Gender-specificities in Alzheimer's disease and mild cognitive impairment.

BACKGROUND: Amnestic Mild Cognitive Impairment (MCI) is a condition with an increased risk for developing Alzheimer's disease (AD). Presently, gender differences are neglected in the assessment of MCI and AD. METHODS: We examined verbal and visuospatial episodic memory in 143 subjects diagnosed as healthy controls (HC; N = 48, Mini-Mental State Examination (MMSE) 29.2 +/- 1.0 (mean +/- standard deviation)), MCI (N = 43,MMSE 28.5 +/- 1.4), and AD (N = 49, MMSE 25.1 +/- 2.2). FINDINGS: Female HC and MCI subjects performed better on verbal episodic memory tasks than males. In contrast, visuospatial episodic memory was better in male than female AD patients. CONCLUSIONS: We interpret the results in light of a gender-specific cognitive reserve and conclude that the gender-specificity of neuropsychological performance needs to be accounted for in clinical diagnosis of Alzheimer's disease.

Neurological and psychiatric practitioners' views on Alzheimer's disease and treatment thereof.

BACKGROUND: General views of practitioners shape medical routine. This study surveyed general views of neurological and psychiatric practitioners in Germany on Alzheimer's disease (AD). METHODS: 850 surveys were distributed and 637 (75%) recovered. RESULTS: 36% of practitioners reported not having used therapies for medical conditions other than dementia in patients with AD for reasons of limited compliance in these patients. Efficacy of antidementia drugs (donepezil, galantamine, memantine, rivastigmine) was rated on a 5-point scale (very good, good, satisfactory, sufficient, insufficient) regarding memory, attention and concentration, aggression, depression, activities of daily living, and dependency on caregivers. 87% of practitioners reported an at least satisfactory effect on at least 2 domains. Practitioners estimated that about 20% of caregivers are treated for psychiatric disorders such as depression. Practitioners that were more aware of caregivers' needs for psychiatric treatment more frequently reported positive feedback of caregivers concerning improvement of the patients in everyday life. Nursing home admission was estimated to result from both progression of dementia and diminished forces of the caregivers. CONCLUSIONS: Neurological and psychiatric practitioners perceive antidementia drugs as effective in multiple domains in AD. Appreciation of the overall success of treatment requires consideration of the patient-caregiver dyad.

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.

Spatial performance in a complex maze is associated with persistent long-term potentiation enhancement in mouse hippocampal slices at early training stages.

Long-term potentiation (LTP) and long-term depression (LTD) are principal reflections of synaptic plasticity that have been implicated in learning and memory. We have previously shown that spatial learning in a newly validated complex maze is accompanied by depression of hippocampal CA1 synaptic activity in hippocampal slices of trained mice ("behavioral LTD"). In the present study, we investigated whether behavioral LTD is accompanied by alterations of subsequent LTP induced by high-frequency stimulation (HFS). Moreover, we were interested in the time course of such alterations in relation to training stage. Animals underwent 1, 2, and 8 days of spatial training in the complex maze, respectively. Hippocampal slices were taken 24 h after the last training session. We found a simultaneous decrease of basal synaptic response and increase of HFS induced LTP magnitude compared with slices of untrained animals. Synaptic plasticity was not influenced by repeated running wheel exercise in an additional control group without spatial learning. The mentioned alterations occurred already after day 2 of maze exploration parallel to the most pronounced improvement of behavioral performance but did not change thereafter until day 8 despite further learning progress. They were also found when animals were trained for 2 days and kept at rest for a subsequent 6 days. In conclusion, spatial learning may be reflected by distinct and persistent measurable alterations of synaptic plasticity in hippocampal CA1 neurons at early training stages.

Augmented Reality: Sustaining Autonomous Way-Finding in the Community for Older Persons with Cognitive Impairment.

BACKGROUND: Impairment of autonomous way-finding subsequent to a multitude of neurodegenerative and other diseases impedes independence of older persons and their everyday activities. OBJECTIVE: It was the goal to use augmented reality to aid autonomous way-finding in a community setting. DESIGN: A spatial map and directional information were shown via head-up display to guide patients from the start zone on the hospital campus to a bakery in the nearby community. SETTING: Hospital campus and nearby community. PARTICIPANTS: Patients with mild cognitive impairment (age 63 to 89). INTERVENTIONS: A head-up display was used to help patients find their way. MEASUREMENTS: Time needed to reach goal and number of assists needed. RESULTS: With use of augmented reality device, patients preceded along the correct path in 113 out of 120 intersections. Intermittent reassurance was needed for most patients. Patients affirmed willingness to use such an augmented reality device in everyday life if needed or even pay for it. CONCLUSION: Augmented reality guided navigation is a promising means to sustain autonomous way-finding as a prerequisite for autonomy of older persons in everyday activities. Thus, this study lays ground for a field trial in the community using assistive technology for older persons with cognitive impairment.

