0.92, specificity = 0.65), and DSM-III showed intermediate values (sensitivity = 0.76, specificity = 0.80). We conclude that the investigator or clinician who wishes to ensure that patients classified as AD are more likely to be AD should choose DSM-III, whereas the investigator who wishes to include the greatest number of AD cases, seldom assigning a diagnosis of no AD to a true case, should choose NINCDS.     

Quantitative changes in mesial temporal volume, regional cerebral blood flow, and cognition in Alzheimer's disease.

Twenty-six patients with moderately severe Alzheimer's disease (AD) and 16 normal control subjects were studied using either quantitative magnetic resonance imaging (MRI) measures of mesial temporal atrophy (15 patients with AD and 16 normal control subjects) and/or quantitative radioactive iodine 123-N-isopropyl-iodoamphetamine single-photon emission computed tomography (SPECT) assessment of regional cerebral blood flow (20 patients with AD and eight normal control subjects). Nine individuals with AD and eight normal control subjects underwent both structural and functional imaging. On MRI, patients and controls were best discriminated using left amygdala and entorhinal cortex volumes, and on SPECT they were best discriminated by relative left temporoparietal cortex blood flow. Combining these MRI and SPECT measures yielded 100% discrimination. Relative left temporoparietal SPECT regional cerebral blood flow and left superior temporal gyral MRI volume correlated best with severity of cognitive deficit in patients with AD. Mesial temporal MRI atrophy exceeded generalized cerebral shrinkage. Both SPECT and MRI regional changes accorded with areas known to be affected by AD neuropathology.     

Research evaluation and prospective diagnosis of dementia with Lewy bodies.

OBJECTIVE: To evaluate the relative merits of recently developed criteria for dementia with Lewy bodies (DLBs) in a longitudinal study of dementia. DESIGN: The diagnosis of DLBs was used in combination with other clinical diagnosis. Patients were classified primarily based on the NINCDS-ADRDA (National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association) clinical criteria for probable or possible Alzheimer disease, or with other disease process that can cause dementia (eg, Parkinson disease), and secondarily according to the consensus guidelines for DLBs. This "double" clinical diagnosis was implemented to capture different pathological entities. The neuropathological diagnosis of Lewy bodies was made with monoclonal antibodies against alpha-synuclein. SETTING: Multidisciplinary research clinic. RESULTS: Prospective application of the consensus guidelines for DLBs from January 1, 1997, to September 29, 2000, identified 11 patients having the diagnosis of probable DLBs and 35 having possible DLBs. The diagnosis of probable or possible DLBs was associated with probable Alzheimer disease in 34 patients, with possible Alzheimer disease in 5 patients, with Parkinson disease in 2 patients, and with other disease processes in 2 patients. Three patients were diagnosed as having probable DLBs alone. An autopsy was performed in 26 of the cases who were clinically examined during the study period. Cortical Lewy bodies were identified in 13 cases; 4 had had premortem diagnosis of DLBs (sensitivity, 30.7%; specificity, 100%). CONCLUSIONS: The prospective validation of the clinical criteria for DLBs showed poor accuracy in this series. We believe that current criteria for DLBs are useful when DLBs occur in isolation, but have low sensitivity when Lewy bodies coexist with the pathological abnormalities of Alzheimer disease.     

Clinicopathological validation study of four sets of clinical criteria for vascular dementia.

OBJECTIVE: The authors' goal was to validate the clinical criteria for vascular dementia of the State of California Alzheimer's Disease Diagnostic and Treatment Centers (ADDTC), the National Institute for Neurological Disorders and Stroke-Association Internationale pour la Recherche et l'Enseignement en Neurosciences (NINDS-AIREN), DSM-IV, and ICD-10. METHOD: Sensitivity and specificity were assessed by comparing the clinical with the neuropathological diagnosis of 89 autopsied patients with dementia from a geriatric and psychiatric hospital. All cases were reviewed by a clinician and a neuropathologist who were blind to each other's findings. RESULTS: Neuropathologically there were 20 cases of vascular dementia, 23 cases of mixed dementia, and 46 cases of Alzheimer's disease among the autopsied patients. The sensitivity was 0.50 for DSM-IV criteria for vascular dementia, 0.70 for ADDTC criteria for possible vascular dementia, 0.55 for NINDS-AIREN criteria for possible vascular dementia, 0.20 for ICD-10 criteria for vascular dementia, 0.25 for ADDTC criteria for probable vascular dementia, and 0.20 for NINDS-AIREN criteria for probable vascular dementia. Specificity was 0.84, 0.78, 0.84, 0.94, 0.91, and 0.93, respectively. The proportion of cases clinically classified as vascular dementia ranged from 0% to 13% for neuropathologically confirmed cases of Alzheimer's disease and 9% to 39% for neuropathologically confirmed cases of mixed dementia. There was no statistically significant relationship between the neuropathological diagnosis and three of the clinical criteria sets studied (ICD-10 criteria for vascular dementia and ADDTC and NINDS-AIREN criteria for probable vascular dementia). CONCLUSIONS: Clinical criteria for vascular dementia are not interchangeable. The ADDTC criteria for possible vascular dementia are the most sensitive for the detection of vascular dementia; however, the DSM-IV criteria for vascular dementia and the NINDS-AIREN criteria for possible vascular dementia may be more effective in excluding mixed dementia. Given their inability to detect the vast majority of cases of vascular dementia, the ICD-10 criteria for vascular dementia and the ADDTC and NINDS-AIREN criteria for probable vascular dementia should be revised.     

