Protein synthesis in the posterior cingulate cortex in Alzheimer's disease

Background: Neuroimaging studies using ¹⁸F‐fluoro‐2‐deoxy‐D‐glucose positron emission tomography (FDG‐PET) and single photon emission computed tomography (SPECT) have shown that the posterior cingulate cortex (PCC) is the primary and most prominent area of cerebral metabolic and perfusional decrement in early Alzheimer's disease (AD). We carried out the present preliminary study to investigate whether a decline of cerebral blood flow (CBF) in the PCC in early to moderate AD was accompanied with that of cerebral protein synthesis (CPS). Methods: We carried out both N‐isopropyl‐p‐[123I] iodoamphetamine SPECT (IMP‐SPECT) and L‐[methyl‐11C] methionine positron emission tomography (MET‐PET) in eight AD patients with apolipoprotein E epsilon 4 allele in the early to moderate stage. We also carried out IMP‐SPECT in eight healthy controls (HC). We located 32 regions of interest (ROI), and values of regional MET or IMP uptakes were averaged in five regions; the frontal lobe (FL), the parietal lobe (PL), the medial temporal lobe (MTL), PCC and the occipital lobe. Furthermore, the values in the FL, PL, MTL and PCC were divided by values in the occipital areas, and normalized values of regional CBF (rCBF) and CPS (rCPS) were calculated. Then, the rCBF in the FL, PL, MTL and PCC were compared between AD and HC. In addition, the rCBF and rCPS were compared in the FL, PL, MTL and PCC of AD. Results: The rCBF in the PCC, but not in the other three regions, was significantly lower in AD than in HC. The rCBF was significantly lower than rCPS in the PCC, but rCBF and rCPS were comparable in the other three regions in AD. Conclusions: The CBF reduction in the PCC in AD was partly caused by neuronal loss in the PCC and partly supported the hypothesis that CBF reduction in the PCC was a result of functional deafferentation by neural degeneration in areas other than the PCC.     

Apolipoprotein E Genotype and Early Alzheimer''s Disease: A Longitudinal SPECT Study

BACKGROUND AND PURPOSE: To determine the association of the apolipoprotein E (APOE) genotype and longitudinal changes of regional cerebral blood flow (rCBF) in Alzheimer's disease (AD). Previous reports have yielded conflicting results concerning this association. METHODS: A retrospective cohort study was performed. rCBF was noninvasively measured using 99mTc-ethyl cysteinate dimer single-photon emission computed tomography in 23 patients with probable AD at the very early stage and at a mean interval of 24 months, as well as in 55 age-matched healthy volunteers. Patients were classified into 2 groups according to the presence of the epsilon 4 allele: 11 epsilon 4 carriers and 12 noncarriers. Correction for partial volume effects (PVEs) was performed in all patients using gray matter volume measured by magnetic resonance imaging. Statistical parametric mapping was used for the analysis of absolute rCBF data and the adjusted rCBF images of relative flow distribution. RESULTS: In the baseline study, both carriers and noncarriers showed significant decreases of absolute and adjusted rCBF in the psoterior cingulate gyri and precunei. After PVE correction, carriers showed a greater spread of areas with significant rCBF reduction from the parietotemporal to the frontal area than noncarriers during the follow-up period compared to healthy volunteers. Moreover, carriers showed a significant decline of absolute rCBF in the frontal cortex from the baseline to the follow-up study. CONCLUSIONS: The authors' study suggests that the APOE epsilon 4 allele is associated with the faster progression of AD, and PVE correction may be necessary for accurate assessments of SPECT studies of AD.     

