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Biomedical subjects

R Mielke

Publications and source records attributed to R Mielke.

At least 37 records · Page 2Linked to original sources
PubMed1998

Normal and pathological aging--findings of positron-emission-tomography.

Normal aging of the brain is predominantly characterized by metabolic changes in the prefrontal cortex. While in middle age there is a trend to hyperfrontality, PET demonstrates in old age a decline of regional cerebral glucose metabolism in frontal areas. In progeric diseases, clinically apparent as premature aging, the metabolic pattern is similar like in normal aging but qualitatively more severe. In patients with the diagnosis of probable Alzheimer's disease (AD) hypometabolism in early dementia is typically present in heteromodal association areas. Hypometabolism then spreads to other cortical and subcortical regions suggesting a characteristic pattern of degeneration that reflects selective vulnerability within limbic-cortical networks. Synaptic plasticity, clinically apparent as cognitive reserve capacity, can be assessed by PET under specific cognitive activation. In AD it is reduced in comparison to age-matched normals and may be influenced by drugs giving trophic support to neurochemical systems.

Aging↗
PubMed1998

Propentofylline in the treatment of vascular dementia and Alzheimer-type dementia: overview of phase I and phase II clinical trials.

Pathophysiologic processes common to both vascular (multi-infarct) dementia and dementia of the Alzheimer type may include microglial activation with resultant generation of inflammatory cytokines and neurotoxic free radicals, decreased secretion of nerve growth factor by astrocytes, excess release of glutamate with associated neurotoxicity, and loss of cholinergic neurons. The functional benefits and neuroprotective effects of propentofylline (PPF) stem from its interference with these overlapping pathways of neurodegeneration. The clinical pharmacology and safety of PPF were studied in a number of phase I studies in healthy young and elderly adults and in patients with renal or hepatic impairment. These studies have shown that PPF 300 mg t.i.d. is safe and well tolerated when taken on an empty stomach 1 h before meals. In a randomized, double-blind phase II study involving 190 elderly subjects with clinically and psychometrically documented mild to moderate dementia, 12 weeks of PPF therapy produced significantly greater improvements than placebo in Gottfries-Bråne-Steen (GBS) scores, Mini-Mental State Examination (MMSE) scores, and Clinical Global Impression (CGI) ratings. A subsequent phase II study using positron emission tomography (PET) revealed that cortical glucose metabolism improved significantly in patients with vascular dementia after 12 weeks of PPF treatment but deteriorated significantly with placebo. A third phase II study, which enrolled patients with Alzheimer-type dementia, demonstrated that PPF significantly enhanced functional reserve, as reflected by increases in regional cerebral glucose metabolism after stimulation with a verbal memory task. In contrast, patients randomized to placebo exhibited a significant decline in functional activation and significant worsening in their MMSE scores over the course of this 12-week study. Propentofylline proved to be safe, well tolerated, and free of severe side effects in all three of these phase II trials. Phase I trial results suggest that significant food interactions occur with PPF, indicating that the drug should be taken on an empty stomach 1 h before meals. Phase II trial results indicate that PPF yields clinically measurable improvements in the symptoms of dementia and prevents loss of stimulation-related increases in glucose metabolism over a treatment period of 3 months. Whether these results indicate that PPF can slow the progression of dementia can be determined only by long-term trials specifically designed to determine the drug's effect on disease progression.

Aged↗
PubMed1997

Widespread functional deficits in perception-related networks demonstrated by PET in a case with simple visual seizures.

PURPOSE: To study benzodiazepine receptor (BZR) density and functional deficits in occipital lobe epilepsy. METHODS: A 39-year-old man who had simple partial visual seizures after neurosurgical transtentorial extirpation of a pinealoma was studied by EEG, magnetic resonance imaging (MRI), and positron emission tomography (PET) of [18F]2-fluoro-2-deoxy-D-glucose (FDG) at rest and during visual activation task and[11C]flumazenil (FMZ). RESULTS: Electroencephalographic recordings were nonspecific, and MRI did not reveal any morphologic anomaly in the occipital lobe. Flumazenil-PET demonstrated a small epileptogenic region in the right visual association cortex and FDG-PET showed hypometabolism in a corresponding location and thalamic diaschisis. Stimulation of occipital metabolism by a continuous visual recognition task improved significantly the contrast between the dysfunctional zone and its surround. CONCLUSIONS: As BZR deficits are restricted to a small region, widespread hypometabolism in networks involved in visual information processing indicates an extensive functional deactivation by the epileptogenic focus.

Adult↗
PubMed1996

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.

Aged↗
PubMed1996

Visual versus auditory memory stimulation in patients with probable Alzheimer's disease. A PET study with 18 FDG.

Patients with probable Alzheimer's 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 patient's failure in memory tasks.

