TY - JOUR A1 - Booker, Anke A1 - Jacob, Louis E. C. A1 - Rapp, Michael Armin A1 - Bohlken, Jens A1 - Kostev, Karel T1 - Risk factors for dementia diagnosis in German primary care practices JF - International psychogeriatrics N2 - Background: Dementia is a psychiatric condition the development of which is associated with numerous aspects of life. Our aim was to estimate dementia risk factors in German primary care patients. Methods: The case-control study included primary care patients (70-90 years) with first diagnosis of dementia (all-cause) during the index period (01/2010-12/2014) (Disease Analyzer, Germany), and controls without dementia matched (1:1) to cases on the basis of age, sex, type of health insurance, and physician. Practice visit records were used to verify that there had been 10 years of continuous follow-up prior to the index date. Multivariate logistic regression models were fitted with dementia as a dependent variable and the potential predictors. Conclusions: Risk factors for dementia found in this study are consistent with the literature. Nevertheless, the associations between statin, PPI and antihypertensive drug use, and decreased risk of dementia need further investigations. KW - dementia KW - Alzheimer KW - risk factors KW - statins Y1 - 2016 U6 - https://doi.org/10.1017/S1041610215002082 SN - 1041-6102 SN - 1741-203X VL - 28 SP - 1059 EP - 1065 PB - Cambridge Univ. Press CY - New York ER - TY - GEN A1 - Booker, Anke A1 - Jacob, Louis E. C. A1 - Rapp, Michael Armin A1 - Bohlken, Jens A1 - Kostev, Karel T1 - Risk factors for dementia diagnosis in German primary care practices T2 - Postprints der Universität Potsdam : Humanwissenschaftliche Reihe N2 - Background: Dementia is a psychiatric condition the development of which is associated with numerous aspects of life. Our aim was to estimate dementia risk factors in German primary care patients. Methods: The case-control study included primary care patients (70-90 years) with first diagnosis of dementia (all-cause) during the index period (01/2010-12/2014) (Disease Analyzer, Germany), and controls without dementia matched (1:1) to cases on the basis of age, sex, type of health insurance, and physician. Practice visit records were used to verify that there had been 10 years of continuous follow-up prior to the index date. Multivariate logistic regression models were fitted with dementia as a dependent variable and the potential predictors. Results: The mean age for the 11,956 cases and the 11,956 controls was 80.4 (SD: 5.3) years. 39.0% of them were male and 1.9% had private health insurance. In the multivariate regression model, the following variables were linked to a significant extent with an increased risk of dementia: diabetes (OR: 1.17; 95% CI: 1.10-1.24), lipid metabolism (1.07; 1.00-1.14), stroke incl. TIA (1.68; 1.57-1.80), Parkinson's disease (PD) (1.89; 1.64-2.19), intracranial injury (1.30; 1.00-1.70), coronary heart disease (1.06; 1.00-1.13), mild cognitive impairment (MCI) (2.12; 1.82-2.48), mental and behavioral disorders due to alcohol use (1.96; 1.50-2.57). The use of statins (OR: 0.94; 0.90-0.99), proton-pump inhibitors (PPI) (0.93; 0.90-0.97), and antihypertensive drugs (0.96, 0.94-0.99) were associated with a decreased risk of developing dementia. Conclusions: Risk factors for dementia found in this study are consistent with the literature. Nevertheless, the associations between statin, PPI and antihypertensive drug use, and decreased risk of dementia need further investigations. T3 - Zweitveröffentlichungen der Universität Potsdam : Humanwissenschaftliche Reihe - 449 KW - dementia KW - Alzheimer KW - risk factors KW - statins Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-413441 IS - 449 ER - TY - JOUR A1 - Meiberth, Dix Urs A1 - Rapp, Michael Armin A1 - Jessen, Frank T1 - Gedächtnisambulanzstrukturen in Deutschland – Ergebnisse einer Klinikbefragung JF - Psychiatrische Praxis N2 - Ziel der Studie Erfassung der Strukturen zur Frühdiagnostik von Demenzen an Krankenhäusern in Deutschland. Methodik Fragebogenerhebung. Ergebnisse 14 % von 1758 kontaktierten Einrichtungen antworteten. 