Molecular Mechanisms of Disease PDF Lecture Outline 2024-11-27

2024-11-27 Molecular Mechanisms of Disease NROC36H3F © Arruda Carvalho UTSC Please fill out the Course Evaluations ☺ 1 ...

2024-11-27 Molecular Mechanisms of Disease NROC36H3F © Arruda Carvalho UTSC Please fill out the Course Evaluations ☺ 1  2024-11-27 Molecular Mechanisms of Disease NROC36H3S © Arruda Carvalho UTSC Lecture Outline Framework Alzheimer’s Disease Parkinson’s Disease Channelopathies Amyotrophic Lateral Sclerosis Trinucleotide Repeat Diseases Huntington's Disease Fragile X Syndrome Autism Spectrum Disorders © Arruda © 2018 Arruda Carvalho Carvalho UTSC winterUTSC term 2  2024-11-27 Lecture Outline Framework Alzheimer’s Disease Parkinson’s Disease Channelopathies Amyotrophic Lateral Sclerosis Trinucleotide Repeat Diseases Huntington's Disease Fragile X Syndrome Autism Spectrum Disorders © Arruda © 2018 Arruda Carvalho Carvalho UTSC winterUTSC term Functional Fluctuations in Neurological Disease and Underlying Mechanisms Caregiver descriptions of patients’ best and worst performances within the same day: ‘Although at times the patient “was nonsensical, confused, and mumbled incoherently,” at other times, “she was almost as she was.” ‘The wife of another patient reported that at one point, “he kept looking for the exit, couldn’t find the bedroom or the bathroom and had trouble recognizing me,” whereas, at another, “he was alert, opened the door, and greeted me after work. He knew me and seemed pleased to see me.” It is unlikely that changes in neuronal number account for rapid and reversible fluctuations in neurological functions Thus, some neurological impairments that are associated with neurodegenerative conditions might be caused by neuronal dysfunction rather than neuronal loss Palop et al., Nature 2006 © Arruda Carvalho UTSC 3  2024-11-27 Neurodegenerative Disorders Affect Neural Activity at Multiple Levels “ Neurodegenerative disorders can disrupt molecular pathways, synapses, neuronal subpopulations and local circuits in specific brain regions, as well as higher-order neural networks. Abnormal network activities may result in a vicious cycle, further impairing the integrity and functions of neurons and synapses, for example, through aberrant excitation or inhibition” Palop et al., Nature 2006 © Arruda Carvalho UTSC Neurodegenerative Disorders Affect Neural Activity at Multiple Levels Palop et al., Nature 2006 © Arruda Carvalho UTSC 4  2024-11-27 Neurodegenerative Disorders Affect Neural Activity at Multiple Levels Luscher and Huber, Neuron, 2010 © Arruda Carvalho UTSC Neuronal Function as a Major Therapeutic Target in Neurological Disease Gradual neurological decline Functional fluctuations Palop et al., Nature 2006 © Arruda Carvalho UTSC 5  2024-11-27 Lecture Outline Framework Alzheimer’s Disease Parkinson’s Disease Channelopathies Amyotrophic Lateral Sclerosis Trinucleotide Repeat Diseases Huntington's Disease Fragile X Syndrome Autism Spectrum Disorders © Arruda © 2018 Arruda Carvalho Carvalho UTSC winterUTSC term AD Patients Display Major Synaptic Loss Terry et al., Ann Neurol 1991 Comparison of the microdensitometrical measurements of synaptophysin-like immunoreactivity between age-matched control subjects and patients with Alzheimer's disease (AD) in the midfrontal (MF) and inferior parietal (IP) region. The patients with AD presented an average 40% loss (p < 0.001) of synapse density. © Arruda Carvalho UTSC 6  2024-11-27 Synaptic Loss is the Major Correlate of Cognitive Decline in AD Correlation between synaptic density loss in midfrontal cortex (MF) and worse performance in cognitive tests [e.g. Mini-Mental State Exam (MMSE), a widely used test of cognitive function] Terry et al., Ann Neurol 1991 © Arruda Carvalho UTSC Alzheimer’s Disease: Numbers 30 million people worldwide living with AD 564,000 Canadians are currently living with dementia 937,000 The number of Canadians who will be living with the disease in 15 years 1.1 million The number of Canadians affected directly or indirectly by the disease $10.4 billion The annual cost to Canadians to care for those living with dementia Source: Alzheimer Society of Canada © Arruda Carvalho UTSC 7  2024-11-27 Alzheimer’s Disease: Symptoms and Etiology Mild cognitive impairment at initial stages probably caused by early synaptic dysfunction in brain structures essential for memory encoding and storage, such as the hippocampus and entorhinal cortex Slow, progressive loss of memory and global decline of cognitive functions Typically, within a decade or so patients die being unable to carry out activities of daily living and relying on others for care In a low proportion of cases (