Publications by authors named "Mathias Jucker"

131 Publications

Segregation of functional networks is associated with cognitive resilience in Alzheimer's disease.

Brain 2021 Mar 16. Epub 2021 Mar 16.

Dementia Research Centre, University College London, Queen Square, London, UK.

Cognitive resilience is an important modulating factor of cognitive decline in Alzheimer's disease, but the functional brain mechanisms that support cognitive resilience remain elusive. Given previous findings in normal aging, we tested the hypothesis that higher segregation of the brain's connectome into distinct functional networks represents a functional mechanism underlying cognitive resilience in Alzheimer's disease. Using resting-state functional MRI, we assessed both resting-state-fMRI global system segregation, i.e. the balance of between-network to within-network connectivity, and the alternate index of modularity Q as predictors of cognitive resilience. We performed all analyses in two independent samples for validation: First, we included 108 individuals with autosomal dominantly inherited Alzheimer's disease and 71 non-carrier controls. Second, we included 156 amyloid-PET positive subjects across the spectrum of sporadic Alzheimer's disease as well as 184 amyloid-negative controls. In the autosomal dominant Alzheimer's disease sample, disease severity was assessed by estimated years from symptom onset. In the sporadic Alzheimer's sample, disease stage was assessed by temporal-lobe tau-PET (i.e. composite across Braak stage I & III regions). In both samples, we tested whether the effect of disease severity on cognition was attenuated at higher levels of functional network segregation. For autosomal dominant Alzheimer's disease, we found higher fMRI-assessed system segregation to be associated with an attenuated effect of estimated years from symptom onset on global cognition (p = 0.007). Similarly, for sporadic Alzheimer's disease patients, higher fMRI-assessed system segregation was associated with less decrement in global cognition (p = 0.001) and episodic memory (p = 0.004) per unit increase of temporal lobe tau-PET. Confirmatory analyses using the alternate index of modularity Q revealed consistent results. In conclusion, higher segregation of functional connections into distinct large-scale networks supports cognitive resilience in Alzheimer's disease.
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http://dx.doi.org/10.1093/brain/awab112DOI Listing
March 2021

Modeling autosomal dominant Alzheimer's disease with machine learning.

Alzheimers Dement 2021 Jan 21. Epub 2021 Jan 21.

German Center for Neurodegenerative Diseases, Munich, Germany.

Introduction: Machine learning models were used to discover novel disease trajectories for autosomal dominant Alzheimer's disease.

Methods: Longitudinal structural magnetic resonance imaging, amyloid positron emission tomography (PET), and fluorodeoxyglucose PET were acquired in 131 mutation carriers and 74 non-carriers from the Dominantly Inherited Alzheimer Network; the groups were matched for age, education, sex, and apolipoprotein ε4 (APOE ε4). A deep neural network was trained to predict disease progression for each modality. Relief algorithms identified the strongest predictors of mutation status.

Results: The Relief algorithm identified the caudate, cingulate, and precuneus as the strongest predictors among all modalities. The model yielded accurate results for predicting future Pittsburgh compound B (R  = 0.95), fluorodeoxyglucose (R  = 0.93), and atrophy (R  = 0.95) in mutation carriers compared to non-carriers.

Discussion: Results suggest a sigmoidal trajectory for amyloid, a biphasic response for metabolism, and a gradual decrease in volume, with disease progression primarily in subcortical, middle frontal, and posterior parietal regions.
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http://dx.doi.org/10.1002/alz.12259DOI Listing
January 2021

Conference report: dementia research and care and its impact in Switzerland.

Swiss Med Wkly 2020 Nov 5;150:w20376. Epub 2020 Dec 5.

Old Age Psychiatry, Department of Psychiatry, University Hospital of Lausanne, and University of Zürich, Department of Geriatric Psychiatry, University Hospital of Zürich, Switzerland.

In October 2019, a Swiss panel of experts met for the Dementia Summit in Brunnen, Switzerland, to discuss the latest scientific findings on basic and clinical research, as well as practical and political approaches to the challenges of dementia disorders in Switzerland. Here, we present the conference summary. To study pathophysiological changes, as well as the underlying mechanism of fluid biomarker changes, excellent experimental approaches, including transgenic mouse models, are available. Current knowledge about presymptomatic disease progression is largely derived from the longitudinal study of individuals with autosomal dominant mutations (Dominantly Inherited Alzheimer Network). Importantly, more than one third of identified dementia risk factors can be modified. For example, sleep disturbances are not only associated with dementia and neurodegeneration in specific brain regions, but also precede cognitive decline and contribute to the development of brain pathology. Regarding the neuropsychological examination of dementia disorders, standardised tests of social cognition, one of the six cognitive domains that must be assessed according to the fifth edition of the Diagnostic and Statistical Manual for Mental Disorders, are missing, but now under development. The most important new therapeutic approach in the treatment of Alzheimer’s disease is the current attempt to prevent β-amyloid accumulation. While until now clinical studies have failed because of side effects or insufficient clinical effectiveness, Biogen recently announced positive results of high doses of aducanumab, a monoclonal antibody against β-amyloid. Other approaches also show promise. In China, sodium oligomannate has been approved to treat Alzheimer's disease. The substance suppresses gut bacterial amino acids-shaped neuroinflammation to inhibit Alzheimer’s disease progression. Assistive technologies for dementia patients can help identify relevant information for care and nursing, as well as measurements for clinical interventions. Dementia patients have a high risk of developing delirium, even in the home environment. Therefore, it is necessary to use and further develop multi-disciplinary and systematic detection and prevention strategies. Homecare models for dementia patients with multidisciplinary teams have been established and evaluated and should be expanded. Dementia is the third-leading cause of death in Switzerland. In palliative care for severe dementia, the improvement of quality of life is of primary importance. The goals of the National Dementia Strategy, to increase the quality of life in those affected and to reduce taboos surrounding the disease, are still unrealised. The need for further national and regional engagement in order to implement the different findings of the strategy has largely been acknowledged, and these implementations have become the core tasks of a national dementia platform.
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http://dx.doi.org/10.4414/smw.2020.20376DOI Listing
November 2020

Acute targeting of pre-amyloid seeds in transgenic mice reduces Alzheimer-like pathology later in life.

Nat Neurosci 2020 12 16;23(12):1580-1588. Epub 2020 Nov 16.

Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.

Amyloid-β (Aβ) deposits are a relatively late consequence of Aβ aggregation in Alzheimer's disease. When pathogenic Aβ seeds begin to form, propagate and spread is not known, nor are they biochemically defined. We tested various antibodies for their ability to neutralize Aβ seeds before Aβ deposition becomes detectable in Aβ precursor protein-transgenic mice. We also characterized the different antibody recognition profiles using immunoprecipitation of size-fractionated, native, mouse and human brain-derived Aβ assemblies. At least one antibody, aducanumab, after acute administration at the pre-amyloid stage, led to a significant reduction of Aβ deposition and downstream pathologies 6 months later. This demonstrates that therapeutically targetable pathogenic Aβ seeds already exist during the lag phase of protein aggregation in the brain. Thus, the preclinical phase of Alzheimer's disease-currently defined as Aβ deposition without clinical symptoms-may be a relatively late manifestation of a much earlier pathogenic seed formation and propagation that currently escapes detection in vivo.
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http://dx.doi.org/10.1038/s41593-020-00737-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7783656PMC
December 2020

Risk of Transmissibility From Neurodegenerative Disease-Associated Proteins: Experimental Knowns and Unknowns.