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 Alzheimer's 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.

Mechanisms of hypoxic tolerance in presymptomatic APP23 transgenic mice.

In the B6-Tg (ThylAPP)23Sdz (APP23tg) transgenic mouse model of Alzheimer's disease hypoxic tolerance is impaired prior to amyloid deposition. We therefore investigated mechanisms known to mediate resistance to hypoxic episodes in presymptomatic APP23tg and appropriate control strains. The mRNA expression levels in the hippocampus of adenosine receptor subtypes A1 and A3, estrogen receptors alpha and beta, progesterone receptor, and neuronal and endothelial nitric oxide synthase were investigated with semi-quantitative RT-PCR. Mice were pretreated in vivo with a low dose of 3-nitropropionate, an inhibitor of succinic dehydrogenase, known to mediate hypoxic tolerance within 1h. We found increased expression levels in presymptomatic, untreated APP23tg animals of adenosine A3 receptor mRNA and estrogen receptor alpha mRNA. In addition, we observed an increase in nNOS expression levels upon mild cellular hypoxia induced by 3-NP in transgenic but not in wild-type animals. We conclude that overexpression of human APP results in differential expression of receptors conferring hypoxic tolerance prior to amyloid deposition. Up-regulation of nNOS expression levels upon hypoxic challenge in APP23tg transgenic animals may therefore reflect a selective vulnerability in these animals even before amyloid deposition.

Increased hypoxic tolerance by chemical inhibition of oxidative phosphorylation: "chemical preconditioning".

A short ischemic episode preceding sustained ischemia is known to increase tolerance against ischemic cell death. We report early-onset long-lasting neuroprotection against in vitro hypoxia by preceding selective chemical inhibition of oxidative phosphorylation: "chemical preconditioning." The amplitude of CA1 population spikes (psap) in hippocampal slices prepared from control animals (control slices) was 31 +/- 27% (mean +/- SD) upon 45-min recovery from 15-min in vitro hypoxia. In slices prepared from animals treated in vivo with 20 mg/kg 3-nitropropionate (3-np) 1-24 h prior to slice preparation (preconditioned slices), psap improved to 90 +/- 15% (p < 0.01). Posthypoxic oxygen free radicals were reduced to 65 +/- 10% (mean +/- SD) of control in preconditioned slices (p < 0.05). Posthypoxic neuronal density improved from 52 +/- 15% (mean +/- SD) in control slices to 97 +/- 23% in preconditioned slices (p < 0.001). Glibenclamide, an antagonist at KATP-channels, partly reversed increased hypoxic tolerance. We conclude that chemical preconditioning induces early-onset long-lasting tolerance against in vitro hypoxia. Ultimately, this strategy may be applicable as a neuroprotective strategy in humans.

Do the benefits of currently available treatments justify early diagnosis and treatment of amyotrophic lateral sclerosis? Arguments against.

Recent in vitro and experimental animal studies strongly indicate that motor neuron diseases, like other neurodegenerative diseases, may be preceded by a long preclinical period. Clinical studies have suggested that the beneficial effects of neuroprotection in human amyotrophic lateral sclerosis (ALS) may be due to a preferential effect on early phases of the disease. However, the aim of this article is to review the potential arguments that there is no justification for early neuroprotective treatment of ALS. Controversies concerning the clinical neuroprotective effects of riluzole in mice and humans exist. Side effects of riluzole are emphasized and the data that appear to indicate that ALS has a long preclinical period are questioned. On the basis of these doubts and skepticisms, we conclude that it may be premature to treat ALS early without addressing the major objections in future studies in a controlled manner.

Failure of neuronal ion exchange, not potentiated excitation, causes excitotoxicity after inhibition of oxidative phosphorylation.

