Matthias W. Riepe

Brain activation during human navigation: gender-different neural networks as substrate of performance

Visuospatial navigation in animals and human subjects is generally studied using maze exploration. We used functional MRI to observe brain activation in male and female subjects as they searched for the way out of a complex, three-dimensional, virtual-reality maze. Navigation activated the medial occipital gyri, lateral and medial parietal regions, posterior cingulate and parahippocampal gyri as well as the right hippocampus proper. Gender-specific group analysis revealed distinct activation of the left hippocampus in males, whereas females consistently recruited right parietal and right prefrontal cortex. Thus we demonstrate a neural substrate of well established human gender differences in spatial-cognition performance.

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

Patients with probable Alzheimers 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 Alzheimers 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 Alzheimers disease patients revealed superiority of hippocampal activation. Contrasting Alzheimers 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 Alzheimers 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 Alzheimers 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.

Inhibition of hippocampal function in mild cognitive impairment: targeting the cholinergic hypothesis.

Mild cognitive impairment (MCI) is a condition with an increased risk of developing Alzheimers disease. Chief complaint and diagnostic criterion in subjects with mild cognitive impairment is memory failure. We hypothesized that cholinergic malfunction may underlie memory impairment in these subjects and applied a low dosage of an acetylcholinesterase inhibitor and modulator of nicotinic acetylcholine receptors, galantamine (4 mg bid), for 7 days. We used neuropsychological tests to investigate attention, cognitive flexibility, verbal and visual short-term and working memory, susceptibility to interference and episodic memory and functional magnetic resonance imaging to assess spatial navigation both prior to and after treatment. Late episodic learning and delayed recall improved on treatment as did recruitment of the hippocampal region during spatial navigation. Performance in all other neuropsychological measures remained unchanged. We show that an increase of cholinergic neurotransmission in subjects with MCI specifically improves hippocampal function and thus that a cholinergic deficit is functionally relevant in subjects with MCI. Malfunction of the cholinergic system may be tackled pharmacologically via the inhibition of acetylcholinesterase even when the impairment is slight.

Neuroprotection and neuronal dysfunction upon repetitive inhibition of oxidative phosphorylation

Repetitive inhibition of oxidative phosphorylation is an established model of neurodegeneration. In contrast, a single mild treatment can be neuroprotective-chemical preconditioning. Repetitive chemical inhibition of oxidative phosphorylation may thus be a tool to study deterioration and improvement of cellular hypoxic tolerance and subsequent differential regulation of cellular responses in the same model. We investigated murine hippocampal function upon repetitive intraperitoneal injections of 3-nitropropionate (3-NP; 20 mg/kg body weight), an inhibitor of mitochondrial complex II. With a 2-day interval of repetitive in vivo treatment with 3-NP, posthypoxic recovery of population spike amplitude was below control. In contrast, even after nine in vivo treatments with 3-NP at 4-day intervals, an almost complete recovery of population spike amplitude was observed. Nerve growth factor (NGF) as assessed by ELISA and expression of beta-amyloid precursor protein (APP) mRNA increased upon nine treatments at 2-day intervals, but remained at control levels with 4-day intervals. In contrast, brain-derived neurotrophic factor (BDNF) as assessed by ELISA increased with the latter treatment. Expression of mRNA for adenosine-A1 and -A3 receptors and endothelial and neuronal nitric oxide synthase remained at control level for both treatment intervals. We conclude that the time interval between mild, subclinical repetitive inhibition of oxidative phosphorylation determines hippocampal neuronal impairment and integrity and modulates NGF and BDNF differently. Decreased hypoxic tolerance and increased APP expression upon repetitive inhibition of oxidative phosphorylation at short time intervals may thus trigger a vicious cycle and be a cofactor for neuronal dysfunction in cerebral hypoxia and neurodegenerative diseases.

Visualization of defective mitochondrial function in skeletal muscle fibers of patients with sporadic amyotrophic lateral sclerosis

The mitochondrial function in skeletal muscle was investigated in skeletal muscle biopsies of 26 patients with sporadic amyotrophic lateral sclerosis (ALS) and compared with investigations of 28 age-matched control muscle samples and biopsies of 6 patients with spinal muscular atrophy (SMA) and two patients with Tay-Sachs disease. In comparison to the control, SMA and Tay-Sachs biopsies, we observed in the ALS samples a significant about two-fold lower activity of complex I of mitochondrial respiratory chain. To visualise the distribution of the mitochondrial defect in skeletal muscle fibers we applied confocal laser-scanning microscopy and video fluorescence microscopy of NAD(P)H and fluorescent flavoproteins. The redox change of mitochondrial NAD(P)H and flavoproteins on addition of mitochondrial substrates, ADP, or cyanide were determined by measurement of fluorescence intensities with dual-photon UV-excitation and single-photon blue excitation. In skeletal muscle fibers of ALS patients with abnormalities of mitochondrial DNA (multiple deletions, n=1, or lower mtDNA levels, n=14) we observed a heterogeneous distribution of the mitochondrial defects among individual fibers and even within single fibers. In some patients (n=3) a mitochondrial defect was also detectable in cultivated skin fibroblasts. These findings support the viewpoint that the observed impairment of mitochondrial function in muscle of certain ALS patients is caused by an intrinsic mitochondrial defect which may be of pathophysiological significance in the etiology of this neurodegenerative disease.

The role of excitotoxicity in ALS : what is the evidence?

