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Neurodegenerative disease-overview


Neurodegenerative diseases – an overview

Yunwu Zhang

What is Neurodegeneration?
Neurodegeneration “neuro” – nerve cells (neurons) “degeneration” -- a process of losing structure or function. Etymologically, neurodegeneration corresponds to any pathological condition primarily affecting neurons. Practically, neurodegeneration refers to progressive loss of structure or function of neurons, including death of neurons.

What is neurodegenerative disease?
Neurodegenerative disease is a condition in which neuronal cells of the brain and spinal cord are gradually and progressively lost, leading to nervous system dysfunction. There are hundreds of neurodegenerative diseases, which represent a large group of neurological disorders with heterogeneous clinical and pathological expressions affecting specific subsets of neurons in specific functional anatomic systems.

Diseases related to CNS but not neurodegenerateive disease
Some diseases such a neoplasm, edema, hemorrhage, and trauma of the nervous system, which are not primary neuronal diseases, are not considered to be neurodegenerative disorders. Diseases of the nervous system that implicate not neurons per se but rather their attributes, such as the myelin sheath as seen in multiple sclerosis, are not neurodegenerative disorders either, nor are pathologies in which neurons die as the result of a known cause such as hypoxia, poison, metabolic defects, or infections. (controversial)

Neurodegenerative diseases
Current situation The populations of most countries, especially industrialized countries, are aging, and an ever-increasing number of people are afflicted with neurodegenerative diseases. According to the National Institute of Neurological Disorders and Stroke, there are more than 600 neurologic disorders (including neurodegenerative diseases) with approximately 50 million people affected each year.

Neurodegenerative diseases
Social and financial effects These diseases cost the economy billions of dollars each year in direct health care costs and lost opportunities; it is estimated that $100 billion per year is spent on Alzheimer disease (AD) alone in US. In addition to the financial costs, there is an immense emotional burden on patients and their caregivers. As the number of elderly citizens increases, these costs to society also will increase.

Neurodegenerative diseases
Current treatments To date, several approved drugs do, to some extent, alleviate symptoms of several neurodegenerative diseases, but their chronic use is often associated with debilitating side effects and none seems to stop the progression of the degenerative process. In keeping with this, the development of effective preventive or protective therapies has been impeded by the limitations of our knowledge of the causes and the mechanisms by which neurons die in neurodegenerative diseases.

Ronald Reagan (Alzheimer’s disease)

John Nash (Schizophrenia)

Muhammad Ali (Parkinson’s disease)

bovine spongiform encephalopathy (mad cow disease)

Neurodegenerative disease
Classification Accurate classification is almost impossible, why? 1. Among the hundreds of neurodegenerative diseases, many appear to overlap with one another clinically and pathologically; 2. In diseases such as multisystem atrophy in which several areas of the brain are affected, different combinations of lesions can give rise to different clinical pictures; 3. The same neurodegenerative process, especially at the beginning, can affect different areas of the brain, making a given disease appear very different from a symptomatic standpoint. Hence, the most popular categorization of neurodegenerative disorders is still based on the predominant clinical feature or the topography of the predominant lesion, or often on a combination of both.

Neurodegenerative disease Classification Neurodegenerative diseases can be crudely divided into two groups according to phenotypic effects, although these are not mutually exclusive: 1. Conditions causing problems with movements, such as ataxia; 2. Conditions affecting memory and conditions related to dementia.