Comparison of brain perfusion in corticobasal degeneration and Alzheimer's disease

To compare brain perfusion between corticobasal degeneration (CBD) and Alzheimer's disease (AD), we measured regional cerebral blood flow (rCBF) semiquantitatively with single-photon emission computed tomography in 10 patients with CBD and 16 with AD. There was no significant difference in age or illness duration between the patients with CBD and AD. Mini-Mental State Examination scores were significantly lower in the AD patients than in the CBD patients. All CBD patients showed asymmetric akinetic-rigid syndrome and limb apraxia. Four CBD patients were demented, and 1 AD patient had parkinsonism. Compared with 12 age-matched control subjects, the average of the left and right rCBF values for the CBD patients was significantly reduced in the prefrontal, anterior cingulate (AC), medial premotor, sensorimotor (SM), posterior parietal (PP) and superior temporal (ST) cortices as well as in the basal ganglia (BG) and thalamus (Th), while the prefrontal, PP and ST cortices were significantly hypoperfused in the AD patients. In the CBD patients, rCBF was significantly less in the AC and SM cortices, and in the Th and BG, and significantly greater in the PP cortex than in the AD patients. Interhemispheric differences of rCBF in the inferior prefrontal and SM cortices were significantly greater in the CBD patients than the AD patients. It is concluded that rCBF comparison may aid in differentiating CBD from AD.     

Regional cerebral blood flow measured by99mTc-HMPAO SPECT differs in subgroups of Alzheimer's disease

Summary Alzheimer's disease (AD) is a heterogeneous entity. Identifying AD subtypes might have impact in patients' response to different treatment strategies. We designed a study to examine regional cerebral blood flow (rCBF) in AD subtypes. To identify AD subtypes, we performed a cluster analysis including performance on memory, language, visuospatial, praxis, and executive functions. The rCBF measured by^99mTc-HMPAO SPECT was referred to the cerebellum. We examined 35 patients fulfilling the NINCDS-ADRDA criteria of probable AD and 13 age and sex-matched healthy cognitively intact controls. AD patients were at the early stage of the disease, their mean Mini-Mental Status (MMS) score (S.D.) was 22.5 (3.6). The cluster analysis revealed two AD subgroups: AD1 (N=12) and AD2 (N=23). The subgroups did not differ in age, sex, or global clinical severity as assessed by MMS and Brief Cognitive Rating Scale (BCRS). Both subgroups had equally impaired memory. The AD2 group was inferior to the AD1 group on verbal, visuospatial, praxic, and executive functions. The AD1 group showed reduced rCBF ratios in the temporal and parietal cortices and the amygdala compared to controls. The AD2 group differed from controls in the rCBF ratios of frontal, temporal, parietal, occipital, basal ganglia, and amygdaloid regions bilateral and from AD1 in the rCBF ratios of frontal and temporal cortices. In AD patients, the rCBF ratios did not correlate with MMS or BCRS scores. In contrast, several significant correlations were found between decreases rCBF ratios and impairment of memory and other cognitive functions. In conclusion, a cluster analysis on neuropsychological test performance identified two AD subgroups that differed on the neuropsychological profile and on the rCBF in spite of similar global clinical severity.     

Single-Photon Emission Computed Tomography Studies of Regional Cerebral Blood Flow in Multiple Infarct Dementia

Multiinfarct dementia (MID) and Alzheimer's disease (AD), both characterized by a decline in cognitive function, are often difficult to differentiate and may coexist. This study reports the findings of single-photon emission computed tomography (SPECT) using [²³¹]N-isopropyl-p-iodoamphetamine to determine cerebral blood flow patterns in patients with MID (n = 11 ), as compared with patients with AD (n = 22) and nondemented control subjects (n = 12). Data were acquired at two tomographic levels for dorsolateral frontal, parietal, orbitofrontal, and temporal areas of the cortex. Analyses of variance revealed that the blood flow pattern for the MID group was very similar to that in the AD patients, with both groups showing hypoperfusion in the temporal area, although blood flow in the left parietal region was lower for the patients with AD. When normal regional cerebral blood flow (rCBF) was defined as within 2 standard deviations of control values, most of the patients with MID had normal rCBF, while a few patients showed abnormal rCBF in all regions. In contrast, the majority of AD patients showed abnormal rCBF in the temporal part of the cortex. This suggests that while AD is characterized by hypoperfusion in the temporal and parietal areas, there is no characteristic rCBF pattern in MID. These findings emphasize the need to use multiple modalities when clinically evaluating patients with MID.     

