Rüdiger Mielke

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.

EEG power changes are related to regional cerebral glucose metabolism in vascular dementia

OBJECTIVEnIn patients with vascular dementia (VD), the relationship between the EEG power within the 4 frequency bands and the regional metabolic disturbances was investigated.nnnMETHODSnTwenty-eight patients (age 69.0+/-6.54 years) with VD according to NINDS-AIREN criteria underwent quantitative EEG recording, according to the 10-20 system, and fluodeoxyglucose F18 positron emission tomography (PET) at resting condition within 24 h. EEG power FFT-analysis was performed for delta (2-3.5 Hz), theta (4-7.5 Hz), alpha (8-13 Hz) and beta (13.5-20 Hz) frequency bands. Regional EEG power bands were related to regional glucose metabolism in anatomically defined regions corresponding to locations of the 10-20 system.nnnRESULTSnCorrelation between slow frequency band power and glucose metabolism was found. A widespread inverse relationship of delta power to metabolism was found between various regions; additionally, delta power was negatively correlated to cerebral glucose metabolism in individual regions. Frontal theta power correlated especially with thalamic CMRglc. Alpha power correlated directly with metabolism in the occipital lobe. No significant relationships were found between beta power and metabolism.nnnCONCLUSIONnWe conclude that EEG power in VD is linked to glucose metabolism, indicating specific regional dependencies.

Activation PET as an Instrument to Determine Therapeutic Efficacy in Alzheimer's Diseasea

Forty patients with probable Alzheimers disease (AD) were selected from a pool of 80 patients and assigned to 4 groups. Each received either social support, cognitive training only, or cognitive training in combination with pyritinol or phosphatidylserine. Treatment duration was 6 months. Before and after treatment the patients underwent neuropsychological testing as well as measurement of the regional cerebral metabolic rate for glucose using positron emission tomography (PET) and 2[18F]‐fluoro‐2‐deoxy‐D‐glucose (FDG). Before treatment, the groups were comparable in respect to resting and activated glucose pattern achieved by a visual recognition task. They did not differ in scores of a neuropsychological test battery. After the treatment period the group with cognitive training + phosphatidylserine showed a significant glucose enhancement during the stimulation tasks in various brain regions, and an improvement in cognitive functioning compared to the other groups. The group with cognitive training + pyritinol had better stimulation effect as that of the social support group indicating that a combination of cognitive training + pharmacological intervention was superior than that of cognitive training alone.

Apolipoprotein E polymorphism influences the cerebral metabolic pattern in Alzheimer's disease

In 49 patients with the clinical diagnosis of probable Alzheimers disease (AD) apoE genotyping as well as regional cerebral glucose metabolism (rCMRGI) using positron emission tomography (PET) of [18F]2-fluoro-2-deoxy-D-glucose (FDG) were studied. The metabolic pattern was condensed to a ratio by dividing the rCMRGI of typically affected regions (temporo-parietal and frontal association cortex) by the rCMRGI of the least affected regions (primary cortical areas, basal ganglia, cerebellum and brainstem). Epsilon4-heterozygotes and epsilon4-homozygotes were grouped together, and also those lacking the epsilon4-allele (non-epsilon4). For the metabolic pattern we found a significant correlation to severity of dementia in both groups (epsilon4: r = 0.49, P = 0.05; non-epsilon4: r = 0.59, P = 0.006). On ANCOVA severity of dementia and epsilon4 status were independent predictors of the cerebral metabolic pattern (P = 0.01). These differences may be attributed to epsilon4 dependent histopathologic changes.

Impaired benzodiazepine receptor binding in peri-lesional cortex of patients with symptomatic epilepsies studied by [C- 11]-flumazenil PET

Individual benzodiazepine receptor (BZR) binding of peri‐lesional cortex was investigated in symptomatic epilepsies. Eleven patients aged 19–44u2003years were studied whose diagnosis was established by medical history, clinical, electroencephalographic, and magnetic resonance imaging (MRI) findings. Three‐dimensional [11C]‐flumazenil (FMZ) positron emission tomography and MRI scans were obtained and coregistered. Lesions (five low‐grade brain tumours, one AV malformation, one cavernoma, one cystic lesion of unknown aetiology, one traumatic brain injury, one post‐operative and one post‐haemorrhagic defect) were outlined on individual MRI scans. Adjacent to those lesions, and in homologous contralateral structures, FMZ binding was analysed in four pairs of cortical 9u2003×u20039‐mm regions of interest (ROIs) placed on transaxial and coronal slices, respectively, as well as in the lesion volume and its mirror region. Percentage asymmetry ratios were calculated and those at or outside the 90–110% range were operationally defined significant. Peri‐lesional FMZ binding asymmetries ranged from 70 to 125%, lesional asymmetries from 38 to 82%. Only one patient showed no significant change, whilst nine exhibited significant reductions of FMZ binding in at least one ROI (3u2003×u20031, 4u2003×u20032, 1u2003×u20033, 1u2003×u20034), and significant increases were observed in two ROIs of another patient. Therefore, peri‐lesional disturbances of BZR binding are common but variable in location. Because a close correlation between regional decreases in FMZ binding and spiking activity was recently demonstrated in neocortical epilepsies, abnormal peri‐lesional FMZ binding may bear some relation to the mechanisms of epileptogenesis in symptomatic epilepsies.