J Neuropathol Exp Neurol 2020 11;79(11):1141-1146

Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.

Recent studies in animal models demonstrate that certain misfolded proteins associated with neurodegenerative diseases can support templated misfolding of cognate native proteins, to propagate across neural systems, and to therefore have some of the properties of classical prion diseases like Creutzfeldt-Jakob disease. The National Institute of Aging convened a meeting to discuss the implications of these observations for research priorities. A summary of the discussion is presented here, with a focus on limitations of current knowledge, highlighting areas that appear to require further investigation in order to guide scientific practice while minimizing potential exposure or risk in the laboratory setting. The committee concluded that, based on all currently available data, although neurodegenerative disease-associated aggregates of several different non-prion proteins can be propagated from humans to experimental animals, there is currently insufficient evidence to suggest more than a negligible risk, if any, of a direct infectious etiology for the human neurodegenerative disorders defined in part by these proteins. Given the importance of this question, the potential for noninvasive human transmission of proteopathic disorders is deserving of further investigation.
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http://dx.doi.org/10.1093/jnen/nlaa109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577514PMC
November 2020

Potential human transmission of amyloid β pathology: surveillance and risks.

Lancet Neurol 2020 10 16;19(10):872-878. Epub 2020 Sep 16.

Department of Neurosurgery, University Hospitals Leuven, Leuven, Belgium.

Studies in experimental animals show transmissibility of amyloidogenic proteins associated with prion diseases, Alzheimer's disease, Parkinson's disease, and other neurodegenerative diseases. Although these data raise potential concerns for public health, convincing evidence for human iatrogenic transmission only exists for prions and amyloid β after systemic injections of contaminated growth hormone extracts or dura mater grafts derived from cadavers. Even though these procedures are now obsolete, some reports raise the possibility of iatrogenic transmission of amyloid β through putatively contaminated neurosurgical equipment. Iatrogenic transmission of amyloid β might lead to amyloid deposition in the brain parenchyma and blood vessel walls, potentially resulting in cerebral amyloid angiopathy after several decades. Cerebral amyloid angiopathy can cause life-threatening brain haemorrhages; yet, there is no proof that the transmission of amyloid β can also lead to Alzheimer's dementia. Large, long-term epidemiological studies and sensitive, cost-efficient tools to detect amyloid are needed to better understand any potential routes of amyloid β transmission and to clarify whether other similar proteopathic seeds, such as tau or α-synuclein, can also be transferred iatrogenically.
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http://dx.doi.org/10.1016/S1474-4422(20)30238-6DOI Listing
October 2020

Medin aggregation causes cerebrovascular dysfunction in aging wild-type mice.

Proc Natl Acad Sci U S A 2020 09 8;117(38):23925-23931. Epub 2020 Sep 8.

German Center for Neurodegenerative Diseases (DZNE), 72076 Tübingen, Germany;

Medin is the most common amyloid known in humans, as it can be found in blood vessels of the upper body in virtually everybody over 50 years of age. However, it remains unknown whether deposition of Medin plays a causal role in age-related vascular dysfunction. We now report that aggregates of Medin also develop in the aorta and brain vasculature of wild-type mice in an age-dependent manner. Strikingly, genetic deficiency of the Medin precursor protein, MFG-E8, eliminates not only vascular aggregates but also prevents age-associated decline of cerebrovascular function in mice. Given the prevalence of Medin aggregates in the general population and its role in vascular dysfunction with aging, targeting Medin may become a novel approach to sustain healthy aging.
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http://dx.doi.org/10.1073/pnas.2011133117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7519322PMC
September 2020

Sequence of Alzheimer disease biomarker changes in cognitively normal adults: A cross-sectional study.

Neurology 2020 12 1;95(23):e3104-e3116. Epub 2020 Sep 1.

From the Division of Public Health Sciences (J.L.), Department of Surgery, Siteman Cancer Center Biostatistics Core (J.L.), Division of Biostatistics (J.L., F.A., E.G., C.X.), Knight Alzheimer Disease Research Center (F.A., E.G., A.M.F., T.B., P.M., J.H., R.J.B., J.C.M., R.J.P., C.X.), Department of Neurology (E.M.M., A.M.F., J.H., R.J.B., J.C.M., R.J.P.), Department of Radiology (T.B., P.M.), Department of Pathology (J.C.M., R.J.P.), Department of Immunology (J.C.M., R.J.P.), and Department of Psychiatry (C.C.), Washington University School of Medicine, St. Louis, MO; The Florey Institute (C.L.M.), University of Melbourne, Australia; Department of Neurology (M.S.A.), Johns Hopkins University School of Medicine, Baltimore, MD; Wisconsin Alzheimer's Institute and Alzheimer's Disease Research Center (S.C.J.), University of Wisconsin-Madison School of Medicine and Public Health; Geriatric Research Education and Clinical Center (S.C.J.), William S. Middleton Veterans Memorial Hospital, Madison, WI; German Center for Neurodegenerative Diseases (J.V.); Department of Neurology (J.V.), Ludwig-Maximilians-Universität München, Munich, Germany; Department of Neurology (J.C.), Massachusetts General Hospital, Harvard Medical School, Boston; Hertie-Institute for Clinical Brain Research (M.J.), University of Tübingen; German Center for Neurodegenerative Diseases (M.J.), Tübingen, Germany; Department of Pathology and Laboratory Medicine (B.G.), Indiana University, Indianapolis; Department of Neurology (N.R.G.-R.), Mayo Clinic, Jacksonville, FL; Neuroscience Research Australia (P.R.S.), Randwick; School of Medical Sciences (P.R.S.), University of New South Wales, Sydney, Australia; and Department of Clinical Neuroscience (H.M.), Osaka City University Medical School, Abenoku, Osaka, Japan.

Objective: To determine the ordering of changes in Alzheimer disease (AD) biomarkers among cognitively normal individuals.

Methods: Cross-sectional data, including CSF analytes, molecular imaging of cerebral fibrillar β-amyloid (Aβ) with PET using the [C] benzothiazole tracer Pittsburgh compound B (PiB), MRI-based brain structures, and clinical/cognitive outcomes harmonized from 8 studies, collectively involving 3,284 cognitively normal individuals 18 to 101 years of age, were analyzed. The age at which each marker exhibited an accelerated change (called the change point) was estimated and compared across the markers.