Effect of age on regional cerebral blood flow patterns in Alzheimer's disease patients

The purpose of this study was to explore the influence of age on regional cerebral blood flow (rCBF) patterns in patients with Alzheimer's disease (AD). Single photon emission computed tomography (SPECT) was performed in 79 patients with AD, including 31 younger and 48 older patients divided according to age at examination (<70 and > or = 70 years), and the SPECT data were analyzed using three-dimensional stereotactic surface projection. Although no significant differences in severity and duration of disease between the two groups were found, there were some differences in rCBF patterns. Patients with younger AD had a more severe decrease of rCBF in the parietotemporal and posterior cingulate cortex, while patients with older AD had a more severe decrease of rCBF in the medial temporal region and medial frontal lobe. This observer-independent analysis of SPECT data provides an objective assessment of cortical rCBF abnormalities in patients with AD and is useful in demonstrating the differences in rCBF patterns between younger and older patients with AD.     

Cerebral correlates of the progression rate of the cognitive decline in probable Alzheimer's disease

OBJECTIVE: To evaluate the possible relation between the rate of cognitive deterioration in patients with probable Alzheimer's disease (AD) and the distribution pattern of neural dysfunction. METHODS: The regional cerebral blood flow (rCBF) was measured in rapidly and slowly progressing groups of AD patients using single-photon emission computed tomography and was compared between the groups. While controlling for demographic and clinical factors that could be associated with the stage and prognosis of the illness, the deterioration rate of the Mini Mental State Examination (MMSE) score was significantly greater in the rapidly progressing group than that in the slowly progressing group. RESULTS: The rCBF in the right posterodorsal, anterior and superior prefrontal cortices and the inferior parietal cortex was significantly lower in the rapidly progressing patients. Moreover, lower perfusion in these regions correlated significantly with rapid deterioration in the MMSE. CONCLUSIONS: These findings suggest that the rCBF values in these cortical regions could be useful in predicting which AD patients will show a relatively rapid cognitive decline.     

Cerebral blood flow and cognitive responses to rivastigmine treatment in Alzheimer's disease

Twenty seven patients with mild AD were enrolled in a prospective open label controlled study of rivastigmine. Assessments included a range of neuropsychiatric and behavioural measures and rCBF using HMPAO SPECTat baseline, three and six months. Significant enhancement of frontal, parietal and temporal brain blood flow with related psychometric improvement was observed in twelve of the treated patients. A pattern of reduced rCBF and cognitive performance was observed in four unresponsive and eleven untreated patients. The results suggest that alterations in the clinical and cognitive status of patients receiving a cholinesterase inhibitor are paralleled by changes in rCBF. Longitudinal assessment with repeated imaging offers a method of better understanding the effects of cholinesterase inhibition on the AD brain.     

Quantitative analysis of brain perfusion SPECT in Alzheimer's disease using a fully automated regional cerebral blood flow quantification software, 3DSRT

PURPOSE: The clinical symptoms of Alzheimer's disease (AD) show great diversity depending on the clinical stage. We investigated the correlation of regional cerebral blood flow (rCBF) changes and the clinical severity of AD patients. METHODS: Thirty-nine AD patients and 16 normal subjects participated in this study. AD patients were divided into three subgroups by clinical severity. Quantitative brain perfusion SPECT analyses were performed using a rCBF quantification software, 3DSRT. RESULTS: In mild AD, significant decreases of rCBF were detected in the bilateral parietal, angular gyrus, pericallosal, thalamus, right temporal and left hippocampal regions. Moderate AD patients showed significantly lower blood flow than those with mild AD only to the right hippocampus. Analysis of the severe AD group revealed a nearly diffuse decrease of rCBF throughout the cerebral cortex except for part of the frontal lobe compared with moderate patients. CONCLUSIONS: These results were consistent with previous findings demonstrated by qualitative analysis of CBF. The decreased thalamic blood flow was noteworthy as this finding has rarely been reported. In consideration of the structure and function of the Papez circuit, which connects the medial temporal lobe and thalamus, a remote metabolic effect might be the cause of lower rCBF in the thalamus.     

