Dr Claire Shepherd in Brain Bank lab

Sydney Brain Bank

FACILITY INFORMATION

Update on Parkinson’s disease studies using brain tissue

Several interesting and diverse clinicopathological studies (where disease information is correlated with pathology) have been performed recently with the information available to us from our brain donors. One such study looked at the progression of pathology in patients with Parkinson’s disease (PD) and found that in most cases the progression is not rapid at all but rather it takes more than 13 years (on average) before a phase of the disease with a more rapid decline commences. Fewer than 10% of patients have a more rapid decline and future studies need to investigate these patients more closely to try and identify what it is that causes this and how these patients can be identified early in their disease course. Another study found that 83% of individuals with PD will develop some degree of dementia after 20 years. This may seem a rather depressing statistic, but in bringing awareness to the community it gives people with PD and their carers the opportunity to think ahead and prepare for what may happen in the future.

Studies examining the pathology alone of brain tissue have also provided some interesting insights into disease mechanisms. One region of the brain that is particularly targeted by abnormal protein deposits in Lewy body diseases (that is, PD, PD with dementia and dementia with Lewy bodies) is the intralaminar thalamus. This region contains several subregions, called nuclei, which were shown in a recent study to have specific patterns of cell and tissue loss and accumulations of Lewy bodies that relate to the severity of Lewy body pathology throughout the rest of the brain, aging and the presence of dementia and visual hallucinations.

DNA studies examining normal differences in genes that a certain percentage of the population has (known as polymorphisms) have found that polymorphisms in genes responsible for inherited PD can cause either an increased or decreased risk of developing PD, depending on which one of the gene is involved. Another polymorphism associated with a familial PD gene has been found to affect the age of onset of the disease.

Update on studies using brain tissue from other Parkinsonian disorders

Another subset of rarer movement disorders are multiple system atrophy (MSA) and progressive supranuclear palsy (PSP). A project using tissue from donors with MSA has demonstrated that a protein present in Lewy bodies called LRRK2 was also present early in the formation of glial cytoplasmic inclusions (GCI), the pathological characteristic of MSA. LRRK2 may be an important factor in the disease as its expression increased with the amount of GCIs, myelin degradation and cell loss. PSP can be difficult to treat as it often exhibits an unsatisfactory response to levadopa therapy. More widespread loss of cells of the extranigral A10 region of the substantia nigra was recently discovered (compared to PD cases, who usually have an adequate response to levadopa), indicating that these cells may be required for a good response to levadopa therapy.

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Caress the Detail: A Comprehensive MRI Atlas of the in Vivo Human Brain

This project aims to deliver the most comprehensive, detailed and stereotaxically accurate MRI atlas of the canonical human brain. In human neuroscience, researchers and clinicians almost always investigate images obtained from living individuals. Yet, there is no satisfactory MRI atlas of the human brain in vivo or post-mortem. There are some population-based atlases, which valiantly solve a number of problems, but they fail to address major needs. Most problematically, they segment only a small number of brain structures, typically about 50, and they are of limited value for the interpretation of a single subject/patient. In contrast to population-based approaches, the present project will investigate normal, living subjects in detail. We aim to define approximately 800 structures, as in the histological atlas of Mai, Majtanik and Paxinos (2016), and, thus, provide a “gold standard” for science and clinical practice. We will do this by obtaining high-resolution MRI at 3T and 7T of twelve subjects through a collaboration with Markus Barth from the Centre for Advanced Imaging at the University of Queensland (UQ). The limited number of subjects will allow us to image each for longer periods, obtaining higher resolution and contrast, and to invest the required time to produce unprecedented detail in segmentation. We will produce an electronic atlas for interpreting MR images, both as a tablet application and as an online web service. The tablet application will provide a convenient and powerful exegesis of brain anatomy for researchers and clinicians. The open access web service will additionally provide images, segmentation and anatomical templates to be used with most common MR-analysis packages (e.g., SPM, FSL, MINC, BrainVoyager). This will be hosted in collaboration with UQ, supporting and complementing their population-based atlas.
PROJECT