Lukas Scheef

Volume reduction of the entorhinal cortex in subjective memory impairment

To examine the biological basis of subjective memory impairment (SMI), defined as the feeling of memory worsening with normal memory performance, we measured the volume of the entorhinal cortex (EC) and the hippocampus in SMI subjects, patients with mild cognitive impairment (MCI), patients with Alzheimers disease (AD) and healthy controls (CO). Compared with controls, the EC was smaller in the SMI group (left: p=0.060; right: p=0.045) and in the other two groups in the following order: CO>SMI>MCI>AD. The same sequence was observed with regard to hippocampal volumes, but the volume reduction of the left hippocampus in the SMI group only reached a trend towards significance (p=0.072) and the right was not significantly smaller compared with controls (p=0.37). Compared with controls the average (left/right) volume reduction of the EC was 18% (SMI), 26% (MCI) and 44% (AD). The mean volume reduction of the hippocampus was 6% (SMI), 16% (MCI) and 19% (AD). Our results mirror the temporal sequence of neurodegeneration in AD and support the concept of SMI as the first clinical manifestation of dementia.

Glucose metabolism, gray matter structure, and memory decline in subjective memory impairment

Objective: To identify biological evidence for Alzheimer disease (AD) in individuals with subjective memory impairment (SMI) and unimpaired cognitive performance and to investigate the longitudinal cognitive course in these subjects. Method: [18F]fluoro-2-deoxyglucose PET (FDG-PET) and structural MRI were acquired in 31 subjects with SMI and 56 controls. Cognitive follow-up testing was performed (average follow-up time: 35 months). Differences in baseline brain imaging data and in memory decline were assessed between both groups. Associations of memory decline with brain imaging data were tested. Results: The SMI group showed hypometabolism in the right precuneus and hypermetabolism in the right medial temporal lobe. Gray matter volume was reduced in the right hippocampus in the SMI group. At follow-up, subjects with SMI showed a poorer performance than controls on measures of episodic memory. Longitudinal memory decline in the SMI group was associated with reduced glucose metabolism in the right precuneus at baseline. Conclusion: The cross-sectional difference in 2 independent neuroimaging modalities indicates early AD pathology in SMI. The poorer memory performance at follow-up and the association of reduced longitudinal memory performance with hypometabolism in the precuneus at baseline support the concept of SMI as the earliest manifestation of AD.

Volume Loss of the Medial Temporal Lobe Structures in Subjective Memory Impairment

Background/Aims: Subjective memory impairment (SMI) has been suggested as a manifestation of Alzheimer’s Disease (AD) preceding mild cognitive impairment (MCI). In this study, we determined the volumes of the hippocampus, the entorhinal cortex (EC) and the amygdala to provide biological evidence for AD in SMI. Methods: Regional volumetric measures were manually traced on 3-Tesla MRI scans. Results: Total brain volume did not differ between the groups. Individuals with SMI had reduced volumes of the hippocampus bilaterally (right p = 0.001; left p < 0.001), the bilateral EC (right p = 0.031, left p = 0.006) and the right amygdala (p = 0.01) compared to the control group. Conclusion: Volume reduction of bilateral hippocampus, bilateral EC and right amygdala supports the concept of SMI as a very early manifestation of AD prior to MCI. SMI may indicate awareness of a degenerative process that can still be functionally compensated.

DNA sequence variants of the FKBP5 gene are associated with unipolar depression

FKBP5 is a glucocorticoid receptor-regulating co-chaperone of hsp-90 and, therefore, is suggested to play a role in the regulation of the hypothalamic-pituitary-adrenocortical system and the pathophysiology of depression. Previously, three studies identified single nucleotide polymorphisms (SNPs) in the FKBP5 gene associated with response to antidepressants, and one study found an association with diagnosis of depression. We selected five markers from the region of interest. A case-control sample comprising 268 German in-patients with recurrent unipolar depression, and 284 German controls recruited from the general population were available. Association of the selected FKBP5 sequence variants with clinical depression were analysed. In addition, we explored association with treatment response by (a) the Hamilton Depression Rating Scale and (b) the dexamethasone/corticotrophin-releasing hormone (Dex/CRH) test, as well as association with hippocampal volumes in a subpopulation of 110 patients. For three of the five investigated SNPs we were able to show association with the diagnosis of depression. In the subpopulation of 110 patients, diagnosis-related alleles were also associated with the reduction of cortisol secretion in the Dex/CRH test during a 4-wk treatment period, while psychopathological changes were not associated. Furthermore, diagnosis-related alleles were associated with reduction of the hippocampal volume. This study extends the replicated association of a promoter SNP with antidepressant response on a biological level by demonstrating normalization of the cortisol response under Dex/CRH stimulation during treatment. Furthermore, several of the investigated SNPs were associated with the disease status and the intermediate phenotype of hippocampal volume.

