Brain perfusion follow-up in Alzheimer's patients during treatment with acetylcholinesterase inhibitors.

UNLABELLED: Transient cognitive and behavioral stabilization of patients with Alzheimer's disease (AD) is the main goal of long-term acetylcholinesterase inhibitor (AChEI) therapy, but response to treatment is variable and, indeed, only some of the patients are stabilized. This is usually assessed by means of clinical and neuropsychologic scales, whereas functional neuroimaging could allow objective evaluation of the topographic correlates of the effect of therapy on brain functioning. The aim of this study was to evaluate brain perfusion changes by SPECT in AD patients during chronic AChEI therapy in relation to their cognitive evolution. METHODS: Forty-seven consecutive outpatients with mild-to-moderate probable AD (as defined by the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association and the Diagnostic and Statistical Manual of Mental Disorders [4th edition criteria] and a score of > or =15 on the Mini-Mental State Examination [MMSE]) were enrolled in 2 centers over a 1-y period and underwent SPECT with 99mTc-hexamethylpropyleneamine oxime at the time of enrollment (t(0)). All of them started AChEI therapy. Nine patients were lost at follow-up, and drugs were withdrawn from 3 patients. Of the remaining 35 patients, who received regular AChEI therapy (donepezil, 5 or 10 mg/d; rivastigmine, 6 or 9 mg/d) throughout the observation period, only the 31 patients receiving donepezil were considered to avoid the possible confounding effect of different drugs. The 31 patients completed the study and a second SPECT examination was performed 15.0 +/- 3.0 mo later (t(1)). They were divided into stabilized (17 patients) and nonstabilized (14 patients) subgroups on the basis of the minimum expected annual rate of decline of the MMSE score, derived from a meta-analysis of the literature. SPECT data were analyzed by means of statistical parametric mapping. RESULTS: At baseline, the stabilized and nonstabilized patients were comparable for age, sex distribution, education, MMSE scores, memory impairment (selective reminding test [SRT]), apolipoprotein E genotype, AChEI dose regimen, and SPECT findings. The SRT scores decreased significantly (P < 0.01) in the nonstabilized subgroup but not in the stabilized subgroup. No significant difference was found between the baseline and repeated SPECT data in the stabilized subgroup. In contrast, in the nonstabilized subgroup a significant perfusion reduction was found in the frontal, temporal, and parietal superficial cortex and in the occipital precuneus in the right hemisphere and in the frontal and mesial temporal cortex in the left hemisphere. On repeated SPECT, regional cerebral blood flow was significantly lower in a left frontal region in the nonstabilized group than in the stabilized group. CONCLUSION: The regional cerebral blood flow decreases in several cortical regions in AD patients with cognitive deterioration despite long-term AChEI therapy, similar to that observed in untreated patients, whereas it remains stable in AD patients with stabilized cognitive performance during therapy.

Voxel-based mapping of cortical ischemic damage using Tc 99m L,L-ethyl cysteinate dimer SPECT in acute stroke.

BACKGROUND AND PURPOSE: When performed soon after stroke onset, single-photon emission computed tomography (SPFCT) with hexamethylpropylenamine oxime or Tc 99m L,L-ethyl cysteinate dimer (ECD) has significant added predictive value compared to neurological scores. With ECD SPECT, the degree of tracer uptake reduction predicts neurological recovery, and using a 40% threshold to characterize irreversibly damaged tissue (IDT), significant correlations have been observed. However, correlations between this uptake threshold and tissue outcomes have not been assessed. The purpose of this study was to validate the 40% ECD uptake threshold for the probabilistic mapping of IDT using an automatic, voxel-based approach. METHODS: In 10 acute stroke patients, the authors first compared early ECD SPECT and late coregistered magnetic resonance imaging (MRI) data and assessed for IDT and "tissue at risk" (i.e., tissue with ECD uptake below and above 40%) the percentage of voxels ultimately infarcted and noninfarcted on late brain MRI. They then assessed the correlations between the volumes of brain tissue compartments and subsequent neurological recovery. Finally, to assess whether visual SPECT analysis is reliable compared to the more complex voxel-based approach, the authors compared the predictive value of the 2 methods for neurological recovery. RESULTS: The majority of IDT voxels (average = 84%), defined by ECD uptake < 40%, evolved toward infarction, and 51.8% to 100% of at-risk voxels (average = 89%) escaped infarction. The extent of IDT correlated significantly with neurological recovery (P = .0009). There was good agreement between visual and voxel-based analyses (P = .0004). CONCLUSION: The results support the validity of the ECD uptake thresholds chosen, suggesting that ECD uptake can reflect neuronal viability and that ECD SPECT can be useful for the early detection of potentially salvageable tissue and irreversible damage. These preliminary results encourage the use of this method in a clinical setting for fast decision making in choosing acute therapy.