Relationship between thyroid hormone levels and regional cerebral blood flow in Alzheimer disease

Subclinical thyroid disease and even variations in thyroid function within the normal range is associated with cognitive function and a risk of Alzheimer disease (AD). Several studies reported the effect of thyroid hormones on cerebral blood flow. The aim of this study was to objectively evaluate regional cerebral blood flow (rCBF) in association with thyroid hormone levels within the normal range in patients with AD. Serum thyroid-stimulating hormone (TSH), free T3, and free T4 levels were measured in 62 patients with AD (23 men and 39 women; age 56 to 91 y; mean age 77.3 y) and 27 control subjects (9 men and 18 women; age 61 to 93 y; mean age 75.8 y). The 99mTc ethylcysteinate dimer single photon emission computed tomography was performed in all subjects. The rCBF in the region of interest was measured by the noninvasive Patlak plot method and calculated using FineSRT, which is a fully automated region of interest technique. No significant correlation was found between thyroid hormone levels and Mini-Mental State Examination scores or global CBF values. Serum levels of TSH, but not free T3 or free T4, were significantly inversely correlated with rCBF in the middle and inferior temporal regions of right cerebral hemisphere in patients with AD. Control subjects showed no significant correlation between thyroid hormone levels and rCBF. Although these findings of a regional relationship must be considers preliminary, this study proposed the hypothesis that altered TSH levels within the normal range may be related to brain perfusion in right temporal region.     

The investigation of Alzheimer''s disease with single photon emission tomography.

Twenty patients satisfying standard clinical criteria for Alzheimer's disease (AD) and six age-matched normal controls were studied using 99mTc hexamethyl-propyleneamine oxime and single photon emission tomography. The AD patients had lower regional cerebral blood flow (rCBF) in the temporal and posterior parietal lobes compared to controls. AD patients with apraxia and aphasia had lower rCBF in the lateral temporal and posterior parietal lobes than AD patients without these features. Within the AD group, correlations were found between neuropsychological tests and rCBF: praxis correlated with posterior parietal activity, memory with left temporal lobe activity and language with activity throughout the left hemisphere.     

Cerebral blood flow patterns in Binswanger's disease: a SPECT study using three-dimensional stereotactic surface projections

We investigated regional cerebral blood flow (rCBF) patterns in Binswanger's disease (BD) patients using single photon emission computed tomography (SPECT). SPECT data on 22 patients with BD were analyzed using three-dimensional stereotactic surface projections (3D-SSP) and were compared with those of 22 patients with Alzheimer's disease (AD). rCBF patterns in patients with BD were different from those with AD. The BD group had greater CBF reduction in the frontal and anterior cingulate cortices, while the AD group had greater CBF reduction in the temporoparietal and posterior cingulate cortices. However, the rCBF pattern of each patient was more variable, and could be divided into three patterns: anterior cerebral hypoperfusion, posterior cerebral hypoperfusion, and diffuse cerebral hypoperfusion patterns. A distinct CBF reduction in the temporoparietal and/or posterior cingulate cortices, indistinguishable from the CBF pattern observed in AD, was demonstrated in 8 of 22 (36%) patients with BD, in particular there was bilateral hemispheric involvement with a diffuse hypoperfusion pattern. Although no pathological confirmation could be performed, some of the BD patients with CBF reduction in the posterior cerebral cortices may represent additional changes in the brain due to AD. In the future, a longitudinal study including pathology will be needed to determine whether these patients have coexisting AD pathology.     

Alcohol dependence is associated with blunted dopamine transmission in the ventral striatum.