Aged↗
PubMed1996

MRI-guided flumazenil- and FDG-PET in temporal lobe epilepsy.

In temporal lobe epilepsy (TLE) patients without lesions, major hippocampal sclerosis, or atrophy on magnetic resonance imaging (MRI), the localizing power of [11C]flumazenil (FMZ) and 2-[18F]fluoro-2-deoxy-D-glucose (FDG) was compared using high-resolution positron emission tomography (PET) studies and individually coregistered MRI scans. Following complete clinical, neuropsychological, and electrophysiological evaluation, benzodiazepine receptor density was assessed using the FMZ equilibrium method. Thirty minutes later, interictal FDG-PET was performed under resting conditions. PET images were matched to three-dimensionally coregistered, T1-weighted MRI. Each temporal lobe (TL) was divided into 12 volumes of interest. The regional FMZ data were normalized with respect to average cortical values. For each patient the right-left asymmetries of rCMRGlc and normalized FMZ data were calculated. In 7 to 10 patients, mesial TL structures showed reduced FMZ binding, with a decrease by at least 10% in the affected TL. Reductions of 10% or more of rCMRGlc usually were more widespread than FMZ reductions and often involved lateral temporal cortex. The regions of most pronounced disturbances are not necessarily identical in both methods. Three patients had a complex correspondence of lateralization with PET, neuropsychological, and EEG data. In 4 patients, lateralization was less clear from EEG or neuropsychological results but was still consistent with lateralization by PET. In 3 of 10 patients, however, major discrepancies were found. These data suggest that the combination of neuropsychological testing, EEG, and MRI-guided FMZ- and FDG-PET will help to select patients with clearly defined epileptogenic foci especially in mesial TLE. Even in cases without MRI lesions, TL epileptic foci can be lateralized with consistency across the methods; FMZ-PET shows the pathologic focus more circumscribed than FDG-PET.

Adult↗
PubMed1996

Vascular dementia: perfusional and metabolic disturbances and effects of therapy.

Positron emission tomography (PET) has elucidated basic pathophysiological mechanism that produce the cognitive decline in vascular dementia (VD). The typical pattern of glucose metabolism seen in VD with scattered areas of focal cortical and subcortical hypometabolism differs from that in AD with marked hypometabolism affecting the association areas. The total volume of metabolically inactive tissue is significantly related to severity of dementia. Rather than the quantity of tissue destruction, the critical effect may be the quantity of cortical hypometabolism caused by subcortically induced disconnection. Studies with HMPAO SPECT have shown focal deficits in VD and AD patients that are comparable to those seen with FDG PET. In mildly demented patients performance for the classification AD versus VD is much better by PET because it might be more sensitive for imaging small functional pathological changes. A longitudinal analysis of rCMRGl in VD showed that the progression of dementia can be delayed by the adenosine uptake blocker propentofylline and that neuropsychological and metabolic changes are closely related.

Brain↗
PubMed1996

Regional cerebral glucose metabolism and postmortem pathology in Alzheimer's disease.

In four patients with an antemortem diagnosis of probable Alzheimer's disease (AD) regional cerebral glucose metabolism (rCMRGl) was studied prospectively by positron emission tomography (PET) and compared with postmortem semiquantitative neuropathology. The interval between the last PET study and autopsy was 1.3 +/- 0.8 years. In comparison with age-matched controls, the AD patients showed predominant temporoparietal hypometabolism spreading to other cortical and subcortical regions during serial PET scans. All patients had neuropathological findings typical for AD. There was a significant relationship between rCMRGl and density of senile plaques (SP) in one patient (tau b = -0.86, P < 0.05). SP were distributed quite homogeneously in all regions examined. Neurofibrillary tangles (NFT) were concentrated focally in the hippocampus-amygdala-entorhinal complex. In the context of widespread developing cortical hypometabolism, the predilection of NFT for involvement in limbic areas suggests a disruption of projection neurons as the pathogenetic process of cortical dysfunction.

Aged↗
PubMed1995

Genomic organization of a mouse type I activin receptor.

We have characterized the genomic organization of a mouse type I activin receptor. Using the mouse tsk7L cDNA, 4 overlapping lambda clones containing the activin receptor IA (ActRIA) gene were isolated from a mouse 129 Sv genomic library. The mouse ActRIA gene is encoded by 10 exons and spans approximately 40 kb. The size of the introns was determined and the intron/exon boundaries were sequenced. Primer extension analysis of the 5' non-translated region using RNA from different organs or tissues revealed a strong transcription start site 68 nucleotides upstream of the ATG. Knowledge of the structure of the ActRIA gene is essential for the production of ActRIA deficient mice by homologous recombination.

Activin Receptors↗
PubMed1995

Cognitive impairment in Alzheimer's disease correlates with ventricular width and atrophy-corrected cortical glucose metabolism.

