Vjera Holthoff

Discrimination between Alzheimer Dementia and Controls by Automated Analysis of Multicenter FDG PET

A new diagnostic indicator of FDG PET scan abnormality, based on age-adjusted t statistics and an automated voxel-based procedure, is presented and validated in a large data set comprising 110 normal controls and 395 patients with probable Alzheimers disease (AD) that were studied in eight participating centers. The effect of differences in spatial resolution of PET scanners was minimized effectively by filtering and masking. In controls FDG uptake declined significantly with age in anterior cingulate and frontolateral perisylvian cortex. In patients with probable AD decline of FDG uptake in posterior cingulate, temporoparietal, and prefrontal association cortex was related to dementia severity. These effects were clearly distinct from age effects in controls, suggesting that the disease process of AD is not related to normal aging. Women with probable AD had significantly more frontal metabolic impairment than men. The new indicator of metabolic abnormality in AD-related regions provided 93% sensitivity and specificity for distinction of mild to moderate probable AD from normals, and 84% sensitivity at 93% specificity for detection of very mild probable AD (defined by Mini Mental Score 24 or better). All regions related to AD severity were already affected in very mild AD, suggesting that all vulnerable areas are affected to a similar degree already at disease onset. Ventromedial frontal cortex was also abnormal. In conclusion, automated analysis of multicenter FDG PET is feasible, provides insights into AD pathophysiology, and can be used potentially as a sensitive biomarker for early AD diagnosis.

Multicenter Standardized 18F-FDG PET Diagnosis of Mild Cognitive Impairment, Alzheimer's Disease, and Other Dementias

This multicenter study examined 18F-FDG PET measures in the differential diagnosis of Alzheimers disease (AD), frontotemporal dementia (FTD), and dementia with Lewy bodies (DLB) from normal aging and from each other and the relation of disease-specific patterns to mild cognitive impairment (MCI). Methods: We examined the 18F-FDG PET scans of 548 subjects, including 110 healthy elderly individuals (“normals” or NLs), 114 MCI, 199 AD, 98 FTD, and 27 DLB patients, collected at 7 participating centers. Individual PET scans were Z scored using automated voxel-based comparison with generation of disease-specific patterns of cortical and hippocampal 18F-FDG uptake that were then applied to characterize MCI. Results: Standardized disease-specific PET patterns were developed that correctly classified 95% AD, 92% DLB, 94% FTD, and 94% NL. MCI patients showed primarily posterior cingulate cortex and hippocampal hypometabolism (81%), whereas neocortical abnormalities varied according to neuropsychological profiles. An AD PET pattern was observed in 79% MCI with deficits in multiple cognitive domains and 31% amnesic MCI. 18F-FDG PET heterogeneity in MCI with nonmemory deficits ranged from absent hypometabolism to FTD and DLB PET patterns. Conclusion: Standardized automated analysis of 18F-FDG PET scans may provide an objective and sensitive support to the clinical diagnosis in early dementia.

MCI conversion to dementia and the APOE genotype: A prediction study with FDG-PET.

Objectives: To investigate whether the combination of fluoro-2-deoxy-d-glucose (FDG) PET measures with the APOE genotype would improve prediction of the conversion from mild cognitive impairment (MCI) to Alzheimer disease (AD). Method: After 1 year, 8 of 37 patients with MCI converted to AD (22%). Differences in baseline regional glucose metabolic rate (rCMRglc) across groups were assessed on a voxel-based basis using a two-factor analysis of variance with outcome (converters [n = 8] vs nonconverters [n = 29]) and APOE genotype (E4 carriers [E4+] [n = 16] vs noncarriers [E4−] [n = 21]) as grouping factors. Results were considered significant at p < 0.05, corrected for multiple comparisons. Results: All converters showed reduced rCMRglc in the inferior parietal cortex (IPC) as compared with the nonconverters. Hypometabolism in AD-typical regions, that is, temporoparietal and posterior cingulate cortex, was found for the E4+ as compared with the E4− patients, with the E4+/converters (n = 5) having additional rCMRglc reductions within frontal areas, such as the anterior cingulate (ACC) and inferior frontal (IFC) cortex. For the whole MCI sample, IPC rCMRglc predicted conversion to AD with 84% overall diagnostic accuracy (p = 0.003). Moreover, ACC and IFC rCMRglc improved prediction for the E4+ group, yielding 100% sensitivity, 90% specificity, and 94% accuracy (p < 0.0005), thus leading to an excellent discrimination. Conclusion: Fluoro-2-deoxy-d-glucose-PET measures may improve prediction of the conversion to Alzheimer disease, especially in combination with the APOE genotype.

