Horst J. Koch

Cerebrospinal fluid tau and β-amyloid in Alzheimer patients, disease controls and an age-matched random sample

We prospectively evaluated the diagnostic accuracy of cerebrospinal fluid (CSF)-beta-amyloid1-42 (Abeta42), -total-tau (tau) and -phosphorylated-tau181 (p-tau181) as measured by sandwich ELISAs in the clinical routine of a community state hospital to discriminate between patients with Alzheimers disease (AD), healthy controls (HC), non-AD-dementias, a group composed of various psychiatric disorders (non-AD-dementias, mental diseases) and an age-matched random sample (RS) (total N=219). By comparing patients with AD to HC as reference, tau revealed sensitivity (sens)/specificity (spec) of 88%/80%, p-tau(181) 88%/80%, tau/Abeta42-ratio 81%/85% and phospho-tau(181)/Abeta42-ratio 81%/78%. Discriminative power between HC and all dementias under investigation was estimated lower for tau (78%/77%) and p-tau(181) (73%/79%). Relative to patients with AD, ROC analysis for the RS revealed highest sens/spec for p-tau181 (79%/77%) and p-tau181/Abeta42 ratio (78%/75%). Differentiation between AD versus a group made of patients with various psychiatric disorders was optimised by using CSF-p-tau181 (80%/77%). Under clinical routine conditions current CSF-biomarkers show a substantial capacity to discriminate between AD and HC as reference and to mark off AD patients from RS and heterogeneous diagnostic groups composed of non-AD dementias and other psychiatric conditions. Despite a residual substantial overlap between the groups, we conclude that current CSF markers are well suited to support AD-related diagnostic procedures in every-day clinics.

Observation on the integrity of the blood-brain barrier after microbubble destruction by diagnostic transcranial color-coded sonography.

To investigate alteration of the blood‐brain barrier from ultrasonic contrast agent destruction by diagnostic transcranial color‐coded sonography using gadolinium‐enhanced magnetic resonance imaging.

NMDA-antagonism (Memantine): An Alternative Pharmacological Therapeutic Principle in Alzheimers and Vascular Dementia

Memantine, a non-competitive NMDA antagonist, has been clinically used in the treatment of dementia in Germany for over ten years. The rationale for this indication is strongly related to the physiological and to the pathological role of glutamate in neurotransmission. Physiologically, NMDA receptors mediate synaptic plasticity by acting as a coincidence detector. Only those synapses that show temporally and spatially discrete activation of NMDA receptors undergo plastic changes secondary to Ca++ influx after rapid unblocking of Mg++, thus crucially contributing to memory and learning processes. The voltage-dependency of Mg++ is so pronounced that under pathological conditions it leaves the NMDA channel upon moderate depolarisation, thus interrupting memory and learning. Its pharmacological properties allow memantine to rapidly leave the NMDA channel upon transient physiological activation by synaptic glutamate (restoring significant signal transmission), but to block the sustained activation of low glutamate concentration under pathological conditions, i.e. to protect against excitotoxicity as a pathomechanism of neurodegenerative disorders. Memantine acts as a neuroprotective agent in various animal models based on both neurodegenerative and vascular processes as it ameliorates cognitive and memory deficits. Memantine has shown to be effective and safe in the treatment of dementia, particularly Alzheimers disease, in controlled clinical trials. Provided that the dose is slowly increased it is generally well tolerated and safe up to 20 and 30 mg per day, with intake preferably in the morning. The compound is completely absorbed after oral intake with Cmax values after 6 hours, undergoes little metabolism and has a terminal elimination half life between 60 and 100 hours. Due to its low potential of interaction, memantine can be combined with acetylcholinesterase inhibitors, the mainstay of current symptomatic treatment of Alzheimers disease and it is suited in elderly patients receiving multiple drug therapy.

Hospital admission circumstances and prevalence of frontotemporal lobar degeneration: a multicenter psychiatric state hospital study in Germany.

Frontotemporal lobar degeneration (FTLD) is a heterogenous, non-Alzheimer’s disease, dementia complex with variable clinical presentation. We carried out a prospective nationwide hospital-based clinico-epidemiologic study in geriatric psychiatry to estimate the prevalence and admission circumstances of patients with FTLD. During a 4-week period 33 patients with clinical FTLD were prospectively ascertained in 36 psychiatric state hospitals in Germany with a total catchment area of >20,000,000 people. The relative portion of FTLD patients within the primary dementia population accounted for 1.9%. The estimated prevalence of FTLD in Germany was 47.9/100,000 population aged between 45 and 79 years. The admission circumstances were mainly behavioral disturbances (54.5%), unclear syndromes of dementia (18.1%) and further remarkably heterogeneous psychiatric syndromes. FTLD is a common cause of dementia in geriatric psychiatry with a variable clinical presentation that could mimic most of the major psychiatric diseases. Patients with FTLD may be older than previously assumed (mean age at admission 63.9 years) and show their maximum age-related prevalence between 60 and 70 years (78.7/100,000).