We compared the correlation of PET and MRI with neuropsychological tests in 26 patients with probable Alzheimer's disease (AD). The width of the temporal horns and the third ventricle, regional metabolic rates of glucose (rCMRGlu) and the proportion of cerebrospinal fluid space in mesial temporal and temporoparietal cortical regions were measured with three-dimensionally coregistered PET and MRI in two planes perpendicular to the Sylvian fissure. Highly significant correlations between rCMRGlu and neuropsychological tests were found mainly in the temporoparietal cortex, with and without correction for atrophy. Correlations of similar magnitude were seen also between most tests and the width of the temporal horns and third ventricle. Changes in the third ventricle and mesial temporal lobe were best seen with MRI, whereas PET most clearly depicted alterations in neocortical association areas. These two aspects of the disease correlated with the severity of dementia to a similar degree.

Aged↗
PubMed1995

P300 in Alzheimer's disease: relationships to dementia severity and glucose metabolism.

In 45 patients (aged 48-85 years) with probable Alzheimer's disease (AD) according to current research criteria (NINCDS-ADRDA) with different stages of dementia severity (Mini Mental Status Examination (MMSE) 7-27) the auditory evoked P300 waves were mapped and regional cerebral metabolic rates of glucose were measured by positron emission tomography of 2-[18F]fluoro-2-deoxy-D-glucose. Age adjusted P300 latency was significantly correlated to dementia severity (r = -0.33, p = 0.028), but no significant relationships were found for P300 amplitudes. Dependencies existed among cortical glucose metabolic rates and MMSE with the highest correlation coefficient for the metabolic ratio of regions typically affected and non-affected in AD (r = 0.75, p = 0.0001). A significant correlation was also calculated between P300 latency and metabolic ratio (r = -0.44, p = 0.002), but no relationships were observed among P300 amplitudes and glucose metabolic rates of individual brain regions. These results indicate that P300 latency and metabolic rates but not P300 amplitudes qualify as measures of severity in AD. The lack of regional correlations among P300 amplitudes and glucose metabolism is not consistent with a cortical contribution to P300 generation.

Aged↗
PubMed1995

Dysfunction of visual cortex contributes to disturbed processing of visual information in Alzheimer's disease.

The relation between visual impairment and regional cerebral metabolic rate of glucose (rCMRGl) was studied in 31 patients with probable Alzheimer's disease (AD) by using positron emission tomography with 18F-2-fluoro-2-deoxy-D-glucose. To exclude any precortical cause of visual dysfunction only patients were included who had amplitudes and latencies of visually evoked potentials (flash and pattern reversal) within the normal range. Visual information processing was evaluated psychometrically by a fragmented picture test (FPT), which is a combined perception (identification score) and memory (reidentification score) task and refers to Gollin's incomplete pictures. The identification and reidentification scores were significantly worse than in normals. Reductions of the rCMRGl in the primary visual fields, and in the secondary visual fields were found. A significant partial correlation with adjustment for age between the reidentification score of the FPT and the rCMRGl of the secondary visual fields (r = -.39, p < .05) in AD patients was found, indicating involvement of the secondary visual cortex in the pathological changes in AD.

Aged↗
PubMed1995

[Premorbid intelligence diagnosis with the MWT-B(Multiple Choice Word Test-B) in patients with Alzheimer disease].

The usefulness of the multiple-choice word test (MWT-B) was tested as a measure for premorbid intelligence in 107 patients with probable Alzheimer's disease following the NINCDS-ADRDA criteria. The patients were allocated to three groups according to severity of dementia: mild (n = 40), moderate (n = 41) and severe (n = 26). Dementia severity was assessed with the Mini Mental State Test (MMST). The mean of the raw values of the MWT-B (maximum 37) in the group with mild dementia was 28.0 (SD = 5.57), in the group with moderate dementia 23.3 (SD = 8.01), and in the group with severe dementia 6.7 (SD = 8.44), indicating a parallel worsening with the other tests. The MWT-B value of the whole sample correlated with the MMST value (r = 0.70); a significant correlation still existed in patients with mild and moderate dementia. These results confirm that the MWT-B is relevant for dementia. The rate of cerebral glucose metabolism, measured with positron emission tomography (PET) and 18F-fluorodeoxy-glucose (FDG) correlated significantly with the MWT-B scores in the Alzheimer-sensitive temporoparietal region (r = 0.43; P = 0.001) and frontal brain region (r = 0.37; P < 0.05). Whether or not it can be used as a screening measure of dementia will have to be decided on the basis of its scales for sensitivity and specificity.

Aged↗
PubMed1994

HMPAO SPET and FDG PET in Alzheimer's disease and vascular dementia: comparison of perfusion and metabolic pattern.

