neurodegenerative disease neurodegenerative disease a neurodegenerative disease is caused by the progressive loss of structure or function of neurons, in the process known as neurodegeneration. such neuronal damage may ultimately involve cell death. neurodegenerative diseases include amyotrophic lateral sclerosis, multiple sclerosis, parkinson's disease, alzheimer's disease, huntington's disease, multiple system atrophy, and prion diseases. neurodegeneration can be found in the brain at many different levels of neuronal circuitry, ranging from molecular to systemic. because there is no known way to reverse the progressive degeneration of neurons, these diseases are considered to be incurable; however research has shown that the two major contributing factors to neurodegeneration are oxidative stress and inflammation. biomedical research has revealed many similarities between these diseases at the subcellular level, including atypical protein assemblies (like proteinopathy) and induced cell death. these similarities suggest that therapeutic advances against one neurodegenerative disease might ameliorate other diseases as well. neurodegenerative diseasenormal brain on left contrasted with structural changes shown in brain on right of person with alzheimer's disease, the most common neurodegenerative diseasespecialtyneurology, psychiatry within neurodegenerative diseases, it is estimated that 55 million people worldwide had dementia in 2019, and that by 2050 this figure will increase to 139 million people. specific disorders alzheimer's disease comparison of brain tissue between healthy individual and alzheimer's disease patient, demonstrating extent of neuronal death main article: alzheimer's disease alzheimer's disease (ad) is a chronic neurodegenerative disease that results in the loss of neurons and synapses in the cerebral cortex and certain subcortical structures, resulting in gross atrophy of the temporal lobe, parietal lobe, and parts of the frontal cortex and cingulate gyrus. it is the most common neurodegenerative disease. even with billions of dollars being used to find a treatment for alzheimer's disease, no effective treatments have been found. however, clinical trials have developed certain compounds that could potentially change the future of alzheimer's disease treatments. within clinical trials stable and effective ad therapeutic strategies have a 99.5% failure rate. reasons for this failure rate include inappropriate drug doses, invalid target and participant selection, and inadequate knowledge of pathophysiology of ad. currently, diagnoses of alzheimer's is subpar, and better methods need to be utilized for various aspects of clinical diagnoses. alzheimer's has a 20% misdiagnosis rate. ad pathology is primarily characterized by the presence of amyloid plaques and neurofibrillary tangles. plaques are made up of small peptides, typically 39–43 amino acids in length, called amyloid beta (also written as a-beta or aβ). amyloid beta is a fragment from a larger protein called amyloid precursor protein (app), a transmembrane protein that penetrates through the neuron's membrane. app appears to play roles in normal neuron growth, survival and post-injury repair. app is cleaved into smaller fragments by enzymes such as gamma secretase and beta secretase. one of these fragments gives rise to fibrils of amyloid beta which can self-assemble into the dense extracellular amyloid plaques. parkinson's disease main article: parkinson's disease parkinson's disease (pd) is the second most common neurodegenerative disorder. it typically manifests as bradykinesia, rigidity, resting tremor and posture instability. the crude prevalence rate of pd has been reported to range from 15 per 100,000 to 12,500 per 100,000, and the incidence of pd from 15 per 100,000 to 328 per 100,000, with the disease being less common in asian countries. pd is primarily characterized by death of dopaminergic neurons in the substantia nigra, a region of the midbrain. the cause of this selective cell death is unknown. notably, alpha-synuclein-ubiquitin complexes and aggregates are observed to accumulate in lewy bodies within affected neurons. it is thought that defects in protein transport machinery and regulation, such as rab1, may play a role in this disease mechanism. impaired axonal transport of alpha-synuclein may also lead to its accumulation in lewy bodies. experiments have revealed reduced transport rates of both wild-type and two familial parkinson's disease-associated mutant alpha-synucleins through axons of cultured neurons. membrane damage by alpha-synuclein could be another parkinson's disease mechanism. the main known risk factor is age. mutations in genes such as α-synuclein (snca), leucine-rich repeat kinase 2 (lrrk2), glucocerebrosidase (gba), and tau protein (mapt) can also cause hereditary pd or increase pd risk. while pd is the second most common neurodegenerative disorder, problems with diagnoses still persist. problems with the sense of smell is a widespread symptom of parkinson's disease (pd), however, some neurologists question its efficacy. this assessment method is a source of controversy among medical professionals. the gut microbiome might play a role in the diagnosis of pd, and research suggests various ways that could revolutionize the future of pd treatment. huntington's disease main article: huntington's disease huntington's disease (hd) is a rare autosomal dominant neurodegenerative disorder caused by mutations in the huntingtin gene (htt). hd is characterized by loss of medium spiny neurons and astrogliosis. the first brain region to be substantially affected is the striatum, followed by degeneration of the frontal and temporal cortices. the striatum's subthalamic nuclei send control signals to the globus pallidus, which initiates and modulates motion. the weaker signals from subthalamic nuclei thus cause reduced initiation and modulation of movement, resulting in the characteristic movements of the disorder, notably chorea. huntington's disease presents itself later in life even though the proteins that cause the disease works towards manifestation from their early stages in the humans affected by the proteins. along with being a neurodegenerative disorder, hd has links to problems with neurodevelopment. hd is caused by polyglutamine tract expansion in the huntingtin gene, resulting in the mutant huntingtin. aggregates of mutant huntingtin form as inclusion bodies in neurons, and may be directly toxic. additionally, they may damage molecular motors and microtubules to interfere with normal axonal transport, leading to impaired transport of important cargoes such as bdnf. huntington's disease currently