Ataxia
Ataxia is a neurological sign and symptom consisting of gross incoordination of muscle movements. Ataxia is an aspecific clinical manifestation implying dysfunction of parts of the nervous system that coordinate movement, such as the cerebellum. Several possible causes exist for these patterns of neurological dysfunction.

http://www.dinf.ne.jp/doc/english/global/david/dwe002/dwe002g/dwe00211g18.gif

Types of ataxia
1. Cerebellar ataxia Cerebellar ataxia indicates ataxia due to dysfunction of the cerebellum. This causes a variety of elementary neurological deficits. How and where these abnormalities manifest depend on which cerebellar structures are lesioned, and whether the lesion is bilateral or unilateral.
Behavior Problem solving Intellect Judgment Coordination of movement Sense of and appreciation from touch Language

Vision Reading

Auditory and visual memories Music Fear

Proprioception Balance Posture Cardiac, respiratory and vasomotor center Motor and sensory pathway to body and face Vital center, cardiac, respiratory, vasomotor

Types of ataxia
2. Sensory ataxia Sensory ataxia indicates ataxia due to loss of proprioception (sensitivity to joint and body part position), which generally depends on dysfunction of the dorsal columns of the spinal cord, since they carry proprioceptive information up to the brain; in some cases, the cause may instead be dysfunction of the various brain parts that receive that information, including the cerebellum, thalamus, and parietal lobes. Six exteroceptive senses (sight, taste, smell, touch, hearing, and balance) by which we perceive the outside world; Interoceptive senses, by which we perceive the pain and the stretching of internal organs; Proprioception is a third distinct sensory modality that provides feedback solely on the status of the body internally. It is the sense that indicates whether the body is moving with required effort, as well as where the various parts of the body are located in relation to each other.

Types of ataxia
3. Vestibular ataxia Vestibular ataxia indicates ataxia due to dysfunction of the vestibular system, which in acute and unilateral cases is associated with prominent vertigo, nausea and vomiting. In slow-onset, chronic bilateral cases of vestibular dysfunction, these characteristic manifestations may be absent, and dysequilibrium may be the sole presentation.

Semicircular canal system: rotational movement; Otoliths in saccule and utricle: lineal translation.

Causes of ataxia
1. Focal lesions Any type of focal lesion of the central nervous system (such as stroke, brain tumor, multiple sclerosis will cause the type of ataxia corresponding to the site of the lesion: cerebellar if in the cerebellum, sensory if in the dorsal spinal cord (and rarely in the thalamus or parietal lobe), vestibular if in the vestibular system (including the vestibular areas of the cerebral cortex).

Start from here

Causes of ataxia
2. Exogenous substances Exogenous substances that cause ataxia mainly do so because they have a depressant effect on central nervous system function. The most common example is ethanol, which is capable of causing overlapping cerebellar and vestibular ataxia. Other examples include both prescription drugs (e.g. most antiepileptic drugs have cerebellar ataxia as a possible unwanted effect) and recreational drugs (e.g. ethanol, caffeine, cannabis, tobacco).

Causes of ataxia
3. Vitamin B12 deficiency Vitamin B-12 is one of eight B vitamins which is important for the normal functioning of the brain and nervous system, and for the formation of blood. It is normally involved in the metabolism of every cell of the body, especially affecting DNA synthesis and regulation, but also fatty acid synthesis and energy production. Biosynthesis of the basic structure of the vitamin B12 can only be accomplished by bacteria, humans have to uptake it from the environment. B12 deficiency may cause pernicious anemia. Neurological signs of B12 deficiency, which can occur without anemia, include sensory disturbances due to damage to peripheral nerves caused by demyelination and irreversible nerve cell death. Symptoms include numbness, tingling of the extremities, disturbed coordination and, if not treated in time, an ataxic gait, a syndrome known as subacute combined degeneration of spinal cord.

Dementia
Introduction Dementia is the progressive decline in cognitive function due to damage or disease in the brain beyond what might be expected from normal aging. Particularly affected areas may be memory, attention, language, and problem solving. Especially in the later stages of the condition, affected persons may be disoriented in time (not knowing what day of the week, day of the month, month, or even what year it is), in place (not knowing where they are), and in person (not knowing who they are). Like ataxia, dementia is a non-specific term encompassing many disease processes. Nor is dementia exclusively observed in neurodegenerative disorders: dementia is also frequently observed in ischemic, metabolic, toxic, infectious, and traumatic insults of the brain.

