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Publications of the University of Eastern Finland Dissertations in Health Sciences
isbn 978-952-61-0720-2
Publications of the University of Eastern Finland Dissertations in Health Sciences
is se rt at io n s
| 104 | Gabriela Spulber | Imaging the progression from Mild Cognitive Impairment to Alzheimer’s diseaseGabriela Spulber Imaging the progression from
Mild Cognitive Impairment to
Alzheimer’s disease Gabriela Spulber
Imaging the progression from Mild Cognitive Impairment to Alzheimer’s disease
Alzheimer’s disease (AD) is the most common cause of cognitive impairment in older people and can be diagnosed only at dementia stage. There is a pressing need for timely identification of AD so that interventions can begin early.
This thesis focuses on identifying structural MRI parameters that differentiate between stable and progressive mild cognitive impairment (MCI) subjects prior to clinical conversion to AD. Results from this work indicate that
structural MRI biomarkers support the assessment of progression to AD, and are therefore integral components in the evaluation of MCI patients.
GABRIELA SPULBER
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ABSTRACT
£ȂȱȱǻǼȱȱȱȱȱȱ¢ȱȱȱ
ȱȱȱǯȱȱȱȱȱȱȱ¢ȱȱȱȱȱǰȱȱȱ
ǰȱ ȱǰȱȱȱ¢ǯȱȱ
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ȱȱȱȱȱǻǼȱ ȱȱȱȱ¢ȱǻǼȱȱ
