Biomedical subjects

Matthias W Riepe

Publications and source records attributed to Matthias W Riepe.

14 recordsLinked to original sources

PubMed2006

Hippocampal synaptic depression following spatial learning in a complex maze.

Activity-dependent alteration in synaptic efficacy is referred to as synaptic plasticity and is the believed hallmark of any learning process. Here we employed a recently validated complex maze for spatial training and investigated the impact of repeated and extensive training on basal synaptic transmission of the hippocampal Schaffer collateral-CA1 synaptic connection in vitro. In the present experiments, male CD-1 mice were trained in a complex maze for eight consecutive days five times a day. Subsequently, input-output functions of field excitatory postsynaptic potentials (fEPSPs) recorded in the CA1 area following stimulation of the Schaffer collateral-commissural fiber pathway were analyzed in acute hippocampal slices. We found a marked right shift of the fEPSP response in trained compared to untrained animals while fiber volley size remained unchanged. The findings provide evidence for a direct implication of homosynaptic hippocampal long-term depression in a spatial learning paradigm.

Animals↗

PubMed2006

The stamp of ancestry: roots of behavioral and neuronal impairment in adulthood.

Exposure of pregnant animals to noxious conditions affects neuronal function in the offspring. However, exposure or treatment of the maternal animal during pregnancy affects both ancestor and offspring. In the present study, female CD-1 mice were repetitively treated with 3-nitropropionate (3-np), a selective inhibitor of succinic dehydrogenase, exclusively prior to mating. Clinically, mice appeared normal during treatment. Five days after cessation of treatment animals were mated with control male animals. At 4 months of age spatial learning, LTP, NADH autofluorescence, and hypoxic tolerance were alike in controls and the offspring of treated female ancestors. However, an additional metabolic challenge in the offspring unmasks impairment of spatial learning, diminution of long-term potentiation (LTP), an altered protein microenvironment of mitochondrial enzymes, and reduced hypoxic tolerance. We conclude that the exposure of maternal ancestors to subclinical repetitive impairment of oxidative phosphorylation fosters impairment of behavior and neuronal function in the adult offspring, becoming apparent only on additional challenge. This finding may ultimately help to understand the causes of neuronal impairment or even neuropsychiatric disease in old age.

Age Factors↗

PubMed2006

Spatial navigation in complex and radial mazes in APP23 animals and neurotrophin signaling as a biological marker of early impairment.

Impairment of hippocampal function precedes frontal and parietal cortex impairment in human Alzheimer's disease (AD). Neurotrophins are critical for behavioral performance and neuronal survival in AD. We used complex and radial mazes to assess spatial orientation and learning in wild-type and B6-Tg(ThylAPP)23Sdz (APP23) animals, a transgenic mouse model of AD. We also assessed brain content of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3). Performance was alike in wild-type and APP23 animals in the radial maze. In contrast, performance in the complex maze was better in wild-type than APP23 animals. Contrary to the wild-type, hippocampal BDNF levels decreased on training in APP23 animals. Hippocampal and frontal cortex NGF levels in APP23 animals correlated with the time to solve the complex maze, but correlated inversely with escape time in wild-type animals. NT-3 levels were alike in wild-type and APP23 animals and were unchanged even after training. Both types of mazes depend on hippocampal integrity to some extent. However, according to the cognitive mapping theory of spatial learning, the complex maze because of the increased complexity of the environment most likely depends more strongly on preserved hippocampal function than the radial maze in the working memory configuration applied here. Greater impairment in complex maze performance than in radial maze performance thus resembles the predominant affliction of the loss of hippocampal function in human AD. NGF and BDNF levels on maze learning are different in wild-type and transgenic animals, indicating that biological markers of AD may be altered on challenge even though equilibrium levels are alike.

Amyloid beta-Protein Precursor↗

PubMed2005

Cholinergic enhancement of episodic memory in healthy young adults.