Dementia
Epidemiology The prevalence of dementia is rising as the global life expectancy is rising. Particularly in Western countries, there is increasing concern about the economic impact that dementia will have in future, older populaces. Though reports of some of the longest living people claim them to be free of it, it is a disease which is strongly associated with age; 1% of those aged 60-65, 6% of those aged 75-79, and 45% of those aged 95 or older suffer from the disease.

Dementia
Diagnosis The final diagnosis of dementia is made on the basis of the clinical picture, increasingly with neuroimaging results for backup. For research purposes, the diagnosis depends on both a clinical diagnosis and a pathological diagnosis (i.e., based on the examination of brain tissue, usually from autopsy).

Diagnosis of Dementia I. Cognitive test Proper differential diagnosis between the types of dementia will require, at the least, referral to a specialist. Some brief (5-15 minutes) tests have good reliability and can be used in the office or other setting to evaluate cognitive status. Mini-mental state examination (MMSE) A brief 30-point questionnaire test. In the time span of about 10 minutes, it samples various functions, including arithmetic, memory and orientation. MMSE is widely used with small modifications. An MMSE score under 24 (out of a possible score of 30) suggests a need for further evaluation. Scores must be interpreted in the context of the person's educational and other background, and the particular circumstances (for example, a person in great pain will not be expected to do well on many tests of mental ability). Abbreviated mental test score (AMTS) AMTS is to assess elderly patients for the possibility of dementia. An AMTS score of less than six (out of a possible score of ten). Modified Mini-Mental State examination (3MS) 3MS is a modification of MMSE. The modification is designed to sample a broader variety of cognitive functions, cover a wider range of difficulty levels, and enhance the reliability and the validity of the scores. 3MS may have higher sensitivity than MMSE. Other examinations The Cognitive Abilities Screening Instrument (CASI), the clock drawing test (CDT), etc.

Diagnosis of Dementia
An AMTS questionnaire sample:

Diagnosis of Dementia
Diagnosis (continued) II. Laboratory tests Routine blood tests are also usually performed to rule out treatable causes. III. Imaging Computed tomography (CT), magnetic resonance imaging (MRI), Single Photon Emission Computed Tomography (SPECT), and positron emission tomography (PET) can be used for brain scan to elucidate severe brain damages caused by neurodegenerative diseases.

A PET brain scans comparing a normal brain (left) with the brain of a person with Alzheimer's disease. http://www.minddisorders.com/A-Br/Alzheimer-sdisease.html

http://neurogenesis.iord.org/disorders.html

Neurodegenerative disease
Classification (continued) Neurodegenerative diseases can also be categorized based on affected regions and then further classified based on its main clinical features: 1. Cerebral cortex Dementing (e.g. AD) and nondementing conditions. 2. Basal ganglia Diseases that predominantly involve the basal ganglia are essentially characterized by abnormal movements. Based on the phenomenology of the abnormal movements, diseases of the basal ganglia can be classified as hypokinetic (e.g. PD) or hyperkinetic (e.g. HD). 3. Brain stem and Cerebellum There are three main neuropathological types: cerebellar cortical atrophy (lesion confined to the Purkinje cells and the inferior olives), pontocerebellar atrophy (lesion affecting several cerebellar and brain structures), and Friedreich ataxia (lesion affecting the posterior column of the spinal cord, peripheral nerves, and the heart).

Neurodegenerative disease
Classification (continued) 4. Spinal cord Among the neurodegenerative diseases that predominantly affect the spinal cord are ALS and spinal muscular atrophy, in which the most severe lesions are found in the anterior part of the spinal cord, and Friedreich ataxia, in which the most severe lesions are found in the posterior part of the spinal cord. 5. Unknown regions There is one group of neurological diseases that are often, but not always, considered neurodegenerative because of their chronic course and unknown etiopathogenesis but that, unlike those described above, show no apparent structural abnormalities (e.g. schizophrenia). Various brain-imaging studies and electrophysiological investigations have revealed significant functional abnormalities in all of these singular neurodegenerative disorders but have not yet enabled us to unravel their chemical neuroanatomical substrates.

