Marc Hofmann

Age Dependency of Changes in Cerebral Hemoglobin Oxygenation during Brain Activation: A Near-Infrared Spectroscopy Study

We used near-infrared spectroscopy (NIRS) to study noninvasively the influence of aging on changes in the local concentration of oxygenated hemoglobin ([HbO2]), reduced hemoglobin ([HbR]), and total hemoglobin ([HbT] = [HbR] + [HbO2]) during activation of brain function. Young subjects (n = 12; age, 28 ± 4 years) performing calculation tasks showed an increase in [HbO2] [mean (arbitrary units) ± SD, 2.36 ± 1.07] and [HbT] (2.24 ± 1.13) in the frontal cortex, while [HbR] (−0.11 ± 0.48) decreased. Elderly subjects (n = 17; age, 52 ± 10 years) showed a significantly lower mean increase (p < 0.05) in [HbO2] and [HbT] levels (1.21 ± 1.38 and 0.72 ± 1.41, respectively). Regression analysis supports the hypothesis of an age-dependent decline in the activation-induced local increase in [HbO2] (y = −0.241x + 20.062; r = −0.431, p < 0.05) as well as [HbT] (y = −0.346x + 22.496; r = −0.568, p < 0.05). We conclude that NIRS is a promising approach for studying changes in Hb oxygenation during brain activation in physiological aging.

Interactive computer-based cognitive training in patients with Alzheimer's disease

The present paper presents data from ten patients suffering from mild to moderate Alzheimers disease (AD), all of whom were trained to use an interactive computer-based program. Using photographs of the patient and his or her personal surroundings, an everyday task of relevance to the patient was simulated on a PC-touch screen, which the patient was trained to operate. After three weeks of training (three to four sessions a week), the patients needed less help in performing the programs, they became faster, and eight out of ten made fewer mistakes. The results were most pronounced in patients with a poor performance at the beginning, and there was no difference between early-onset (EO) and late-onset (LO) AD patients. Although the training was generally well received, there was no evidence of a general cognitive improvement, and it remains an open question whether the results achieved with PC training can be transferred to real-life situations.

Interactive computer-training as a therapeutic tool in Alzheimer’s disease

The current study sought to evaluate a novel kind of interactive computer-based cognitive training (ICT) in Alzheimers disease (AD). AD patients (N = 9), age- and gender-matched patients with a major depressive episode (N = 9), and healthy control subjects (N = 10) were trained to use an ICT program that relates to activities of daily living (ADL). Digital photographs of a shopping route were implemented in a close-to-reality simulation on a computer touch-screen. The task was to find a predefined shopping route, to buy three items, and to answer correctly 10 multiple-choice questions addressing knowledge related to the virtual tasks. Training performance was rated using the number of mistakes (wrong way), time needed for the tasks, number of correct multiple-choice answers, and of repeat of instruction. Compared to normal controls and depressed patients, AD patients performed significantly worse with regard to all variables. Within a 4-week training period including 12 sessions, however, substantial training gains were observed, including a significant reduction of mistakes. Training effects were sustained until follow-up 3 weeks later. The performance of the depressed patients and the normal controls improved as well, with no difference between the two groups. Self-reported effects revealed that the training was well perceived. Thus, the task performance of AD patients improved substantially and subjects appeared to have liked this approach to ICT. New interactive media, therefore, may yield interesting opportunities for rehabilitation and (psycho)therapeutic interventions.