RATIONALE: Acetylcholine esterase (AchE) inhibitors are known to remediate symptoms of Alzheimer's disease. However, only few systematic data exist on the effects of cholinergic treatment on cognitive functions in normal subjects. OBJECTIVE: This study evaluated the effects of donepezil, an inhibitor of AchE, on cognitive performance in young and healthy subjects. METHODS: We used a randomised double-blind parallel group placebo-controlled repeated measures design to investigate changes of cognitive functions in a group of 30 young healthy male subjects (mean age 23.9 years+/-2.24 SD) upon application of donepezil or placebo for 30 days. Attentional and executive functions, visual and verbal short-term and working memory, semantic memory, as well as verbal and visual episodic memory were investigated using an extensive neuropsychological test battery. RESULTS: Time-by-group interactions demonstrated significant drug effects that were specific to episodic memory in both the verbal and visual domain. Additionally, donezepil significantly improved long-term visual episodic recall. In none of the other functions under investigation any significant treatment effects were observed. CONCLUSION: Given this specific drug effect and the well-known relevance of the hippocampal region for episodic memory, we conclude that this region appears to be the major target of cholinergic enhancement in healthy subjects due to long-term inhibition of AchE.

Adult↗

PubMed2005

Screening for cognitive impairment: a triage for outpatient care.

The current increase in aged individuals in number and proportion of the general population warrants dependable strategies to improve early detection of cognitive impairment. It was the goal of the present study to develop a triage for bedside testing and outpatient services. In a prospective clinical cohort study at the outpatient Memory Clinic, University of Ulm, Germany, 232 subjects were diagnosed with Alzheimer's disease [AD; NINCDS-ADRDA criteria; n = 66; age 65.9 +/- 7.3 years (mean +/- SD); Mini Mental State Examination (MMSE) score 23.4 +/- 4.1], mild cognitive impairment (MCI; criteria of Petersen et al.; n = 48; age 66.4 +/- 7.1 years; MMSE score 28.3 +/- 1.5), and major depressive disorder (DSM-IV criteria; n = 61; age 63.4 +/- 8.0 years; MMSE score 28.6 +/- 1.6). Diagnosis was secured with extensive neuropsychological, clinical, radiological, and laboratory investigations. Six brief screening tests including the Memory Impairment Screen (MIS), Letter Sorting Test (LST), Verbal Fluency (VF), and Clock Drawing Test (CDT) were assessed independently from the diagnostic procedure. We compared single items and composite scores. LST yielded a diagnostic accuracy of 0.81 and 0.62 for AD and MCI patients versus controls, respectively. With the MIS, diagnostic accuracy was 0.89 and 0.71, respectively. With a combination of LST, MIS, VF, and CDT, a sensitivity for AD and MCI patients of 1.00 and 0.83 was achieved. Thus, single-item screening (e.g. LST, VF) taking little more than 1 min and suitable for bedside testing or brief screening in the general practitioner's office yields diagnostic accuracy comparable to standard laboratory tests for other diseases. A composite of screening tests suitable for application in general outpatient care in neurological and psychiatric services reliably detects patients with AD and MCI.

Aged↗

PubMed2005

Improved posthypoxic recovery in vitro on treatment with drugs used for secondary stroke prevention.

Besides aspirin several new drugs for inhibition of platelet aggregation and 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibition are used in secondary stroke prevention. Pharmacology and clinical effects, however, are not fully explained by current understanding of underlying mechanisms. Population spike amplitude (PSAP), an established marker of slice integrity, was measured during hypoxia and recovery thereof in hippocampal slices from control CD1 mice (25-35 g) and animals pretreated in vivo with a single i.p. injection of clopidogrel, ticlopidine, or atorvastatine at different time intervals and dosages. Posthypoxic recovery of PSAP was 20 +/- 35% in control CD1 mice. Upon pretreatment with clopidogrel (1-24 h, 0.5-2 mg/kg body weight) an increase up to 81 +/- 20% (p < 0.01 to control) was observed at 1h interval and 1mg/kg. Application of ticlopidine (1-24 h, 1-4 mg/kg body weight) resulted in an improvement of posthypoxic recovery to 61 +/- 41% (p < 0.05 to control) while administration of atorvastatine (1-24 h, 1-4 mg/kg body weight) caused an increase up to 87 +/- 31% (p < 0.01 to control) at 1h interval and 2 mg/kg. On application of these substances in vitro the NADH autofluorescence spectrum in hippocampal slices is blue-shifted suggesting an alteration of oxidative metabolism. The present data demonstrate a shared neuroprotective effect of agents known to inhibit platelets (acetylsalicylic acid, clopidogrel, and ticlopidine) and HMG-CoA reductase (atorvastatine). The time course of this neuroprotective action in the current experimental study (onset within an hour, duration of several hours in contrast to several days) resembles clinical practice in dosing these substances. We hypothesize that an increase of hypoxic tolerance resulting from mild mitochondrial inhibition by these substances is a principal constituent of the effectiveness of these drugs.

