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.

[Dementia guidelines: what should come to general practice--an interdisciplinary consensus of physicians in private practice]. / Demenzleitlinien: was in der Praxis ankommen sollte--Ein interdisziplinärer Konsens von Praktikern.

BACKGROUND: Guidelines of Medical Societies aim at supporting the quality of medical care in general, and particularly in private practice. Usually, physicians in private practice are not part of the expert committees of medical societies that author guidelines. Guidelines represent a consensus appraising evidence from clinical studies on efficacy and side effects but also evaluating aspects of the health care system such as costs. Guidelines commonly do not account for regional specifics. Transfer of knowledge from guidelines to general practice, therefore, is incomplete. METHODS: We describe a consensus of neuropsychiatric and general physicians (n=12; 10 to 38 years of professional experience) on prioritization of diagnostic and therapeutic procedures for patients with Alzheimer's dementia as judged by relevance and practicability compared to the guideline of the Society for General Medicine (DEGAM-guideline No. 12) and the S3-guideline dementia of the German Society for Psychiatry, Psychotherapy and Neuropsychiatry (DGPPN). RESULTS: If patients and proxies do not oppose diagnosis, e. g. in cases of progressive impairment of memory with everyday relevance, the appropriate diagnostic procedures should be performed for every patient. Age or setting in which the patients live, in itself are no reason to limit antidementia therapy. Symptom fluctuations or decline of individual symptoms are compatible with treatment success. Clinical scales may only be used as supportive means to evaluate disease progression. CONCLUSION: Diagnosis and treatment of dementia are experienced as complex tasks by physicans in private practice. Practicing physicians need to adapt guidelines of medical societies on local and individual specifics.

Verbal episodic memory and endogenous estradiol: an association in patients with mild cognitive impairment and Alzheimer's disease.

In the continuum of patients with Alzheimer's disease (AD), mild cognitive impairment (MCI), and normal controls, a possible association of verbal memory and endogenous estradiol (E(2)) levels was investigated. Verbal episodic memory was measured with a german version of the California verbal memory test (CVLT). Results were controlled for apolipoprotein E (ApoE) phenotype. We studied 37 controls, 32 MCIs and 117 ADs. Groups differed in all trials of the CVLT (P < 0.001) and in E(2) levels (P < 0.001). E2 levels differed significantly between groups only among females (P < 0.001). In females correcting for age and ApoE, there was an overall correlation between CVLT delayed recall and level of E(2) (P = 0.025). Stepwise regression analyses found E(2) level to be a significant predictor for CVLT delayed recall (P < 0.001). It may be concluded that lower E(2) levels occur more in the course of the disease than may be considered as a risk factor per se.

An unbiased, staged, multicentre, validation strategy for Alzheimer's disease CSF tau levels.

Newly proposed diagnostic criteria for Alzheimer's disease include cerebrospinal fluid (CSF) tau levels as one core supportive criterion. The published high sensitivity and specificity figures for CSF tau levels in Alzheimer's disease are offset by the large range of proposed cutoff values (9.6 pg/mL to 1140 pg/mL). This study aimed to provide guidance on how to establish, validate and audit CSF tau cutoff values using an unbiased, two-stage multicentre strategy. Both receiver operator characteristics (ROC) optimised and population-based cutoff values were calculated on a pilot dataset (n=99), validated in a large dataset (n=560) and then compared to the literature. The data suggest using an ROC optimised cutoff level of 323+/-51.7 pg/mL allowing for the published inter-laboratory coefficient of variation of 16%. This cutoff level was confirmed in a prospective audit (n=100). As demand for CSF tau levels will increase globally, the accuracy of local CSF hTau cutoff levels can be compared against this benchmark.

Applying new research criteria for diagnosis of early Alzheimer's disease: sex and intelligence matter.

Alzheimer's disease (AD) can be diagnosed according to new research criteria proposed recently (Dubois et al., 2007). Diagnosis is made on grounds of episodic memory deficits and one pathological biomarker: cerebrospinal fluid (CSF) or structural/functional imaging. Goal was to investigate the dependence of episodic memory function on material (verbal, visuospatial), gender and premorbid intellectual ability (IQ). The new research criteria of AD were applied retrospectively using data of 68 patients (Mini-Mental-Status Examination, MMSE >/= 22) from a university memory clinic. Women with lower IQ performed worse on visuospatial episodic memory than women with higher IQ and men with the same IQ. Thus, women with lower IQ appear to be particularly vulnerable to visuospatial episodic memory deficits despite similar CSF tau values indicating a similar activity of the neurodegenerative process. Gender, premorbid IQ, and visuospatial material need to be considered in the assessment of episodic memory breakdown applying the newly proposed research criteria for the diagnosis of AD.