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VII
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ȱȱȱȱȱȱȱȱ£Ȃȱǯȱȱ
§Ȭȱ¢ǰȱ¢ȱǰȱŘŖŗŘǯȱ
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ȱǻǼDZȱşŝŞȬşśŘȬŜŗȬŖŝŘŖȬŘȱ ȱǻǼDZȱşŝŞȬşśŘȬŜŗȬŖŝŘŗȬşȱ ȱǻǼDZȱŗŝşŞȬśŝŖŜȱ ȱǻǼDZȱŗŝşŞȬśŝŗŚȱ ȬDZȱŗŝşŞȬśŝŖŜȱ ȱ
TIIVISTELMÄ
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ȱȱȱȱ¢ȱȱȱ¢ȱȱǯȱȱȱ ȱȱȱȱȬȱȱ
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¢ȱǯȱȱǰȱȱ¢ȱȱ ȱ¢ȱȱǰȱȱȱ¢ȱȱ
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¢ȱȱȱ DZȱȱȱȱ ȱȱǯȱȱȱ¢ȱȱ
ȱ ¢ȱ ¢ȱ ȱ ǯȱ ǭǰȱ ǭǰȱ ǭǰȱ ǭǰȱ
ǭǰȱ ǭǰȱ ǰȱ ǭǰȱ ǰȱ ȱ ȱ ȱ ȱ ȱ ȱ ǯȱ
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XIII
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ǯȱȱ¢ȱȱ¢ȱȱ¢ȱȱȱȱȱȱȱ¢ȱȱǯȱȱ
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ȱ ȱ ȱ ©ȱ ©ǯȱ ȱ ȱ ©ȱ ȱ ȱ ȱ ȱ ©ȱ Éöȱ óȱ
ȱ©ȱ©ǯȱóȱóȱóȱȱȱȬöȱȱȱȱöȱöǯȱȱ
¢ȱȱǰȱȱ¢ȱȱǯȱȱȱ ȱȱǰȱ¢ȱȱȱȱ
ȱ ȱ ȱ ȱ ǯȱ ȱ ȱ ȱ ȱ ȱ ȱ ¢ȱ ȱ ǰȱ ǰȱ ȱ ȃȄȱȱȱȱȱȱȱȱ¢ȱ¢ȱȱȱǯȱȱȱȱ
ȱȱȱǷȱ©ȱȱȱöǷȱ
¢ȱȱjȱȱȱ¢ȱȱǯȱȱ ȱȱ¢ȱȱȱ¢ȱ ȱ
ȱȱȱȱȱǯȱȱȱȱȱȱ¢ȱȱȱȱ¢ȱȱ¢ȱȂȱ ǯȱ
ȱ¢ȱȱȱ¢ȱȱȱȱ£ȱȱ¢ȱǯȱȱȱȱȱȱ
¢ȱȱ¢ȱǷȱ
¡Ƿȱȱȱȱȱȱȱ¢ǯȱȱȱǷȱ ȱ
ȱȱȱ ȱ ȱȱȱȱ ȱȱȱȱȱȱ ȱ
DZȱȱȱȱȱ¢ȱȱȱȱȱŜǰȱȬ ȬŘŖŖśȬŖŗşŘŗŝǰȱ ȱ ȱȱ ȱ ǰȱ ¢ȱ ȱ ȱ ǰȱ
ȱȱȱȱȱȱȱǰȱȱǰȱ ȱ ȱ ȱ ŝŖŖŜŞȦŖśǰȱ ȱ ȱ ŝȱ ȱ ǰȱ ȱ ǰȱ
ǰȱȱãȱ ȱ§ǰȱȱȱȱȱ ȱǰȱ
ȱȱȱȱȱȱȱ£ȇȱǰȱ ȱȱǯȱ ŘŘŚřŘŞǰȱ ȱ ȱ ȱ ¢ȱ ȱ ȱ ȱ ȱ ǰȱ ȱ ȱ
ȱȱȱ¢ȱǯȱ ȱ
ȱ
ǰȱȱŘŖŗŘȱ
ȱȱ
ȱ ȱ
ȱ ȱ
XV
ȱȱȱȱȱ
ȱ ȱ
ȱȱȱȱȱȱ ȱȱDZȱȱ ȱȱ
ȱ ǰȱȱǰȱȱǰȱȱǰȱȱǰȱȱǰȱȱ ǰȱ ȱ ǰȱ ȱǰȱ ȱ ǰȱ ȱ ǰȱ ȱ ǰȱ ȱ ǯȱ
ȱ ȱ ¢ȱ ȱ ȱ ȱ ȱ ȱ ȱ £ȇȱ ǯȱ