Prognostic relevance of quantitative topographical EEG in patients with poststroke aphasia.

In this prospective study we analyzed the prognostic value of topographical quantitative EEG (qEEG) in poststroke aphasia. Twenty-three right-handed patients (ages 56 +/- 12 years) with different types of aphasia were studied. Quantitative EEG under resting conditions and an aphasia test battery were applied twice, 2 and 8 weeks after a stroke. EEG power fast Fourier transform was performed for delta (2-3.5 Hz), theta (4-7.5 Hz), alpha (8-13 Hz), and beta (13.5-20 Hz) frequency bands. EEG abnormalities within and outside speech relevant areas are related to restitution of poststroke aphasia. In the ischemic regions they indicate local disturbances; outside they reflect failures in neuronal networks involved in the generation and propagation of the alpha rhythm.

Propentofylline improves regional cerebral glucose metabolism and neuropsychologic performance in vascular dementia

In a double-blind, placebo-controlled trial in thirty patients with mild to moderate vascular dementia (VD) according to DSM-III-R criteria, the effects of the adenosine uptake blocker propentofylline (HWA 285) on regional cerebral glucose metabolism (rCMRGl) was studied using positron emission tomography of 2-[18F]fluoro-2-deoxy-D-glucose (FDG). 25 subjects completed the 3-months study. Propentofylline significantly improved relative rCMRGl in the motor cortex, while relative rCMRGl in the placebo treated group worsened significantly. Neuropsychologically, visual information processing was improved in the propentofylline group and we observed a trend towards a slowing of the progression of cognitive deterioration in patients with VD. The results of the longitudinal analysis showed further that neuropsychological and metabolic changes are closely related. These findings justify a large-scale clinical trial to prove therapeutic efficacy.

Visual versus Auditory Memory Stimulation in Patients with Probable Alzheimer's Disease A PET Study with 18 FDGa

Patients with probable Alzheimers disease were either stimulated with a continuous visual recognition task (n = 18) or with a continuous auditory recognition task during PET measurement with 18 FDG. The PET scanner was a Siemens CTI, ECAT EXACT with 5 mm transaxial and 6 mm axial resolution. The global stimulation effects were nearly identical in both groups and increased of 4.17 ± 8.14% in the auditory stimulated group and of 4.03 ± 11.78% in the visual stimulated group. Beyond regional stimulation effects in both groups a common cerebellar stimulation effect was measured. It is concluded that the cerebellar stimulation effect reflects a modality independent cognitive process and that the only small enhancement of global glucose metabolism indicates disturbed stimuli processes and finally explained the patients failure in memory tasks.

Temporomesial epileptogenic focus in benign epilepsy of childhood with occipital paroxysms (BEOP)

Abstract A 17-year-old female suffered three simple partial visual seizures at the ages of 12,13 and 17 years. Magnetic resonance imaging (MRI) did not show any focal cerebral anomaly. Because of typical changes in electroencephalography, benign epilepsy of childhood with occipital paroxysms (BEOP) was diagnosed. To study benzodiazepine receptor density and functional changes in this particular variety of idiopathic localization-related epilepsy, positron emission tomography (PET) of 11C-flumazenil and 18F-2-fluoro-2-deoxy-D-glucose was performed at rest and during an emotional speech activation task. Flumazenil-PET demonstrated a small epileptogenic focus in the left amygdaloid body and FDG-PET showed hypometabolism in the amygdala and hippocampus. Stimulation by an emotional speech task produced a distinct pattern of regional activation, including the left amygdala and hippocampus. We conclude that functional neuroimaging by PET is a valid method to detect small epileptogenic foci, even when no anatomic...

Age-Dependent Changes of the Metabolic Pattern in Patients with Alzheimer’s Disease

Since the first description of Alzheimer’s disease (AD) by Alois Alzheimer (1910) and its introduction by Kraepelin in 1910, the influence of age on the background of different psychopathological and apparative criteria has been discussed. Whether AD should be considered as a uniform manifestation or classified into a presenile and a senile type as a possible means of differentiation of subtypes by age remains controversial. Even Alzheimer waived this concept of presenile disease and applied his term to all presenile and senile disease types showing the characteristic typical macroscopic and microscopic pattern (Alzheimer 1911). Nonetheless, the terms dementia of Alzheimer type and senile dementia of Alzheimer type (DAT and SDAT) were introduced (Katzman 1976) with an arbitrary cutoff age of 65 years.