Neuronal cell death during impaired energy metabolism is often attributed to increased activity at glutamate receptors, but this increase has not been directly demonstrated. We recorded responses to glutamate and N-methyl-D-aspartate in hippocampal slice CA1 neurons and glia while inhibiting mitochondrial complex II with 3-nitropropionic acid. As the period of inhibition increased, neuronal depolarization following bath application of glutamate (5 mM) or N-methyl-D-aspartate (50 microM) increased dramatically. However, depolarization upon iontophoresis of glutamate and N-methyl-D-aspartate decreased with time. A transient hyperpolarization, reflecting electrogenic sodium pump activity, was present immediately after responses to iontophoretic glutamate agonists. In the presence of the inhibitor, this hyperpolarization decreased and eventually disappeared. Even the repolarization seen upon washing of the iontophoretic or bath application of glutamate or N-methyl-D-aspartate was incomplete. Glial depolarization upon bath application of glutamate increased during inhibition, while glial depolarization upon application of N-methyl-D-aspartate decreased. Application of the N-methyl-D-aspartate antagonists aminophosphonovaleric acid (100 microM) or MK-801 (20 microM) resulted in a delay of further depolarization when applied early during the terminal decay of membrane potential following metabolic inhibition. We conclude that during impaired oxidative phosphorylation the failure of repolarizing mechanisms, not potentiated neuronal depolarization by excitants, is the primary cause of the terminal depolarization. Large glial depolarization increases the demand for neuronal ion exchange which cannot be met in situations of reduced energy metabolism. Our results provide further evidence that acute and chronic blockade of energy metabolism have different effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Impaired hypoxic tolerance and altered protein binding of NADH in presymptomatic APP23 transgenic mice.

It is being discussed whether impairment of energy metabolism is a final common pathway of neurodegeneration or initiates the neurodegenerative cascade. The goal was to investigate hypoxic tolerance and oxidative energy metabolism in 4-month-old, presymptomatic B6-Tg(ThylAPP)23Sdz (APP23) mice, a transgenic mouse model of Alzheimer's disease. Posthypoxic recovery of the population spike amplitude in hippocampal region CA1 upon stimulation of Schaffer collaterals in region CA3 (15 min hypoxia, 45 min recovery) was 43+/-46% (mean+/-S.D.) vs. 19+/-35% (P<0.05) in slices from wild-type and transgenic animals, respectively. Fluorescence lifetime sensitive spectroscopy of NADH in the CA1 pyramidal cell layer (gate set for detection of protein-bound NADH) showed a wavelength maximum at 455.3+/-1.6 nm (mean+/-S.D.) in controls and 453.5+/-2.4 nm (P<0.05) in mutants. We conclude that hypoxic tolerance is impaired in presymptomatic APP23 mice and occurs prior to extracellular deposition of amyloid plaques. Impaired energy metabolism may thus partake in initiating the neurodegenerative cascade in a transgenic model of Alzheimer's disease. The blue shift of the spectrum of NADH in mutant mice indicates an altered protein microenvironment of energy metabolism under control conditions.

Amyotrophic lateral sclerosis and glutamate.

Amyotrophic lateral sclerosis is a progressive fatal disorder devastating the spinal cord and brain in humans. Excitotoxicity has been suggested to be involved in the pathogenesis of amyotrophic lateral sclerosis. This hypothesis has driven a wealth of basic research and stimulated development of neuroprotective therapies for chronic neurodegenerative disorders. As a result of these efforts, riluzole, an antiglutamatergic drug, has been established in the therapy of amyotrophic lateral sclerosis. A transgenic mouse showing features of amyotrophic lateral sclerosis has been subsequently engineered enabling studies of the disease in vivo. However, despite considerable progress, the etiology of amyotrophic lateral sclerosis remains obscure and the disturbances in excitatory neurotransmission should by no means be regarded as exclusive to the pathogenesis of the disease.

Increase of cellular hypoxic tolerance by erythromycin and other antibiotics.

Antibiotics are used extensively, but in addition to their anti-infectious effects some inhibit cellular energy metabolism. We investigated hypoxic tolerance following in vivo pretreatment with erythromycin and kanamycin, or in vitro pretreatment with ampicillin. Recovery of the CA1 population spike amplitude in hippocampal slices upon 15 min hypoxia improved time-dependently following single i.p. in vivo pretreatment with erythromycin (maximum at 6 h: recovery 90+/-7% (mean s.d.) vs 30% in untreated controls; p<0.01). The hypoxia-induced increase in NADH was smaller in slices that recovered from hypoxia. We conclude that antibiotics increase cellular hypoxic tolerance to a varying extent. Use of antibiotics in experimental studies may, therefore, distort conclusions about hypoxic sensitivity and confounding mechanisms. In contrast, antibiotics may provide an effective strategy to induce chemical preconditioning in humans.

Adenosine receptor up-regulation: initiated upon preconditioning but not upheld.