Brain perfusion in Alzheimer's disease with and without apathy: a SPECT study with statistical parametric mapping analysis.

Alzheimer's disease (AD) is clinically characterized by cognitive symptoms that, in combination with behavioral disturbances, significantly interfere with activities of daily living. These behavioral disorders contribute to the clinical heterogeneity of the disease and probably express different pathophysiological processes. Apathy is one of the most frequent behavioral disorders in AD. The aim of this study was to evaluate brain perfusion of AD patients with and without apathy (as determined by the Neuropsychiatric Inventory) compared with that in healthy elderly subjects. A total of 15 AD patients without apathy (AD/NA; mean age 76.6) and 15 AD patients with apathy (AD/A; mean age 77.6) were studied. Brain perfusion was measured by 99mTc-labeled bicisate (ECD) single-photon emission tomography (ECD SPECT). The images of the two AD subgroups were compared by means of statistical parametric mapping (SPM 99) to corresponding images of 11 healthy elderly control subjects (obtained from the Society of Nuclear Medicine database). Compared with the healthy elderly subjects, the apathy-free AD subgroup had significantly lower perfusion of inferior temporal regions (left fusiform gyrus, left parahippocampal area) and occipital regions (left gyrus lingualis). The apathy subgroup had significantly decreased perfusion of the left anterior cingulate, the right inferior and medial gyrus frontalis, the left orbitofrontal gyrus and the right gyrus lingualis. The differences in the brain areas with reduced perfusion between the apathy-free subjects (mainly the posterior regions) and the apathetic subjects (mainly the anterior regions) indicate that behavioral disorders such as apathy participate in the heterogeneity of brain perfusion in AD.

99mTc-HMPAO and 99mTc-ECD perform differently in typically hypoperfused areas in Alzheimer's disease.

Technetium-99m hexamethylpropylene amine oxime (HMPAO) and (99m)Tc- N, N"-1,2-ethylene diylbis- l-cysteine diethyl ester dihydrochloride (ECD) yield significantly different images of cerebral perfusion owing to their particular pharmacokinetics. The aim of this study was to assess the topography, extension and statistical significance of these differences in Alzheimer's disease (AD). Sixty-four patients with mild to moderate AD were retrospectively selected by two European centres. Two series of patients, including 32 studied with (99m)Tc-HMPAO single-photon emission tomography (SPET) and 32 studied with (99m)Tc-ECD SPET, were matched for sex, age (+/-3 years) and severity of cognitive impairment as assessed by the Mini-Mental State Examination (MMSE) (+/-2 points), following a case-control procedure. SPET data were processed using SPM99 software (uncorrected height threshold: P=0.001). (99m)Tc-ECD SPET gave significantly higher uptake ratio values than (99m)Tc-HMPAO SPET in several symmetrical clusters, including the right and left occipital cuneus, the left occipital and parietal precuneus, and the left superior and middle temporal gyri. (99m)Tc-HMPAO SPET gave significantly higher uptake ratio values than ECD in two smaller clusters, including the hippocampus in both hemispheres. In AD, relative brain uptake of (99m)Tc-HMPAO and (99m)Tc-ECD is different in several brain regions, some of which are typically involved in AD, such as the precuneus and the hippocampus. These differences confirm the need for specific normal databases, but their impact on routine SPET reports in AD is not known and deserves an ad hoc investigation.

