Mixed cerebral pathologies and cognitive aging
Prof. Dr. habil. Stefanie Schreiber
Group Leader
Haus 64, Raum 328
Leipziger Str. 44
39120 Magdeburg

stefanie.schreiber@dzne.de
 +49 391 67-15001

Cerebral small vessel disease and amyloid β (Aβ) deposits are common features of the aging brain. They are presumed to act together to accelerate cognitive aging and dementia development. We here focus on the interplay and the possible causal relationship between small vessel wall damage, i.e. blood-brain barrier breakdown, and the accumulation of pathological proteins, such as Ab. Our research thereby focusses on human and experimental data.

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We work in the field of human and experimental cerebral small vessel disease (CSVD). Our human research focusses on large cohort-studies of patients suffering from hypertensive arteriopathy (HA) and cerebral amyloid angiopathy (CAA), with a special interest in understanding the meaning of patients displaying both – HA- and CAA-related features. We further study CSVD patients applying ultra-high resolution 7T MRI, lifestyle and cognitive testing as well as advanced biomarker research (together with Prof. Dr. Emrah Düzel & Prof. Dr. Anne Maass, DZNE Magdeburg).

 

Experimentally, we use the spontaneously hypertensive stroke-prone rat (SHRSP), a valid non-transgenic model of CSVD, to investigate the interplay between HA and CAA. Using the intravital 2-photon microscopy we showed that HA progresses in a temporal and age-dependent manner, starting from small vessel wall damage, proceeding to cerebral blood flow (CBF) reduction, non-occlusive and finally occlusive thrombus formation (figure 1A-E). In addition to an advanced vascular damage / thrombus formation wall-adherent Aβ accumulations in terms of CAA could be detected (Figure 1D-E). Consequently, the formation and development of CAA seems to occur faster in the presence of a (severe) HA.

Together with the group of Prof. Dr. Alexander Dityatev, DZNE Magdeburg, we further focus on the relationship between CSVD, extracellular matrix remodeling and synaptic plasticity in several experimental models of small vessel disease.

We additionally work on the understanding of the genetic background of CSVD (together with Prof. Dr. Michael Sendtner, Institute of Clinical Neurobiology, University of Würzburg), and how this relates to the behavior of the experimental CSVD models (together with Prof. Dr. Axel Becker, Institute for Pharmacology and Toxicology, Otto-von-Guericke University Magdeburg).

Together with Prof. Dr. Ildiko Dunay, Institute of Inflammation and Neurodegeneration, Otto-von-Guericke University Magdeburg, our focus lies on the investigation of blood-brain barrier breakdown, neurovascular unit damage and stroke-related inflammation in CSVD.

Figure 1: Non-amyloid HA cascade related CAA development in SHRSP.

A demonstrates non-pathological vessels without any HA phenomena (A, stage 0). Non-amyloid HA-related changes are initiated by small vessel wall damage and blood flow reductions indicated by the accumulation of Dextran and erythrocytes in the small vessel wall (B, stage 1A) or Dextran in the small vessel lumen (C, stage 1B). The walls of small vessels with subsequent formation of non-occlusive (D) or occlusive thrombi (E) accompanied by a significant reduction of red blood cell flow velocity are prone to accumulate (peri)vascular amyloid deposits in terms of CAA.

CAA, cerebral amyloid angiopathy; HA, hypertensive arteriopathy; SHRSP, spontaneously hypertensive stroke-prone rats.

Jandke et al. 2018 Brain Pathology

The second focus of the group is the understanding of the pathophysiology and disease progression of amyotrophic lateral sclerosis (ALS; together with Prof. Dr. Stefan Vielhaber, University Clinic for Neurology, Otto-von-Guericke University Magdeburg). We therefore apply ultra-high resolution 7T MRI of the motor cortex (together with Dr. Esther Kühn, Institute of Cognitive Neurology and Dementia Research, Otto-von-Guericke University Magdeburg) and of the peripheral nervous system as well as 7T magnetic resonance neurography (MRN) and nerve ultrasound fusion imaging. Together with Prof. Dr. Ildiko Dunay we further investigate the existence of an inflammatory phenotype in ALS.

Key Publications

Schreiber S, Spotorno N, Schreiber F, Acosta-Cabronero J, Kaufmann J, Machts J, Debska-Vielhaber G, Garz C, Bittner D, Hensiek N, Dengler R, Petri S, Nestor P, Vielhaber S. Significance of CSF NfL and tau in ALS. Journal of Neurology. 2018 Oct 31; 265:2633-2645. doi: 10.1007/s00415-018-9043-0
Acosta-Cabronero J, Machts J, Schreiber S, Abdulla S, Kollewe K, Petri S, Spotorno N, Kaufmann J, Heinze HJ, Dengler R, Vielhaber S, Nestor PJ. Quantitative susceptibility MRI to detect brain iron in amyotrophic lateral sclerosis. Radiology. 2018 Jul 24; 289 doi: 10.1148/radiol.2018180112
Jandke S, Garz C, Schwanke D, Sendtner M, Heinze HJ, Carare RO, Schreiber S. The association between hypertensive arteriopathy and cerebral amyloid angiopathy in spontaneously hypertensive stroke-prone rats. Brain Pathol. 2018 Nov 05; 28:844-859. doi: 10.1111/bpa.12629
Stefanie Schreiber, Frank Schreiber, Grazyna Debska-Vielhaber, Cornelia Garz, Nathalie Hensiek, Judith Machts, Susanne Abdulla, Reinhard Dengler, Susanne Petri, Peter J. Nestor, Stefan Vielhaber. Differential involvement of forearm muscles in ALS does not relate to sonographic structural nerve alterations. Clinical Neurophysiology. 2018 Jun 30; 129:1438-1443. doi: 10.1016/j.clinph.2018.04.610
Schreiber S, Schreiber F, Lockhart S, Horng A, Bejanin A, Landau S, Jagust W. AD-signature neurodegeneration and APOE genotype in MCI SNAP. JAMA Neurology. 2017 Jun 01; 74:650-659. doi: 10.1001/jamaneurol.2016.5349

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