Action Potentials↗

PubMed2004

Graded reoxygenation with chemical inhibition of oxidative phosphorylation improves posthypoxic recovery in murine hippocampal slices.

Rapid and complete tissue reoxygenation is a prime goal of present stroke therapy. However, reoxygenation may trigger detrimental cascades that partially antagonize beneficial effects. It was our goal to investigate selective grading of reoxygenation with targeting of single mitochondrial complexes in murine hippocampal slices. Population spike amplitude (PSAP) and NADH were measured during hypoxic hypoxia (15 min) and recovery (45 min). With onset of reoxygenation, slices were treated for different times with amobarbital (1 mM), malonate (2 mM), or cyanide (1 mM), inhibitors of mitochondrial complex I, II, or IV, respectively. Other slices were treated with nicotinamide (1 mM). Posthypoxic recovery of PSAP increased from 32% +/- 43% of onset in control slices to 52% +/- 59% (P <.05) upon treatment with amobarbital for 1 min and to 62% +/- 37% (P <.05) upon treatment with malonate. With nicotinamide, posthypoxic recovery improved to 73% +/- 25% (P <.05). Oxidation of NADH was prolonged upon treatment with amobarbital, whereas no change in NADH oxidation was observed with malonate and nicotinamide. Thus, grading of reoxygenation with selective targeting of mitochondrial complex I or II but not of complex IV improves outcome upon reoxygenation in murine hippocampal slices.

Action Potentials↗

PubMed2003

Screening for cognitive impairment in patients with acute stroke.

BACKGROUND: Formal assessment of cognitive impairment is rare in acute stroke, yet. It was the goal to utilize easy-to-apply established screening tests to assess cognitive impairment from any cause in patients with acute ischemic stroke. METHODS: 209 consecutive patients (69.8 +/- 13.3 years, mean +/- SD; 117 male, 92 female) admitted to an acute stroke unit, which serves as a community stroke center, and diagnosed as having acute cerebral ischemia from any cause were investigated within 24 h of stroke onset and in part followed up after 3 months. Orientation and aphasia were assessed with the ADAScog subscales orientation and aphasia, verbal memory with Buschke's Memory Impairment Screen, and concentration/working memory with a letter sorting test. RESULTS: On admission, 74.6% were impaired on the Memory Impairment Screen, 77.0% on the letter sorting test, 45.0 and 24.9% on the ADAScog subscales aphasia and orientation. Results of the Memory Impairment Screen and letter sorting test were similar at the follow-up after 3 months. CONCLUSION: Formal brief assessment of cognitive deficits with tests not requiring motor capabilities in unselected patients with an acute cerebral ischemic event reveals widespread deficits. This needs to be considered when obtaining informed consent from the patients and instructing them. Routine formalized screening may thus improve care for patients with acute stroke. Patients with impairment on admission should be followed up, diagnosed concerning preexisting or poststroke dementia with a more extensive workup and eventually treated.

Acute Disease↗

PubMed2003

Differential regulation of 5' splice variants of the glutamate transporter EAAT2 in an in vivo model of chemical hypoxia induced by 3-nitropropionic acid.