has no effective treatments that would modify the disease. multiple sclerosis main article: multiple sclerosis multiple sclerosis (ms) is a chronic debilitating demyelinating disease of the central nervous system, caused by an autoimmune attack resulting in the progressive loss of myelin sheath on neuronal axons. the resultant decrease in the speed of signal transduction leads to a loss of functionality that includes both cognitive and motor impairment depending on the location of the lesion. the progression of ms occurs due to episodes of increasing inflammation, which is proposed to be due to the release of antigens such as myelin oligodendrocyte glycoprotein, myelin basic protein, and proteolipid protein, causing an autoimmune response. this sets off a cascade of signaling molecules that result in t cells, b cells, and macrophages to cross the blood-brain barrier and attack myelin on neuronal axons leading to inflammation. further release of antigens drives subsequent degeneration causing increased inflammation. multiple sclerosis presents itself as a spectrum based on the degree of inflammation, a majority of patients experience early relapsing and remitting episodes of neuronal deterioration following a period of recovery. some of these individuals may transition to a more linear progression of the disease, while about 15% of others begin with a progressive course on the onset of multiple sclerosis. the inflammatory response contributes to the loss of the grey matter, and as a result current literature devotes itself to combatting the auto-inflammatory aspect of the disease. while there are several proposed causal links between ebv and the hla-drb1*15:01 allele to the onset of ms – they may contribute to the degree of autoimmune attack and the resultant inflammation – they do not determine the onset of ms. amyotrophic lateral sclerosis main article: amyotrophic lateral sclerosis amyotrophic lateral sclerosis (als) or lou gehrig's disease is a disease in which motor neurons are selectively targeted for degeneration. amyotrophic lateral sclerosis (als) is a neurodegenerative disorder that negatively impacts the upper motor neurons (umns) and lower motor neurons (lmns). in 1993, missense mutations in the gene encoding the antioxidant enzyme cu/zn superoxide dismutase 1 (sod1) were discovered in a subsets of patients with familial als. this discovery led researchers to focus on unlocking the mechanisms for sod1-mediated diseases. however, the pathogenic mechanism underlying sod1 mutant toxicity has yet to be resolved. more recently, tdp-43 and fus protein aggregates have been implicated in some cases of the disease, and a mutation in chromosome 9 (c9orf72) is thought to be the most common known cause of sporadic als. it is diagnosed by skeletal muscle weakness that progresses gradually. early diagnosis of als is harder than with other neurodegenerative diseases as there are no highly effective means of determining its early onset. currently, there is research being done regarding the diagnosis of als through upper motor neuron tests. the penn upper motor neuron score (pumns) consists of 28 criteria with a score range of 0-32. a higher score indicates a higher level of burden present on the upper motor neurons. the pumns has proven quite effective in determining the burden that exists on upper motor neurons in affected patients. independent research provided in vitro evidence that the primary cellular sites where sod1 mutations act are located on astrocytes. astrocytes then cause the toxic effects on the motor neurons. the specific mechanism of toxicity still needs to be investigated, but the findings are significant because they implicate cells other than neuron cells in neurodegeneration. batten disease main article: batten disease batten disease is a rare and fatal recessive neurodegenerative disorder that begins in childhood. batten disease is the common name for a group of lysosomal storage disorders known as neuronal ceroid lipofuscinoses (ncls) – each caused by a specific gene mutation, of which there are thirteen. since batten disease is quite rare, its worldwide prevalence is about 1 in every 100,000 live births. in north america, cln3 disease (juvenile ncl) typically manifests between the ages of 4 to 7. batten disease is characterized by motor impairment, epilepsy, dementia, vision loss, and shortened lifespan. a loss of vision is common first sign of batten disease. loss of vision is typically preceded by cognitive and behavioral changes, seizures, and loss of the ability to walk. it is common for people to establish cardiac arrhythmias and difficulties eating food as the disease progresses. batten disease diagnosis depends on a conflation of many criteria: clinical signs and symptoms, evaluations of the eye, electroencephalograms (eeg), and brain magnetic resonance imaging (mri) results. the diagnosis provided by these results are corroborated by genetic and biochemical testing. no effective treatments were available to prevent the disease from being widespread before the past few years. in recent years, more models have been created to expedite the research process for methods to treat batten disease. creutzfeldt–jakob disease main article: creutzfeldt-jakob disease creutzfeldt–jakob disease (cjd) is a prion disease that is characterized by rapidly progressive dementia. misfolded proteins called prions aggregate in brain tissue leading to nerve cell death. variant creutzfeldt–jakob disease (vcjd) is the infectious form that comes from the meat of a cow that was infected with bovine spongiform encephalopathy, also called mad cow disease. risk factor further information: aging brain the greatest risk factor for neurodegenerative diseases is aging. mitochondrial dna mutations as well as oxidative stress both contribute to aging. many of these diseases are late-onset, meaning there is some factor that changes as a person ages for each disease. one constant factor is that in each disease, neurons gradually lose function as the disease progresses with age. it has been proposed that dna damage accumulation provides the underlying causative link between aging and neurodegenerative disease. about 20–40% of healthy people between 60 and 78 years old experience discernable decrements in cognitive performance in several domains including working, spatial, and episodic memory, and processing speed. risks from viral exposures according to one biobank study a study using electronic health records indicates that 45 (with 22 of these being replicated with the uk biobank) viral exposures can significantly elevate risks of neurodegenerative disease, including up to 15 years after infection. mechanisms genetics