Near Infrared Spectroscopy in the Diagnosis of Alzheimer's Disease

Near infrared spectroscopy (NIRS) is a new technique that permits noninvasive monitoring of cerebral blood and tissue oxygenation. Recently, we and others have shown that NIRS measurements are sensitive enough to follow changes in cerebral hemoglobin oxygenation due to activation of brain function. Based on these findings we have assessed the influence of aging as well as the influence of neurodegeneration on cerebral hemoglobin oxygenation during mental work. The typical NIRS pattern in young healthy subjects while performing calculation tasks measured in the frontal cortex were increases in oxygenated hemoglobin [HbO2] and total hemoglobin [HbT] while reduced hemoglobin [HbR] decreased. Elderly healthy subjects showed a significant lower mean increase in [HbO2] and [HbT] levels. Regression analysis revealed an age‐dependent decline in activation‐induced local increase of [HbO2] as well as [HbT]. Furthermore, we monitored changes in cerebral hemoglobin oxygenation in the frontal cortex while patients with probable Alzheimers disease (AD) performed cognitive tasks. Whereas elderly healthy subjects (as well as patients with major depression, age‐associated memory impairments or vascular dementia) again showed clear increases in the local concentrations of [HbO2] and [HbT] during brain activation, AD patients showed significant decreases compared to the baseline levels in both variables that were most pronounced in the parietal cortex. To clarify whether the different patterns in cerebral hemoglobin oxygenation during cognitive activation were due to an altered functional brain organization in AD or to alterations in the cerebrovascular response to neuronal activation, we are currently performing simultaneous NIRS and (015‐H20‐)PET measurements during performance of a cognitive task (Stroop test). Our finding of a regional reduced oxygen supply during activation of brain function may be of relevance to the development and the time course of neurodegeneration.

The PHA-induced calcium signal in lymphocytes is altered after blockade of K+-channels in Alzheimer's disease

Several lines of evidence indicate that alterations in intracellular calcium homeostasis with sustained elevation of free calcium ions ([Ca2+]i) might be important in the pathophysiology of Alzheimers disease (AD). Recent studies with peripheral blood-cells have demonstrated that investigation of regulatory mechanisms in calcium homeostasis might be more promising than determining only resting or stimulated [Ca2+]i values. With respect to the importance of potassium (K+)-channels in intracellular calcium regulation we have investigated whether a potassium channel dysfunction, already demonstrated for AD fibroblasts (Etcheberrigaray et al., 1993, Proceedings of National Academy of Sciences USA, 90, 8209-8213), could be observed in circulating lymphocytes as well. Thus, we studied the influence of the K(+)-channel inhibitor tetraethylammonium (TEA) on basal and PHA-stimulated [Ca2+]i in lymphocytes from AD (n = 20), non-demented depressed patients (n = 15) and age-related healthy controls (n = 23). Preincubation of lymphocytes with 100 mmol/l TEA resulted in a 45.5 +/- 8.8% inhibition (mean +/- SD) of the PHA induced rise in [Ca2+]i in healthy controls and 37.3 +/- 11.3% inhibition in depressed patients. With lymphocytes of AD patients, this effect of TEA was significantly reduced (23.2 +/- 8.8%, p < .001). If the individual data are considered there was almost no overlap between AD patients and healthy controls, since only three (15%) AD patients responded to TEA with > 30% inhibition, but only one of the controls (5%) responded with < 30% inhibition. Besides the reduced signal-inhibition by blockade of K(+)-channels we have observed a delayed response of AD lymphocytes in [Ca2+]i rise after PHA stimulation, suggesting that functional plasticity of the cells is reduced. Although the significance and molecular basis of this K(+)-channel dysfunction are not yet determined, the presented data are of great significance because of diagnostic reasons and especially because this model thus offers a possibility to investigate functional cellular alterations in vivo.

Evidence of a Genetic Basis of Morgagni-Stewart-Morel Syndrome

We report two 71-year-old female monozygotic twins presenting with advanced hyperostosis frontalis interna, obesity, shortness and cognitive impairment. They both have suffered from generalized seizures since their early adulthood. Moreover, the patients showed some additional conditions only occurring in one individual or the other such as migraine, marked recurrent depressive disorder or polyarthrosis. The symptoms common to both twins appear to correspond to the Morgagni-Stewart-Morel syndrome and indicate a genetic basis of this disorder as these features occur in genetically identical patients.