Tenascin-C protein is induced by Transforming Growth Factor-ß1 but does not correlate with time to tumor progression in high-grade gliomas

SummaryBackgroundTenascin-C is an extracellular matrix protein known to correlate with prognosis in patients with glioblastoma, probably by stimulation of invasion and neoangiogenesis. Transforming Growth Factor-ß1 (TGF-ß1) plays an important role in the biology of high-grade gliomas, partly by regulating invasion of these tumors into parenchyma. This study was designed to evaluate if TGF-ß1 induces the expression and deposition of Tenascin-C in the extracellular matrix of high-grade gliomas which may be pivotal for the invasion of these tumors into healthy parenchyma.MethodsA series of 20 high-grade gliomas was stained immunohistochemically with Tenascin-C- and TGF-ß1- specific antibodies. Expression levels of both proteins were evaluated and correlated with each other, time to progression and molecular and morphological markers of invasion. A quantitative PCR assay was performed evaluating the induction of Tenascin-C mRNA by treatment with TGF-ß1 in vitro.ResultsTenascin-C was expressed in 18 of 19 (95%) evaluable tumors, whereas 14 of 20 tumors (70%) expressed TGF-ß1 in a significant percentage of cells. Treatment with TGF-ß1 did induce the expression of Tenascin-C at the mRNA and protein level in vitro. The expression of Tenascin-C and TGF-ß1 did neighter statistically correlate with each other nor with time to progression.ConclusionIn our series, Tenascin-C and TGF-ß1 were expressed in the vast majority of high-grade gliomas. We could not detect a correlation of one of the proteins with time to progression. Nevertheless, we describe induction of Tenascin-C by TGF-ß1, possibly providing a mechanism for the invasion of high-grade gliomas into healthy parenchyma.

Static posturography in aging and Parkinson's disease

Introduction: In clinical practice, evaluation of postural control is based on the neurological examination, including Rombergs test, examination of gait and performance of pull test as part of the Unified Parkinsons Disease Rating Scale (UPDRS). The goal of our study was to identify posturographic parameters since quantitative technical methods for the measurement of postural control are not established in clinical routine yet. Methods: In this cross-sectional study design we examined patients with Parkinsons disease (PD) (Hoehn and Yahr < 3; PD n = 12) on a static posturographic platform (eyes open and eyes closed), performing a standard Rombergs test during neurological examination and compared the results with an age-matched healthy adult control (HAC n = 10) and a healthy young control (HYC n = 21). Results: In the platform Rombergs test with open eyes, the patients with PD showed a significantly greater mean sway [PD: 14.98 vs. HAC: 8.77 (mm), p < 0.003 vs. HYC 7.80 (mm)], greater mean radius [PD: 28.31 vs. HAC: 16.36 (mm), p < 0.008 vs. HYC: 14.19 (mm)] and greater marked area [PD: 2.38 vs. HAC: 0.88 (cm2), p < 0.016 vs. HYC: 0.78 (cm2)] compared to the HAC. The Rombergs test with closed eyes revealed a significantly greater mean sway [PD: 13.83 vs. HAC: 10.12 (mm), p < 0.033 vs. HYC: 5.82 (mm)] and greater mean radius [PD: 25.03 vs. HAC: 18.15 (mm), p < 0.045 vs. HYC: 9.11 (mm)] compared to both groups. Conclusions: The platform Romberg-test with closed eyes detected significant differences in elderly people and patients with Parkinsons disease, which could be objectively quantified with static posturography testing. Age alone showed significant changes, only detectable with closed eyes. Therefore, balance testing with a new computerized approach could help to identify balance problems in a geriatric assessment in clinical routine, especially with the parameters marked area and mean sway.