Regional cerebral metabolism in early Alzheimer’s disease with clinically significant apathy or depression

BACKGROUND Alzheimers disease (AD) is clinically characterized by cognitive impairment and behavioral disturbances. The aim of the study was to identify regional alterations in brain function associated with neuropsychiatric symptoms in early AD. METHODS Patients underwent measures of cerebral glucose metabolism applying positron emission tomography (PET) and (18)F-fluorodeoxyglucose. Neuropsychiatric symptoms were assessed using the Neuropsychiatric Inventory (NPI). Positron emission tomography images of patients suffering a neuropsychiatric symptom of clinical significance (NPI subscore for a specific item >/=4 points) were compared with the images of patients without the specific symptom under study (NPI subscore for a specific item = 0 points). RESULTS A total of 53 patients with AD (Mini-Mental State Examination [MMSE] 22.5 +/- 2.94 points) entered the study. Of all symptoms, apathy and depression were most frequently encountered. The patient group with apathy (n = 17) revealed significant decreases in left orbitofrontal regions when compared with patients free of apathy. Depression of clinical significance (n = 10) was associated with hypometabolism in dorsolateral prefrontal regions. CONCLUSIONS These findings support the notion that different functional circuits underlie apathy and depression in early AD.

Anosognosia in Very Mild Alzheimer’s Disease but Not in Mild Cognitive Impairment

Objective: To study awareness of cognitive dysfunction in patients with very mild Alzheimer’s disease (AD) and subjects with mild cognitive impairment (MCI). Methods: A complaint interview covering 13 cognitive domains was administered to 82 AD and 79 MCI patients and their caregivers. The patient groups were comparable according to age and education, and Mini Mental State Examination (MMSE) scores were ≧24 in all cases. The discrepancy between the patients’ and caregivers’ estimations of impairments was taken as a measure of anosognosia. Results: Self-reports of cognitive difficulties were comparable for AD and MCI patients. However, while in comparison to caregivers MCI patients reported significantly more cognitive impairment (p < 0.05), AD patients complained significantly less cognitive dysfunctions (p < 0.001). Conclusions: While most MCI patients tend to overestimate cognitive deficits when compared to their caregiver’s assessment, AD patients in early stages of disease underestimate cognitive dysfunctions. Anosognosia can thus be regarded as a characteristic symptom at a stage of very mild AD (MMSE ≧24) but not MCI. Accordingly, medical history even in mildly affected patients should always include information from both patient and caregiver.

Changes in brain metabolism associated with remission in unipolar major depression

Objective:  Functional brain correlates of remission in patients with major depressive disorder (MDD) are measured with positron emission tomography (PET) and 18F‐fluorodeoxyglucose.

18FDG PET in vascular dementia : differentiation from Alzheimer's disease using voxel-based multivariate analysis

The brain metabolic pattern of vascular dementia (VaD) remains poorly characterized. Univariate voxel-based analysis ignores the functional correlations among structures and may lack sensitivity and specificity. Here, we applied a novel voxel-based multivariate technique to a large (18F)2-fluoro-2-deoxy-D-glucose positron emission tomography data set. The sample consisted of 153 subjects, one-third each being probable subcortical VaD, probable Alzheimer disease (AD) (matched for Mini-Mental-State examination (MMSE) and age), and normal controls (NCs). We first applied principal component (PC) analysis and removed PCs significantly correlated to age. The remainders were used as feature vectors in a canonical variate analysis to generate canonical variates (CVs), that is, linear combinations of PC-scores. The first two CVs efficiently separated the groups. CV1 separated VaD from AD with 100% accuracy, whereas CV2 separated NC from demented subjects with 72% sensitivity and 96% specificity. Images depicting CV1 and CV2 showed that lower metabolism differentiating VaD from AD mainly concerned the deep gray nuclei, cerebellum, primary cortices, middle temporal gyrus, and anterior cingulate gyrus, whereas lower metabolism in AD versus VaD concerned mainly the hippocampal region and orbitofrontal, posterior cingulate, and posterior parietal cortices. The hypometabolic pattern common to VaD and AD mainly concerned the posterior parietal, precuneus, posterior cingulate, prefrontal, and anterior hippocampal regions, and linearly correlated with the MMSE. This study shows the potential of voxel-based multivariate methods to highlight independent functional networks in dementing diseases. By maximizing the separation between groups, this method extracted a metabolic pattern that efficiently differentiated VaD and AD.

