Peter Schönknecht

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.

Impairment in basal limbic function in schizophrenia during affect recognition

Patients with schizophrenia routinely fail to perform affect recognition tasks as accurately as healthy controls. The investigation of performance-related changes in cerebral activation in healthy subjects may facilitate the understanding of adaptation processes to different levels of difficulty and help to interpret the activation changes found in schizophrenic patients. Nine first hospitalized partly remitted schizophrenic patients and 10 healthy controls participated in an fMRI study with a facial affect discrimination and labeling task. Seven of the 10 healthy subjects were reexamined with changed stimulus conditions adapted according to the mean accuracy scores detected in schizophrenic patients. Controls showed a significantly increased activation of the right gyrus frontalis medialis with rising task difficulty during both tasks. The schizophrenic patients demonstrated a significantly decreased activation of the anterior cingulate during facial affect discrimination and of the amygdala-hippocampal complex bilaterally during facial affect labeling. In addition, an increased activation of the gyrus frontalis medialis bilaterally became apparent in the schizophrenic patients. It is suggested that the latter may reflect a compensatory effort for deficits in more basal limbic functions.

Cognitive activity, education and socioeconomic status as preventive factors for mild cognitive impairment and Alzheimer's disease

Growing epidemiological evidence suggests that premorbid participation in cognitive leisure activities (CLA) reduces the risk of dementia by increasing cognitive reserve. We investigated the differential effect of CLA, education, and socioeconomic status (SES) on the development of mild cognitive impairment (MCI) and Alzheimers disease (AD). Participants in the prospective population-based ILSE study (*1930-1932; 12-year follow-up) were examined in three examination waves (t1:1993/94; t2:1997/98; t3:2005/07). In total, 381 subjects of the original cohort (n=500) were re-examined at t3. Of these subjects 29% received the diagnosis of MCI and 7% of AD. Subjects participated in a thorough psychogeriatric examination and neuropsychological testing. Moreover, they took part in a detailed autobiographical interview and completed questionnaires including socio-demographic data and current frequency of participation in CLA. Subjects who were highly cognitively active at t1 had a significantly reduced risk of developing MCI/AD at t3 (scores adjusted for education, SES, gender, and depressive symptoms). Additionally, high education and high SES separately reduced the risk of MCI and AD. Our results confirm the hypothesis that a high level of CLA acts as a protective factor against the development of MCI and AD by increasing cognitive reserve. This effect is not accounted for by important potential confounders.

Cerebrospinal fluid 24S-hydroxycholesterol is increased in patients with Alzheimer's disease compared to healthy controls

Experiments in cell cultures indicate that accumulation of cholesterol in hippocampal neurons results in an accelerated cleavage of amyloid precursor protein into amyloidogenic components. To be eliminated from the brain, cholesterol is converted to 24S-hydroxycholesterol which may reflect cerebral cholesterol turnover. We investigated cerebrospinal fluid (CSF) concentrations of 24S-hydroxycholesterol in a group of 14 Alzheimers disease (AD) patients and ten healthy controls without any cognitive deficits or psychiatric or neurological disorders. To exclude potential effects of circulating plasma cholesterol on CSF 24S-hydroxycholesterol levels, only patients and controls with cholesterol levels in the normal range of 150-230 mg/dl were included. We found significantly elevated 24S-hydroxycholesterol CSF but not plasma levels in AD patients compared with healthy controls. Our results demonstrate that CSF 24S-hydroxycholesterol is increased in AD. This effect does not seem to be triggered by plasma cholesterol levels since the latter did not significantly differ between groups.

International quality control survey of neurochemical dementia diagnostics.

UNLABELLED Currently, neurochemical dementia diagnostics (NDD) are increasingly entering routine clinical neurochemistry, offering improved early and differential diagnosis of dementias. However, there is an obvious lack of standardization in pre-analytical sample handling and systematic quality surveys. Therefore, in this study, 14 laboratories in Germany, Austria, and Switzerland were given aliquots of a human cerebrospinal fluid (CSF) sample, and were asked to measure Alzheimers disease (AD) biomarkers (amyloid beta (Abeta) peptides, total Tau protein, and phosphorylated Tau protein (P-tau(181P))) according to their routine protocols. RESULTS The inter-laboratory coefficients of variation of the results obtained by the laboratories participating in this study were in the range of 20-30%. Although the results of this quality control survey are promising, the quality of measurements has to be further optimized.

Cholinergic receptor subtypes and their role in cognition, emotion, and vigilance control: an overview of preclinical and clinical findings.

RationaleThe cholinergic system has long been linked to cognitive processes. Two main classes of acetylcholine (ACh) receptors exist in the human brain, namely muscarinic and nicotinic receptors, of which several subtypes occur.ObjectivesThis review seeks to provide an overview of previous findings on the influence of cholinergic receptor manipulations on cognition in animals and humans, with particular emphasis on the role of selected cholinergic receptor subtypes. Furthermore, the involvement of these receptor subtypes in the regulation of emotion and brain electrical activity as measured by electroencephalography (EEG) shall be addressed since these domains are considered to be important modulators of cognitive functioning.ResultsIn regard to cognition, the muscarinic receptor subtypes have been implicated mainly in memory functions, but have also been linked to attentional processes. The nicotinic α7 receptor subtype is involved in working memory, whereas the α4β2* subtype has been linked to tests of attention. Both muscarinic and nicotinic cholinergic mechanisms play a role in modulating brain electrical activity. Nicotinic receptors have been strongly associated with the modulation of depression and anxiety.ConclusionsCholinergic receptor manipulations have an effect on cognition, emotion, and brain electrical activity as measured by EEG. Changes in cognition can result from direct cholinergic receptor manipulation or from cholinergically induced changes in vigilance or affective state.