BACKGROUND: A decrease in dopamine type 2 receptors (D2) and mesolimbic dopamine transmission predisposes animals to consume alcohol. This study measured D2 receptors and dopamine transmission in human alcohol-dependent (AD) subjects using positron emission tomography (PET) and [11C]raclopride. METHODS: Fifteen AD and 15 healthy control (HC) subjects were scanned before and after a psychostimulant challenge (amphetamine .3 mg/kg intravenous). The outcome measures for baseline D2 receptor availability were binding potential (BP) and the equilibrium partition coefficient (V3'). Amphetamine-induced [11C]raclopride displacement was measured as the difference in V3' between the two scans. RESULTS: [11C]raclopride BP was significantly reduced by 16.6% in the limbic striatum, 19.2% in the associative striatum, and 21.3% in the sensorimotor striatum in AD subjects compared with HC. The alcohol-dependent subjects showed a blunting of amphetamine-induced dopamine release in the limbic striatum: [11C]raclopride displacement was -5.2% +/- 3.6% in AD subjects compared with -13.0% +/- 8.8% in HC. However, no significant difference in [11C]raclopride displacement was seen in the associative (-4.6% +/- 5.8% in AD subjects vs. -6.7 +/- 5.4% in HC) and sensorimotor (-12.3% +/- 7.3% in AD subjects vs. -13.7 +/- 7.5% in HC) subdivisions of the striatum between the two groups. CONCLUSIONS: Alcohol dependence was associated with a decrease in D2 receptors in each striatal subdivision, whereas amphetamine-induced dopamine release was reduced in the limbic striatum only.     

Assessment of regional blood flow in cerebral motor and sensory areas in patients with spinal cord injury

We assessed the presence and the degree of alteration of the regional blood flow (rCBF) as visualized by Tc-99m HMPAO brain rest SPECT in the sensory motor cortex and subcortical structure in spinal cord injury (SCI) patients, who suffered from various levels of motor and sensory function loss. Twenty-two patients (mean age: 42.1+/-13.4 years, 18 M, 4 F) and 11 control subjects (mean age: 32.2+/-6.4 years, 8 M, 3 F) participated in this study. The spinal cord injury group was consisted of 2 groups (14 paraplegic and 8 tetraplegic patients). The corticocortical rCBF ratios were calculated by using region of interests obtained from 34 cortical areas on coronal slices. Significantly reduced rCBF were measured from 11 cortical areas in tetraplegic patients and 11 cortical areas in paraplegic patients. Some of these areas were different in each group. In the tetraplegic group, significant reduction was observed in the following rCBF areas: left anterior cingulate gyrus, left medial supplementary motor area, bilateral front and back aspects of posterior cingulate gyrus, right lateral primary motor area, right medial primary sensory area, bilateral putamen, and right cerebellum. In the paraplegic group, reduced rCBF areas were as follows: bilateral anterior cingulate gyrus, right lateral supplementary motor area, left front aspect of posterior cingulate gyrus, left lateral primary motor area, bilateral back aspects of posterior cingulate gyrus, right medial primary sensory area, left lateral primary sensory area and bilateral putamen. In conclusion, in some of the movement-cortical and subcortical areas having significantly reduced blood flow in SCI may be helpful to demonstrate the disrupted areas of rCBF by SPECT. We believe that it may be useful if these findings should be considered during the evaluations related to the reorganization in SCI cases.     

Age-related impairment of cerebral blood flow response to KATP channel opener in Alzheimer’s disease mice with presenilin-1 mutation