¢ȱȱǰȱřŗDZŗŜŖŗȬśǰȱŘŖŗŖǯȱ
II ȱ ǰȱ ȱ ǰȱ ȱ ǰȱ ȱ ǰȱ ȱ ǰȱ ȱ ǰȱ
ȱǰȱȱǰȱȱǰȱȱǯȱȱȱȱȱȱ
¢ȱ ȱ ¢ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱȱ ǯȱ
ȱ£ȱȱŘŖŗŘȱǽȱȱȱǾ ȱ
III ȱ ǰȱȱǰȱȱǰȱȱǰȱȱǰȱÙ£ ȱǰȱȱǰȱ
ȱǰȱȱǰȱȱǰȱȱȱȱȱǯȱȱȬȱ
¡ȱȱȱ¢ȱȱ£ȂȱȬȱȱȱȱȱ
ȱȱȱǯȱȱȱǯ
ȱǰȱȱ ǰȱ§ȱǰȱããȱǰȱȱǰȱ ãȱǰȱȱǰȱ
ȱǰȱȱǰȱȱǯȱȱȱȱȱȬȱ
ȱȱȱ£ȇȱȱȱȱȱǯȱ¢ȱ
ȱǰȱřŘDZŗśśŞȬŝŗǰȱŘŖŗŗǯȱ ȱ
ȱȱ ȱȱ ȱȱȱȱȱ¢ȱ ǯȱ ȱ
ȱ
ȱ ȱ
XVII
ȱ
ȱ
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śȱȱȱȱǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯȱřř śǯŗȱȱȱ¢ȱȱǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯȱřř śǯŘȱ¢ȱȱ¢ȱǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯȱřŚ śǯŘǯŗȱȱ¢ȱȱȱȱȱǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯȱřŚ śǯŘǯŘȱ¢ȱȱȱ¢ȱǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯȱřś śǯřȱȱȱ¡ȱȱ¢ȱǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯȱřŜ śǯŚȱȱȱ¢ȱȱ¢ȱȱǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯȱřŞ ŜȱȱǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯȱŚŖ ŝȱȱǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯǯȱŚŘ DZȱ ȱȱȬȱ
ȱ ȱ
XIX
ȱ
ȱ ȱ ȱȱ¡ȱ
ȱ ¢ȱȱ ȱ ȱ £ȇȱȱ
ȱ ȱ ȱȱȱȱ ȱ ȱ ¢ȱȱȱ
ΆŚŘȱ ȱ Άȱȱ
ȱ ȱ ȱ¢ȱȱ ȱ ȱ ȱȱ
ȱ ȱ ȱȱ ȱ ȱ ¢ȱȱ ȱ ȱ ȱȱ ȱ ȱ ȱ ȱȱȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ¢ȱ ȱ ȱ ȱ£Ȃȱȱ
ȱ ȱȱȱ¢ȱ
ŗȱȱ ȱȱȱ¢ȱ ȱ ȱ ȱȱȱ¢ȱ ȱ ȱ ȱȱȱ
ȱ ȱ ȱ¢ȱ
ȱȱ ȱȱ¡ȱ ȱ ȱ ȱȱȱ ȱ ȱ ȱȱȱ ȱ ȱ ¢ȱȱ
ȱ Ȭ¢ȬȬȱ
ȱ ȱ ȱȱȱ
ȱ ȱ ȱȱȱȱȱ ȱ ȱ ȱȱ
ȱ ȱ ȱȱ¡ȱ
ȱ ȱ ȱȱȱ Ȭȱȱ ¢ȱȱ ȱ ȱ ¢ȱȱ ȱ ȱ ȱȱȱ
ȱ ȱ ȱȱȱȱ
ȱ ȱ ȱȱ