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.

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.

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.

Cognitive estimation in mild Alzheimer's disease.

In everyday life, we often estimate rather than know. We investigated in an experimental approach modality-specific cognitive estimation in patients with mild Alzheimer's disease (AD). Estimation of weight, size, number, and time prior and subsequent to observation of a moving object was assessed in healthy controls (HC; n = 49; 62.5 +/- 7.8 years (mean +/- standard deviation); MMSE 29.2 +/- 1.1) and patients with AD (NINCDS-ADRDA, DSM IV; n = 42; 75.0 +/- 9.5 years; p < 0.001 to HC; MMSE 22.8 +/- 2.9; p < 0.001 to HC). In HC none of the estimation tasks correlated with age or general intellectual ability. AD patients were impaired for estimation of time and weight while estimation of number, size, and distance was not impaired. Estimation of time that a marble will need to roll down a marble track was associated with lower scores for verbal fluency and higher scores for clock drawing in the AD group and estimation of time subsequent to observation was associated with higher scores in clock drawing. Time estimation for moving objects as well as the ability to correct oneself on observation is impaired in patients with very mild AD. This argues for caution in tasks such as car driving already in this stage. Errors in estimation of time observed indicate temporo-parietal impairment while errors on estimation prior to observation of the moving object indicate additional frontal lobe impairment.

Gender- and region-specific expression of insulin receptor protein in mouse brain: effect of mild inhibition of oxidative phosphorylation.

Insulin receptors (IR) and inhibition of oxidative metabolism have been suggested to partake in the pathophysiological cascade of neurodegenerative disorders. The goal of this study was to investigate gender- and region-specificity of insulin receptor protein expression in mouse brain subsequent to a mild hypoxic episode. Tissue was prepared from untreated male and female mice and animals pretreated in vivo with 20 mg/kg body weight i.p. 3-nitroproprionic acid (3-np; an inhibitor of succinic dehydrogenase) 1 hr prior to tissue preparation. IR expression in control animals was alike in males and females during proestrus and estrus but reduced during diestrus. On pretreatment, IR protein expression decrease in hippocampus in males but remained alike in other regions and females. In summary, IR protein expression is regionally different in males and females, gender-dependent, and modulated during the stages of the estrus cycle in females. Contrary to expectations it is not modified on mild inhibition of oxidative phosphorylation in any region in females and altered in hippocampus solely in males. The latter effect, however, warrants further scrutiny concerning participation in pathophysiological cascades affecting the hippocampus such as in Alzheimer's disease.

Screening for cognitive impairment in Parkinson's disease--which marker relates to disease severity?

The frequency and pattern of cognitive deficits in Parkinson's disease (PD) is under discussion. We assessed 157 consecutive subjects with PD (66.4 +/- 8.9 years (mean +/- standard deviation); average duration of disease 3.5 +/- 1.3 years; average Hoehn and Yahr stage 2.4 +/- 0.9) diagnosed in centers specialized for the diagnosis and treatment of PD with brief tests for memory (Memory Impairment Screen), attention (Letter Sorting Test) and semantic fluency (category animals). Impaired memory was observed in about one half of the subjects regardless of severity of disease as assessed by staging according to Hoehn and Yahr. With greater severity, free recall was impaired and subjects required the cues to recall the items. Performance in the Letter Sorting Test and the semantic fluency task declined with increasing Hoehn and Yahr stage, also. We conclude that cognitive deficits are frequent in PD. Further analyses reveal that even in selected screening tests (e.g. semantic fluency) a significant impairment with increasing disease severity (Hoehn and Yahr stage) as opposed to disease duration alone can be demonstrated.

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.

Cholinergic treatment: what are the early neuropathological targets?

Defining the regions of the brain displaying the neuropathological lesions that cause Alzheimer's disease (AD) will facilitate deeper investigation into their pathophysiology. In addition, this would allow the effects of AD treatment to be specifically monitored in those regions. Cognitive decline in AD begins with failings of episodic memory and spatial orientation in patients with very mild AD. Clinical and experimental data show that the brain regions primarily involved in memory impairment early in AD are the hippocampus and the medial temporal lobe. Is it possible to prevent the development of pathophysiology in these regions? The neuroprotective effect of cholinesterase inhibitors has been demonstrated in a number of different models, including protection of cortical neurons in models of oxygen-glucose deprivation and glutamate-induced toxicity, and protection against the effects of hippocampal mitochondrial dysfunction in transgenic mouse models of AD. These preclinical data are supported by extensive clinical data indicating that maximum benefit is gained through early initiation of treatment with donepezil and suggest that the benefits afforded by donepezil may extend beyond those of a purely symptomatic treatment.

