Approximately one billion people in the world suffer from neurological disorders, defined as progressive loss of neurological functions, including dementia, strokes, multiple sclerosis, epilepsy, migraine, brain injuries, cancer and neuroinfections.
Brain related disability-adjusted life-years (DALYs)
The burden of brain disorders can be measured by the impact on quality of life and mortality. Worldwide 250 million years are lost or lived with a disability (10% of total) and approximately 10 million people (16% of total) dye as a direct consequence of a neurological disorder. The main cause of disability-adjusted life-years (DALYs) are 1) stroke, 2) headaches, including migraine (13.1%) as well as headaches related to medication (3.7) and tension (0.9%). 3) infectious & immune related diseases, including meningitis (10.1%), encephalitis (3.4%), tetanus (1.4%) and multiple sclerosis (0.5%) 4) neurodegenerative disorders, including Alzheimer’s disease (9.5%), Parkinson’s disease (0.8%) and motor neuron disease (0.4%), 5) cancers of the brain, 6) epilepsy.
Stroke, neurodegenerative disorders and infectious & immune related disease are the most deathly among neurological disorders.
GBD 2015 Neurological Disorders Collaborator Group., Global, regional, and national burden of neurological disorders during 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet Neurol. (2017)
In addition, there are several mental illnesses such as depression and anxiety, as well as substance abuse related disorders adding to the numbers of global DALYs related to the brain. The global burden of mental illness is difficult to estimate due to overlap between different disorders, grouping of categories and the relation of chronic pain to other disorders. Mental illness such as major depression, anxiety disorders, schizophrenia and bipolar disorder, summarized as mental illness is estimated to account for 1-13% of global DALYs.
Global Burden of Disease Study 2013 Collaborators., Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. (2015)
The neurodegenerative disorders result in a progressive degeneration of nerve cells, examples of disorders include Alzheimer´s disease (AD), the tremor associated Parkinson´s disease (PD) caused by degeneration of dopaminergic neurons, multiple sclerosis (MS) which is an immune-mediated disorder affecting myelination of neuronal axons, amyotrophic lateral sclerosis (ALS) affecting motor function and Huntington´s disease (HD). A selection of publications, providing prevalence were investigated to estimate the number of people with these neurodegenerative diseases in the US 2018. An estimate of 5.7 million Americans of all ages are living with AD, approximate 880 000 Americans live with PD. With the prevalence of 149.2 per 100 000 individuals 488 000 people are estimated to live with MS, and with the prevalence of 5.2 per 100 000 population 17 014 people in the US is estimated to have ALS. And finally, 14 742 people are estimated to live with HD, based on an estimated prevalence of 4.5 per 100 000 individuals.
Table 1. Number of patients in USA suffering from some selected neurodegenerative disorders
Hebert LE et al., Alzheimer disease in the United States (2010-2050) estimated using the 2010 census. Neurology. (2013)
Parkinson’s disease (PD) is the second most common neurological disease. Age is the main risk factor, only 4% of the patients are under the age of 50 years, the rate is higher for men than female. Tremor, rigidity and bradykinesia were traditionally the three mayor motor symptoms associated with PD. Later, asymmetry, resting tremor and response to levodopa (dopamine precursor which increases the level of dopamine in the brain) treatment were added as important characteristics of PD. Death of dopaminergic neurons in the Substantia nigra is the main cause of motor control problems. The reason and process behind the loss of neuronal function is not yet fully understood. Genetics seems to play a role since α-synuclein (SNCA) has been associated with cases of PD. Other genes suggested to be involved in PD, are leucine-rich repeat kinase 2 (LRRK2) and PTEN-induced kinase 1 (PINK1). It is proposed that the traditional motor associated symptoms of PD are more related to the late PD stage, while other areas of the brain might be affected earlier than the Substantia nigra. There is no cure for PD, but numerous treatments exist to treat the symptoms thus improving quality of life. The most used treatment is the dopamine replacement: L-dopa, which proved to be more potent than Dopamine receptor agonists.
Braak H et al., Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging. (2003)
3D imaging of the dopaminergic neurons of the brain
This video briefly shows 3D imaging of the dopaminergic neurons in Substantia nigra region of the brain, using light sheet microscopy and immunostaining. The Substantia nigra brain region is primarily affected in Parkinson's disease patients. The full length movie with more details focuses on Parkinson´s disease and includes an interview with Prof Per Svenningsson, Karolinska Institute, found here.