Reduced cerebral glucose metabolism in patients at risk for Alzheimer's disease

While significantly reduced glucose metabolism in fronto-temporo-parietal and cingulate cortices has been demonstrated in Alzheimers disease (AD) compared with controls, cerebral glucose metabolism in patients with mild cognitive impairment who subsequently develop AD is less well-defined. In the present study we measured cerebral glucose metabolism by positron emission tomography (PET) with (18)F-2-fluoro-2-deoxy-D-glucose in 14 patients with aging-associated cognitive decline (AACD), 44 patients with AD, and 14 healthy control subjects at baseline. The AACD patients were clinically followed up, and conversion to AD was determined. Compared with controls, AACD patients had significantly reduced glucose metabolism in the right precuneus, posterior cingulate, right angular gyrus, and bilateral middle temporal cortices, while the respective deficits were more pronounced in AD patients and also involved the frontal cortices. AACD patients who subsequently converted to AD (AACD-converters) showed more extended metabolic changes which also involved the frontal and temporal cortices, right cingulate gyrus, right thalamus, and bilateral precuneus.

Topography of callosal atrophy reflects distribution of regional cerebral volume reduction in Alzheimer's disease

It has been suggested that regional corpus callosum atrophy in Alzheimers disease (AD) may serve as an in vivo index of neuronal loss in the neocortex. In this study total and regional size of the corpus callosum was evaluated with respect to the volumes of the frontal, temporal, and parietal lobes in 38 patients with AD (NINCDS-ADRDA criteria) using quantitative magnetic resonance imaging. Twenty healthy subjects matched for age and gender served as a control group. All quantitative measurements were performed by manual tracing using personal computer-based software. Both total size and the five measured regional subsections were significantly smaller in AD when compared to the control subjects. The severity of dementia was significantly correlated with the size of the middle sections of the corpus callosum (rostral body and midbody). Within the AD group, the rostral body of the corpus callosum was significantly correlated with the frontal lobe volumes, the midbody was correlated with the temporal lobe volumes, and size of the splenium was correlated with the parietal lobe volumes. We conclude that callosal atrophy in AD reflects the severity and pattern of cortical neuronal damage. Correlations between regional callosal atrophy and severity of dementia indicate that interhemispheric cortico-cortical disconnection may contribute to the dementia syndrome.

Brain morphometry reproducibility in multi-center 3T MRI studies: A comparison of cross-sectional and longitudinal segmentations

Large-scale longitudinal multi-site MRI brain morphometry studies are becoming increasingly crucial to characterize both normal and clinical population groups using fully automated segmentation tools. The test-retest reproducibility of morphometry data acquired across multiple scanning sessions, and for different MR vendors, is an important reliability indicator since it defines the sensitivity of a protocol to detect longitudinal effects in a consortium. There is very limited knowledge about how across-session reliability of morphometry estimates might be affected by different 3T MRI systems. Moreover, there is a need for optimal acquisition and analysis protocols in order to reduce sample sizes. A recent study has shown that the longitudinal FreeSurfer segmentation offers improved within session test-retest reproducibility relative to the cross-sectional segmentation at one 3T site using a nonstandard multi-echo MPRAGE sequence. In this study we implement a multi-site 3T MRI morphometry protocol based on vendor provided T1 structural sequences from different vendors (3D MPRAGE on Siemens and Philips, 3D IR-SPGR on GE) implemented in 8 sites located in 4 European countries. The protocols used mild acceleration factors (1.5-2) when possible. We acquired across-session test-retest structural data of a group of healthy elderly subjects (5 subjects per site) and compared the across-session reproducibility of two full-brain automated segmentation methods based on either longitudinal or cross-sectional FreeSurfer processing. The segmentations include cortical thickness, intracranial, ventricle and subcortical volumes. Reproducibility is evaluated as absolute changes relative to the mean (%), Dice coefficient for volume overlap and intraclass correlation coefficients across two sessions. We found that this acquisition and analysis protocol gives comparable reproducibility results to previous studies that used longer acquisitions without acceleration. We also show that the longitudinal processing is systematically more reliable across sites regardless of MRI system differences. The reproducibility errors of the longitudinal segmentations are on average approximately half of those obtained with the cross sectional analysis for all volume segmentations and for entorhinal cortical thickness. No significant differences in reliability are found between the segmentation methods for the other cortical thickness estimates. The average of two MPRAGE volumes acquired within each test-retest session did not systematically improve the across-session reproducibility of morphometry estimates. Our results extend those from previous studies that showed improved reliability of the longitudinal analysis at single sites and/or with non-standard acquisition methods. The multi-site acquisition and analysis protocol presented here is promising for clinical applications since it allows for smaller sample sizes per MRI site or shorter trials in studies evaluating the role of potential biomarkers to predict disease progression or treatment effects.

Reduced olfactory bulb and tract volume in early Alzheimer's disease—A MRI study

Olfactory dysfunction has been reported to occur already in the early stages of Alzheimers disease (AD) and to increase with disease severity. In neuropathological research, the deposition of neurofibrillary tangles and neuritic plaques in the olfactory bulb and tract (OBT) of AD patients has been consistently demonstrated. We used high-resolution magnetic resonance imaging (MRI) to determine the volume of the OBT in 21 patients with early AD and in 21 healthy comparison subjects. The OBT was manually traced on consecutive coronal slices. When compared to healthy controls, right, left and mean OBT volumes were significantly reduced in patients with AD (p<0.01). In AD patients, the mean OBT volume was significantly correlated with global cognitive performance as determined by the mini-mental state examination (r=0.605; p=0.004). Manual tracing on MRI images revealed OBT atrophy to be present early in the course of AD. Since the respective findings were associated with cognitive impairment, they may contribute to early recognition and diagnosis of the disease.