Results: Accelerated changes in CSF Aβ (Aβ) occurred at 48.28 years of age and in Aβ/Aβ ratio at 46.02 years, followed by PiB mean cortical standardized uptake value ratio (SUVR) with a change point at 54.47 years. CSF total tau (Tau) and tau phosphorylated at threonine 181 (Ptau) had a change point at ≈60 years, similar to those for MRI hippocampal volume and cortical thickness. The change point for a cognitive composite occurred at 62.41 years. The change points for CSF Aβ and Aβ/Aβ ratio, albeit not significantly different from that for PiB SUVR, occurred significantly earlier than that for CSF Tau, Ptau, MRI markers, and the cognitive composite. Adjusted analyses confirmed that accelerated changes in CSF Tau, Ptau, MRI markers, and the cognitive composite occurred at ages not significantly different from each other.

Conclusions: Our findings support the hypothesized early changes of amyloid in preclinical AD and suggest that changes in neuronal injury and neurodegeneration markers occur close in time to cognitive decline.
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http://dx.doi.org/10.1212/WNL.0000000000010747DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734923PMC
December 2020

Prominent microglial inclusions in transgenic mouse models of α-synucleinopathy that are distinct from neuronal lesions.

Acta Neuropathol Commun 2020 08 12;8(1):133. Epub 2020 Aug 12.

German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.

Alpha-synucleinopathies are a group of progressive neurodegenerative disorders, characterized by intracellular deposits of aggregated α-synuclein (αS). The clinical heterogeneity of these diseases is thought to be attributed to conformers (or strains) of αS but the contribution of inclusions in various cell types is unclear. The aim of the present work was to study αS conformers among different transgenic (TG) mouse models of α-synucleinopathies. To this end, four different TG mouse models were studied (Prnp-h[A53T]αS; Thy1-h[A53T]αS; Thy1-h[A30P]αS; Thy1-mαS) that overexpress human or murine αS and differed in their age-of-symptom onset and subsequent disease progression. Postmortem analysis of end-stage brains revealed robust neuronal αS pathology as evidenced by accumulation of αS serine 129 (p-αS) phosphorylation in the brainstem of all four TG mouse lines. Overall appearance of the pathology was similar and only modest differences were observed among additionally affected brain regions. To study αS conformers in these mice, we used pentameric formyl thiophene acetic acid (pFTAA), a fluorescent dye with amyloid conformation-dependent spectral properties. Unexpectedly, besides the neuronal αS pathology, we also found abundant pFTAA-positive inclusions in microglia of all four TG mouse lines. These microglial inclusions were also positive for Thioflavin S and showed immunoreactivity with antibodies recognizing the N-terminus of αS, but were largely p-αS-negative. In all four lines, spectral pFTAA analysis revealed conformational differences between microglia and neuronal inclusions but not among the different mouse models. Concomitant with neuronal lesions, microglial inclusions were already present at presymptomatic stages and could also be induced by seeded αS aggregation. Although nature and significance of microglial inclusions for human α-synucleinopathies remain to be clarified, the previously overlooked abundance of microglial inclusions in TG mouse models of α-synucleinopathy bears importance for mechanistic and preclinical-translational studies.
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http://dx.doi.org/10.1186/s40478-020-00993-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425556PMC
August 2020

Loss of function of the mitochondrial peptidase PITRM1 induces proteotoxic stress and Alzheimer's disease-like pathology in human cerebral organoids.

Mol Psychiatry 2020 Jul 7. Epub 2020 Jul 7.

German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.

Mutations in pitrilysin metallopeptidase 1 (PITRM1), a mitochondrial protease involved in mitochondrial precursor processing and degradation, result in a slow-progressing syndrome characterized by cerebellar ataxia, psychotic episodes, and obsessive behavior, as well as cognitive decline. To investigate the pathogenetic mechanisms of mitochondrial presequence processing, we employed cortical neurons and cerebral organoids generated from PITRM1-knockout human induced pluripotent stem cells (iPSCs). PITRM1 deficiency strongly induced mitochondrial unfolded protein response (UPR) and enhanced mitochondrial clearance in iPSC-derived neurons. Furthermore, we observed increased levels of amyloid precursor protein and amyloid β in PITRM1-knockout neurons. However, neither cell death nor protein aggregates were observed in 2D iPSC-derived cortical neuronal cultures. On the other hand, over time, cerebral organoids generated from PITRM1-knockout iPSCs spontaneously developed pathological features of Alzheimer's disease (AD), including the accumulation of protein aggregates, tau pathology, and neuronal cell death. Single-cell RNA sequencing revealed a perturbation of mitochondrial function in all cell types in PITRM1-knockout cerebral organoids, whereas immune transcriptional signatures were substantially dysregulated in astrocytes. Importantly, we provide evidence of a protective role of UPR and mitochondrial clearance against impaired mitochondrial presequence processing and proteotoxic stress. Here, we propose a novel concept of PITRM1-linked neurological syndrome whereby defects of mitochondrial presequence processing induce an early activation of UPR that, in turn, modulates cytosolic quality control pathways. Thus, our work supports a mechanistic link between mitochondrial function and common neurodegenerative proteinopathies.
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http://dx.doi.org/10.1038/s41380-020-0807-4DOI Listing
July 2020

Serum neurofilament light chain levels are associated with white matter integrity in autosomal dominant Alzheimer's disease.

Neurobiol Dis 2020 08 6;142:104960. Epub 2020 Jun 6.

The Florey Institute, University of Melbourne, Parkville, VIC, Australia.

Neurofilament light chain (NfL) is a protein that is selectively expressed in neurons. Increased levels of NfL measured in either cerebrospinal fluid or blood is thought to be a biomarker of neuronal damage in neurodegenerative diseases. However, there have been limited investigations relating NfL to the concurrent measures of white matter (WM) decline that it should reflect. White matter damage is a common feature of Alzheimer's disease. We hypothesized that serum levels of NfL would associate with WM lesion volume and diffusion tensor imaging (DTI) metrics cross-sectionally in 117 autosomal dominant mutation carriers (MC) compared to 84 non-carrier (NC) familial controls as well as in a subset (N = 41) of MC with longitudinal NfL and MRI data. In MC, elevated cross-sectional NfL was positively associated with WM hyperintensity lesion volume, mean diffusivity, radial diffusivity, and axial diffusivity and negatively with fractional anisotropy. Greater change in NfL levels in MC was associated with larger changes in fractional anisotropy, mean diffusivity, and radial diffusivity, all indicative of reduced WM integrity. There were no relationships with NfL in NC. Our results demonstrate that blood-based NfL levels reflect WM integrity and supports the view that blood levels of NfL are predictive of WM damage in the brain. This is a critical result in improving the interpretability of NfL as a marker of brain integrity, and for validating this emerging biomarker for future use in clinical and research settings across multiple neurodegenerative diseases.
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http://dx.doi.org/10.1016/j.nbd.2020.104960DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7363568PMC
August 2020

Autosomal Dominantly Inherited Alzheimer Disease: Analysis of genetic subgroups by Machine Learning.