Approximately 50 million people are affected by dementia globally and it is estimated that Alzheimer’s disease (AD) accounts for about 60-70% of these. Symptoms of AD include progressive memory loss, decline in cognitive functions and altered behaviors, such as increased aggression. The main pathological hallmarks of Alzheimer’s disease are extracellular plaques containing a 4kDa peptide beta-amyloid derived from amyloid precursor protein (APP) and intracellular tangles composed of an hyperphosphorylated form of the microtubules associated protein tau (MAPT). Other causes of dementia are vascular dementia characterized by mini-brain infarcts (20-30%), dementia with Lewy Bodies (DLB; 10-15%) a neurodegenerative related to Parkinson’s disease with accumulations of the synaptic protein α-synuclein (SNCA) in brain regions involved in cognitive functions and fronotemporal lobe degeneration (5-10%) a disorder with shared pathological processes with the motoneuron disease ALS and Alzheimer's disease. Proteins associated with frontotemporal dementia are tau protein (MAPT) and mRNA binding proteins TDP43 (TARDBP) and FUS (FUS).
Selkoe DJ., Alzheimer's disease: genes, proteins, and therapy. Physiol Rev. (2001)
Figure 1. Immunofluorescence stianing using antibody targeting amyolid plaque in Alzheimer´s disease brain in red.
3D imaging of brain with Alzheimer´s disease
This video briefly shows 3D imaging of Alzheimer´s disease using light sheet microscopy and immunostaining. The location of tau tangles and beta-amyloid plaques (APP, MAPT) are shown. The full length movie with more details also includes an interview with Prof Tomas Hökfelt, Karolinska Institute, found here
Cancers of the brain
Metastasis is the most common form of malignant intracranial tumors, it is estimated to be up to 10 times more common than primary malignant brain tumors. Brain metastasis is associated with severe cancer progression and poor prognosis. Brain metastasis occur in 10-30% of adults with cancer, common primary sites for brain metastasis are lung, breast, kidney and skin cancers. Primary intracranial tumors are thus more uncommon than other types of cancers, originating in peripheral tissue types. Cancer development is associated with cell division, i.e. if only a limited number of cells divide in the brain the risk of developing cancer is low in comparison to tissue types that include daily cell division.
Of intracranial primary tumors, the benign meningioma originating from the meninges accounts for about 20-30%. Non-meningiothelial mesenchymal and neuronal tumors are deriving from different cell types in the brain and are examples of rare primary intracranial tumors only accounting for a few percentages of incidences. Gliomas are tumors with an estimated origin from glial cells, accounting for approximate 30% of the primary intracranial tumors and include astrocytoma, oligodendrocytoma and ependymoma. Approximate 80% of all malignant intracranial primary tumors are gliomas, where glioblastoma (GB) is the most common of malignant intracranial primary tumors as well as the deadliest with a mean 5-year survival rate at 5%.
Example of the histological morphology of astrocytoma, oligodendrocytoma and GB are found here. In the Pathology Atlas, GB is explored using transcriptomic data from TCGA relating gene expression with patient survival. Immunohistochemical images, providing protein profiles, are available for a number patients with glioma, high or low grade.
Lu-Emerson C et al., Brain metastases. Continuum (Minneap Minn). (2012)
Proteins detected in glioma
According to the TCGA expression data 14004 genes are expressed in GB, out of which 13755 are also detected in normal human brain. The estimated origin of glioma is glial cells of the brain, also supported by the fact that many glial specific proteins are found to be expressed in glioma, such as the astrcoytic glial fibrillary acidic protein (GFAP) and S100 calcium binding protein B (S100B) as well as oligodendocyte specific myelin binding protein (MBP) and oligodendrocyte transcription factor 2 (OLIG2).
Out of the 2587 genes classified as brain elevated, 1825 genes are found to be expressed above cut off in the TCGA GB cancer samples. Many of those are not glial specific proteins but simply expressed because the tumor is located in the brain and parts of normal tissue is included in the tumor sample or some normal tissue functions still remain, such as SLC17A7 and SNAP25 located to neuropil or processes in the brain tissue, which is also detected in glioma tissue. However, there are also proteins localized to neuronal cell bodies in normal brain which is detected in cancer cells. REEP2 is detected in subsets of neurons in normal brain but also classified as an unfavorable prognostic marker in GB based on gene expression and survival data from TCGA.