Activation of adenosine receptors is part of the endogenous defense against cerebral hypoxia and ischemia. However, it is not known which adenosine receptor subtypes mediate hypoxic tolerance upon chemical preconditioning. Selective A3 receptor mRNA up-regulation to 135 +/- 34% (mean +/- s.d.; p<0.05) was observed 1 h after preconditioning with 3-nitropropionate while A1 receptor mRNA levels remained unchanged (94 +/- 23%; n.s.). After 24h A3 and A1 receptor mRNA expression were both at control level. Further treatment in vitro resulted in a selective A3 receptor mRNA reduction. We conclude that the early (onset within hours) but not the late (duration of days) neuroprotection upon chemical preconditioning is associated with a selective up-regulation of A3 receptor mRNA. Detection of A3 receptor mRNA is very sensitive to prolonged stress in vitro.

NADH in the pyramidal cell layer of hippocampal regions CA1 and CA3 upon selective inhibition and uncoupling of oxidative phosphorylation.

N2-laser-induced fluorescence in combination with the time and spectral resolution of fluorescent NADH molecules allows on-line measurement of relative NADH concentration with high spatial resolution (diameter of optical fibre 200 microns, lambda(exc) = 337 nm, lambda(det) = 460 nm). Energy metabolism was impaired in submerged rat hippocampal slices using the inhibitors amytal, 3-nitropropionate (3-np), sodium cyanide (1 mM each) and the uncoupling agent 2,4-DNP (200 microM). A microprocessor-controlled repeated positioning of the optical fibre in CA1 and CA3 pyramidal cell layers, and CA1 stratum radiatum (CA1SR). Time-dependently, NADH fluorescence increased reversibly upon perfusion with amytal and cyanide. It was unchanged by perfusion with 3-np for 40 min and rapidly decreased upon perfusion with 2,4-DNP. The CA1/CA3 ratio of NADH fluorescence mildly decreased to 0.92 +/- 0.04 (mean +/- S.D.) at 10 min (P < 0.05) and 0.89 +/- 0.05 at 20 min (P < 0.01) upon perfusion with amytal. The CA1/CA3 ratio increased to 1.56 +/- 0.28 at 10 min (P < 0.01) and 1.29 +/- 0.35 at 20 min (P < 0.05) upon application of 2,4-DNP. Fluorescence in CA1SR was similar to fluorescence in CA1 upon perfusion with 2,4-DNP and similar to CA3 upon perfusion with amytal. We conclude that NADH fluorescence can be measured with high regional selectivity and specificity in hippocampal slices. Selective inhibition of mitochondrial complex I and uncoupling of energy metabolism differentially impair NADH concentration in different hippocampal areas.

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

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.

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

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.

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.

Early-onset tolerance in rat global cerebral ischemia induced by a mitochondrial inhibitor.

It was studied whether a subtoxic dose of the mitochondrial neurotoxin, 3-nitropropionic acid (3-NPA), can initiate early-onset tolerance induction for subsequent ischemic injury. Wistar rats were pretreated for 3 h by intraperitoneal 3-NPA (20 mg/kg body weight; n=13) or solvent (n=12). Fifteen minutes global cerebral ischemia was induced by bilateral carotid artery occlusion and hypobaric hypotension. rCBF and tissue hemoglobin oxygen saturation were measured by laser Doppler scanning and a microspectrophotometric method. Ischemic insult and brain temperature were identical in both groups. Body weight and neurological scores recovered in the pretreated group but further deteriorated in the non-treated group (P<0.05). Quantitative histology demonstrated a better neuronal density in neocortex and hippocampal CA2, CA3, and CA4 of pretreated animals (P<0.05).

Strain dependence of receptor regulation on chemical preconditioning in mice hippocampus.

While one current focus for studying mechanisms of disease is investigation of transgenic mice confounding effects of the background strain often are neglected. We investigated mRNA expression of known markers of hypoxic tolerance by a semiquantitative RT-PCR (adenosine receptors (A1 and A3), nitric oxide synthases (eNOS and nNOS), APP production, progesterone receptor, and estrogen receptors alpha and beta) in CD-1, C3H, and B6 mice. We found differences in the baseline mRNA expression of adenosine A3 receptors in C3H mice and neuronal NOS in B6 mice as well as a distinct regulation of adenosine A3 receptors and estrogen receptor beta (no changes in C3H and B6 compared to upregulation in CD-1) on treatment of animals with a low dosage of 3-nitropropionate (20mg/kg body weight, i.p.). We conclude that the choice of background strain may confound interpretation of the effects of specific transgens in the study of the mechanisms of primary and induced hypoxic tolerance.