60 research outputs found
CSF biomarkers are differentially linked to brain areas high and low in noradrenaline, dopamine and serotonin across the Alzheimer’s disease spectrum
No full textAbstract Neurotransmitter systems of noradrenaline, dopamine, serotonin and acetylcholine are implicated in cognitive functions such as memory, learning and attention and are known to be altered in neurodegenerative diseases like Alzheimer’s disease. Specific brain structures involved in these systems, e.g. the locus coeruleus, the main source of noradrenaline in the cortex, are in fact affected earliest by Alzheimer’s disease tau pathology. Preserved volumetric neurotransmitter specific brain areas could therefore be an important neural resource for cognitive reserve in aging. The aim of this study was to determine whether volumes of brain areas known to be high in neurotransmitter receptors are relatively preserved in individuals with lower levels of Alzheimer’s disease pathology. Based on the Human Protein Atlas for neurotransmitter receptor distribution, we distinguished between ‘areas high and low’ in noradrenaline, dopamine, serotonin and acetylcholine and assessed associations of atrophy in those areas with CSF amyloid-ß 42/40, CSF phosphorylated tau protein and cognitive function across healthy controls (n = 122), individuals with subjective cognitive decline (n = 156), mild cognitive impairment or mild Alzheimer’s disease dementia (n = 126) using structural equation modelling. CSF pathology markers were inversely correlated and showed a stronger association with disease severity, suggesting distinguishable interrelatedness of these biomarkers depending on the stage of Alzheimer’s disease dementia. Across groups, amyloid pathology was linked to atrophy in areas high as well as low in neurotransmitter receptor densities, while tau pathology did not show any significant link to brain area volumes for any of the neurotransmitters. Within disease severity groups, individuals with more amyloid pathology showed more atrophy only in ‘areas high in noradrenaline’, whereas for dopamine tau pathology was linked to higher volumes in areas low in receptor density possibly indicating compensatory mechanisms. Furthermore, individuals with more tau pathology showed a selective decrease in memory function while amyloid pathology was related to a decline in executive function and language capacity as well as memory function. In summary, our analyses highlight the benefits of investigating disease-relevant factors in Alzheimer’s disease using a multivariate multigroup approach. Assessing multivariate dependencies in different disease stages and across individuals revealed selective links of pathologies, cognitive decline and atrophy in particular for areas modulated by noradrenaline, dopamine and serotonin
Altered limbic functional connectivity in individuals with subjective cognitive decline: Converging and diverging findings across Chinese and German cohorts
No full textApplication of IVDr NMR spectroscopy to stratify Parkinson’s disease with absolute quantitation of blood serum metabolites and lipoproteins
No full textAbstract The challenge of early detection and stratification in Parkinson’s disease (PD) is urgent due to the current emergence of mechanism-based disease-modifying treatments. In here, metabolomic and lipidomic parameters obtained by a standardized and targeted in vitro diagnostic research (IVDr) platform have a significant potential to address therapy-related questions and generate improved biomarker panels. Our study aimed to use IVDr nuclear magnetic resonance (NMR) spectroscopy to quantify metabolites and lipoproteins in PD blood serum from different cohorts to stratify metabolically driven subtypes of idiopathic and genetic PD. Serum aliquots from three neurodegeneration biobank cohorts (287 samples in total, including 62 PD patient samples with GBA mutation, 98/43 PD patient samples of early/late stages of disease duration, 20 PD samples from patients with mutations in recessive PD genes and some smaller subgroups of mitochondrial and double mutation cases) were prepared and analyzed with IVDr NMR spectroscopy, covering 39 blood serum metabolites and 112 lipoprotein parameters. Uni- and multivariate