Interrelated neuropsychological and anatomical evidence of hippocampal pathology in the at-risk mental state.

BACKGROUND Verbal learning and memory deficits are frequent among patients with schizophrenia and correlate with reduced magnetic resonance imaging (MRI) volumes of the hippocampus in these patients. A crucial question is the extent to which interrelated structural-functional deficits of the hippocampus reflect a vulnerability to schizophrenia, as opposed to the disorder per se. METHOD We combined brain structural measures and the Rey Auditory Verbal Learning Test (RAVLT) to assess hippocampal structure and function in 36 never-medicated individuals suspected to be in early (EPS) or late prodromal states (LPS) of schizophrenia relative to 30 healthy controls. RESULTS Group comparisons revealed bilaterally reduced MRI hippocampal volumes in both EPS and LPS subjects. In LPS subjects but not in EPS subjects, these reductions were correlated with poorer performance in RAVLT delayed recall. CONCLUSIONS Our findings suggest progressive and interrelated structural-functional pathology of the hippocampus, as prodromal symptoms and behaviours accumulate, and the level of risk for psychosis increases. Given the inverse correlation of learning and memory deficits with social and vocational functioning in established schizophrenia, our findings substantiate the rationale for developing preventive treatment strategies that maintain cognitive capacities in the at-risk mental state.

A role of the basal ganglia and midbrain nuclei for initiation of motor sequences.

The mesial premotor cortex is crucial for planning sequential procedures and movement initiation. With event-related (ER) functional magnetic resonance imaging (fMRI) it has been possible to separate mesial premotor activation before, during, and after self-initiated movements and, thereby, to distinguish advance planning from execution. The mesial premotor cortex is part of distributed cortico-basal ganglia-thalamo-cortical networks but, to date, the subcortical contributions to self-initiated movements are far less well understood. Using ER fMRI at 3T in 12 right-handed male volunteers, we studied the subcortical activation preceding an automated four-digit finger sequence that was either self-initiated or triggered externally by a visual cue. Beyond typical cortical activation increases in fronto-parietal regions, both initiation modes induced consistent subcortical activation in basal ganglia, midbrain (substantia nigra), and ipsilateral cerebellum. The planning phase of the internally initiated condition, when contrasted with the externally triggered condition, was associated with enhanced activity in frontal regions (mesial premotor cortex/rostral cingulate zone, dorsolateral prefrontal cortex), parietal regions (precuneus, inferior parietal cortex, encroaching onto V5/MT), insula, contralateral anterior putamen and midbrain (bilateral red nucleus/subthalamic nucleus). These data demonstrate the impact of initiation mode on planning-related activity in the ventral basal ganglia and interconnected midbrain nuclei, thereby stressing the crucial role of distributed cortico-basal ganglia-thalamo-cortical networks for self-initiated automated motor repertoires. Involvement of the substantia nigra during planning, as shown here, indicates dopaminergic gating of motor sequences.