β2-receptor density on mononuclear blood cells in patients suffering from neuroleptic-induced akathisia (NIA)

The effectiveness of beta-blockers in the treatment of neuroleptic-induced akathisia (NIA) suggests that beta-adrenergic overactivity is involved in the manifestation of NIA. As an approach to understanding this postulated overactivity, we investigated the beta 2-receptor density on mononuclear blood cells in 21 patients suffering from NIA as well as in 12 patients without NIA. The beta 2-receptor density in NIA-positive patients was significantly higher than that in NIA-negative patients (t = 2.84; p = .008). The NIA-positive patients were treated with 20 mg propranolol t.i.d. for 5 days. The beta 2-receptor density in treatment responders did not differ significantly from that in non-responders. Our results indicate that beta 2-receptors on mononuclear cells in patients with NIA may be of a certain degree of importance. With the prerequisites of replicability as well as correlation of this parameter with therapeutic success of beta-blockers, it may be considered as a predictor for treatment response.

Nicht-invasive Messung der zerebralen Hämoglobin-Oxygenierung mit Hilfe der Nah-Infrarot-Spectroskopie (NIRS) bei normalem Altern und bei der Alzheimer Demenz

Funktionelle Neuroimaging-Methoden, wie z. B. die Positronen-EmissionsTomographie, haben das Verstandnis fur den cerebralen Stoffwechsel bei physiologischen Alterungsvorgangen und bei der Demenz wesentlich erweitert. Daruberhinaus besteht ein wachsendes Interesse an optischen Methoden, die in der Lage sind, mit neuronaler Aktivitat verbundene Signale zu messen. Die sogenannte Nahinfrarot-Spectroskopie (near infrared spectroscopy, NIRS) basiert auf der relativen Transparenz von Gewebe fur Licht im nahen Infrarotbereich (700–900 nm). Dieses „optische Fenster“ (near IR „optical window“) ermoglicht die nichtinvasive Messung endogener Chromophore, wie z. B. Hamoglobin oder Cytochromoxidase [1]. Die zum jetzigen Zeitpunkt valide erfasbaren NIRS Variablen sind oxygeniertes Hamoglobin [HbO2], deoxygeniertes (reduziertes) Hamoglobin [HbR] und Gesamthamoglobin (total hemoglobin [HbT] (= [HbO2] + [HbR]) (zur Ubersicht siehe [2]. Unter der Annahme eines konstanten Hamatokrit wahrend der Untersuchung, werden Veranderungen des [HbT] als Indikator fur Veranderungen des cerebralen Blutvolumens angesehen [3]. Die Quantifizierung einer weiteren NIRS-Variable, der Cytochromoxidase (Cytochrom aa3) ist derzeit Gegenstand intensiver Forschung. Kurzlich konnten unsere und andere Arbeitsgruppen zeigen, das die ^NIRS, |angewandt in einer Reflektionstechnik, sensitiv genug ist, um Veranderungen der cerebralen Hamoglobin-Oxygenierung wahrend cerebraler Aktivierung durch verschiedene Paradigmen zu erfassen [4–7].

Individualisiertes, computergestütztes Gedächtnistraining bei Alzheimer-Patienten

Ein haufiger Kritikpunkt an konventionellen kognitiven Trainingsprogrammen fur Patienten mit Hirnleistungsstorungen ist deren fehlende Alltagsrelevanz. Wir berichten deshalb uber erste kasuistische Erfahrungen mit einem neu entwickelten, individualisierten, computergestutzten Gedachtnistraining bei vier Patienten mit wahrscheinlicher Alzheimer’scher Demenz. Durch die Integration von Fotos aus der personlichen Umgebung oder der Biographie des Patienten wurde eine individuell auf den Betreffenden abgestimmte alltags- und personlichkeitsrelevante Aufgabenstellung an einem beruhrungsempfindlichen Bildschirm simuliert und trainiert. Ziel war ein auf den jeweiligen Schweregrad der kognitiven Beeintrachtigungen abgestimmtes interaktives Training a) der sozialen Kompetenz, b) der raumlichen Orientierung und ein Ansprechen c) emotionaler Bereiche z. B. durch die Verwendung biographischen Materials.