52 % berichteten über ein entsprechendes Angebot, zum großen Teil mit leitlinienorientierten Verfahren, wie Liquordiagnostik. Das Diagnosespektrum umfasste zu 46 % Demenzen und zu 41 % Diagnosen der leichten oder subjektiven kognitiven Störung. Schlussfolgerung Leitlinienbasierte Diagnostik und Früherkennungskonzepte sind in Gedächtnisambulanzen weitgehend etabliert. N2 - Objective To assess the structures for early and differential diagnosis of dementia in hospitals in Germany. Methods Written questionnaire to all German hospitals. Results 14 % of 1.758 hospitals responded. Of those, 52 % reported to offer a special service for early dementia diagnosis, mostly on an outpatient basis. The applied methods were in agreement with the national guideline for diagnosis and treatment of dementias, including technical diagnostics, such as neuroimaging and cerebrospinal fluid examinations. 46 % of the diagnostic spectrum were dementia. 41 % were either diagnosed as mild cognitive impairment (MCI) or as subjective cognitive decline (SCD). Conclusion Despite mostly insufficient reimbursement, a large proportion of the responding hospitals offer a specialized service, which largely adheres to guideline-based diagnostic procedures. The concepts of at-risk and prodromal stages of dementia seem to be largely established. T2 - Memory Clinics in Germany - Results of a Hospital Survey KW - dementia KW - Alzheimer KW - memory clinic KW - early diagnosis KW - Demenz KW - Alzheimer KW - Gedächtnisambulanz KW - Frühdiagnose Y1 - 2019 U6 - https://doi.org/10.1055/a-0825-9049 SN - 0303-4259 SN - 1439-0876 VL - 46 IS - 4 SP - 213 EP - 216 PB - Thieme CY - Stuttgart ER - TY - THES A1 - Kittner, Madeleine T1 - Folding and aggregation of amyloid peptides T1 - Faltung und Aggregation von Amyloidpeptiden N2 - Aggregation of the Amyloid β (Aβ) peptide to amyloid fibrils is associated with the outbreak of Alzheimer’s disease. Early aggregation intermediates in form of soluble oligomers are of special interest as they are believed to be the major toxic components in the process. These oligomers are of disordered and transient nature. Therefore, their detailed molecular structure is difficult to access experimentally and often remains unknown. In the present work extensive, fully atomistic replica exchange molecular dynamics simulations were performed to study the preaggregated, monomer states and early aggregation intermediates (dimers, trimers) of Aβ(25-35) and Aβ(10-35)-NH2 in aqueous solution. The folding and aggregation of Aβ(25-35) were studied at neutral pH and 293 K. Aβ(25-35) monomers mainly adopt β-hairpin conformations characterized by a β-turn formed by residues G29 and A30, and a β-sheet between residues N27–K28 and I31–I32 in equilibrium with coiled conformations. The β-hairpin conformations served as initial configurations to model spontaneous aggregation of Aβ(25-35). As expected, within the Aβ(25-35) dimer and trimer ensembles many different poorly populated conformations appear. Nevertheless, we were able to distinguish between disordered and fibril-like oligomers. Whereas disordered oligomers are rather compact with few intermolecular hydrogen bonds (HBs), fibril-like oligomers are characterized by the formation of large intermolecular β-sheets. In most of the fibril-like dimers and trimers individual peptides are fully extended forming in- or out-of-register antiparallel β-sheets. A small amount of fibril-like trimers contained