Gerhard W. Eschweiler

Stage-dependent BDNF serum concentrations in Alzheimer’s disease

Summary.Alzheimer’s disease (AD) is characterized by cognitive decline and loss of neurons in specific brain regions. Recent findings have suggested an involvement of brain-derived neurotrophic factor (BDNF) in the pathogenesis of AD. BDNF is an endogenous protein involved in the maintenance of neuronal function, synaptic plasticity and structural integrity in the adult brain.To our knowledge, the present pilot study assessed for the first time BDNF serum and CSF concentrations in 30 patients with different stages of AD in comparison to 10 age-matched non-demendet controls. AD patients were divided in two groups according to their MMSE score: Group 1 (n = 15) in early stages with MMSE scores ≥21 (mean of 25.5) and Group 2 (n = 15) with more severe stages of dementia with MMSE scores <21 (mean of 13.3).As main results, we found in patients with early stages of probable AD significantly increased BDNF serum concentrations as compared to more severe stages of AD (p < 0.0001) and age-matched healthy controls (p = 0.028). BDNF serum values in all AD patients correlated significantly with MMSE scores (r = 0.486; p < 0.0001). Levels of BDNF were below the detection limit of the assay in unconcentrated CSF samples of AD patients and non-demendet controls.In summary, BDNF serum values are increased in early stages of Alzheimer’s disease, which may reflect a compensatory repair mechanism in early neurodegeneration and could also contribute to increased degradation of beta-amyloid (Abeta). During the course of the disease, BDNF is decreasing, which correlates with the severity of dementia. The decrease of BDNF may constitute a lack of trophic support with an increase of Abeta accumulation and thus contribute to progressive degeneration of specific regions in the AD-affected brain. BDNF should be further evaluated as a candidate marker for clinical diagnosis and therapeutic monitoring in Alzheimer’s disease.

Treatment with the selective muscarinic ml agonist talsaclidine decreases cerebrospinal fluid levels of Aβ42 in patients with Alzheimer's disease

The amyloid p-peptides Aβ40 and Aβ42 are highly amyloidogenic constituents of brain Pamyloid plaques in Alzheimers disease (AD). Lowering their formation may be achieved by modulating the activities of proteases that cleave the amyloid precursor protein (AβPP), including α-β-, and γ-secretases. Talsaclidine is a functionally selective muscarinic ml agonist that stimulates non-amyloidogenic a-secretase processing in vitro. We compared cerebrospinal fluid (CSF) levels of Aβ40 and Aβ42 measured by ELISA before and at the end of 4 weeks of treatment with talsaclidine. The medication was administered in a double- blind, placebo-controlled, and randomized clinical study to 40 patients with AD. Talsaclidine (n=34) decreased CSF levels of Aβ42 by a median of 19% (p < 0.001) as compared to baseline. The mean diflerence between CSF levels of Aβ42 before and after treatment with talsaclidine (n=34) was -46.73 (SD) pg/ml as compared to 0.8 (SD)pg/ml with placebo (n=6) (p < 0.05). CSF levels of Aβ40 increased during treatement with placebo (n=6) while they remained stable during treatment with talsaclidine (n=31) (1.118±1.710 ng/ ml, and-0.170A0.967 ng/ml, respectively; p < 0.05). These data show that treatment with the ml agonist talsaclidine reduced Aβ peptides, and particularly Aβ42, in AD patients, suggesting it as a potential amyloid lowering therapy of AD.

Exercise-induced normalization of decreased BDNF serum concentration in elderly women with remitted major depression

Major depression (MD) has been associated with decreased brain-derived neurotrophic factor (BDNF) serum levels, while antidepressant drugs were found to increase these decreased BDNF levels. We investigated if this is also caused by a single exercise session in elderly women with remitted MD. In our study 35 elderly women with a (partially) remitted depressive episode of unipolar depression according to DSM-IV criteria within the last year and 20 age-matched healthy female controls were included. Depression severity was assessed by HAMD. Serum levels of BDNF were measured by ELISA. Blood samples were taken during the rest period before beginning the exercise including spiroergometry, at the end of the exercise and after a 30-min recovery period. At baseline MD patients showed significantly decreased BDNF serum levels compared to healthy female controls. After a single 30-min exercise period, we found a significant increase of BDNF serum levels in MD patients towards values comparable with the baseline levels of the healthy controls, followed by a significant decrease after 30 min rest, while the healthy controls showed only a mild but non-significant increase. In conclusion, a single exercise session leads to a significant up-regulation and transient normalization of BDNF serum levels in elderly women with remitted MD. This mechanism may contribute to the beneficial therapeutic and relapse-preventing effects of physical activity on MD.

