UNIVERSITY DEPARTMENT OF NEUROLOGY

Mixed cerebral pathologies and cognitive aging

Head

schreiber_stefanie

PD Dr. med. Stefanie Schreiber
senior physician neurology

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Staff

Cornelia Garz

Head and project coordination
Cornelia Garz, technician

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niklassSolveig

Methodological spectrum of 2-photon imaging 
Solveig Niklass, MSc biosystems technology
PhD student

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Friederike Held

Perivascular Aβ-drainage mechanisms and transmission electron microscopy
Friederike Held
MD student

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laemmlinNaomie

Untersuchungen des endothelialen Transkriptoms an der SHRSP
Naomie Lämmlin
MD student

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Daniel Schwanke102

Temporal cascade of age-dependent mixed cerebral pathologies in SHRSP and in human brains
Daniel Schwanke
MD student

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MaxScheifele102

Retinal biomarkers to predict the mixed pathologies of the aging brain
Maximilian Scheifele
MD student

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Mike Baur102x146

Longitudinale Studien am Modell der spontan-hypertensiven stroke prone Ratte (SHRSP)
Mike Baur
MD student

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Alumni

Luiza Stanaszek Matrix metalloproteinases and extracellular matrix
Luiza Stanaszek, MSc, PhD
Biotechnology

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Celine Büche Pharmacological modifications of mixed cerebral pathologies
Dr. rer. nat. Celine Zoe Büche
Pharmacist

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Anni Schulze102 Anni Schulze
MD student

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Annette Wilisch-Neumann102x146 Project coordination, cerebral small vessel disease and neurodegeneration
Dr. rer. nat. Annette Wilisch-Neuman
Biologist/Molecular biologist

Collaborations

Topic

Mixed cerebral pathologies including cerebral small vessel disease (CSVD), amyloid β (Aβ) deposits and neurodegeneration are common features of the aging brain. In their sum they are presumed to accelerate cognitive aging and dementia development. The causal interplay between those mixed pathologies has been barely investigated so far. Indeed, the development of progressive prevention and therapeutic strategies against cognitive aging and dementia provides the detailed understanding of the interaction between all those neuropathological players.

The work of the group thus focuses on the investigation and the modification of the natural interaction between CSVD, Aβ accumulations and neurodegeneration in the aging brain. Moreover, we try to understand the impact of age-dependent renal microvascular changes on mixed cerebral pathologies (brain-kidney-axis). We therefore use spontaneously hypertensive stroke-prone rats (SHRSP), a valid non-transgenic model of chronic kidney disease, CSVD and mixed cerebral pathologies and, a broad methodological spectrum including conventional histology, immunohistochemistry, western blot techniques, zymography, transmission electron microscopy (in cooperation with Roxana Carare) as well as multimodal intravital imaging methods including intravital microscopy (2PM), high-field MRI (in cooperation with Christoph Kleinschnitz and Mirko Pham), small animal PET (in cooperation with Christoph Kleinschnitz) and intracerebral stereotactic injections.

Translational data reliability is currently under investigation in cooperation with Prof. William Jagust, Helen Wills Neuroscience Institute, University of California, Berkeley, USA using multimodal imaging methods including FDG-, amyloid-, tau-PET and MRI.

mischpathologien

Figure: Age-dependent mixed cerebral pathologies in spontaneously hypertensive stroke-prone rats (SHRSP). CSVD is initiated by an early endothelial damage of the capillary bed which itself results from age-dependent activity increase of various matrix metalloproteinases (Zymo) in pericytes (Ng2, A, arrow). Subsequently, astrocytes (GFAP) are activated (B, arrows) and blood brain barrier breakdown occurs as indicated by plasma protein (IgG, Dextran) accumulations (B & C, arrow heads). In parallel, capillary basement membrane thickening (D, arrow) with local collagen depositions (E, arrow) develop. Small vessel wall damage results in an activated coagulatory state with non-occluding erythrocyte thrombi (Ery, F & G, arrows). Adjacent to CSVD features SHRSP spontaneously show neurodegeneration in terms of intraneuronal hyperphosphorylated (p)tau (H, arrows) and perivascular Aβ-deposits (I-K, arrows). D & E transmission electron microscopy, thanks to Alan Morris and Roxana Carare, Southampton, UK, I congo red staining, G & K intravital 2-photon imaging, DAPI nuclei staining. Taken from Schreiber et al., 2014, Bueche et al., 2014, Niklass et al., 2014, Braun et al., 2012..