Inf Fusion 2020 Jun 7;58:153-167. Epub 2020 Jan 7.

Department of Signal Theory, Telematics and Communications, University of Granada, Granada (Spain).

Despite subjects with Dominantly-Inherited Alzheimer's Disease (DIAD) represent less than 1% of all Alzheimer's Disease (AD) cases, the Dominantly Inherited Alzheimer Network (DIAN) initiative constitutes a strong impact in the understanding of AD disease course with special emphasis on the presyptomatic disease phase. Until now, the 3 genes involved in DIAD pathogenesis (PSEN1, PSEN2 and APP) have been commonly merged into one group (Mutation Carriers, MC) and studied using conventional statistical analysis. Comparisons between groups using null-hypothesis testing or longitudinal regression procedures, such as the linear-mixed-effects models, have been assessed in the extant literature. Within this context, the work presented here performs a comparison between different groups of subjects by considering the 3 genes, either jointly or separately, and using tools based on Machine Learning (ML). This involves a feature selection step which makes use of ANOVA followed by Principal Component Analysis (PCA) to determine which features would be realiable for further comparison purposes. Then, the selected predictors are classified using a Support-Vector-Machine (SVM) in a nested k-Fold cross-validation resulting in maximum classification rates of 72-74% using PiB PET features, specially when comparing asymptomatic Non-Carriers (NC) subjects with asymptomatic PSEN1 Mutation-Carriers (PSEN1-MC). Results obtained from these experiments led to the idea that PSEN1-MC might be considered as a mixture of two different subgroups including: a first group whose patterns were very close to NC subjects, and a second group much more different in terms of imaging patterns. Thus, using a k-Means clustering algorithm it was determined both subgroups and a new classification scenario was conducted to validate this process. The comparison between each subgroup . NC subjects resulted in classification rates around 80% underscoring the importance of considering DIAN as an heterogeneous entity.
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http://dx.doi.org/10.1016/j.inffus.2020.01.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7153760PMC
June 2020

A soluble phosphorylated tau signature links tau, amyloid and the evolution of stages of dominantly inherited Alzheimer's disease.

Nat Med 2020 03 11;26(3):398-407. Epub 2020 Mar 11.

Dementia Research Centre, Institute of Neurology, University College London, London, UK.

Development of tau-based therapies for Alzheimer's disease requires an understanding of the timing of disease-related changes in tau. We quantified the phosphorylation state at multiple sites of the tau protein in cerebrospinal fluid markers across four decades of disease progression in dominantly inherited Alzheimer's disease. We identified a pattern of tau staging where site-specific phosphorylation changes occur at different periods of disease progression and follow distinct trajectories over time. These tau phosphorylation state changes are uniquely associated with structural, metabolic, neurodegenerative and clinical markers of disease, and some (p-tau217 and p-tau181) begin with the initial increases in aggregate amyloid-β as early as two decades before the development of aggregated tau pathology. Others (p-tau205 and t-tau) increase with atrophy and hypometabolism closer to symptom onset. These findings provide insights into the pathways linking tau, amyloid-β and neurodegeneration, and may facilitate clinical trials of tau-based treatments.
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http://dx.doi.org/10.1038/s41591-020-0781-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7309367PMC
March 2020

Association of Longitudinal Changes in Cerebrospinal Fluid Total Tau and Phosphorylated Tau 181 and Brain Atrophy With Disease Progression in Patients With Alzheimer Disease.

JAMA Netw Open 2019 12 2;2(12):e1917126. Epub 2019 Dec 2.

Department of Neurology, Washington University in St Louis, St Louis, Missouri.

Importance: The amyloid/tau/neurodegeneration (A/T/N) framework uses cerebrospinal fluid (CSF) levels of total tau (tTau) as a marker of neurodegeneration and CSF levels of phosphorylated tau 181 (pTau181) as a marker of tau tangles. However, it is unclear whether CSF levels of tTau and pTau181 have similar or different trajectories over the course of Alzheimer disease.

Objectives: To examine the rates of change in CSF levels of tTau and pTau181 across the Alzheimer disease course and how the rates of change are associated with brain atrophy as measured by magnetic resonance imaging.

Design, Setting, And Participants: This cohort study was set in tertiary research clinics. Each participant was a member of a pedigree with a known mutation for dominantly inherited Alzheimer disease. Participants were divided into 3 groups on the basis of the presence of a mutation and their Clinical Dementia Rating score. Data analysis was performed in June 2019.

Main Outcomes And Measures: Rates of change of CSF tTau and pTau181 levels and their association with the rate of change of brain volume.

Results: Data from 465 participants (283 mutation carriers and 182 noncarriers) were analyzed. The mean (SD) age of the cohort was 37.8 (11.3) years, and 262 (56.3%) were women. The mean (SD) follow-up duration was 2.7 (1.5) years. Two or more longitudinal CSF and magnetic resonance imaging assessments were available for 160 and 247 participants, respectively. Sixty-five percent of mutation carriers (183) did not have symptoms at baseline (Clinical Dementia Rating score, 0). For mutation carriers, the annual rates of change for CSF tTau and pTau181 became significantly different from 0 approximately 10 years before the estimated year of onset (mean [SE] rates of change, 5.5 [2.8] for tTau [P = .05] and 0.7 [0.3] for pTau 181 [P = .04]) and 15 years before onset (mean [SE] rates of change, 5.4 [3.9] for tTau [P = .17] and 1.1 [0.5] for pTau181 [P = .03]), respectively. The rate of change of pTau181 was positive and increased at the early stages of the disease, showing a positive rate of change starting at 15 estimated years before onset until 5 estimated years before onset (mean [SE], 0.4 [0.3]), followed by a positive but decreasing rate of change at year 0 (mean [SE], 0.1 [0.3]) and then negative rates of change at 5 years (mean [SE], -0.3 [0.4]) and 10 years (mean [SE], -0.6 [0.6]) after symptom onset. In individuals without symptoms (Clinical Dementia Rating score, 0), the rates of change of CSF tTau and pTau181 were negatively associated with brain atrophy (high rates of change in CSF measures were associated with low rates of change in brain volume in asymptomatic stages). After symptom onset (Clinical Dementia Rating score, >0), an increased rate of brain atrophy was not associated with rates of change of levels of both CSF tTau and pTau181.

Conclusions And Relevance: These findings suggest that CSF tTau and pTau181 may have different associations with brain atrophy across the disease time course. These results have implications for understanding the dynamics of disease pathobiology and interpreting neuronal injury biomarker concentrations in response to Alzheimer disease progression and disease-modifying therapies.
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http://dx.doi.org/10.1001/jamanetworkopen.2019.17126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6991202PMC
December 2019

Cryo-EM structure and polymorphism of Aβ amyloid fibrils purified from Alzheimer's brain tissue.

Nat Commun 2019 10 29;10(1):4760. Epub 2019 Oct 29.