V-shaped peptides forming parallel β-sheets. The dimensions of extended and V-shaped oligomers correspond well to the diameters of two distinct morphologies found for Aβ(25-35) fibrils. The transition from disordered to fibril-like Aβ(25-35) dimers is unfavorable but driven by energy. The lower energy of fibril-like dimers arises from favorable intermolecular HBs and other electrostatic interactions which compete with a loss in entropy. Approximately 25 % of the entropic cost correspond to configurational entropy. The rest relates to solvent entropy, presumably caused by hydrophobic and electrostatic effects. In contrast to the transition towards fibril-like dimers the first step of aggregation is driven by entropy. Here, we compared structural and thermodynamic properties of the individual monomer, dimer and trimer ensembles to gain qualitative information about the aggregation process. The β-hairpin conformation observed for monomers is successively dissolved in dimer and trimer ensembles while instead intermolecular β-sheets are formed. As expected upon aggregation the configurational entropy decreases. Additionally, the solvent accessible surface area (SASA), especially the hydrophobic SASA, decreases yielding a favorable solvation free energy which overcompensates the loss in configurational entropy. In summary, the hydrophobic effect, possibly combined with electrostatic effects, yields an increase in solvent entropy which is believed to be one major driving force towards aggregation. Spontaneous folding of the Aβ(10-35)-NH2 monomer was modeled using two force fields, GROMOS96 43a1 and OPLS/AA, and compared to primary NMR data collected at pH 5.6 and 283 K taken from the literature. Unexpectedly, the two force fields yielded significantly different main conformations. Comparison between experimental and calculated nuclear Overhauser effect (NOE) distances is not sufficient to distinguish between the different force fields. Additionally, the comparison with scalar coupling constants suggest that the chosen protonation in both simulations corresponds to a pH lower than in the experiment. Based on this analysis we were unable to determine which force field yields a better description of this system. Dimerization of Aβ(10-35)-NH2 was studied at neutral pH and 300 K. Dimer conformations arrange in many distinct, poorly populated and rather complex alignments or interlocking patterns which are rather stabilized by side chain interactions than by specific intermolecular hydrogen bonds. Similar to Aβ(25-35) dimers, transition towards β-sheet-rich, fibril-like Aβ(10-35) dimers is driven by energy competing with a loss in entropy. Here, transition is mediated by favorable peptide-solvent and solvent-solvent interactions mainly arising from electrostatic interactions. N2 - Die Aggregation des Amyloid β (Aβ) Peptids zu Amyloidfibrillen wird mit dem Ausbruch der Alzheimer Krankheit in Verbindung gebracht. Die toxische Wirkung auf Zellen wird vor allem den zeitigen Intermediaten in Form von löslichen Oligomeren zugeschrieben. Aufgrund deren ungeordneter und flüchtiger Natur kann die molekulare Struktur solcher zeitigen Oligomere oft experimentell nicht aufgelöst werden. In der vorliegenden Arbeit wurden aufwendige atomistische Replica-Exchange-Molekulardynamik-Simulationen durchgeführt, um die molekulare Struktur von Monomeren und Oligomeren der Fragmente Aβ(25-35) und Aβ(10-35)-NH2 in Wasser zu untersuchen. Die Faltung und Aggregation von Aβ(25-35) wurde bei neutralem pH und 293 K untersucht. Monomere dieses Fragments bilden hauptsächlich β-Haarnadelkonformationen im Gleichgewicht mit Knäulstrukturen. Innerhalb der β-Haarnadelkonformationen bilden die Residuen G29 und A30 einen β-turn, während N27–K28 and I31–I32 ein β-Faltblatt bilden. Diese