Abstract It is well accepted that excitotoxic mechanisms contribute to the pathogenesis of acute neuronal death in stroke, epilepsy, or brain trauma. It is less widely acknowledged that excitotoxic mechanisms play a role in the pathogenesis of chronic neurological disorders, in particular neurodegenerative diseases. However, evidence is accumulating that this mechanism is indeed part of the pathogenesis of late-onset neurodegenerative diseases. One of the clinical examples may be amyotrophic lateral sclerosis, a disease in which antiexcitotoxic strategies have neuroprotective effects in both, an established animal model and in man. In addition, there is accumulating neuropathological, pathobiochemical and pathophysiological evidence which indicates that excitotoxic mechanisms are part of the pathogenesis of the human disease and consequently part of the mechanisms explaining selective vulnerability (“pathoclisis”) in the human motor system.

Chemical preconditioning: A cytoprotective strategy

Brief ischemic or hypoxic episodes may increase or decrease tolerance towards subsequent severe ischemia in heart and brain. A similar phenomenon is observed after mild chemical inhibition of oxidative phosphorylation — chemical preconditioning. We have shown that chemical preconditioning can be induced by chemical inhibition of mitochondrial complex I and mito-chondrial complex II. With a time interval of three hours between chemical pretreatment and massive inhibition of oxidative phosphorylation, recovery of population spike amplitude in hippocampal region CA1 after stimulation of the Schaffer collaterals was 31 ± 9% in controls, 98 ± 14% after i.p. treatment with 1 mg/kg body weight haloperidol, an inhibitor of mitochondrial complex I and 90 ± 7% with pretreatment with 3-np, an inhibitor of mitochondrial complex II. Activation of ATP regulated potassium channels partakes in mediating the preconditioning effect. We conclude that chemical preconditioning is a practical prophylactic pharmacologic strategy to increase hypoxic tolerance. (Mol Cell Biochem 174: 249#x2013;254, 1997)

The neurofilament heavy chain (NfHSMI35) in the cerebrospinal fluid diagnosis of Alzheimer's disease

Background/Aims: Attempting to improve the cerebrospinal fluid (CSF) diagnosis of Alzheimer’s disease (AD), the neurofilament heavy chain isoform, NfHSMI35 was compared to other CSF markers [total tau, phospho-tau, amyloid beta 1–42 (Aβ42), the ratio of amyloid beta fragments Aβ42/Aβ40 (Aβ ratio)]. Methods: CSF levels were determined in patients with AD (n = 109), mild cognitive impairment (MCI, n = 25), frontotemporal dementia (n = 15), vascular dementia (VD, n = 41), and controls (n = 58). Results: CSF NfHSMI35 was elevated in AD and VD as compared to controls (p < 0.05). Total tau was higher in AD as compared to controls (p < 0.05). CSF phospho-tau was elevated in AD as compared to controls and VD (p < 0.05 each). CSF Aβ42 and Aβ ratios in AD were lower than in MCI and controls (p < 0.05 each). Conclusion: The diagnostic potential of NfHSMI35 is not superior to that of other CSF markers.

NMDA-antagonists reverse increased hypoxic tolerance by preceding chemical hypoxia

Glutamate antagonists mitigate hypoxic damage upon acute inhibition of energy metabolism. The goal of this study was to investigate their effect on increased hypoxic tolerance induced by preceding chemical inhibition of energy metabolism. While recovery of population spike amplitude (psap) is 30% of onset in slices prepared from control animals (15 min hypoxia, 45 min recovery), recovery exceeds 90% in slices prepared from animals that underwent mild chemical hypoxia in vivo by treatment with 20 mg/kg 3-nitropropionic acid 1 h prior to slice preparation (p-slices). In p-slices perfused for 5 min with D(-)-2-amino-5-phosphonopentanoic acid (APV) (100 microM) 45 min prior to hypoxia, recovery declines to 42 +/- 13% (mean +/- SEM). In contrast, posthypoxic recovery after similar perfusion with 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) (10 microM) is 72 +/- 15% (P < 0.05). We conclude that increased hypoxic tolerance is abolished by N-methyl-D-aspartate (NMDA)-antagonists but not non-NMDA-antagonists.

Transient Global Amnesia: Evidence against vascular ischemic etiology from diffusion weighted imaging

Abstract. The etiology of Transient Global Amnesia (TGA) is still obscure. Diffusion-Weighted-Imaging (DWI) provides conflicting evidence concerning a possible vascular ischemic cause in mesiotemporal structures including the hippocampal region. The question remains open whether conflicting observations resulted from different observation times. DWI was performed at a time interval with known sensitivity for detection of ischemia. Ten patients (5 male, 5 female; mean age of 63 ± 9, range 41–71 years) with typical TGA were investigated at an average delay of 18 hours (range 6 to 44 hours) between onset of symptoms and magnetic resonance imaging (transversal DW-, T1W- and T2W-MRI). Five patients received apparent-diffusion-coefficient (ADC)-mapping. Cerebrovascular studies (ECG, TTE and extra/transcranial dopplersonographic and duplexultrasonic investigation) and EEG were normal in all patients. DW-MRI-sequences and ADC-maps, if performed, were normal in all patients. Conventional T2W-MRI in 3 out of 10 patients showed microangiopathic subcortical changes and lacunar strokes of older origin. We conclude that TGA does not result from a vascular ischemic etiology in the majority of cases.