Defective glutamate uptake has been implicated as a pathogenic event of neuronal damage related to cerebral ischemia and hypoxia. In several models of ischemia-hypoxia, a reduced immunoreactivity and altered RNA expression of excitatory amino acid transporter 2 (EAAT2), the major excitatory amino acid transporter, have been reported. However, the gene regulation of EAAT2 under these conditions is incompletely understood. In this study, we investigated alternative splicing of EAAT2 in an in vivo mouse model of chemical hypoxia as induced by 3-nitropropionic acid (3-NP). The neurotoxin 3-NP is an inhibitor of mitochondrial energy production. Furthermore, it is known to inhibit glutamate reuptake directly, representing at least one of the mechanisms responsible for 3-NP-induced neurodegeneration. Here we report an expression analysis of five known (mEAAT2/5UT1-5) and two novel (mEAAT2/5UT6, -7) 5' splice variants of EAAT2 using semiquantitative PCR. The RNA expression was studied at 2, 12, 24, 48, and 72 hr and 7 days after 3-NP administration. mEAAT2/5UT4 and mEAAT2/5UT5 were up-regulated in the frontal cortex and down-regulated in the hippocampus 12-72 hr after chemical hypoxia. In the cerebellum, there was an increased expression of mEAAT2/5UT4 and a down-regulation of mEAAT2/5UT5. mEAAT2/5UT3 show a different regional expression pattern, being regulated in the cerebellum only. mEAAT2/5UT1-7 encoded distinct 5' regulatory sequences, including conserved elements of translational control. It is easily conceivable that expression alterations of 5' splice variants of EAAT2 are related to glutamate transporter malfunction after chemical hypoxia. Our findings contribute to the hypothesis that RNA splicing events can serve as a molecular mechanism of posthypoxic gene regulation.

Alternative Splicing↗

PubMed2003

Alike performance during nonverbal episodic learning from diversely imprinted neural networks.

Performance on neuropsychological testing permits inferences to be made regarding neural networks required to solve the task. In healthy young human subjects it is common sense that differential performance in cognitive tasks results from recruitment of different neural networks and that alike performance results from recruitment of alike neural networks. It was the goal of the present study to investigate whether these assumptions are also valid in cross-cultural studies. To address this, we used functional MRI during a nonverbal episodic memory task with repeated learning of abstract geometric patterns. Behavioural performance in this task was alike over repeated trials in native Chinese and Caucasian subjects. Given this equivalent performance, the distinct pattern of neuronal activation observed is interpreted as the outcome of different culturally imprinted processing routines. In the 'what' and 'where' framework of visuo-spatial processing initial learning in Chinese subjects activated the dorsal stream for analysis of spatial features whereas Caucasians recruited the ventral stream for object identification. With repeated learning Chinese subjects integrated visuo-spatial processing to object coding and vice versa. Thus, imprints of culture result in activation of distinct neural networks and mandate monitoring of both behavioural performance and neural recruitment in cross-cultural studies of cognition.

Adult↗

PubMed2002

Subjective memory complaints: objective neural markers in patients with Alzheimer's disease and major depressive disorder.

Patients with probable Alzheimer's disease and depressive patients frequently present with subjective memory complaints. Objective distinction of underlying neuronal substrate malfunction and early cross-sectional differential diagnosis have been elusive thus far. We used repetitive learning and free recall of abstract geometric patterns during functional magnetic resonance imaging to assess episodic memory in older subjects (ages 56-64 years) who sought first-time medical attention with subjective memory complaints and were diagnosed with probable Alzheimer's disease (NINCDS-ADRDA criteria; ages 51-67 years) or major depressive disorder (DSM-IV; ages 50-65 years). Contrasting healthy seniors or depressive patients with Alzheimer's disease patients revealed superiority of hippocampal activation. Contrasting Alzheimer's disease patients with seniors showed bilateral prefrontal activity as a correlate of futile compensation of episodic memory failure. Contrasting patients who had major depressive disorder with seniors or patients who had Alzheimer's disease showed bilateral activation of the orbitofrontal cortex and the anterior cingulate. Subjective memory complaints may be classified objectively and very early with functional magnetic resonance imaging of episodic memory in groups of patients with Alzheimer's disease and depressive syndrome. This may facilitate drug trials with evaluation of specific treatments, but further studies will be needed to establish the differential diagnosis for the individual patient.