statistics were used to identify metabolism-driven changes under consideration of typical confounders such as age, sex and disease duration and set into context with clinical biomarkers such as CSF concentrations of alpha-synuclein, neurofilament light chain, and tau protein. Based on the different PD subgroups we performed a total of eight different comparisons. Highlights from these comparisons include increased citrate and dimethylglycine with a decrease of creatinine and methionine in healthy controls and early PD group compared to GBA, PD late and recessive PD. We furthermore identified decreased HDL-3 free cholesterol in genetic PD cases compared to sporadic subject samples (sum of the PD early and PD late groups). Considering medication, we found that the levodopa equivalent daily dose (LEDD) is mostly positively correlated with tyrosine and citrate in sporadic PD compared to pyruvate and phenylalanine in genetic PD. Cerebrospinal fluid levels of alpha-synuclein were negatively correlated with alanine. Further metabolites and lipoproteins with discriminatory power for double mutation PD cases involved ornithine, 2-aminobutyrate and 2-hydroxybutyrate as well as for mitochondrial phenotypes via LDL phospholipid, apolipoprotein and cholesterol subfractions. Quantitative IVDr NMR serum spectroscopy is able to stratify PD patient samples of different etiology and can contribute to a wider understanding of the underlying metabolism-driven alterations e.g. in energy, amino acid, and lipoprotein metabolism. Though our overall cohort was large, major confounders such as age, sex and medication have a strong impact. That is why absolute quantification and detailed patient knowledge about metabolic confounders, is a premise for future translation of NMR serum spectroscopy to routine PD diagnostics
Phänotypisierung neurodegenerativer Erkrankungen am Beispiel der Alzheimer-Erkrankung
No full textHintergrund: In einer alternden Bevölkerung stellt die Alzheimer-Erkrankung als häufigste Demenzform eine zunehmende Herausforderung für unsere Gesellschaft dar. Die Erkenntnisse aus der Forschung der letzten Jahrzehnte haben zu einem zunehmend besseren Verständnis der Pathomechanismen und zu zuverlässigeren Diagnosestellungen geführt. Dennoch werden atypische Verläufe und prodromale Stadien oft nicht erkannt. Um diese sicherer identifizieren zu können, ist neben der Entwicklung von paraklinischen Biomarkern die Kenntnis der typischen Präsentation des Krankheitsbildes, seiner selteneren Manifestationsformen und das Wissen um prodromale Symptome von Bedeutung. Ziel dieser Arbeit war es, unterschiedliche Ansätze der Phänotypisierung der Alzheimer-Krankheit und ihrer Vorstufen zu untersuchen.
Methodik: 1. Phänotypisierung über Data Mining: Es wurde mittels eines halbautomatisierten Data Mining-Verfahrens eine Liste mit Symptom-beschreibenden Begriffen erstellt, die in mit dem MeSH-Schlagwort „Alzheimer Disease“ annotierten Abstracts häufiger vorkamen als im Rest der PubMed-Datenbank. 2. Klinische Phänotypisierung über neuropsychologische Testverfahren: Es wurden neuropsychologische Daten von 168 Teilnehmern der longitudinalen Beobachtungsstudie DELCODE des Deutschen Zentrums für neurodegenerative Erkrankungen (DZNE) ausgewertet.
Ergebnisse: 1. Nach der oben beschriebenen Methode konnte eine Liste mit 90 klinischen Beschreibungen der Alzheimer-Erkrankung erstellt werden, die neben typischen Symptomen der Alzheimer-Erkrankung auch seltene, z.T. nur kasuistisch beschriebene Symptome, beinhaltete. 2. Mittels neuropsychologischer Testverfahren ließen sich Patienten in einem leichtgradigen Stadium einer Alzheimer-Demenz von Gesunden sowie von Probanden in einem möglichen Prodromalstadium unterscheiden. Eine besonders gute Aussagekraft für die diagnostische Abgrenzung fand sich dabei für Verfahren, die das verbale und das figurale episodische Gedächtnis, die kognitive Flexibilität, die verbale Flüssigkeit und die psychomotorische Geschwindigkeit testen. Bei möglichen Vorstufen einer Alzheimer-Demenz erwiesen sich v.a. Tests des verzögerten Abrufs und des Wiedererkennens gelernter verbaler Informationen als zeitsensible Messinstrumente. Außerdem prädizierten sie am besten eine Konversion zur Alzheimer-Demenz im Folgejahr.
