Introduction Neurodegeneration is an umbrella term for the progressive loss of structure or function of neurons. Such as : (i) Alzheimers disease (ii) Parkinsons disaese (iii) Huntingtons disease There are many parallels between different neurodegenerative disorders including atypical protein assemblies as well as induced cell death. Neurodegeneration can be found in many different levels of neuronal circuitry ranging from molecular to systemic.

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60-80% 10-20% 15-25% 10% 5%

Stages of Alzheimers Disease

Pre-dementia Early Moderate Advanced

The disease course is divided into four stages, with progressive patterns of cognitive and functional impairments.

Pre-dementia Stage The first symptoms are often mistakenly attributed to ageing or stress These early symptoms can affect the most complex daily living activities. The most noticeable deficit is memory loss, which shows up as difficulty in remembering recently learned facts and inability to acquire new information. Subtle problems with the executive functions of attentiveness, planning, flexibility, and abstract thinking, or impairments in semantic memory (memory of meanings, and concept relationships) can also be symptomatic of the early stages of AD. Apathy can be observed at this stage, and remains the most persistent neuropsychiatric symptom throughout the course of the disease The preclinical stage of the disease has also been termed mild cognitive impairment

Early Stage AD In people with AD the increasing impairment of learning and memory eventually leads to a definitive diagnosis. In a small portion of them, difficulties with language, executive functions, perception (agnosia), or execution of movements (apraxia) are more prominent than memory problems. AD does not affect all memory capacities equally. Older memories of the person's life (episodic memory), facts learned (semantic memory), and implicit memory (the memory of the body on how to do things, such as using a fork to eat) are affected to a lesser degree than new facts or memories. Language problems are mainly characterised by a shrinking vocabulary and decreased word fluency, which lead to a general impoverishment of oral and written language. In this stage, the person with Alzheimer's is usually capable of communicating basic ideas adequately. While performing fine motor tasks such as writing, drawing or dressing, certain movement coordination and planning difficulties (apraxia) may be present but they are commonly unnoticed

Moderate Stage AD Progressive deterioration eventually hinders independence, with subjects being unable to perform most common activities of daily living. Speech difficulties become evident due to an inability to recall vocabulary, which leads to frequent incorrect word substitutions (paraphasias). Reading and writing skills are also progressively lost. Complex motor sequences become less coordinated as time passes and AD progresses, so the risk of falling increases. Memory problems worsen, and the person may fail to recognise close relatives. Long-term memory, which was previously intact, becomes impaired. Behavioural and neuropsychiatric changes: wandering, irritability and labile affect, leading to crying, outbursts of unpremeditated aggression. Approximately 30% of people with AD develop illusionary misidentifications and other delusional symptoms Subjects also lose insight of their disease process and limitations (anosognosia). Urinary incontinence can develop. These symptoms create stress for relatives and caretakers, which can be reduced by moving the person from home care to other long-term care facilities.

Advanced Stage AD During the final stage of AD, the person is completely dependent upon caregivers. Language is reduced to simple phrases or even single words, eventually leading to complete loss of speech. Despite the loss of verbal language abilities, people can often understand and return emotional signals. Although aggressiveness can still be present, extreme apathy and exhaustion are much more common results. Muscle mass and mobility deteriorate to the point where they are bedridden lose the ability to feed themselves. AD is a terminal illness, with the cause of death typically being an external factor, such as infection of pressure ulcers or pneumonia, not the disease itself.

Causes of Alzheimers disease The cause for most Alzheimer's cases is still essentially unknown (except cases where genetic differences have been identified). Several competing hypotheses exist trying to explain the cause of the disease: 1. Cholinergic hypothesis 2. Amyloid hypothesis 3. Tau hypothesis 4. Other hypotheses

Histopathologic image of senile plaques seen in the cerebral cortex of a person with Alzheimer's disease of presenile onset.

Enzymes act on the APP (amyloid precursor protein) and cut it into fragments. The beta-amyloid fragment is crucial in the formation of senile plaques in AD.

Senile plaques

Tau hypothesis In this model, hyperphosphorylated tau begins to pair with other threads of tau. Eventually, they form neurofibrillary tangles inside nerve cell bodies. When this occurs, the microtubules disintegrate, collapsing the neuron's transport system. This may result first in malfunctions in biochemical communication between neurons and later in the death of the cells. In Alzheimer's disease, changes in tau protein lead to the disintegration of microtubules in brain cells.

Other hypotheses Herpes simplex virus type 1 has also been proposed to play a causative role in people carrying the susceptible versions of the apoE gene. age-related myelin breakdown in the brain. Iron released during myelin breakdown is hypothesised to cause further damage. Homeostatic myelin repair processes contribute to the development of proteinaceous deposits such as beta-amyloid and tau. Oxidative stress and dys-homeostasis of biometal (biology) metabolism may be significant in the formation of the pathology. AD individuals show 70% loss of locus coeruleus cells that provide norepinephrine. This suggests that degeneration of the locus ceruleus might be responsible for increased -Amyloid deposition in AD brains.

