PM_Lect.14 _Personalized Medicine in Neurology (1).pdf

Personalized Medicine in Neurology Expected Learning outcomes Types of Neurodegenerative diseases Causes Current available treatment Approach to Personalized Neurology Introduction Neurons are the building blocks of the nervous system which includes the brain and spinal cord. Neurodegenerative disea...

Personalized Medicine in Neurology Expected Learning outcomes Types of Neurodegenerative diseases Causes Current available treatment Approach to Personalized Neurology Introduction Neurons are the building blocks of the nervous system which includes the brain and spinal cord. Neurodegenerative diseases Neurodegenerative diseases are chronic disorders that lead to a progressive loss of neuronal functions and gradually compromise the normal activities of the human brain. They refer to a range of conditions which primarily affect the the human brain and spinal cord, which result in progressive degeneration and / or death of nerve cells. This causes problems with movement (ataxias), or mental functioning (dementia). Neurodegeneration start some years before the clinical symptoms appear, after which patients need special therapies to face the disabilities including memory loss, speech difficulties and motor impairment. Many of the neurodegenerative diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), are clinically heterogeneous disorders with a strong genetic component that can present variable clinical courses, which prevent the application of the same treatment to all patients, even when they have the same pathology. Dementias are responsible for the greatest burden of neurodegenerative diseases, with Alzheimer’s representing approximately 60-70% of dementia cases. The multifactorial and complex nature of Neurodegenerative diseases Genetic factors is one of the major factor contributing to the pathogenesis of neurodegenerative diseases. Overproduction of reactive oxygen species during oxidative stress plays a key role in the pathophysiology of AD and PD based on the sensitivity of glial cells and neurons to reactive oxygen species resulting in neuronal damage. Mitochondrial dysfunction and impaired mitochondrial dynamics (size, movement, shape) have been identified as key factors in the etiology of neurodegeneration. Excessive metal (Cu, Zn, Pb, Fe) accumulation in human brain is a causative factor in the induction of oxidative stress and mitochondrial dysfunction resulting in neurological disorders Neurodegeneration Major Neurodegenerative diseases Primary brain regions affected in major neurodegenerative diseases § ALS Spinal cord Brain stem Clinical manifestations reflect distinct and overlapping neuronal circuits that progressively degenerate in various neurodegenerative diseases. Causes of Neurodegeneration Misfolded Protein accumulation Parkinson’s Disease Parkinson’s disease ( PD) is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta which innervates the dorsal striatum In PD , nigral dopamine neurons die from a combination of factors including Genetic vulnerability, Oxidative stress, Proteasomal dysfunction, Abnormal kinase activity, environmental factors. Without dopamine, the brain is unable to transmit messages between nerve cells, resulting in a decrease in muscle function. When 80% of dopamine producing cells are damaged , the symptoms of Parkinson’s disease start to appear. Parkinson’s Disease - characterized by the loss of midbrain neurons that synthesize the neurotransmitter dopamine 13 Alzheimer’s Disease Alzheimer’s disease is a progressive neurodegenerative disorder that slowly impairs memory and cognitive function. The brain has billions of neurons , each with an axon and many dendrites. To stay healthy, neurons communicate with each other, carry out metabolism and repair themselves. AD disrupts all three of these essential jobs. AD slowly destroys memory and thinking skills , eventually even the ability to carry out simplest tasks. It is the most common cause of dementia. Alzheimer’s Disease Amyotrophic Lateral Sclerosis (ALS) also Referred as “Lou Gehrig” disease ALS is caused by the selective loss of both spinal and upper motor neurons. Neurodegeneration is mainly in the motor cortex , brain stem and spinal cord. Riluzole is an approved drug useful in ALS. The neurons that die are responsible for controlling voluntary muscles and the ability to move. The person become weak and paralyzed. Lou Gehrig Stephen Hawking Genetic basis and causes of ALS Sporadic ALS - viruses, bacteria, biotoxins, minerals, heavy metals, pesticides, physical damage through occupational or sporting hazards, military service. Huntington’s Disease (HD) Huntington ‘s disease is a rapidly progressive neurodegenerative disease that leads to dementia. Usually not identified until the patient is in their early 30’s HD is autosomal dominant – one abnormal copy of the gene can cause the disease. The HD gene is a very large gene, located on chromosome 4 , in the p-arm (4p16.3). A parent with HD will have a 50% chance of passing it onto their child. There are no carriers for HD. Huntington’s Disease -Therapy Personalized Neurology approach The ultimate objective is to understand the molecular causes of neurodegenerative diseases and to find effective targeted therapies. Identify biomarkers that allow identification of each subtype. Then it will be possible to understand, with certainty, which sub-variant the individual patient is affected by and make the treatment personalized. Identify the genetic as well as epigenetic modifiers and non-genetic factors, such as nutrition, smoking habits, physical exercise, family history, chemical exposure, microbiome or the concomitant presence of other pathologies, These can influence the dynamic of neurodegenerative evolution. NGS technologies, allow the collection a huge amount of digital genetic data, can help to define not only the complete molecular signatures of the disease, but also the cascade of events that induce or maintain such signatures. For example, differential transcriptome analyses of pathological vs. healthy brain tissue allow for the examination of protein-coding genes, non-coding RNAs or splicing events that are differentially expressed in the two conditions. Combining all these data, it is possible to provide an “omic” profile of the patients, discover networks and possibly contribute to better understand the neurological disease mechanisms. Genome-wide association studies (GWAS) and NGS allow us to identify preclinical disease stages, formulate an adequate differential diagnosis and provide early and optimized therapeutic strategies to replace classical treatments Personalized or precision medicine aims to customize medical practice with a focus on the individual, based on the use of genetic tests, the identification of biomarkers and the development of targeted drugs. Biomarker profiles and categories The precision drug development for AD Spectrum of AD and the corresponding cognitive and biomarker state of trial participants (A, amyloid abnormalities; T, tau abnormalities; N, neurodegeneration) AD drug development Conceptual framework for translating brain protein networks into clinical biomarkers Biomarkers for Alzheimer’s disease Cerebrospinal fluid (CSF) and plasma Aβ42/Aβ40 ratio, as well as amyloid positron emission tomography (PET) are direct markers of Aβ pathology. In response to Aβ pathology, neurons phosphorylate and secrete tau at increased rate, resulting in increased total and phosphorylated tau (T-tau and P-tau) concentrations in CSF and in increased P-tau concentration in plasma. CSF and plasma tau may thus be considered neuronal response markers to Aβ. The most direct biomarker for tangle pathology is tau PET. CSF and plasma P-tau concentrations also increase in tau PET-positive individuals, but the increase happens well before tau pathology is detectable on PET. Axons are rich in tau and neurofilament light (NFL) that leak into the CSF and blood during neuroaxonal degeneration. The best-established imaging biomarker for neurodegeneration is volumetric magnetic resonance imaging (MRI) of the brain. Leading synaptic biomarkers are neurogranin (Ng) in CSF, as well as SV2A- and fluorodeoxyglucose (FDG) PET. The best-established astrocytic biomarker is CSF YKL-40 and there are also promising data on CSF and plasma glial fibrillary acidic protein (GFAP) as an astrocytic activation/degeneration marker. The best-established biomarkers for microglia are CSF soluble triggering receptor expressed on myeloid cells 2 (sTREM2) and translocator protein (TSPO) PET. Established Model systems for studying neurodegeneration Established experimental models of disease can be categorized into three main areas: in vitro, ex vivo and in vivo. Any Questions ?