 

References

Schreiber S, Landau SM, Fero A, Schreiber F, Jagust WJ. Comparison of Visual and Quantitative Florbetapir F18 Positron Emission Tomography Analysis in Predicting Mild Cognitive Impairment Outcomes. JAMA Neurology. in press

Bueche CZ, Garz C, Stanaszek L, Niklass S, Kropf S, Bittner D, Härtig W, Reymann KG, Heinze HJ, Carare RO, Schreiber S. Impact of N-Acetylcysteine on Cerebral Amyloid-β Plaques and Kidney Damage in Spontaneously Hypertensive Stroke-Prone Rats. J Alzheimers Dis. 2014;42 Suppl 3:S305-13.

Schreiber S, Drukarch B, Garz C, Niklass S, Stanaszek L, Kropf S, Bueche C, Held F, Vielhaber S, Attems J, Reymann KG, Heinze HJ, Carare RO, Wilhelmus MM. Interplay Between Age, Cerebral Small Vessel Disease, Parenchymal Amyloid-β, and Tau Pathology: Longitudinal Studies in Hypertensive Stroke-Prone Rats. J Alzheimers Dis. 2014;42 Suppl 3:S205-15.

Niklass S, Stoyanov S, Garz C, Bueche CZ, Mencl S, Reymann K, Heinze HJ, Carare RO, Kleinschnitz C, Schreiber S. Intravital imaging in spontaneously hypertensive stroke-prone rats-a pilot study. Exp Transl Stroke Med. 2014 Jan 25;6(1):1.

Braun H, Schreiber S. Microbleeds in cerebral small vessel disease. Lancet Neurol. 2013 Aug;12(8):735-6.

Mencl S, Garz C, Niklass S, Braun H, Göb E, Homola G, Heinze HJ, Reymann KG, Kleinschnitz C, Schreiber S. Early microvascular dysfunction in cerebral small vessel disease is not detectable on 3.0 Tesla magnetic resonance imaging: a longitudinal study in spontaneously hypertensive stroke-prone rats. Exp Transl Stroke Med. 2013 Jun 25;5:8.

Bueche CZ, Garz C, Kropf S, Bittner D, Li W, Goertler M, Heinze HJ, Reymann K, Braun H, Schreiber S. NAC changes the course of cerebral small vessel disease in SHRSP and reveals new insights for the meaning of stases - a randomized controlled study. Exp Transl Stroke Med. 2013 Apr 15;5:5. 

Schreiber S, Bueche CZ, Garz C, Braun H. Blood brain barrier breakdown as the starting point of cerebral small vessel disease? - New insights from a rat model. Exp Transl Stroke Med. 2013 Mar 14;5(1):4. 

Braun H, Bueche CZ, Garz C, Oldag A, Heinze HJ, Goertler M, Reymann KG, Schreiber S. Stases are associated with blood-brain barrier damage and a restricted activation of coagulation in SHRSP. J Neurol Sci. 2012 Nov 15;322(1-2):71-6.

Schreiber S, Bueche CZ, Garz C, Kropf S, Angenstein F, Goldschmidt J, Neumann J, Heinze HJ, Goertler M, Reymann KG, Braun H. The pathologic cascade of cerebrovascular lesions in SHRSP: is erythrocyte accumulation an early phase? J Cereb Blood Flow Metab. 2012 Feb;32(2):278-90. 

Schreiber S, Bueche CZ, Garz C, Kropf S, Kuester D, Amann K, Heinze HJ, Goertler M, Reymann KG, Braun H. Kidney pathology precedes and predicts the pathological cascade of cerebrovascular lesions in stroke prone rats. PLoS One. 2011;6(10):e26287.

 

 

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