Diagnosis Alzheimer's disease is usually diagnosed clinically from the patient history, collateral history from relatives, and clinical observations,. Advanced medical imaging with computed tomography (CT) or magnetic resonance imaging (MRI), and with single photon emission computed tomography (SPECT) or positron emission tomography (PET) can be used to help exclude other cerebral pathology or subtypes of dementia. Moreover, it may predict conversion from prodromal stages (mild cognitive impairment) to Alzheimer's disease. Assessment of intellectual functioning including memory testing can further characterise the state of the disease. Medical organisations have created diagnostic criteria to ease and standardize the diagnostic process for practicing physicians.

Clinical Management Five medications are currently used to treat the cognitive manifestations of AD: four are acetylcholinesterase inhibitors (tacrine, rivastigmine, galantamine and donepezil) and the other (memantine) is an NMDA receptor antagonist No drug can actually halt the progression of the disease. Memantine (brand name- Akatinol) a noncompetitive NMDA receptor antagonist first used as an anti-influenza agent. It acts on the glutamatergic system by blocking NMDA receptors and inhibiting their overstimulation by glutamate.

60-80%, >65 years 10-20%, >65 years

15-25%, >65 years 10%, > 53-56 years

Age Gender

Genetic Intellectual disability & Down Syndrome

Non-Modifiable Risk Factors

> 65 years old Female 1.7-2 times higher than male

Mutation in the presenilin genes and amyloid gene (10-15%) Down syndrome: dementia 30-40 years old

Cardiovascular

Life Styles

Modifiable Risk Factors

Vit B12:beef liver, fish, soymilk, cereal, cheese egg Vit B6: Nuts, fish, beef, banana, avocado, spinach.

Risk factors: Middle aged and increased risk with age Hereditary Men (1.5 times more) Environmental exposure to toxins

Parkinsons Disease

Symptoms 4 major symptoms: Rigidity muscles are tensed and contracted Resting tremor trembling which is most obvious when the patient is at rest or when stressed Bradykinesia slowness in initiating movement Loss of postural reflexes or instability poor balance and coordination Non-motor symptoms Anxiety disorders, depression, sleep disturbances, orthostatic hypotension, olfaction dysfunction, dysphagia, sialorrhoea, dementia, psychosis and visual hallucinations

Causes and Pathogenesis of Parkinsons Disease Degeneration of dopaminergic neuron - 50-80% death neuron in the substantia nigra lead to symptoms. Free radicals - Reduced glutathione leads to loss of neuroprotection against free radicals. Neurotoxin - 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), by inhibiting Mitochondrial Complex I leads to cell death via energy deficit Genetic factors - mutation of alpha-synuclein genes, aggregate of Lewy Body

Lewy bodies are aggregates of alpha-synuclein protein together with other proteins, such as ubiquitin, neurofilament protein, and alpha B crystallin. These are observed in the neurons of Parkinsons disease patients

Drugs Used to Treat Parkinsons Disease Dopaminergic Drugs

Generic Name Brand Name Route Pharmacokinetics regarding Parkinsons Disease Amantadine HCl Symmetrel PO Dopamine agonist- increases the amt. of dopamine in brain Bromocriptine mesylate Parlodel PO Dopamine receptor stimulant- encourages the release of dopamine Carbidopa-levodopa Sinemet PO Enters the brain, then converted to dopamine Pergolide myselate Permax PO Produces the same effects as dopamine Pramipexole Mirapex PO Stimulates dopamine receptors Ropinirole HCl Requip PO Inhibits nerve responses Selegiline HCl Carbex, Eldepryl PO Increases dopaminergic activity Tolcapone Tasmar PO Selective inhibitor- slows the metabolism of levodopa, prolonging its effects

Huntingtons disease (HD) 1872: George Huntington In 1983 scientists discovered the Huntington's gene was associated with chromosome 4 . After 10 more years of research, scientists have pinpointed the exact location of Huntington gene to be at 4p16.3 gene site on chromosome 4. The gene was known as IT15 (HTT).

HD is an autosomal dominant genetic disease - 50% chance of transmission from one parent with the disease

Motor Cognitive

psychosocial

Chorea, muscle rigidity, unbalanced gait, tremor, dysphasia and choking

Difficulty processing information and concentration, loss of memory, poor judgment, aphasia

Aggressive antisocial behavior, outburst of yelling and aggression toward others, depression

Symptoms - appear between age 30-50

Pathology of HD Degeneration of neocortical and striatal neurons Leading to imbalance in cortico-basal ganglia-thalamocortical pathways

Clinical management Choreic movements may be partially suppressed by neuroleptics (Tetrabenazine, Respirdal, Seroquel, Zyprexa, Haldol) or benzodiapines (Valium, Ativan, Klonopin). Anti-parkinsonian agents may ameliorate rigidity, however, L-dopa compounds (Sinemet) can increase chorea. Psychiatric disturbances such as depression, aggression, OCD, psychotic symptoms respond well to psychotropic drugs (SSRIs Prozac, Paxil, Celexa) or anti-epileptic medications (Valproic acid).

Globus Pallidus internus (GPi) Improvement of motor function (chorea) No effect on cognitive functions