Relation between laterality and immune response after acute cerebral ischemia

Objective: During the last 2 decades, right/left hemisphere dominance was supposed to affect the immune system differently. Experimental and clinical observations indicate that the left hemisphere plays a crucial role in the development of the immune system. The true relationship between immune response and acute ischemic stroke laterality remains to be elucidated. Methods: We studied acute right-handed stroke patients admitted to a single acute neurology department with a specialized stroke unit. Being part of our clinical protocol, blood samples were taken within the first 24 h after the onset of stroke symptoms. The medical record of each patient was reviewed, and demographic, clinical laboratory (key criteria: C-reactive protein, CRP, and white blood cell count, WBC) and neuroimaging information was retrieved. All data were presented descriptively, and bivariate test statistics, ANOVA (log-transformed data) or linear correlations were calculated. Results: Fifty-six of the 187 patients admitted to our Stroke Unit between October 2003 and March 2004 with different stroke subtypes according to the TOAST criteria were retrospectively evaluated in order to characterize the impact of stroke laterality on immunoregulatory response measured by CRP levels and WBC. Correlation analysis revealed that left-sided ischemic stroke yielded a significantly higher correlation between CRP levels and WBC. Following left-sided stroke, a more marked variability in CRP and WBC was found compared to patients with right-sided ischemic stroke, although ANOVA did not show significant differences between immune response values as a function of stroke subtypes. Conclusions: We identified an association between stroke laterality and immunoregulatory response in patients with acute ischemic stroke. Left-sided stroke may be considered as a direct risk factor for infectious disease or immune deficits and should attract special attention. However, these preliminary results need be confirmed by controlled studies.

Seasonal Patterns of Birth in Patients with Glioblastoma

Seasonal distribution of birth rates was only recently described in patients with high‐grade gliomas. We analyzed 501 cases from the database of a Regional Cancer Center in Bavaria to assess annual periodicity in the birth dates of glioma patients. Prior to analysis, the number of births per month was normalized [number of births×100,000/total number of births in Germany] to obtain birth rates per month. The approximation of the time series data by a one‐year cosine model found that the glioblastoma birth rate exhibits a statistically significant annual variation, with the peak rate in January. Vitamin intake, infections, and other as‐yet‐unknown factors and exposures during pre‐ and perinatal early life may contribute to the seasonality of birth rate in patients with brain tumors.

Memantine: a therapeutic approach in treating Alzheimer's and vascular dementia.

Memantine has been clinically used in the treatment of organic disorders in Germany for over ten years and has now been approved in Europe and also in the US for moderate to severe Alzheimers disease. The rationale for this indication is strongly related to the physiological and pathological role of glutamate in neurotransmission. Glutamate is an agonist of NMDA, kainate and AMPA (ionotropic) receptors, where its influence on NMDA receptors plays an important role with regard to neuronal plasticity effecting memory and learning. Excessive levels of glutamate result in neurotoxicity, in part by overactivation of NMDA receptors. Memantine acts as an uncompetitive antagonist of NMDA receptors and therefore compensates for this overactivation. Furthermore, memantine is a neuroprotective agent in various animal models based on both neurodegenerative and vascular processes, as it ameliorates cognitive and memory deficits. Memantine was effective and safe in several clinical studies, particularly in Alzheimers disease. The compound is completely absorbed after oral intake and undergoes little metabolism. Having a low probability for drug-drug interactions, memantine, in principle, is suited for elderly patients exposed to multiple therapeutic therapies.

Maintenance therapy with 13-cis retinoid acid in high-grade glioma at complete response after first-line multimodal therapy--a phase-II study

AbstractBackground: Approximately 5% of patients with malignant glioma achieve complete response (CR) after first-line combined modality treatment. Although these patients will invariably suffer from tumor recurrence, they usually do not receive any further treatment to maintain remission. According to in vitro and in vivo clinical studies, 13-cis retinoic acid (cRA) may be a promising agent for maintenance therapy in these patients. Objective: We initiated a clinical study to evaluate the feasibility and toxicity of high-dose cRA as maintenance therapy in patients with high-grade glioma in complete remission after first-line multimodal treatment. Methods: A prospective single-arm phase-II study in patients with CR after combined first-line therapy (neurosurgery, radio- and chemotherapy) was performed. Patients were treated with cRA at 60 mg/m2 BS from day 1 to 21 in four-weekly cycles with a dose escalation of up to 100 mg/m2 BS until tumor recurrence. Clinical controls were performed every 4 weeks, magnetic resonance imaging every 8 weeks. Results: Twenty-three patients (10, grade IV; 13, grade III) were evaluable using an intention-to-treat analysis. Treatment was well tolerated for up to 149 weeks with moderate dermatological symptoms in all patients. No grade 4 toxicities were observed. Median time to progression was 41 weeks, median overall survival 74 weeks after inclusion in the protocol. Discussion: There is an urgent need for strategies maintaining remission in patients with malignant glioma. Maintenance therapy with high-dose cRA is feasible and well tolerated over long periods of time. A controlled clinical trial to test the efficacy of cRA as a maintenance treatment in malignant glioma is warranted.