Positron emission tomography demonstrates frontal cortex and basal ganglia hypometabolism in dystonia

We studied 15 dystonic patients with positron emission tomography (PET) and (18F)-2-fluoro-2-deoxy-D-glucose (FDG). The group comprised patients with focal (n = 5), multifocal (n = 1), and generalized (n = 4) dystonia as well as patients with hemidystonia (n = 5). The age at onset was during childhood in four, during adolescence in two, and during adulthood in nine of the subjects. In dystonic patients, global cerebral glucose metabolism was unaltered when compared with normal controls, whereas the pattern of regional cerebral metabolic rate for glucose (rCMR[Glu]) was significantly different (p = 0.0001). rCMR(G1u) was significantly decreased in the caudate and lentiform nucleus and in the frontal projection field of the mediodorsal thalamic nucleus. The study confirms the concept that dystonia is caused by impaired connections between the basal ganglia, the thalamus, and frontal association areas.

A comparison of unawareness in frontotemporal dementia and Alzheimer’s disease

Background: Loss of insight is a core diagnostic feature of frontotemporal dementia (FTD) and anosognosia is frequently reported in Alzheimer’s disease (AD). Aim: To compare unawareness (anosognosia) for different symptoms, measured with a discrepancy score between patient’s and caregiver’s assessment, in AD and FTD. Method: In a prospective, multi-centre study, 123 patients with probable AD, selected according to the NINCDS-ADRDA procedure, were matched for age, sex, education, disease duration and dementia severity to patients with FTD (n = 41), selected according to international consensus criteria. A research complaint questionnaire was used to obtained patient’s and caregiver’s assessment concerning neuropsychological and behavioural symptoms. Data were compared in each group and between groups. Unawareness (measured by discrepancy scores) was compared between patients with AD and FTD. Results: The caregivers generally assessed symptoms more severely than did patients, but both patient groups reported changes in affect (depressive mood or irritability) as their caregivers did. Unawareness was greater in patients with FTD than in patients with AD for language and executive difficulties, and for changes in behaviour and daily activities. Conclusion: The main finding is that unawareness was observed in both patients with FTD and patients with AD for most clinical domains. However, qualitative and quantitative differences showed that lack of awareness was greater in patients with FTD.

Cerebral metabolic correlates of four dementia scales in Alzheimer's disease

Abstract Different scales can be used to evaluate dementia severity in Alzheimer’s disease (AD). They do assess different cognitive or functional abilities, but their global scores are frequently in mutual correlation. Functional imaging provides an objective method for the staging of dementia severity. Positron emission tomography was used to assess the relationship between brain metabolism and four dementia scales that reflect a patient’s global cognitive abilities (mini mental state), caregiver’s evaluation of cognitive impairment (newly designed scale), daily living functioning (instrumental activities of daily living) and global dementia (clinical dementia rating). We wondered whether different clinical dementia scales would be related to severity of metabolic impairment in the same brain regions, and might reflect impairment of common cognitive processes. 225 patients with probable AD were recruited in a prospective multicentre European study. All clinical scales were related to brain metabolism in associative temporal, parietal or frontal areas. A factorial analysis demonstrated that all scales could be classified in a single factor. That factor was highly correlated to decrease of cerebral activity in bilateral parietal and temporal cortices, precuneus, and left middle frontal gyrus. This finding suggests that global scores for all scales provided similar information on the neural substrate of dementia severity. Capitalizing on the neuroimaging literature, dementia severity reflected by reduced metabolism in posterior and frontal associative areas in AD might be related to a decrease of controlled processes.