Diseases of the brain

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) die as a direct consequence of a neurological disorder. The main causes 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 diseases are the most deathly among neurological disorders.

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.

Neurodegenerative disorders

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

Parkinson's Disease

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 major 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.

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.

Dementia

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 a 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 frontotemporal 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).

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

References

Brain related disability-adjusted life-years (DALYs)

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)
PubMed: 28931491 DOI: 10.1016/S1474-4422(17)30299-5

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)
PubMed: 26063472 DOI: 10.1016/S0140-6736(15)60692-4

Vigo D et al., Estimating the true global burden of mental illness. Lancet Psychiatry. (2016)
PubMed: 26851330 DOI: 10.1016/S2215-0366(15)00505-2

Neurodegenerative disorders

Hebert LE et al., Alzheimer disease in the United States (2010-2050) estimated using the 2010 census. Neurology. (2013)
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Marras C et al., Prevalence of Parkinson's disease across North America. NPJ Parkinsons Dis. (2018)
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Mehta P et al., Prevalence of Amyotrophic Lateral Sclerosis - United States, 2015. MMWR Morb Mortal Wkly Rep. (2018)
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Dilokthornsakul P et al., Multiple sclerosis prevalence in the United States commercially insured population. Neurology. (2016)
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Harper PS., The epidemiology of Huntington's disease. Hum Genet. (1992)
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Parkinson's Disease

Braak H et al., Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging. (2003)
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Hughes AJ et al., What features improve the accuracy of clinical diagnosis in Parkinson's disease: a clinicopathologic study. Neurology. (1992)
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Ibáñez P et al., Causal relation between alpha-synuclein gene duplication and familial Parkinson's disease. Lancet. (2004)
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Gilks WP et al., A common LRRK2 mutation in idiopathic Parkinson's disease. Lancet. (2005)
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Valente EM et al., Hereditary early-onset Parkinson's disease caused by mutations in PINK1. Science. (2004)
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Dementia

Selkoe DJ., Alzheimer's disease: genes, proteins, and therapy. Physiol Rev. (2001)
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Gouras GK et al., β-Amyloid peptides and amyloid plaques in Alzheimer's disease. Neurotherapeutics. (2015)
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Hardy J et al., Amyloid deposition as the central event in the aetiology of Alzheimer's disease. Trends Pharmacol Sci. (1991)
PubMed: 1763432 

Makin S., The amyloid hypothesis on trial. Nature. (2018)
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Nemani VM et al., Increased expression of alpha-synuclein reduces neurotransmitter release by inhibiting synaptic vesicle reclustering after endocytosis. Neuron. (2010)
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Baba M et al., Aggregation of alpha-synuclein in Lewy bodies of sporadic Parkinson's disease and dementia with Lewy bodies. Am J Pathol. (1998)
PubMed: 9546347 

Relevant links

Alzheimer´s association

Parkinson´s Fondation

National Institute on Aging

Hjärnfonden

Alzheimerfonden

ParkinsonFonden