Local cerebral blood flow (CBF) responses to neuronal activity are essential for cognition and impaired CBF responses occur in Alzheimer’s disease (AD). In this study, regional CBF (rCBF) responses to the K_ATP channel opener diazoxide were investigated in 3xTgAD, WT and mutant Presenilin 1(PS1_M146V) mice from three age groups using Laser-Doppler flowmetry. The rCBF response was reduced early in young 3xTgAD mice and almost absent in old 3xTgAD mice, up to 30%–40% reduction with altered CBF velocity and mean arterial pressure versus WT mice. The impaired rCBF response in 3xTgAD mice was associated with progression of AD pathology, characterized by deposition of intracellular and vascular amyloid-β (Aβ) oligomers, senile plaques and tau pathology. The nitric oxide synthase (NOS) inhibitor N^ω-nitro-L-arginine abolished rCBF response to diazoxide suggesting NO was involved in the mediation of vasorelaxation. Levels of phosphor-eNOS (Ser1177) diminished in 3xTgAD brains with age, while the rCBF response to the NO donor sodium nitroprusside remained. In PS1_M146V mice, the rCBF response to dizoxide reduced and high molecular weight Abeta oligomers were increased indicating PS1_M146V contributed to the dysregulation of rCBF response in AD mice. Our study revealed an Aβ oligomer-associated compromise of cerebrovascular function in rCBF response to diazoxide in AD mice with PS1_M146V mutation.     

Cerebral perfusion as a diagnostic marker of early Alzheimer's disease

Clinical diagnosis of Alzheimer's disease (AD) is not fully satisfactory, and laboratory markers of this disease are not yet established. We report substantial regional Cerebral Blood Flow (rCBF) abnormalities in patients with documented early stages of the disease, when differential diagnosis is most critical. Thirty-six patients with carefully documented clinical diagnosis of early AD (mean disease duration, 3.25 +/- 1.80 years) and 12 elderly healthy controls participated in rCBF studies using the 133Xe inhalation method. Whole-brain perfusion was significantly (p less than 0.001) lower in the AD group, and a characteristic perfusion deficit was consistently found in temporoparietal cortex of the AD patients. Discriminant analyses demonstrated over 90% correct classification of the two groups. Two subgroups of patients with mildest disease manifestations were equally well discriminated. The similarity of these findings to those in late stages, which have been validated neuropathologically, offers indirect confirmation of validity and specificity. These results suggest that rCBF procedures may provide an accurate and sensitive laboratory marker for early AD.     

Alzheimer's disease and head circumference

OBJECTIVE: Larger brains may contain more neurons and synaptic connections, providing a greater reserve against cognitive decline in Alzheimer's disease (AD). Larger head circumference (HC) may therefore be associated with later detection and diagnosis of AD. We investigated HC in nondemented individuals and AD patients using cross-sectional and prospective analyses. METHODS: The cross sectional analysis compared mean HC between 592 AD patients and 459 nondemented controls. Prospective analysis was based on the same initially normal controls who were followed longitudinally for conversion to dementia. Diagnosis of AD was made by neurologists using NINDS-ADRDA criteria. RESULTS: When compared to AD patients, controls had a significantly larger mean HC by 0.58 cm in men and by 0.31 cm in women, but these differences were no longer significant after adjustment for age and years of education. HC varied inversely with age and directly with years of education but did not vary with presence/absence of dementia in first-degree relatives or with apolipoprotein-E (ApoE) genotype. In the prospective analysis, the hazard ratio for time to conversion to AD was not significant for HC when adjusted for age at entry, ApoE allele status, family history of dementia, gender, and years of education. ApoE allele status, first degree relative with dementia, and baseline age conferred an increased risk for conversion to AD, consistent with other studies. CONCLUSIONS: We observed a smaller HC in AD patients compared to nondemented individuals, but AD per se accounted for little of this difference. HC was not a statistically significant predictor for conversion to AD in our longitudinal group.     