Institute of Protein Biochemistry, Ulm University, Helmholtzstrasse 8/1, 89081, Ulm, Germany.

The formation of Aβ amyloid fibrils is a neuropathological hallmark of Alzheimer's disease and cerebral amyloid angiopathy. However, the structure of Aβ amyloid fibrils from brain tissue is poorly understood. Here we report the purification of Aβ amyloid fibrils from meningeal Alzheimer's brain tissue and their structural analysis with cryo-electron microscopy. We show that these fibrils are polymorphic but consist of similarly structured protofilaments. Brain derived Aβ amyloid fibrils are right-hand twisted and their peptide fold differs sharply from previously analyzed Aβ fibrils that were formed in vitro. These data underscore the importance to use patient-derived amyloid fibrils when investigating the structural basis of the disease.
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http://dx.doi.org/10.1038/s41467-019-12683-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6820800PMC
October 2019

Prion-like spreading of Alzheimer's disease within the brain's connectome.

J R Soc Interface 2019 10 16;16(159):20190356. Epub 2019 Oct 16.

Living Matter Laboratory, Stanford University, Stanford, CA, USA.

The prion hypothesis states that misfolded proteins can act as infectious agents that template the misfolding and aggregation of healthy proteins to transmit a disease. Increasing evidence suggests that pathological proteins in neurodegenerative diseases adopt prion-like mechanisms and spread across the brain along anatomically connected networks. Local kinetic models of protein misfolding and global network models of protein spreading provide valuable insight into several aspects of prion-like diseases. Yet, to date, these models have not been combined to simulate how pathological proteins multiply and spread across the human brain. Here, we create an efficient and robust tool to simulate the spreading of misfolded protein using three classes of kinetic models, the Fisher-Kolmogorov model, the Heterodimer model and the Smoluchowski model. We discretize their governing equations using a human brain network model, which we represent as a weighted Laplacian graph generated from 418 brains from the Human Connectome Project. Its nodes represent the anatomic regions of interest and its edges are weighted by the mean fibre number divided by the mean fibre length between any two regions. We demonstrate that our brain network model can predict the histopathological patterns of Alzheimer's disease and capture the key characteristic features of finite-element brain models at a fraction of their computational cost: simulating the spatio-temporal evolution of aggregate size distributions across the human brain throughout a period of 40 years takes less than 7 s on a standard laptop computer. Our model has the potential to predict biomarker curves, aggregate size distributions, infection times, and the effects of therapeutic strategies including reduced production and increased clearance of misfolded protein.
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http://dx.doi.org/10.1098/rsif.2019.0356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6833337PMC
October 2019

Early Aβ reduction prevents progression of cerebral amyloid angiopathy.

Ann Neurol 2019 10 19;86(4):561-571. Epub 2019 Aug 19.

German Center for Neurodegenerative Diseases, Tübingen, Germany.

Objective: Clinical trials targeting β-amyloid peptides (Aβ) for Alzheimer disease (AD) failed for arguable reasons that include selecting the wrong stages of AD pathophysiology or Aβ being the wrong target. Targeting Aβ to prevent cerebral amyloid angiopathy (CAA) has not been rigorously followed, although the causal role of Aβ for CAA and related hemorrhages is undisputed. CAA occurs with normal aging and to various degrees in AD, where its impact and treatment is confounded by the presence of parenchymal Aβ deposition.

Methods: APPDutch mice develop CAA in the absence of parenchymal amyloid, mimicking hereditary cerebral hemorrhage with amyloidosis Dutch type (HCHWA-D). Mice were treated with a β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitor. We used 3-dimensional ultramicroscopy and immunoassays for visualizing CAA and assessing Aβ in cerebrospinal fluid (CSF) and brain.

Results: CAA onset in mice was at 22 to 24 months, first in frontal leptomeningeal and superficial cortical vessels followed by vessels penetrating the cortical layers. CSF Aβ increased with aging followed by a decrease of both Aβ40 and Aβ42 upon CAA onset, supporting the idea that combined reduction of CSF Aβ40 and Aβ42 is a specific biomarker for vascular amyloid. BACE1 inhibitor treatment starting at CAA onset and continuing for 4 months revealed a 90% Aβ reduction in CSF and largely prevented CAA progression and associated pathologies.

Interpretation: This is the first study showing that Aβ reduction at early disease time points largely prevents CAA in the absence of parenchymal amyloid. Our observation provides a preclinical basis for Aβ-reducing treatments in patients at risk of CAA and in presymptomatic HCHWA-D. ANN NEUROL 2019;86:561-571.
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http://dx.doi.org/10.1002/ana.25562DOI Listing
October 2019

Clinical, pathophysiological and genetic features of motor symptoms in autosomal dominant Alzheimer's disease.

Brain 2019 05;142(5):1429-1440

German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.

Owing to an early and marked deposition of amyloid-β in the basal ganglia, autosomal dominant Alzheimer's disease could distinctly involve motor symptoms. Therefore, we aimed to assess the prevalence and characteristics of motor signs in autosomal dominant Alzheimer's disease. Baseline Unified Parkinson Disease Rating Scale part three scores (UPDRS-III) from 433 participants of the Dominantly Inherited Alzheimer's Network observational study were analysed. Motor symptoms were scrutinized with respect to associations with mutation carrier status, mutation site within PSEN1, basal ganglia amyloid-β as measured by Pittsburgh compound B PET, estimated years to symptom onset and Clinical Dementia Rating Scale-Sum of Boxes. Motor findings in mutation carriers were compared to patients with sporadic Alzheimer's disease using data of the National Alzheimer's Coordination Center. Mutation carriers showed motor findings at a higher frequency (28.4% versus 12.8%; P < 0.001) and severity (mean UPDRS-III scores 2.0 versus 0.4; P < 0.001) compared to non-carriers. Eleven of the 27 UPDRS-III items were statistically more frequently affected in mutation carriers after adjustment for multiple comparisons. Ten of these 11 items were subscale components of bradykinesia. In cognitively asymptomatic mutation carriers, dysdiadochokinesia was more frequent compared to non-carriers (right hand: 3.8% versus 0%; adjusted P = 0.023; left: 4.4% versus 0.6%; adjusted P = 0.031). In this cohort, the positive predictive value for mutation carrier status in cognitively asymptomatic participants (50% a priori risk) of dysdiadochokinesia was 100% for the right and 87.5% for the left side. Mutation carriers with motor findings more frequently were basal ganglia amyloid-β positive (84% versus 63.3%; P = 0.006) and showed more basal ganglia amyloid-β deposition (Pittsburgh compound B-standardized uptake value ratio 2.472 versus 1.928; P = 0.002) than those without. Frequency and severity of motor findings were greater in post-codon 200 PSEN1 mutations (36%; mean UPDRS-III score 3.03) compared to mutations pre-codon 200 PSEN1 (19.3%, P = 0.022; 0.91, P = 0.013). In mutation carriers, motor symptom severity was significantly positively correlated with basal ganglia amyloid-β deposition, Clinical Dementia Rating scores and estimated years to symptom onset. Mutation carriers with a Clinical Dementia Rating global score of 2 exhibited more pronounced motor symptoms than sporadic Alzheimer's disease patients with the same Clinical Dementia Rating global score (mean UPDRS-III scores 20.71 versus 5.96; P < 0.001). With a prevalence of approximately 30% and increasing severity with progression of dementia, motor symptoms are proven as a clinically relevant finding in autosomal dominant Alzheimer's disease, in particular in advanced dementia stages, that correlates with deposition of amyloid-β in the basal ganglia. In a very small per cent of cognitively asymptomatic members of families with autosomal dominant Alzheimer's disease, dysdiadochokinesia may increase the chance of an individual's status as mutation carrier.
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http://dx.doi.org/10.1093/brain/awz050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6735903PMC
May 2019

Emerging cerebrospinal fluid biomarkers in autosomal dominant Alzheimer's disease.