Statistical parametric mapping of (99m)Tc-HMPAO-SPECT images for the diagnosis of Alzheimer's disease: normalizing to cerebellar tracer uptake.

BACKGROUND: For a quantitative comparison of images obtained during (99m)Tc-hexamethylpropylene amine oxime (HMPAO) single-photon emission computed tomography (SPECT), brain activity values are usually normalized to a reference region. In studies of Alzheimer-type dementia (ATD), the cerebellum is often used as a reference region, assuming that it is spared any major pathological involvement. Statistical parametric mapping (SPM) may enhance the evaluation of SPECT scans in ATD patients. However, current SPM software only allows scaling to average whole brain activity (i.e., global normalization). The aim of this study was to develop an easily applied, objective, and reproducible method for determining average cerebellar tracer uptake so that images can be scaled specifically to cerebellar activity prior to the performance of SPM analysis. We also investigated whether cerebellar normalization increases the sensitivity and specificity of SPM analysis of ATD patients compared with global normalization. METHODS: Image files were taken from a parallel study investigating the use of SPECT as a diagnostic tool for early onset of ATD. Two methods for determining cerebellar activity were developed: one manually, using templates, the other automated, using specified coordinates entered into a Matlab routine. Group comparison of ATD patients versus controls (= healthy volunteers and depressed patients) was performed on a voxel-by-voxel basis using SPM 96 on Windows 95. Receiver operator characteristics (ROC) were computed for 20 student raters examining patient and control scans with and without single-subject SPMs. RESULTS: The reduction of cerebral blood flow in the group of ATD patients appeared 1.7 times greater in spatial extent when the tracer uptake was normalized to cerebellum rather than to average whole brain activity. Computing the reverse contrast (reductions in the control group compared with ATD patients) produced clusters of significance in globally normalized images which were not manifest after normalizing to cerebellum. This is consistent with the notion that the cerebellum is spared in ATD. Analysis of the area under the ROC curve showed that cerebellar-normalized SPM produced significantly improved accuracy over perfusion scans alone. CONCLUSION: An easily applied, objective, reproducible method was developed for normalizing images to cerebellum prior to the performance of SPM analysis. Cerebellar normalization produced more extensive abnormalities in SPM analyses of ATD patients than global normalization. Furthermore, cerebellar normalization produced marginally more accurate diagnostic results in single-scan SPM analysis of ATD patients than did global normalization.

Exploración del sistema nervioso central: estado del arte en metodología / Exploring the central nervous system: methodological state of the art

El análisis de la práctica clínica actual demuestra un desfase entre los desarrollos metodológicos publicados y la utilización que de ellos se hace en la práctica clínica. Esta revisión propone una descripción de algunos desarrollos recientes que están próximos a una mayor difusión a propósito de tres indicaciones clásicas: el diagnóstico de la enfermedad de Alzheimer, la evaluación de la neurotransmisión dopaminérgica y el estudio de la epilepsia. En la enfermedad de Alzheimer los métodos de estandarización espacial y la comparación con una base de datos normativa son más útiles en la medida que el observador es menos experimentado y las aproximaciones "orientadas a la rutina" más simples que el SPM parecen prometedoras. La cuantificación es lo esencial del estudio de la neurotransmisión dopaminérgica. La medición de los potenciales de unión está considerablemente sesgado por la penetración septal, la atenuación, la difusión y el efecto de volumen parcial. Es el efecto de volumen parcial que introduce el mayor error. Su corrección es difícil debido a que pasa por un corregisto con imágenes de resonancia magnética. Los resultados de esa corrección son muy sensibles a la precisión de dicho corregistro. El estudio de la epilepsia por sustracción de los SPECT ictal e interictal ha demostrado su valor clínico. Es una operación de fusión de imágenes para la cual los métodos ya están bien definidos.