Regional selectivity of amyloid mRNA expression and neurotrophins on repetitive inhibition of oxidative phosphorylation.

Previously we showed that repetitive inhibition of oxidative phosphorylation impairs synaptic transmission and induces overexpression of amyloid precursor protein mRNA (APP-mRNA) in the hippocampus (Hellweg et al., 2003). Here we show that APP-mRNA remains alike in murine frontal cortex and cerebellum on repetitive treatment with 3-nitropropionate. However, nerve growth factor and brain-derived neurotrophic factor decreased by 28 to 38% in frontal cortex. Taken together, the pattern of change resembles genetic models of Alzheimer's disease with less susceptibility for overexpression of amyloid mRNA in frontal cortex than in hippocampus and reduced neurotrophin levels in frontal cortex. Given the similarity of this pattern to the one observed in human Alzheimer's disease the present model in future may give further insight into the pathophysiology of sporadic Alzheimer's disease.

[18F]FDG-PET in patients with Alzheimer's disease: marker of disease spread.

BACKGROUND: It is not known yet whether temporoparietal glucose hypometabolism in patients with probable Alzheimer's disease (AD) reflects disease severity or different subtypes of patients. METHODS: Twenty-five subjects with mild probable AD [NINCDS-ADRDA criteria; age 65.8 +/- 9.3 years (mean +/- SD); Mini-Mental State Examination (MMSE) 26.0 +/- 3.3] were investigated. [(18)F]FDG-PET data were analyzed visually with raters blinded to the diagnosis and with a quantitative analysis in the region of interest on individual anatomically normalized PET scans. RESULTS: Thirteen of 25 patients showed temporoparietal hypometabolism on visual inspection (PET+; age 65.7 +/- 10.7), 12 patients had normal FDG-PET results (PET-; age 65.9 +/- 8.0; n.s.). The MMSE and immediate reproduction of the Wechsler Memory Scale (WMS-R-I) were 27.7 +/- 1.9 and 31.1 +/- 6.1 in the PET- vs. 24.5 +/- 3.6 (p = 0.012) and 22.0 +/- 7.4 (p = 0.006) in the PET+ group. Immediate and delayed recall in the California Verbal Learning Test and delayed reproduction in the Wechsler Memory Scale were alike. Regression analysis revealed a significant correlation of temporoparietal glucose metabolism with the block span (r = 0.60; p < 0.01) and the WMS-R-I (r = 0.68; p < 0.01) but not with measures of hippocampal function. CONCLUSIONS: Temporoparietal glucose metabolism in patients with very mild AD is a sign of disease spread beyond the temporal lobe. This may aid in establishing objective parameters for future therapeutic studies.

Meningeal derived cerebrospinal fluid proteins in different forms of dementia: is a meningopathy involved in normal pressure hydrocephalus?

OBJECTIVES: In animal models and in vitro studies leptomeninges have been shown to be the origin of neurotrophic substances that support the survival and growth of neuronal cells. Because dementia is associated with neuronal loss, we investigated whether leptomeningeal dysfunction may be involved in the pathogenesis of dementia disorders. METHODS: We analysed the cerebrospinal fluid (CSF) concentrations of the leptomeningeal derived beta trace protein, beta2 microglobulin, and cystatin C. RESULTS: There was a statistically significant difference of the CSF beta trace protein levels among different groups. Patients with idiopathic normal pressure hydrocephalus (NPH) (17.5 (SD 4.3) mg/l) showed significantly lower CSF beta trace protein levels than patients with Alzheimer's disease (23.8 (6.2) mg/l), depression (24.2 (7.3) mg/l), and normal controls (25.3 (4.9) mg/l). To patients with vascular dementia (20.1 (5.6) mg/l) and frontotemporal dementia (21.9 (7.0) mg/l), the difference was not significant. There was no significant difference regarding the CSF and serum concentrations of beta2 microglobulin or cystatin C among the different groups. CONCLUSIONS: We conclude that leptomeningeal dysfunction may be involved in certain types of dementia such as NPH and that reduced CSF beta trace protein levels in patients with NPH may aid in differentiating this difficult to diagnose disorder from other syndromes such as Alzheimer's disease.

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.

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.

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.