Alzheimers Dement 2019 05 4;15(5):655-665. Epub 2019 Mar 4.

Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA; Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA. Electronic address:

Introduction: Four less well-studied but promising "emerging" cerebrospinal fluid (CSF) biomarkers are elevated in late-onset Alzheimer disease (AD): neurogranin, synaptosomal-associated protein-25 (SNAP-25), visinin-like protein 1 (VILIP-1), and chitinase-3-like protein 1 (YKL-40).

Methods: CSF neurogranin, SNAP-25, VILIP-1, and YKL-40 were measured in families carrying autosomal-dominant AD mutations.

Results: The four emerging CSF biomarkers were significantly elevated in the mutation carriers (n = 235) versus noncarriers (n = 145). CSF SNAP-25, VILIP-1, and YKL-40 were altered very early in the AD time course, approximately 15-19 years before estimated symptom onset. All CSF biomarkers predicted important AD-related outcomes including performance on a cognitive composite, brain amyloid burden as measured by amyloid positron emission tomography, and the estimated years from symptom onset.

Discussion: Early abnormalities in CSF tTau, pTau, SNAP-25, VILIP-1, and YKL-40 suggest that synaptic damage, neuronal injury, and neuroinflammation begin shortly after the commencement of brain amyloid accumulation.
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http://dx.doi.org/10.1016/j.jalz.2018.12.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6511459PMC
May 2019

Serum neurofilament dynamics predicts neurodegeneration and clinical progression in presymptomatic Alzheimer's disease.

Nat Med 2019 02 21;25(2):277-283. Epub 2019 Jan 21.

Department of Neurology, Department of Radiology, and Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, USA.

Neurofilament light chain (NfL) is a promising fluid biomarker of disease progression for various cerebral proteopathies. Here we leverage the unique characteristics of the Dominantly Inherited Alzheimer Network and ultrasensitive immunoassay technology to demonstrate that NfL levels in the cerebrospinal fluid (n = 187) and serum (n = 405) are correlated with one another and are elevated at the presymptomatic stages of familial Alzheimer's disease. Longitudinal, within-person analysis of serum NfL dynamics (n = 196) confirmed this elevation and further revealed that the rate of change of serum NfL could discriminate mutation carriers from non-mutation carriers almost a decade earlier than cross-sectional absolute NfL levels (that is, 16.2 versus 6.8 years before the estimated symptom onset). Serum NfL rate of change peaked in participants converting from the presymptomatic to the symptomatic stage and was associated with cortical thinning assessed by magnetic resonance imaging, but less so with amyloid-β deposition or glucose metabolism (assessed by positron emission tomography). Serum NfL was predictive for both the rate of cortical thinning and cognitive changes assessed by the Mini-Mental State Examination and Logical Memory test. Thus, NfL dynamics in serum predict disease progression and brain neurodegeneration at the early presymptomatic stages of familial Alzheimer's disease, which supports its potential utility as a clinically useful biomarker.
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http://dx.doi.org/10.1038/s41591-018-0304-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6367005PMC
February 2019

Seizures as an early symptom of autosomal dominant Alzheimer's disease.

Neurobiol Aging 2019 04 5;76:18-23. Epub 2018 Dec 5.

German Center for Neurodegenerative Diseases (DZNE), Munich, Germany; Department of Neurology, Ludwig-Maximilians-Universität München, München, Germany. Electronic address:

Our objective was to assess the reported history of seizures in cognitively asymptomatic mutation carriers for autosomal dominant Alzheimer's disease (ADAD) and the predictive value of seizures for mutation carrier status in cognitively asymptomatic first-degree relatives of ADAD patients. Seizure occurrence in the Dominantly Inherited Alzheimer Network observational study was correlated with mutation carrier status in cognitively asymptomatic subjects. Of 276 cognitively asymptomatic individuals, 11 (4%) had experienced seizures, and nine of these carried an ADAD mutation. Thus, in the Dominantly Inherited Alzheimer Network population, seizure frequency in mutation carriers was significantly higher than in noncarriers (p = 0.04), and the positive predictive value of seizures for the presence of a pathogenic mutation was 81.8%. Among cognitively asymptomatic ADAD family members, the occurrence of seizures increases the a priori risk of 50% mutation-positive status to about 80%. This finding suggests that ADAD mutations increase the risk of seizures.
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http://dx.doi.org/10.1016/j.neurobiolaging.2018.11.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6572755PMC
April 2019

CSF progranulin increases in the course of Alzheimer's disease and is associated with sTREM2, neurodegeneration and cognitive decline.

EMBO Mol Med 2018 12;10(12)

Chair of Metabolic Biochemistry, Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilians-Universität München, Munich, Germany

Progranulin (PGRN) is predominantly expressed by microglia in the brain, and genetic and experimental evidence suggests a critical role in Alzheimer's disease (AD). We asked whether PGRN expression is changed in a disease severity-specific manner in AD We measured PGRN in cerebrospinal fluid (CSF) in two of the best-characterized AD patient cohorts, namely the Dominant Inherited Alzheimer's Disease Network (DIAN) and the Alzheimer's Disease Neuroimaging Initiative (ADNI). In carriers of AD causing dominant mutations, cross-sectionally assessed CSF PGRN increased over the course of the disease and significantly differed from non-carriers 10 years before the expected symptom onset. In late-onset AD, higher CSF PGRN was associated with more advanced disease stages and cognitive impairment. Higher CSF PGRN was associated with higher CSF soluble TREM2 (triggering receptor expressed on myeloid cells 2) only when there was underlying pathology, but not in controls. In conclusion, we demonstrate that, although CSF PGRN is not a diagnostic biomarker for AD, it may together with sTREM2 reflect microglial activation during the disease.
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http://dx.doi.org/10.15252/emmm.201809712DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6284390PMC
December 2018

Relationship between physical activity, cognition, and Alzheimer pathology in autosomal dominant Alzheimer's disease.

Alzheimers Dement 2018 11 25;14(11):1427-1437. Epub 2018 Sep 25.