Vitamin E and enzymatic/oxidative stress-driven oxysterols in amnestic mild cognitive impairment subtypes and Alzheimer's disease

Oxidative stress,which contributes to neuronal damage, is thought to be a pathophysiologicalmechanism of Alzheimer's disease (AD). Markers of oxidative stress may appear early in the preclinical, mild cognitive impairment (MCI) phase of AD.We investigated the interaction among enzymatic-derived oxysterols (24S-hydroxycholesterol and 27-hydroxycholesterol), markers of oxidative stress, including free radical-related oxysterols (7 hydroxycholesterol and 7-ketocholesterol), and vitamin E in AD patients and two amnestic MCI subtypes, amnestic single-domain MCI (a-MCI) subjects, and multidomain MCI (md-MCI) subjects, compared to healthy control subjects (HC). The study included 37 patients with AD, 24 with a-MCI, 29 with md-MCI, and 24 HC. Plasma assessments were made using isotope dilution-mass spectrometry. Although we found no significant change in free radical- or enzymatic-derived oxysterol concentrations in AD or MCI patients, vitamin E levels corrected for cholesterol were reduced in AD patients compared to HC. Results suggest that AD patients have upregulated cerebral oxidative stress or a nutritional deficit of vitamin E. The oxysterols investigated here are not useful markers for diagnosing AD or MCI.     

The effect of rivastigmine on cognitive functions and regional cerebral blood flow in Alzheimer's disease and vascular dementia: follow-up for 2 years

BACKGROUND AND PURPOSE: The aim of the work was to investigate the effect of treatment with rivastigmine, one of the inhibitors of acetylcholinesterase (AChE-I) on the regional cerebral perfusion (rCBF) and the cognitive functions of the brain in patients with Alzheimer's Disease (AD) and Vascular Dementia (VaD). MATERIAL AND METHODS: The investigations of rCBF were carried out using SPECT (Single Photon Emission Computed Tomography). The results given concern investigations of patients carried out at the onset of the investigation, after 12 months, and 24 months of rivastigmine treatment. RESULTS: In patients with AD it was found that treatment with rivastigmine increases rCBF by 5-7% in the temporal areas during the first 12 months. In the frontal areas the increase was by 3-5%. During the next 12 months rCBF with an accuracy of 2% returned to the initial level, with the exception of the motor cortex, where it remained on the level increased by 5-6%. However, the cognitive functions remained constant during the first 12 months of treatment and decreased significantly during the next 12 months. In patients with VaD rCBF increased in all the regions of the brain except for the temporal posterior regions, and remained at an elevated level for the next 12 months. The cognitive functions deteriorated slowly, but to a much lesser degree than in the case of AD. CONCLUSIONS: From the investigations carried out it follows that treatment with rivastigmine during 24 months prevents a decrease of rCBF in patients with AD. However, the cognitive functions deteriorate after 24 months.     

Muscarinic acetylcholine receptor status in Alzheimer’s disease assessed using (R,R) <Superscript>123</Superscript>I-QNB SPECT

Abstract Background One of the most characteristic changes in Alzheimer's disease (AD) is a deficit in cortical cholinergic neurotransmission and associated receptor changes. Objective To investigate differences in the distribution of M1/M4 receptors using (R, R) ¹²³I-iodo-quinuclidinyl-benzilate (QNB) and single photon emission computed tomography (SPECT) in patients with mild/moderate AD and agematched controls. Also, to compare ¹²³I-QNB uptake to the corresponding changes in regional cerebral blood flow (rCBF) in the same subjects. Methods Forty two subjects (18 AD and 24 healthy elderly controls) underwent ¹²³IQNB and perfusion ^99mTc-exametazime SPECT scanning. Image analysis was performed using statistical parametric mapping (SPM99) following intensity normalisation of each image to its corresponding mean whole brain uptake. Group differences and correlations were assessed using two sample t-tests and linear regression respectively. Results Significant reductions in ¹²³I-QNB uptake were observed in regions of the frontal rectal gyrus, right parahippocampal gyrus, left hippocampus and areas of the left temporal lobe in AD compared to controls (height threshold of p ≤ 0.001 uncorrected). Such regions were also associated with marked deficits in rCBF. No significant correlations were identified between imaging data and clinical variables. Conclusion Functional impairment as measured by rCBF is more widespread than changes in M1/M4 receptor density in mild/moderate AD, where there was little or no selective loss of M1/M4 receptors in these patients that was greater than the general functional deficits shown on rCBF scans.