Positron emission tomography (PET) of 18F-2-fluoro-2-deoxy-D-glucose (FDG) and single-photon emission tomography (SPET) of 99mTc-hexamethylpropylene amine oxime (HMPAO) were performed under identical resting conditions within 3 h in 20 patients with probable Alzheimer's disease (AD), 12 patients with vascular dementia (VD) and 13 normal persons. In the temporoparietal association cortex similar impairment of relative regional cerebral glucose metabolism (rCMRGl) and relative HMPAO uptake (rCBF) was found. In addition PET showed hypometabolism in the occipital association cortex. The functional pattern was condensed to a ratio of regional values of association areas divided by regional values of structures that are typically less affected by AD. In normals this ratio was significantly related to age for PET metabolic data (r = -0.66, P = 0.01). The ratio was significantly lower in AD than in VD and controls for both rCMRGl and rCBF. In AD only, the metabolic ratio was related to severity of dementia (r = 0.54, P = 0.003) and age (r = 0.64, P = 0.003). Metabolic differences between normals and AD patients were less obvious in old age. In contrast, there were no significant correlations between the perfusion ratio and severity of dementia or age. Comparing the metabolic and perfusion ratio by receiver operating characteristic curves, PET differentiated AD from normals only marginally better than SPET. Differentiation between AD and VD was much better achieved by PET. Our results suggest that both PET and SPET can distinguish AD patients from controls, whereas for differentiation between AD and VD SPET is of little value.

Aged↗
PubMed1994

Quantitative topographical EEG compared to FDG PET for classification of vascular and degenerative dementia.

Quantitative topographical EEG was compared with regional glucose metabolism measured by PET with respect to the sensitivity in the classification of mild to moderate dementia. In 24 patients with probable Alzheimer's disease (DAT), 19 patients with vascular dementia (VD) and 15 age-matched healthy controls, global and regional EEG and PET data were analyzed. The metabolic ratio between typically affected and non-affected regions differentiated between DAT and VD (P < 0.001) as well as between DAT and normal controls (P < 0.001) even for the subgroup of mild dementia. In contrast to PET, global EEG changes were more sensitive than regional alterations for the classification into the respective groups. Relative theta power was most sensitive for the differentiation of demented patients irrespective of type of normal controls (P < 0.01), whereas OCC/FR alpha ratio (occipital divided by frontal power) separated between dementia types (P < 0.01) as well as between DAT and normals (P < 0.05). Additionally, EEG may help to grade severity especially in DAT. Combined use of EEG and PET was more discriminative and reached higher diagnostic specificity than each test individually. These results suggest that EEG and PET are complementary diagnostic procedures for the differentiation and classification of dementias.

Aged↗
PubMed1994

Difference of regional cerebral metabolic pattern between presenile and senile dementia of the Alzheimer type: a factor analytic study.

Positron emission tomographic studies using metabolic ratios to represent the contrast between certain brain regions have shown differences of cerebral glucose metabolism between presenile and senile dementia of Alzheimer type (DAT). In this study, factors for regional variance of cerebral metabolism in 61 patients with probable Alzheimer's disease were obtained using principal component analysis (PCA). The difference between two age groups of DAT patients according to age at onset < or = 65 years (n = 30) and > 65 years (n = 31) were investigated. A PCA using nine pairs of cerebral regions normalized to cerebellum for reduction of intersubject variability identified five regional factors for cerebral metabolism: one each for the left and right temporo-parietal cortex, and the other three for frontal cortex, primary visual and sensorimotor cortex, and mesial temporal sensorimotor cortex, and mesial temporal cortex. The age groups differed significantly only in the factor for the right temporo-parietal cortex, with a more prominent metabolic reduction in presenile than senile DAT. Severity of dementia was correlated with the factors for the right and left temporo-parietal cortex. The effect of age at onset on glucose metabolism of the right temporo-parietal cortex was independent from that of dementia severity in DAT.

Age Factors↗
PubMed1994

Visual evoked potentials in Alzheimer's disease: investigations in a PET-defined collective.

Intravital diagnosis of Alzheimer's disease (AD) based clinical and neuropsychological findings alone does not allow sufficient differentiation from other disorders such as vascular dementia. Positron emission tomography (PET) secures intravital diagnosis with high accuracy by determination of a typical metabolic pattern. Numerous publications have proposed visual evoked potentials (VEP) for the detection of AD. In a collective of 15 patients with probable AD according to NINCDS/ADRDA criteria and the typical metabolic pattern of AD, we examined pattern reversal and flash VEPs. The results were compared to those of an age-matched collective of patients without impairment of memory. Neither pattern reversal nor flash VEP were correlated to severity of dementia as determined by the mini-mental status examination (MMSE). The positive results of other investigators are probably due to different patient selection criteria which do not include findings of cerebral glucose metabolism in the definition of AD.

Aged↗