Section for Dementia Research, Department of Cellular Neurology, Hertie Institute for Clinical Brain Research and Department of Psychiatry and Psychotherapy, University of Tübingen, Tübingen, Germany; German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.

Introduction: Little is known about effects of physical activity (PA) in genetically driven early-onset autosomal dominant Alzheimer's disease (AD).

Methods: A total of 372 individuals participating at the Dominantly Inherited Alzheimer Network study were examined to evaluate the cross-sectional relationship of PA with cognitive performance, functional status, cognitive decline, and AD biomarkers in cerebrospinal fluid. Mutation carriers were categorized as high or low exercisers according to WHO recommendations.

Results: Mutation carriers with high PA showed significantly better cognitive and functional performance and significantly less AD-like pathology in cerebrospinal fluid than individuals with low PA. Mutation carriers with high PA scored 3.4 points better on Mini Mental State Examination at expected symptom onset and fulfilled the diagnosis of very mild dementia 15.1 years later compared with low exercisers.

Discussion: These results support a beneficial effect of PA on cognition and AD pathology even in individuals with genetically driven autosomal dominant AD.
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http://dx.doi.org/10.1016/j.jalz.2018.06.3059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6322213PMC
November 2018

Propagation and spread of pathogenic protein assemblies in neurodegenerative diseases.

Nat Neurosci 2018 10 26;21(10):1341-1349. Epub 2018 Sep 26.

Department of Neurology and Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA.

Many neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, are characterized by the progressive appearance of abnormal proteinaceous assemblies in the nervous system. Studies in experimental systems indicate that the assemblies originate from the prion-like seeded aggregation of specific misfolded proteins that proliferate and amass to form the intracellular and/or extracellular lesions typical of each disorder. The host in which the proteopathic seeds arise provides the biochemical and physiological environment that either supports or restricts their emergence, proliferation, self-assembly, and spread. Multiple mechanisms influence the spatiotemporal spread of seeds and the nature of the resulting lesions, one of which is the cellular uptake, release, and transport of seeds along neural pathways and networks. The characteristics of cells and regions in the affected network govern their vulnerability and thereby influence the neuropathological and clinical attributes of the disease. The propagation of pathogenic protein assemblies within the nervous system is thus determined by the interaction of the proteopathic agent and the host milieu.
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http://dx.doi.org/10.1038/s41593-018-0238-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6375686PMC
October 2018

White matter diffusion alterations precede symptom onset in autosomal dominant Alzheimer's disease.

Brain 2018 10;141(10):3065-3080

Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität LMU, Munich, Germany.

White matter alterations are present in the majority of patients with Alzheimer's disease type dementia. However, the spatiotemporal pattern of white matter changes preceding dementia symptoms in Alzheimer's disease remains unclear, largely due to the inherent diagnostic uncertainty in the preclinical phase and increased risk of confounding age-related vascular disease and stroke in late-onset Alzheimer's disease. In early-onset autosomal-dominantly inherited Alzheimer's disease, participants are destined to develop dementia, which provides the opportunity to assess brain changes years before the onset of symptoms, and in the absence of ageing-related vascular disease. Here, we assessed mean diffusivity alterations in the white matter in 64 mutation carriers compared to 45 non-carrier family non-carriers. Using tract-based spatial statistics, we mapped the interaction of mutation status by estimated years from symptom onset on mean diffusivity. For major atlas-derived fibre tracts, we determined the earliest time point at which abnormal mean diffusivity changes in the mutation carriers were detectable. Lastly, we assessed the association between mean diffusivity and cerebrospinal fluid biomarkers of amyloid, tau, phosphorylated-tau, and soluble TREM2, i.e. a marker of microglia activity. Results showed a significant interaction of mutations status by estimated years from symptom onset, i.e. a stronger increase of mean diffusivity, within the posterior parietal and medial frontal white matter in mutation carriers compared with non-carriers. The earliest increase of mean diffusivity was observed in the forceps major, forceps minor and long projecting fibres-many connecting default mode network regions-between 5 to 10 years before estimated symptom onset. Higher mean diffusivity in fibre tracts was associated with lower grey matter volume in the tracts' projection zones. Global mean diffusivity was correlated with lower cerebrospinal fluid levels of amyloid-β1-42 but higher levels of tau, phosphorylated-tau and soluble TREM2. Together, these results suggest that regionally selective white matter degeneration occurs years before the estimated symptom onset. Such white matter alterations are associated with primary Alzheimer's disease pathology and microglia activity in the brain.
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http://dx.doi.org/10.1093/brain/awy229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6158739PMC
October 2018

Longitudinal cognitive and biomarker changes in dominantly inherited Alzheimer disease.

Neurology 2018 10 14;91(14):e1295-e1306. Epub 2018 Sep 14.

From the Department of Neurology (E.M., J.H., V.B., A.M.F., D.M.H., J.C.M., K.P., R.J.B.), Division of Biostatistics (G.W., C.X.), Department of Radiology (B.A.G., T.L.S.B., D.S.M.), and Department of Pathology (N.J.C.), Washington University School of Medicine, Saint Louis, MO; Department of Neuroscience (A.M.J.), Icahn School of Medicine at Mount Sinai, New York, NY; Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia (FLENI) (R.A.), Instituto de Investigaciones Neurológicas Raúl Correa, Buenos Aires, Argentina; University of Pittsburgh School of Medicine (S.B.B., W.K.), PA; College of Physicians and Surgeons (J.N.), Columbia University, New York, NY; Department of Neurology (J.R.), Keck School of Medicine of University of Southern California, Los Angeles; Department of Neurology (B.G., M.F.), Indiana University, Indianapolis; Massachusetts General Hospital (R.A.S., J.C.), Harvard Medical School, Boston; Butler Hospital and Brown University (S.S.), Providence, RI; Department of Neurology (N.R.G.-R.), Mayo Clinic Jacksonville, FL; Neuroscience Research Australia (P.R.S.); School of Medical Sciences (P.R.S.), University of New South Wales, Sydney; The Florey Institute and the University of Melbourne (C.M.), Parkville, Australia; Dementia Research Centre, Institute of Neurology (M.N.R., N.C.F.), University College London, UK; German Center for Neurodegenerative Diseases (DZNE) Munich (J.L.); Department of Neurology (J.L.), Ludwig-Maximilians Universität München; German Center for Neurodegenerative Diseases (DZNE) Tübingen (M.J.); and Hertie-Institute for Clinical Brain Research (M.J.), University of Tübingen, Germany.

Objective: To assess the onset, sequence, and rate of progression of comprehensive biomarker and clinical measures across the spectrum of Alzheimer disease (AD) using the Dominantly Inherited Alzheimer Network (DIAN) study and compare these to cross-sectional estimates.

Methods: We conducted longitudinal clinical, cognitive, CSF, and neuroimaging assessments (mean of 2.7 [±1.1] visits) in 217 DIAN participants. Linear mixed effects models were used to assess changes in each measure relative to individuals' estimated years to symptom onset and to compare mutation carriers and noncarriers.