Increase of BDNF Serum Concentration in Lithium Treated Patients with Early Alzheimer's Disease

Preclinical and clinical studies gave evidence that lithium could be useful in the treatment of Alzheimers disease (AD). In experimental investigations, lithium induces brain-derived neurotrophic factor (BDNF). Recent studies have found a decrease of BDNF in the serum and brains of AD patients with potentially consecutive lack of neurotrophic support. We assessed the influence of a lithium treatment on BDNF serum concentration in a subset of a greater sample recruited for a randomized, single-blinded, placebo-controlled, parallel-group multicenter 10-week study, investigating the efficacy of lithium treatment in AD patients. In AD patients treated with lithium, a significant increase of BDNF serum levels, and additionally a significant decrease of ADAS-Cog sum scores in comparison to placebo-treated patients, were found. Diminution of cognitive impairment was inversely correlated with lithium serum concentration. Upregulation of BDNF might be part of a neuroprotective effect of lithium in AD patients. The results of the present investigation encourage performing studies with longer treatment phases to observe potential positive long-term effects of lithium in AD patients.

Impairment of episodic and semantic autobiographical memory in patients with mild cognitive impairment and early Alzheimer's disease

Autobiographical memory includes the retrieval of personal semantic data and the remembrance of incident or episodic memories. In retrograde amnesias, it has been observed that recall of autobiographical memories of recent events is poorer than recall of remote memories. Alzheimers disease (AD) may also be associated with a temporal gradient (TG) in memory decline, though studies have yielded inconsistent results on this point. They have also yielded inconsistent results on whether AD might differentially affect semantic and episodic remembrance. Here, we compared autobiographical memory of childhood, early adulthood, and recent life among healthy control (HC) subjects, patients with early AD, and patients with amnesic mild cognitive impairment (aMCI). Both the aMCI and AD patients exhibited declines in recall of autobiographical incidents and semantic information. In AD patients, both components of autobiographical memory had a clear TG, with better preservation of memories of childhood than those of early adulthood and recent life. The TG of autobiographical memory decline in AD patients is more compatible with the Cortical Reallocation Theory than with the Multiple Trace Theory of memory consolidation. In contrast to AD patients, aMCI patients exhibited impaired recall of personal facts and autobiographical incidents relating only to recent life. The significant decline in autobiographical memory for recent life that occurred in aMCI patients suggests that deterioration of consolidation of personal facts and events begins with commencement of functional impairment in the hippocampus.

Higher BDNF serum levels predict slower cognitive decline in Alzheimer's disease patients

The neurotrophin brain-derived neurotrophic factor (BDNF) plays a critical role in neuronal survival, synaptic plasticity, and memory. Several recent studies have demonstrated altered BDNF serum levels in Alzheimers disease (AD) patients. However, the association of BDNF serum levels with the rate of cognitive decline in AD patients is still unclear. We demonstrate that BDNF serum levels are significantly decreased in AD patients with fast cognitive decline [decrease of Mini-Mental State Examination (MMSE) score >4/yr; n=12] compared to AD patients with slow cognitive decline (decrease of MMSE score ≤4/yr, n=28) and show a significant correlation with the rate of cognitive decline during 1 yr follow-up. These results suggest that higher BDNF serum levels are associated with a slower rate of cognitive decline in AD patients. Further longitudinal studies are necessary to elucidate the kinetics and the potential role of serum BDNF as a surrogate marker of disease progression in AD patients.

Correlation of Fat Distribution in Whole Body Mri With Generally Used Anthropometric Data

Objectives:Obesity is a commonly known risk for many diseases such as metabolic syndrome and cardiovascular disease. Especially important is the discrimination of the adipose tissue inside the abdomen and the subcutaneous adipose tissue. Aim of this study was to compare the whole body fat distribution, and the volume of different adipose tissue compartments respectively, with anthropometric data. Materials and Methods:Sixty-eight volunteers (20 males, 48 females, 42.3 ± 15.4 years) were investigated in the context of 2 whole body magnetic resonance imaging (MRI) studies which compared the body fat distribution of depressive and bulimic patients with healthy controls. Unpublished data acquired in these studies were analyzed retrospectively.The sample consisted of 38 healthy volunteers, 17 patients with a depressive syndrome and 13 women suffering from bulimia nervosa. Individual body volume, total adipose tissue (TAT) volume, subcutaneous adipose tissue (SCAT) volume at the trunk, and visceral adipose tissue (VAT) volume were determined, using whole body MRI. Additionally, body fat profiles were standardized and a mean body distribution was calculated. Other modalities to acquire body fat content were: skin fold caliper, body impedance (3 different devices) and simple anthropometric data (Waist to Hip Ratio [WHR], Body Mass Index [BMI], distance of the aponeurosis of the rectus abdominis muscle to the ventral rim of the abdominal aorta (measured in MRI images on umbilical level) (AD) and subcutaneous adipose tissue thickness at the same level). The different modalities were correlated with the MRI data. Results:There were highly significant correlations between the skin fold data and TAT (Spearman coefficient 0.668, P ≥ 0.0004) and SCAT (0.662, P ≥ 0.0004). But there was no correlation with VAT. Impedance data revealed significant correlations of TAT and SCAT (Spearman 0.7, P ≥ 0.0004).Simple anthropometric data like waist and hip circumference, WHR, and BMI revealed significant correlations (Spearman coefficient around 0.7–0.4, P < 0.05) with the fat compartments TAT, VAT, and SCAT.The standardized body fat slices and the VAT slices were correlated with the anthropometric data and impedance data to explore specific areas along the body axis where the correlations were higher or weaker. Skinfold data, BMI, and body impedance data yielded significant correlations with TAT along the whole body axis, as well as with VAT in almost the whole analyzed area. However, there was no special body region with locally higher correlations. WHR depicted high correlations with whole VAT, and regional TAT at the abdomen (and not with the other body regions) especially in women. Therefore, it seems to be the best marker for abdominal fat and VAT in this study. Conclusions:We compared different body measures and body fat devices with the whole body fat distribution acquired by MRI. Generally, there were significant correlations of all modalities with body fat content (TAT) and mainly with SCAT. Correlations with VAT compartment were much weaker and an adequate estimation of VAT is, therefore, not possible. Only WHR revealed significant correlations with the fat in the body center, but only in women. If it is important to investigate especially the VAT which is responsible for a higher cardiovascular risk, risk for a metabolic syndrome and that is correlated with the course of different psychiatric diseases, cross sectional techniques such as MRI can not be substituted by simpler methods.