β-Haarnadelkonformationen bildeten den Ausgangspunkt zur Modellierung spontaner Aggregation. Wie zu erwarten, bilden sich eine Vielzahl verschiedener, gering besetzter Dimer- und Trimerkonformationen. Mit Hilfe einer gröberen Einteilung können diese in ungeordnete und fibrillähnliche Oligomere unterteilt werden. Ungeordnete Oligomere bilden kompakte Strukturen, die nur durch wenige intermolekulare Wasserstoffbrückenbindungen (HBB) stabilisiert sind. Typisch für fibrillähnliche Oligomere ist hingegen die Ausbildung großer intermolekularer β-Faltblätter. In vielen dieser Oligomere finden wir antiparallele, in- oder out-of-register β-Faltblätter gebildet durch vollständig ausgestreckte Peptide. Ein kleiner Teil der fibrillähnlichen Trimere bildet parallele, V-förmige β-Faltblätter. Die Ausdehnungen ausgestreckter und V-förmiger Oligomere entspricht in etwa den Durchmessern von zwei verschiedenen, experimentell gefundenen Fibrillmorphologien für Aβ(25-35). Die Umwandlung von ungeordneten zu fibrillähnlichen Aβ(25-35) Dimeren ist energetisch begünstigt, läuft aber nicht freiwillig ab. Fibrillähnliche Dimere haben eine geringere Energie aufgrund günstiger Peptidwechselwirkungen (HBB, Salzbrücken), welche durch den Verlust an Entropie kompensiert wird. Etwa 25 % entsprechen dem Verlust an Konfigurationsentropie. Der restliche Anteil wird einem Verlust an Lösungsmittelentropie aufgrund von hydrophoben und elektrostatischen Effekten zugesprochen. Im Gegensatz zur Umwandlung in fibrillähnliche Dimere, ist die Assoziation von Monomeren oder Oligomeren entropisch begünstigt. Beim Vergleich thermodynamischer Eigenschaften der Monomer-, Dimer- und Trimersysteme zeigt sich im Verlauf der Aggregation, wie erwartet, eine Abnahme der Konfigurationsentropie. Zusätzlich nimmt die dem Lösungsmittel zugängliche Oberfläche (SASA), insbesondere die hydrophobe SASA, ab. In Verbindung damit beobachten wir eine Abnahme der freien Solvatisierungsenergie, welche den Verlust an Konfigurationsentropie kompensiert. Mit anderen Worten, der hydrophobe Effekt in Kombination mit elektrostatischen Wechselwirkungen führt zu einem Ansteigen der Lösungsmittelentropie und begünstigt damit die Aggegation. Die spontane Faltung des Aβ(10-35)-NH2 Monomers wurde für zwei verschiedene Proteinkraftfelder, GROMOS96 43a1 und OPLS/AA, untersucht und mit primären NMR-Daten aus der Literatur, gemessen bei pH 5.6 und 283 K, verglichen. Beide Kraftfelder generieren unterschiedliche Hauptkonformationen. Der Vergleich zwischen experimentellen und berechneten Kern-Overhauser-Effekt (NOE) Abständen ist nicht ausreichend, um zwischen beiden Kraftfeldern zu unterscheiden. Der Vergleich mit Kopplungskonstanten aus Experiment und Simulation zeigt, dass beide Simulationen einem pH-Wert geringer als 5.6 ensprechen. Basierend auf den bisherigen Ergebnissen können wir nicht entscheiden, welches Kraftfeld eine bessere Beschreibung für dieses System liefert. Die Dimerisierung von Aβ(10-35)-NH2 wurde bei neutralem pH und 300 K untersucht. Wir finden eine Vielzahl verschiedener, gering besetzter Dimerstrukturen, welche eher durch Seitenkettenkontakte als durch spezifische HBB stabilisiert sind. Wie bei den Aβ(25-35) Dimeren, ist die Umwandlung zu β-Faltblattreichen, fibrillähnlichen Aβ(10-35) Dimeren energetisch begünstigt, konkurriert aber mit einem Entropieverlust. Die Umwandlung wird in diesem Fall durch elektrostatische Wechselwirkungen zwischen Peptid und Lösungsmittel und innerhalb des Lösungsmittels bestimmt. KW - Amyloid beta KW - Proteinaggregation KW - Alzheimer KW - Molekulardynamik-Simulation KW - Thermodynamische Stabilität KW - amyloid beta KW - protein aggregation KW - Alzheimer KW - molecular dynamics simulation KW - thermodynamic stability Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus-53570 ER -