Results: Longitudinal β-amyloid measures changed first (starting 25 years before estimated symptom onset), followed by declines in measures of cortical metabolism (approximately 7-10 years later), then cognition and hippocampal atrophy (approximately 20 years later). There were significant differences in the estimates of CSF p-tau and tau, with elevations from cross-sectional estimates preceding longitudinal estimates by over 10 years; further, longitudinal estimates identified a significant decline in CSF p-tau near symptom onset as opposed to continued elevations.

Conclusion: These longitudinal estimates clarify the sequence and temporal dynamics of presymptomatic pathologic changes in autosomal dominant AD, information critical to a better understanding of the disease. The pattern of biomarker changes identified here also suggests that once β-amyloidosis begins, additional pathologies may begin to develop less than 10 years later, but more than 15 years before symptom onset, an important consideration for interventions meant to alter the disease course.
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http://dx.doi.org/10.1212/WNL.0000000000006277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6177272PMC
October 2018

Infectious prions do not induce Aβ deposition in an in vivo seeding model.

Acta Neuropathol 2018 06 16;135(6):965-967. Epub 2018 Apr 16.

German Center for Neurodegenerative Diseases (DZNE), Tübingen, 72076, Tübingen, Germany.

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http://dx.doi.org/10.1007/s00401-018-1848-5DOI Listing
June 2018

Innate immune memory in the brain shapes neurological disease hallmarks.

Nature 2018 04 11;556(7701):332-338. Epub 2018 Apr 11.

German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.

Innate immune memory is a vital mechanism of myeloid cell plasticity that occurs in response to environmental stimuli and alters subsequent immune responses. Two types of immunological imprinting can be distinguished-training and tolerance. These are epigenetically mediated and enhance or suppress subsequent inflammation, respectively. Whether immune memory occurs in tissue-resident macrophages in vivo and how it may affect pathology remains largely unknown. Here we demonstrate that peripherally applied inflammatory stimuli induce acute immune training and tolerance in the brain and lead to differential epigenetic reprogramming of brain-resident macrophages (microglia) that persists for at least six months. Strikingly, in a mouse model of Alzheimer's pathology, immune training exacerbates cerebral β-amyloidosis and immune tolerance alleviates it; similarly, peripheral immune stimulation modifies pathological features after stroke. Our results identify immune memory in the brain as an important modifier of neuropathology.
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http://dx.doi.org/10.1038/s41586-018-0023-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6038912PMC
April 2018

Left frontal hub connectivity delays cognitive impairment in autosomal-dominant and sporadic Alzheimer's disease.

Brain 2018 04;141(4):1186-1200

German Center for Neurodegenerative Diseases (DZNE), Bonn, Sigmund-Freud-Str. 27, 53127 Bonn, Germany.

Patients with Alzheimer's disease vary in their ability to sustain cognitive abilities in the presence of brain pathology. A major open question is which brain mechanisms may support higher reserve capacity, i.e. relatively high cognitive performance at a given level of Alzheimer's pathology. Higher functional MRI-assessed functional connectivity of a hub in the left frontal cortex is a core candidate brain mechanism underlying reserve as it is associated with education (i.e. a protective factor often associated with higher reserve) and attenuated cognitive impairment in prodromal Alzheimer's disease. However, no study has yet assessed whether such hub connectivity of the left frontal cortex supports reserve throughout the evolution of pathological brain changes in Alzheimer's disease, including the presymptomatic stage when cognitive decline is subtle. To address this research gap, we obtained cross-sectional resting state functional MRI in 74 participants with autosomal dominant Alzheimer's disease, 55 controls from the Dominantly Inherited Alzheimer's Network and 75 amyloid-positive elderly participants, as well as 41 amyloid-negative cognitively normal elderly subjects from the German Center of Neurodegenerative Diseases multicentre study on biomarkers in sporadic Alzheimer's disease. For each participant, global left frontal cortex connectivity was computed as the average resting state functional connectivity between the left frontal cortex (seed) and each voxel in the grey matter. As a marker of disease stage, we applied estimated years from symptom onset in autosomal dominantly inherited Alzheimer's disease and cerebrospinal fluid tau levels in sporadic Alzheimer's disease cases. In both autosomal dominant and sporadic Alzheimer's disease patients, higher levels of left frontal cortex connectivity were correlated with greater education. For autosomal dominant Alzheimer's disease, a significant left frontal cortex connectivity × estimated years of onset interaction was found, indicating slower decline of memory and global cognition at higher levels of connectivity. Similarly, in sporadic amyloid-positive elderly subjects, the effect of tau on cognition was attenuated at higher levels of left frontal cortex connectivity. Polynomial regression analysis showed that the trajectory of cognitive decline was shifted towards a later stage of Alzheimer's disease in patients with higher levels of left frontal cortex connectivity. Together, our findings suggest that higher resilience against the development of cognitive impairment throughout the early stages of Alzheimer's disease is at least partially attributable to higher left frontal cortex-hub connectivity.
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http://dx.doi.org/10.1093/brain/awy008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5888938PMC
April 2018

Amyloid polymorphisms constitute distinct clouds of conformational variants in different etiological subtypes of Alzheimer's disease.

Proc Natl Acad Sci U S A 2017 12 20;114(49):13018-13023. Epub 2017 Nov 20.

Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany;

The molecular architecture of amyloids formed in vivo can be interrogated using luminescent conjugated oligothiophenes (LCOs), a unique class of amyloid dyes. When bound to amyloid, LCOs yield fluorescence emission spectra that reflect the 3D structure of the protein aggregates. Given that synthetic amyloid-β peptide (Aβ) has been shown to adopt distinct structural conformations with different biological activities, we asked whether Aβ can assume structurally and functionally distinct conformations within the brain. To this end, we analyzed the LCO-stained cores of β-amyloid plaques in postmortem tissue sections from frontal, temporal, and occipital neocortices in 40 cases of familial Alzheimer's disease (AD) or sporadic (idiopathic) AD (sAD). The spectral attributes of LCO-bound plaques varied markedly in the brain, but the mean spectral properties of the amyloid cores were generally similar in all three cortical regions of individual patients. Remarkably, the LCO amyloid spectra differed significantly among some of the familial and sAD subtypes, and between typical patients with sAD and those with posterior cortical atrophy AD. Neither the amount of Aβ nor its protease resistance correlated with LCO spectral properties. LCO spectral amyloid phenotypes could be partially conveyed to Aβ plaques induced by experimental transmission in a mouse model. These findings indicate that polymorphic Aβ-amyloid deposits within the brain cluster as clouds of conformational variants in different AD cases. Heterogeneity in the molecular architecture of pathogenic Aβ among individuals and in etiologically distinct subtypes of AD justifies further studies to assess putative links between Aβ conformation and clinical phenotype.
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http://dx.doi.org/10.1073/pnas.1713215114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5724274PMC
December 2017