Aged↗

PubMed2002

Trans-synaptic increase of hypoxic tolerance in hippocampus upon physical challenge with two-photon microscopy.

Neuronal hypoxic tolerance is modulated by preceding challenges. We investigated hypoxic tolerance in CA1 pyramidal cells of murine hippocampal slices upon preceding physical challenge with two-photon illumination in close spatial proximity to the recorded area, at distant presynaptic neurons, or preceding chemical treatment with acetylsalicylic acid while zinc fluorescence was assessed with fluorescence measurement upon staining with N-(6-methoxy-8-quinolyl)-para-toluenesulfonamide (TSQ). Posthypoxic recovery (15 min hypoxia, 45 min recovery) of CA1 population spike amplitude (PSAP) upon stimulation of Schaffer collaterals in hippocampal region CA3 was 20 +/- 38% (mean +/- SD; n = 15) in control slices. At the end of hypoxia, zinc fluorescence increased to 120 +/- 16% (P < 0.05 to control) in slices that later recovered and 141 +/- 20% in slices that did not recover (P < 0.01 to control; P < 0.05 compared with returns). Multi-photon illumination alone was an appropriate physical challenge to improve hypoxic tolerance, even trans-synaptically. Depending on the number of illuminations posthypoxic PSAP increased up to 84 +/- 25% (P < 0.01 to control) upon illumination of hippocampal region CA1 and 85 +/- 28% (P < 0.01 to control) upon illumination of CA3. With the latter treatment, zinc fluorescence in CA1 increased to 126 +/- 20% before hypoxia (P < 0.05 to control), and no further zinc increase was observed upon subsequent hypoxia. Similar results were obtained upon chemical preconditioning with acetylsalicylate. We conclude that observation of live specimen with multi-photon imaging alters the physiology of neuronal cell ensembles, including hypoxic tolerance, even trans-synaptically at long distances from the imaged area. This is mediated in part through endogenous modulation by zinc. Mild zinc increase improves hypoxic tolerance while pronounced increase predicts neuronal cell death.

Action Potentials↗

PubMedDate not supplied

Variability in memory performance in aged healthy individuals: an fMRI study.

Episodic memory performance varies in older subjects but underlying biological correlates remain as yet ambiguous. We investigated episodic memory in healthy older individuals (n=24; mean age: 64.4+/-6.7 years) without subjective memory complaints or objective cognitive impairment. Episodic memory was assessed with repetitive learning and recall of abstract geometric patterns during fMRI. Group analysis of brain activity during initial learning and maximum recall revealed hippocampal activation. Correlation analysis of brain activation and task performance demonstrated significant hippocampal activity during initial learning and maximum recall in a success-dependent manner. Neither age nor gray matter densities correlated with hippocampal activation. Functional imaging of episodic memory thus permits to detect objectively variability in hippocampal recruitment in healthy aged individuals without subjective memory complaints. Correlation analysis of brain activation and performance during an episodic memory task may be used to determine and follow-up hippocampal malfunction in a very sensitive manner.

Aged↗

PubMedDate not supplied

Neural basis for the cognitive continuum in episodic memory from health to Alzheimer disease.

OBJECTIVE: The authors hypothesize that, behaviorally, episodic memory in health and disease reflects a continuum. METHODS: Subjects (N=12) with very mild Alzheimer disease (AD) and normal subjects (N=24) were investigated with functional magnetic resonance imaging (fMRI) during an episodic memory task. RESULTS: Recruitment of a posterior medio-temporal network was correlated with memory performance across the spectrum from high- and low-performing normal subjects to patients with early AD. CONCLUSIONS: The behavioral spectrum from health to disease in episodic memory function is mirrored neurobiologically with graded recruitment of neuronal activation in medio-temporal regions. The results call for longitudinal assessment of behavioral decline and neuronal recruitment in future studies.

Aged↗