Neurodegenerative disease
Classification (continued) Facilitated by advances in understanding the molecular mechanisms underlying neurodegenerative diseases, there is a trend for classification based on molecular characteristics rather than diseases’ neuropathological hallmarks. Such a classification may be less ambiguous and more clinically and therapeutically practical. Examples: Trinucleotide-repeat diseases: HD (htt), myotonic dystrophy (CNBP and DMPK), etc. Prion diseases: Creutzfeldt-Jakob disease, Gerstmann-StrausslerScheinker syndrome, fetal familial insomnia, etc. Synucleinopathies: PD, progressive supranuclear palsy, diffuse Lewy body dementia, etc. Tauopathies: corticobasal degeneration, frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), Pick disease, etc.

List of Neurodegenerative diseases (partial)
Among the hundreds of neurodegenerative disorders, only a few have been emphasized and extensively studied.

From Ross & Poirier, Nat Med 2004, 10: S10.

Neurodegenerative diseases
Common pathological hallmarks – protein aggregates: In many neurodegenerative disorders, various types of protein aggregates are present in CNS, sparking the idea that these amorphous deposits may play a pathogenic role in the demise of specific subsets of neurons in various brain diseases. However, several lines of evidence suggest that these protein aggregates represent an end stage of a molecular cascade of several steps, and that earlier steps in the cascade may be more directly tied to pathogenesis than these protein aggregates.

Protein aggregates in neurodegenerative diseases

Ross & Poirier, Nat Med 2004, 10: S10.

Neurodegeneration
Cause With few exceptions, the causes of neurodegenerative diseases are essentially unknown, and even when they have been identified, the mechanisms by which they initiate the disease remain, at best, speculative. Deterioration of neurons over time will lead to neurodegeneration and disabilities. Many times neuronal death begins long before the patient will ever experience any symptoms. It can be months or years before any effect is felt. Symptoms are noticed when lots of cells have died and certain parts of the brain have been weakened to the point that they can no longer function properly. The most consistent risk factor for developing a neurodegenerative disorder, especially AD or PD, is increasing age.

Neurodegeneration
Both Genetics and environment play roles in neurodegeneration. Genetics— autosomal dominant trait, e.g. HD (huntingtin gene); autosomal recessive trait, e.g. some familial spastic paraparesis (SPG20, SPG11, etc.); X-linked trait, e.g. spinal and bulbar muscular atrophy (mutation in the androgen receptor gene in X-chromosome); maternally inherited trait, e.g., mitochondrial Leber optic neuropathy (mutations in the mitochondrial genes ND4, ND1 and ND6 subunit genes of complex I).

Neurodegeneration
Genetics and/or environment— PD, AD, and even ALS, of which about 10% of all cases are unequivocally familial. Although rare, these familial cases represent powerful resources to elucidate the molecular bases and, more importantly, the neurodegeneration mechanisms of their respective sporadic variants.

Neurodegeneration
Environment— Any genetic contribution to the neurodegenerative process is minimal. Instead, toxic environmental factors may be the prime suspects in initiating neurodegenerative processes. Supporting this view is the observation that some neurodegenerative conditions arise in geographic or temporal clusters. e.g. The PD-ALS complex once prevalent (in 1950s) in the Chamorros of Guam is presumably due to a toxic compound contained in Cycas circinalis, an indigenous plant commonly ingested as a food or medicine.