ȱ ȱ ȱȱȱ ȱ ȱ ȱȱ
Ȭȱȱ ȱȱ
ȱ ȱ ¡ȱȱ¢ȱ ȱ ȱ ȱȱ
ȱȱ ȱȱ¢ȱ
ȱ ȱ
ȱ
ŗ ȱȱ
ȱ ¢ȱ ŝşȬ¢Ȭȱ ȱ Ȃȱ ȱ ¢ȱ Ȃȱ ȱ ǰȱ ȱ ȱ Dzȱȱ¢ȱȱȱȂǯȱȱ ȱȱǯȱȱ
ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ǯȱ ȱ
ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ǵȱ ȱ ȱ ȱ ȱ
ȱȱ¢ȱǵȱ
1.1 BECOMING OLD
ȱȱȈȱȱȱȱȱȱȱǰȱǰȱȱȱ
Ȉȱ ǻȱ ŘŖŖŜǼǯȱ ȱ ȱ ȱ ȱ ȱ ȱ ¡ȱ ȱ ǰȱ ȱ
ȱȱ¢ȱȱȱȱ¢ǯȱȱȱȱȱȱǰȱȱȱȱȱ
ȱ ǯȱȱ
ȱȱȱȱȱȱ¡ǰȱȱ ȱ¢ȱȱȱȱȱȱ
¢ȱȱȱȱȬ ȱȱȱȱȃȱ¢ȄǰȱȱŗśřŘǯȱȱȱǰȱȱ
ȱǰȱ£¢ǰȱ ȱȱȱȱśŖŖȱ¢ȱȱȱ¢ȱȱȱȱ
¢ȱȱǻȱǰȱȱȱȱǼȱȱȱȱǯȱȱ
ȱȱȱȱȱȈȱǰȱ£ȱȱȱȱȱȱȱȱ
ȱȱȱȱȱȱȱ ȱȱȱȱȱȈȱǻ ȱŗşşŜǼǰȱȱ
¢ȱȱȱȱ¢ȱȱ¢ȱȱǯȱȱȱȱ¢ȱ
ȱ¢ȱǰȱ¢ǰȱȱǯȱȱ
ȱǰȱȱȱȱȱȱȱ¢ȱǰȱȱȱ
Ȭȱȱȱȱȱ¢ȱȱȱȱ¢ǰȱ ȱDZȱȱ ¢ȱȱȱ¢¢ȱȱȱȱȱȱȱ
ȱ¢ȱȱȱȱ ȱ¡ȱȱȱ¢ȱȱ
1.2 THE FRAMEWORK AND FOCUS OF THE THESIS
ȱ¢ȱȱȱȱȱȱȱȱȱȱȱȱ ¢Ȭȱ¢ǰȱ
ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ¢ȱ ȱ
ǯȱ ȱ ȱ ȱ ȱ ȱ ¢ȱ ȱ ȱ ȱ ¢ȱ ȱ ȱ
ȱ ǯȱ ȱ ȱ ȱ ȱ ȱ ¢ȱ ȱ ȱ ȱ
ȱ ȱ ȱ ȱ £ȱ ¢ȱ ȱ ǰȱ ǯȱ ȱ ȱ ȱ Řśȱ
ȱȱ ȱ£ȇȱȱǻǼȱ ȱȱŘŖŖŖǰȱŗřȱȱȱȱȱ
ȱȱǻȱȱǯȱŘŖŖřǼǯȱȱ
ȱȱȱȱȱȱȱȱ¢ȱǰȱȱ¢ȱȱ
ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ǻȱȱǯȱ ŘŖŗŖǼǯȱ ȱ ǰȱ ȱ ȱ
ȱȱǻȬǰȱȬŗŖȱȱȬǼȱ¢ȱȱ ȱȱ ȱ
ȱȱȱȱȱȱ¢ȱȱǰȱȱȱ
ȱ ȱ ȱ ǯȱ ǰȱ ȱ ȱ ȱ ȱ ȱ ȱ
ȱȱ¢ȱȱȱȱȱȱȱȱȱȱȱ ȱȱ
ȱ ǯȱ ǰȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ¢ȱ ȱ
ȱȱȱȱ¢ȱŗȱ¢ȱ ȱȱȱȱȱŘŖśŖȱ¢ȱşȱȱȱ ǻ¢ȱȱǯȱŘŖŖŝǼǯȱȱ
ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ
ǯȱȱȱȱȱȱȱǻǼȱȱ¢ȱȱ¢ȱȱ ǻȱ ȱ ǯȱ ŗşşşǼȱ ȱ ȱ ¢ȱ ȱ ȱ ǯȱ ȱ ȱ
ȱȱȱǰȱȱȱȱȱȱȱȱȱǻȱȱ
ǯȱ ŘŖŖŘǼȱ ¢ȱ ȱ ȱ ¢ȱ ǰȱ ȱ ȱ ȱ ȱ ȱ ȱ
ȱȱȱȱŗŖȬŗśƖȱǻȱȱǯȱŘŖŖŝǼǯȱȱȱȱȱȱ
ȱȱȱȱȱȱȱ ȱȱȱȱȱȱ
ȱȱȱǰȱȱȱȱȱȱȱȱ¢ǯȱȱȱ
ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ǻȱȱǰȱǰȱȱȱǻǼǼȱȱȱȱȱȱ