Prodromal features for Parkinson's disease – baseline data from the TREND study

A number of non‐motor features are known to precede motor manifestations of Parkinsons disease (PD). They are supposed to already represent the prodromal neurodegenerative state in those who later develop PD and are thus called prodromal markers. In this study, three prodromal markers, depression, rapid eye movement behaviour disorder (RBD) and hyposmia, were selected and were related to other prodromal features in elderly individuals without PD.

Aging-related cortical reorganization of verbal fluency processing: a functional near-infrared spectroscopy study

While progressive neurocognitive impairments are associated with aging and Alzheimers disease (AD), cortical reorganization might delay difficulties in effortful word retrieval, which represent one of the earliest cognitive signs of AD. Using functional near-infrared spectroscopy (fNIRS), we investigated cortical hemodynamic responses elicited by phonological and semantic verbal fluency in non-demented, healthy subjects (n = 325; age: 51-82 years). Age predicted bilaterally reduced inferior frontal junction (IFJ) and increased middle frontal and supramarginal gyri activity in both task conditions using multiple regressions. Compared with age the years of education as well as sex (IFJ activation in females > males) partly predicted opposite effects on activation, while task performance was not significant predictor. All predictors showed small effect sizes. IFJ activation was more pronounced during phonological compared with semantic fluency, and higher in the left hemisphere. Age only marginally predicted relative lateralization. Middle frontal and supramarginal gyri activity may compensate for an aging-related decrease in IFJ recruitment during verbal fluency. Longitudinal observations will further investigate these neural changes regarding an early AD prediction, while individuals are still cognitively healthy.

Poor Trail Making Test Performance Is Directly Associated with Altered Dual Task Prioritization in the Elderly – Baseline Results from the TREND Study

Background Deterioration of executive functions in the elderly has been associated with impairments in walking performance. This may be caused by limited cognitive flexibility and working memory, but could also be caused by altered prioritization of simultaneously performed tasks. To disentangle these options we investigated the associations between Trail Making Test performance—which specifically measures cognitive flexibility and working memory—and dual task costs, a measure of prioritization. Methodology and Principal Findings Out of the TREND study (Tuebinger evaluation of Risk factors for Early detection of Neurodegenerative Disorders), 686 neurodegeneratively healthy, non-demented elderly aged 50 to 80 years were classified according to their Trail Making Test performance (delta TMT; TMT-B minus TMT-A). The subjects performed 20 m walks with habitual and maximum speed. Dual tasking performance was tested with walking at maximum speed, in combination with checking boxes on a clipboard, and subtracting serial 7 s at maximum speeds. As expected, the poor TMT group performed worse when subtracting serial 7 s under single and dual task conditions, and they walked more slowly when simultaneously subtracting serial 7 s, compared to the good TMT performers. In the walking when subtracting serial 7 s condition but not in the other 3 conditions, dual task costs were higher in the poor TMT performers (median 20%; range −6 to 58%) compared to the good performers (17%; −16 to 43%; p<0.001). To the contrary, the proportion of the poor TMT performance group that made calculation errors under the dual tasking situation was lower than under the single task situation, but higher in the good TMT performance group (poor performers, −1.6%; good performers, +3%; p = 0.035). Conclusion Under most challenging conditions, the elderly with poor TMT performance prioritize the cognitive task at the expense of walking velocity. This indicates that poor cognitive flexibility and working memory are directly associated with altered prioritization.