Neurodegeneration-cell death
Types of cell death Necrosis Necrosis is the pathological process occurring in cells that are dying from irreparable injuries. It is caused by the progressive, uncontrolled action of degradative enzymes, leading to mitochondrial swelling, nuclear flocculation, and cell lysis.

http://www.medic.usm.my/~pathology/coag.gif

Neurodegeneration-cell death
Types of cell death Apoptosis Apoptosis is the mechanism responsible for the physiological deletion of cells and appears to be intrinsically programmed. It is characterized by distinctive morphologic changes in the nucleus and cytoplasm, caspase cascade activation, chromatin cleavage at regularly spaced sites, and the endonucleolytic cleavage of genomic DNA; (DNA fragmentation); at internucleosomal sites. This mode of cell death serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth.

http://www.bch.msu.edu/faculty/fraker/neutrophil-lg.jpg

Neurodegeneration-cell death
Types of cell death Autophagy (autophagocytosis) Autophagy is a catabolic process involving the degradation of a cell's own components through the lysosomal machinery. It is a tightly regulated process which plays a normal part in cell growth, development, and homeostasis, where it helps maintain a balance between the synthesis, degradation, and subsequent recycling of cellular products. It is a major mechanism by which a starving cell reallocates nutrients from unnecessary processes to more essential processes. it plays an important role in biological metamorphosis of amphibians, in the removal of bone by osteoclasts, and in the degradation of normal cell components in nutritional deficiency states.

http://hopes.stanford.edu/treatmts /pbuildup/f_h03autophagy.jpg

Neurodegeneration-cell death
Neuronal Cell death Because different cell death types are controlled by distinct molecular mechanisms, elucidating the type of cell death for each neurodegenerative disease will be helpful for understanding their pathogenesis. In most neurodegenerative diseases, overt neuropathology, mainly in the form of a focal loss of neurons with reactive gliosis, is seen. Residual neurons may exhibit varying morphologies ranging from an almost normal appearance to a severe distortion with a combination of abnormal features such as process attrition, shape and size alterations of the cell body and nucleus, organelle fragmentation, dispersion of Nissl bodies, cytoplasmic vacuolization, and chromatin condensation. These observations suggest that neuronal cell death are caused by distinct mechanisms in different neurodegenerative diseases.

Fatality in Neurodegenerative diseases
Neurodegeneration is thought to shorten the life expectancy of affected patients. However, In most other neurodegenerative disorders, death is attributed neither to the disease of the nervous system nor to associated extra–nervous system degeneration but rather to the resulting motor and cognitive impairments that increase the risk of fatal accidental falling, aspiration pneumonia, pressure skin ulcers, malnutrition, and dehydration. e.g. Friedreich ataxia, the association of neurodegeneration with heart disease can cause the death of the patient, although, in this case, death is due not to any neuronal loss but instead to serious cardiac problems such as congestive heart failure. Only a few neurodegenerative diseases in which the affected neurological structures impair ability to control or execute such vital functions as respiration, heart rate, or blood pressure are unquestionably deadly. e.g. ALS, in which the loss of lower motor neurons innervating respiratory muscles leads the patient to succumb to respiratory failure.

Neurodegeneration and Aging
Is Aging=neurodegeneration? Pros: Many elderly individuals exhibit mild motor and cognitive alterations reminiscent of those found in neurodegeneration, implying that aging might be a “benign” form of neurodegeneration. This idea was supported by the notion that normal aging, like neurodegeneration, is inevitably associated with neuronal death. Cons: Age-related decline in neuron number via neuronal death is not significantly involved in normal aging, at least with respect to the neocortex and to the hippocampal subregions most implicated in memory, such as entorhinal cortex and CA1.

Neurodegeneration and Aging
Is Aging=neurodegeneration? (continued) Pros: Some pathological features of neurodegeneration, such as the presence of Lewy bodies, so typical of PD, and neurofibrillary tangles (NFTs) and senile plaques, so typical of AD, can be detected in brains of asymptomatic aged individuals, implying that these changes occur “normally” during aging may reflect a “presymptomatic” stage of these diseases. Cons: Because it is impossible to perform longitudinal neuropathological studies, it is impossible to determine whether these individuals would have developed full disease expression if they had lived longer. In fact, hitherto, there been no definitive evidence supporting such a progression. Instead, neuropathological and functional brain-imaging studies have revealed striking quantitative and qualitative differences between aged nondemented and demented individuals, suggesting that aging and neurodegeneration may represent very distinct entities.


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