Distinct striatal regions for planning and executing novel and automated movement sequences

The basal ganglia-thalamo-cortical circuits are viewed as segregated parallel feed back loops crucially involved in motor control, cognition, and emotional processing. Their role in planning novel, as compared to overlearned movement patterns is as yet not well defined. We tested for the involvement of the associative striatum (caudate/anterior putamen) in the generation of novel movement patterns, which is a critical cognitive requirement for non-routine motor behavior. Using event related functional MRI in 14 right-handed male subjects, we analyzed brain activity in the planning phase of four digit finger sequences. Subjects either executed a single overlearned four digit sequence (RECALL), or self-determined four digit sequences of varying order (GENERATE). In both conditions, RECALL and GENERATE, planning was associated with activation in mesial/lateral premotor cortices, motor cingulate cortex, superior parietal cortex, basal ganglia, insula, thalamus, and midbrain nuclei. When contrasting the planning phase of GENERATE with the planning phase of RECALL, there was significantly higher activation within this distributed network. At the level of the basal ganglia, the planning phase of GENERATE was associated with differentially higher activation located specifically within the associative striatum bilaterally. On the other hand, the execution phase during both conditions was associated with a shift of activity towards the posterior part of the putamen. Our data show the specific involvement of the associative striatum during the planning of non-routine movement patterns and illustrate the propagation of activity from rostral to dorsal basal ganglia sites during different stages of motor processing.

Resting-State Perfusion in Nonmedicated Schizophrenic Patients: A Continuous Arterial Spin-labeling 3.0-T MR Study

PURPOSE To determine whether well-described patterns of altered perfusion in schizophrenia can be identified by using continuous arterial spin labeling (CASL) with a whole-brain imaging sequence. MATERIALS AND METHODS This study was approved by the ethics committee of the local institutional review board, and written informed consent was obtained from all subjects. CASL was used to compare cerebral perfusion between 11 nonmedicated patients with schizophrenia and 25 healthy control subjects. Since antipsychotic medication may affect perfusion, only drug-free subjects were examined. Resting-state perfusion, as measured in terms of regional cerebral blood flow, was compared voxel wise by using an analysis of variance design in a statistical parametric mapping program, with patient age and sex as covariates. RESULTS Compared with the healthy control subjects, the schizophrenic patients had extensive areas of hypoperfusion in the frontal lobes bilaterally, in the anterior and medial cingulate gyri, and in the parietal lobes bilaterally. Increased perfusion was observed in the cerebellum, brainstem, and thalamus of the schizophrenic patients as compared with the perfusion in these areas in the control subjects. CONCLUSION CASL in schizophrenia revealed patterns of hypo- and hyperperfusion similar to the perfusion patterns in previously published positron emission tomographic and single photon emission computed tomographic studies. The advantages of CASL, including independence from injected contrast agents, no irradiation, and fast acquisition time, may facilitate intensive perfusion studies of the early recognition of schizophrenia and other psychiatric disorders, as well as longitudinal disease-monitoring research of these conditions.

Gray matter atrophy pattern in elderly with subjective memory impairment.

Individuals with subjective memory impairment (SMI) report worsening of memory without impairment in cognitive tests. Despite normal cognitive performance, they may be at higher risk of cognitive decline compared with individuals without SMI.

Neural correlates of semantic ambiguity processing during context verification.

Understanding the relevant meaning of a word with different meanings (homonym) in a given context requires activation of the neural representations of the relevant meaning and inhibition of the irrelevant meaning. The cognitive demand of such disambiguation is highest when the dominant, yet contextually irrelevant meaning of a polar homonym must be suppressed. This central process (semantic inhibition) for lexico-semantic ambiguity resolution was monitored with fMRI during semantic context verifications. Twenty-two healthy volunteers decided whether congruent or incongruent target words fitted into the contexts established by preceding sentences. Half of the sentences ended with a homonym, thereby allowing to cross the factors ambiguity and semantic congruency. BOLD increases related to the inhibitory attentional control over non-selected meanings during ambiguity processing occurred in a brain network including left dorsolateral prefrontal cortex (DLPFC), bilateral angular gyrus (AG), bilateral anterior superior temporal gyrus (aSTG) as well as right ventromedial temporal lobe. In left DLPFC (BA 46/9) and left AG (BA 39) BOLD activity to target words of the incongruent-ambiguous condition correlated with the individual amount of semantic interference experienced by the subjects. BOLD increases of incongruent versus congruent semantic verifications occurred in bilateral inferior frontal gyrus. The results of the present study suggest a specific role of left DLPFC and AG in the resolution of semantic interference from contextually inappropriate homonym meanings. These fronto-parietal areas might exert inhibitory control over temporal regions in service of attentional selection between relevant and irrelevant homonym meanings, by creating a sufficient activation difference between their respective representations.