Schlussfolgerung: 1. Mit Hilfe von Methoden des Data Mining ist es möglich, eine unvoreingenommene und umfangreiche Phänotypbeschreibung der Alzheimer Erkrankung vorzunehmen. 2. Spezielle neuropsychologische Testverfahren helfen, die Prodromalstadien einer Alzheimer-Erkrankung besser zu charakterisieren. Sie können zudem eine Konversion zur Alzheimer-Demenz anzeigen.Background: In an aging population, Alzheimer's disease, the most common form of dementia, represents an increasing challenge for our society. Research findings in recent decades have led to a better understanding of the pathomechanisms and to more reliable diagnoses. Nevertheless, atypical courses and prodromal stages are often not recognized. In order to be able to identify them more reliably, knowledge of the typical presentation of the disease pattern, its rarer manifestations and knowledge of prodromal symptoms is important in addition to the development of biomarkers. The aim of this study was to investigate different approaches to phenotyping Alzheimer's disease and its prodromal stages.
Methods: 1. Phenotyping via data mining: A list of symptom-describing terms that occurred more frequently in abstracts annotated with the MeSH term "Alzheimer's disease" than in the rest of the PubMed database was compiled using a semi-automated data mining procedure. 2. clinical phenotyping using neuropsychological testing: Neuropsychological data of 168 participants of the longitudinal observational study DELCODE of the German Center for Neurodegenerative Diseases (DZNE) were analysed.
Results: 1. 90 clinical descriptions of Alzheimer's disease could be compiled using the method described above, which included typical symptoms of Alzheimer's disease as well as rare symptoms, some of which were only described casuistically. 2. By means of neuropsychological testing procedures, patients in a mild stage of Alzheimer's dementia could be distinguished from healthy participants and participants with a possible prodromal stage. A particularly good diagnostic differentiation was found for procedures testing verbal and figural episodic memory, cognitive flexibility, verbal fluency and psychomotor speed. In prodromal stages of Alzheimer's dementia, tests of delayed recall and recognition of learned verbal information proved to be time-sensitive instruments. In addition, they best predicted a conversion to Alzheimer's dementia in the following year.
Conclusion: 1. With the help of data mining methods it is possible to provide an unbiased and comprehensive phenotype description of Alzheimer's disease. 2. Neuropsychological test procedures can help to better characterize the prodromal stages of Alzheimer's disease. They can also indicate conversion to Alzheimer's dementia
Relevance of Subjective Cognitive Decline in Older Adults with a First-Degree Family History of Alzheimer’s Disease
No full textBackground: It is unclear whether subjective cognitive decline (SCD) is a relevant clinical marker of incipient Alzheimer’s disease (AD) and future cognitive deterioration in individuals with a family history of AD (FHAD). Objective: To investigate the association of SCD with cross-sectional cerebrospinal fluid (CSF) AD biomarker levels and cognitive decline in cognitively normal older adults with or without a first-degree FHAD. Methods: We analyzed data from cognitively normal individuals with first-degree FHAD (n = 82 “AD relatives”; mean age: 65.7 years (SD = 4.47); 59% female) and a similar group of n = 236 healthy controls without FHAD from the DELCODE study. We measured SCD with an in-depth structured interview from which we derived a SCD score, capturing features proposed to increase likelihood of underlying AD (“SCD-plus score”). We tested whether higher SCD-plus scores were associated with more pathological CSF AD biomarker levels and cognitive decline over time and whether this association varied by group. Results: AD relatives showed higher SCD-plus scores than healthy controls and more cognitive decline over time. Higher SCD-plus scores also related stronger to cognitive change and abnormal CSF AD biomarker levels in the AD relatives as compared to the healthy controls group. Conclusion: Quantification of specific SCD features can provide further information on the likelihood of early AD pathology and cognitive decline among AD relatives. FHAD and SCD appear as synergistically acting enrichment strategies in AD research, the first one as a permanent indicator of genetic risk, the latter one as a correlate of disease progression