Heterogeneity of neocortical cerebral blood flow deficits in dementia of the Alzheimer type: a [99mTc]-d,l-HMPAO SPECT study.

Regional cerebral blood flow (rCBF) was measured with high resolution brain dedicated single photon emission computer tomography (SPECT) and [99mTc]-d,l-hexamethyl-propylene-amine-oxime (HMPAO) in 25 patients with probable Alzheimer's disease and in 25 control subjects, selected according to rigorous inclusion and exclusion criteria. The aim was to analyse the topography of rCBF deficits in individual patients. In the group of patients with Alzheimer's disease as a whole, global CBF was reduced, but a factorial analysis of variance did not show disproportionate reduction of rCBF in any brain region. A parametric analysis of the rCBF data in individual patients was carried out with reference to normal values for internal rCBF ratios and to 13 different abnormal rCBF patterns. These theoretical patterns were predefined by showing significant hypoperfusion in at least one, or in any relevant combination of two, three, or four, of four major brain regions (a left and right frontal and a left and right posterior region). All patients with Alzheimer's disease and none of the control subjects had an abnormal rCBF pattern. Eleven of the 13 different patterns were seen in the patients. Frontal changes were seen in 19 (76%) of the patients, more often than previously reported. No single Alzheimer's disease pattern could be derived from our data. The number of regions with hypoperfusion, but not the presence of frontal changes, correlated significantly with the duration of disease. It is concluded that a clinical diagnosis of probable Alzheimer's disease is associated with heterogeneous patterns of rCBF deficits as measured with SPECT and [99mTc]-d,l-HMPAO. This heterogeneity may reflect different stages of the disease or cognitive subtypes and help explain published discrepancies concerning the topography of hypoperfusion in Alzheimer's disease. An analysis of individual rCBF data may add important information in the investigation of diseases with heterogeneous effects on the brain.     

Regional cerebral blood flow in Alzheimer's disease: classification and analysis of heterogeneity

Neural networks have been successfully applied to brain perfusion images to classify patients with Alzheimer's disease from normal or other patient populations. Given the recognition that Alzheimer's disease constitutes a heterogeneous disorder, the identification of subgroups sharing common functional brain deficits would constitute a further improvement in the utility of such methods. Therefore, we aimed to investigate whether neural networks could discriminate cortical perfusion deficits of patients with Alzheimer's disease from normal brain perfusion. A second step was to identify subgroups of patients sharing similar perfusion deficits. The study population consisted of one group of 92 normal healthy subjects and one group of 132 patients with mild-to-moderate Alzheimer's disease. The patients were diagnosed according to established criteria (DSM-IV and NINCDS-ADRDA). Regional cerebral blood flow was assessed by the non-invasive (133)Xe inhalation method, using a 64-detector system for measurements of blood flow in superficial cortical areas. The regional blood flow values were used as the only input to artificial neural networks with multilayer Perceptron architecture. The networks were trained using the back-propagation updating algorithm. A fourfold cross validation procedure was used in order to obtain the most reliable performance of the networks. The performance of the neural network, measured as the area under the receiver-operating characteristic curve, was 0.94, with a sensitivity for Alzheimer's disease of 86% at a specificity of 90%. An analysis of the relative importance of cortical areas in the discrimination showed that left parietal areas were more important than the right homologous ones. A clustering analysis of the Alzheimer patients identified three or four subgroups of patients with clearly different combinations of blood flow pathology. A consistent finding in all subgroups was a significant deficit in temporoparietal blood flow of both hemispheres. Distinct group differences were seen in frontal, central and occipital areas with different combinations of involvement. This is the first study in which neural networks have been applied to brain perfusion images obtained with the (133)Xe inhalation method. The results demonstrate that a classification of patients with Alzheimer's disease obtained with this method is compatible with the best results obtained with other brain imaging methods. The identification of clearly distinguishable patterns of blood flow pathology in subgroups of patients lends further support to the notion that Alzheimer's disease is a heterogeneous disorder.