ȱ ȱ ȱ ȱ ȱ ǻȱ ȱ ǯȱ ŘŖŖŝǼǯȱ ǰȱ ȱ ȱ ȱ
ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ
ȱȱȱǻȱȱǯȱŘŖŗŗǰȱȱȱǯȱŘŖŗŗǼǯȱȱ
ȱȱȱȱȱ ȱȱȱȱȱȱȱȱȱ
ȱȱȱȱ¢ȱȱȱȱȱȱȱȱȱǻȱȱǯȱ ŘŖŗŖǰȱ ȱȱǯȱ ŘŖŖşǼǰȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ
ȱȱȱ ȱǯȱȱ
ȱȱ ȱ ȱȱȱ ȱȱȱȱȱȱȱ ȱ ȱ ǯȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ǻŗȬ ȱ Ǽȱ ȱ ȱ ȱ ȱ
ǰȱȱȱȱǯȱȱ
ȱ ȱ
3
ȱ
Ř ȱȱȱȱ
2.1 MEASURING CHANGES CAUSED BY DISEASES
ȃȱ ¢ȱ ȱ ȱ ȱ ¢ȱ ȱ ȱ ǰȱ ȱ ¡ȱ ȱ ȱ ǰȱ ¢ȱ ȱ
ȱȱDzȱȱ ȱ¢ȱȱȱǰȱ ȱ¢ȱȱ¡ȱȱȱǰȱ¢ȱ
ȱȱȱȱȱ¢ȱDZȱȱ¢ȱȱȱȱȱ ǰȱȱ¢ȱȱ
¢ǰȱ ȱ ¢ȱ ǰȱ ȱ ȱ ȱ ȱ ȱ ǰȱ ȱ ȱ ȱ ¢ȱ Ȅȱǻȱ
ǰȱŗŞŞřǼǯȱȱ
ȱȱȱȱȱȱȱȱȱȱȱȱ
¢ȱȱȱȱȱȱȱȱȱȱȱȱ¢ȱ ¢ǯȱȱ ȱ
ȱ ȱ ȱ ȱ ȱ ȱ ȱ ¢ȱ ȱ ȱ ȱ ȱ ǰȱ ȱ ȱ ¢ȱ
ȱȱȱȱȱȱȱ¡ȱǻȱȱȱŘŖŖřǼǯȱȱȱȱ
ǰȱȱȱȱȱȱȱȱȱȱ¢ȱǯȱ ȃȱȱȱȱȱ ȱȱȱȱȬ¢ȱȱȱȱȱȱ¢ȱ
ȱȱȱȱ¢ȱȱȄȱǻȱȱȱ¢ȱŗşşŖǼǯȱȱ
ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ
ȱȱȱȱȱȱǯȱȱȱ ȱ ǰȱȱȱȱ
ȱȱȱȱȱȱȱǯȱȱȱȱȱȱȱȱȱȱ
ȱȱ¢ȱȱǯȱȱ Řǯŗǯŗȱȱ
ȱȱȱȱȱȱ¢ȱȱȱȱȱȱȱȱȱȱ
¢ȱȱȱȱȱȱȱȱ¢ȱǻȱŘǯŗǼǯȱȱȱȱȱȱȱ
ȱȱȱȱ¢ȱȱ¢ȱǻȱ¡Ǽȱȱ¢ȱȱȱȱ
ȱȱȱȱDzȱ¢ȱȱȱȱ¢ȱȱȱȱȱ
ȱ Dzȱ ȱ ¢ȱ ȱ £ȱ ȱ ȱ ¢ȱ ȱ ȱ ȱ
ǯȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ
ȱ¢ȱȱ ȱ ȱȱȱȱȱȱ ȱ¢ȱȱ¢ȱ
ȱǯȱȱ
ȱ ȱ ȱ ȱ ȱ ȱ ȱ ǻǼǰȱ ȱ ¢ȱ ȱ ȱ
ȱ ǻ¡Ǽȱ ȱ ȱ ǻ¡Ǽȱ ȱ ȱ ȱ ȱ ȱ
ȱȱȱȱ¡ȱȱǯȱ¡ȱȱȱ ȱȱ ȱ ȱ
ȱȱ£ȱȱŗşśŘȱȱȱȱȱȱǰȱȱȱǯȱ
ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ £ȱ ȱ ȱ ȱ
¢¢ȱ Ȉȱ ȱ ȱ ȱ ȱ ȱ Ȉȱ ȱ ŘŖŖřȱ ǻ ǯ£ǯǼǯȱȱ
ȱ ȱ ȱ ȱ ȱ ȱ ȱ ȱ ¢ȱ ȱ ǻǼǯȱ ȱ ȱ ¢ȱ ȱ
¢ȱȱȱȱȱ ǰȱ ȱȱ¢ȱ¢ȱȱǻǯǯȱ¢ȱȱ
ȱȱşśƖȱ Ǽǯȱȱȱȱ¢ȱȱȱȱȱȱȱȱȱ
ǰȱȱȱȱȱȱȱȱȱȱȱȱ¡ȱȱ
ȱǻ£ȱȱȱŘǯŗǼǯȱȱȱȱȱ£ȱȱȱ
ǰȱ ȱ ȱ ȱ ¡ȱ ȱ ȱ ȱ ¢ȱ ǻǼȱ ȱ ȱ