Design and first baseline data of the DZNE multicenter observational study on predementia Alzheimer's disease (DELCODE)
No full textBACKGROUND: Deep phenotyping and longitudinal assessment of predementia at-risk states of Alzheimer's disease (AD) are required to define populations and outcomes for dementia prevention trials. Subjective cognitive decline (SCD) is a pre-mild cognitive impairment (pre-MCI) at-risk state of dementia, which emerges as a highly promising target for AD prevention.METHODS: The German Center for Neurodegenerative Diseases (DZNE) is conducting the multicenter DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE), which focuses on the characterization of SCD in patients recruited from memory clinics. In addition, individuals with amnestic MCI, mild Alzheimer's dementia patients, first-degree relatives of patients with Alzheimer's dementia, and cognitively unimpaired control subjects are studied. The total number of subjects to be enrolled is 1000. Participants receive extensive clinical and neuropsychological assessments, magnetic resonance imaging, positron emission tomography, and biomaterial collection is perfomed. In this publication, we report cognitive and clinical data as well as apolipoprotein E (APOE) genotype and cerebrospinal fluid (CSF) biomarker results of the first 394 baseline data sets.RESULTS: In comparison with the control group, patients with SCD showed slightly poorer performance on cognitive and functional measures (Alzheimer's Disease Assessment Scale-cognitive part, Clinical Dementia Rating, Functional Activities Questionnaire), with all mean scores in a range which would be considered unimpaired. APOE4 genotype was enriched in the SCD group in comparison to what would be expected in the population and the frequency was significantly higher in comparison to the control group. CSF Aβ42 was lower in the SCD group in comparison to the control group at a statistical trend with age as a covariate. There were no group differences in Tau or pTau concentrations between the SCD and the control groups. The differences in all measures between the MCI group and the AD group were as expected.CONCLUSIONS: The initial baseline data for DELCODE support the approach of using SCD in patients recruited through memory clinics as an enrichment strategy for late-stage preclinical AD. This is indicated by slightly lower performance in a range of measures in SCD in comparison to the control subjects as well as by enriched APOE4 frequency and lower CSF Aβ42 concentration.TRIAL REGISTRATION: German Clinical Trials Register DRKS00007966 . Registered 4 May 2015.</p
Multimodal MRI analysis of basal forebrain structure and function across the Alzheimer's disease spectrum
No full textBACKGROUND: Dysfunction of the cholinergic basal forebrain (cBF) is associated with cognitive decline in Alzheimer’s disease (AD). Multimodal MRI allows for the investigation of cBF changes in-vivo. In this study we assessed alterations in cBF functional connectivity (FC), mean diffusivity (MD), and volume across the spectrum of AD. We further assessed effects of amyloid pathology on these changes. METHODS: Participants included healthy controls, and subjects with subjective cognitive decline (SCD), mild cognitive impairment (MCI), or AD dementia (ADD) from the multicenter DELCODE study. Resting-state functional MRI (rs-fMRI) and structural MRI data was available for 477 subjects, and a subset of 243 subjects also had DTI data available. Differences between diagnostic groups were investigated using seed-based FC, volumetric, and MD analyses of functionally defined anterior (a-cBF) and posterior (p-cBF) subdivisions of a cytoarchitectonic cBF region-of-interest. In complementary analyses groups were stratified according to amyloid status based on CSF Aβ42/40 biomarker data, which was available in a subset of participants. RESULTS: a-cBF and p-cBF subdivisions showed regional FC profiles that were highly consistent with previously reported patterns, but there were only minimal differences between diagnostic groups. Compared to controls, cBF volumes and MD were significantly different in MCI and ADD but not in SCD. The Aβ42/40 stratified analyses largely matched these results. CONCLUSIONS: We reproduced subregion-specific FC profiles of the cBF in a clinical sample spanning the AD spectrum. At least in this multicentric cohort study, cBF-FC did not show marked changes along the AD spectrum, and multimodal MRI did not provide more sensitive measures of AD-related cBF changes compared to volumetry
Longitudinal evidence for a mutually reinforcing relationship between white matter hyperintensities and cortical thickness in cognitively unimpaired older adults
No full textAbstract Background For over three decades, the concomitance of cortical neurodegeneration and white matter hyperintensities (WMH) has sparked discussions about their coupled temporal dynamics. Longitudinal studies supporting this hypothesis nonetheless remain scarce. Methods We applied global and regional bivariate latent growth curve modelling to determine the extent to which WMH and cortical thickness were interrelated over a four-year period. For this purpose, we leveraged longitudinal MRI data from 451 cognitively unimpaired participants (DELCODE; median age 69.71 [IQR 65.51, 75.50] years; 52.32% female). Participants underwent MRI sessions annually over a four-year period (1815 sessions in total, with roughly four MRI sessions per participant). We adjusted all models for demographics and cardiovascular risk. Results Our findings were three-fold. First, larger WMH volumes were linked to lower cortical thickness (σ = -0.165, SE = 0.047, Z = -3.515, P < 0.001). Second, individuals with higher WMH volumes experienced more rapid cortical thinning (σ = -0.226, SE = 0.093, Z = -2.443, P = 0.007), particularly in temporal, cingulate, and insular regions. Similarly, those with lower initial cortical thickness had faster WMH progression (σ = -0.141, SE = 0.060, Z = -2.336, P = 0.009), with this effect being most pronounced in temporal, cingulate, and insular cortices. Third, faster WMH progression was associated with accelerated cortical thinning (σ = -0.239, SE = 0.139, Z = -1.710, P = 0.044), particularly in frontal, occipital, and insular cortical regions. Conclusions Our study suggests that cortical thinning and WMH progression could be mutually reinforcing rather than parallel, unrelated processes, which become entangled before cognitive deficits are detectable. Trial registration German Clinical Trials Register (DRKS00007966, 04/05/2015)
Minor neuropsychological deficits in patients with subjective cognitive decline
No full textObjective: To determine the nature and extent of minor neuropsychological deficits in patients with subjective cognitive decline (SCD) and their association with CSF biomarkers of Alzheimer disease (AD).
Method: We analyzed data from n = 449 cognitively normal participants (n = 209 healthy controls, n = 240 patients with SCD) from an interim data release of the German Center for Neurodegenerative Diseases Longitudinal Cognitive Impairment and Dementia Study (DELCODE). An extensive neuropsychological test battery was applied at baseline for which we established a latent, 5 cognitive domain factor structure comprising learning and memory, executive functions, language abilities, working memory, and visuospatial functions. We compared groups in terms of global and domain-specific performance and correlated performance with different CSF markers of AD pathology.
Results: We observed worse performance (Cohen d = ≈0.25–0.5, adjusted for age, sex differences with analysis of covariance) in global performance, memory, executive functions, and language abilities for the SCD group compared to healthy controls. In addition, worse performance in these domains was moderately (r = ≈0.3) associated with lower CSF β-amyloid42/40 and CSF β-amyloid42/phosphorylated tau181 in the whole sample and specifically in the SCD subgroup.
Conclusions: Within the spectrum of clinically unimpaired (i.e., before mild cognitive impairment) cognitive performance, SCD is associated with minor deficits in memory, executive function, and language abilities. The association of these subtle cognitive deficits with AD CSF biomarkers speaks to their validity and potential use for the early detection of underlying preclinical AD
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