pathology part2

<body topmargin=0 leftmargin=0 marginheight=0 marginwidth=0> <table cellpadding=0 cellspacing=0 border=0><tr> <td valign="top" colspan=2 height=22 BGCOLOR="#FFFFFF" TEXT="#080000" bgproperties="fixed" background="041000d2egerdp.gif"> <div> </div> </td> </tr><tr> <td valign="top" width=145 BGCOLOR="#333399" TEXT="#080000" background="040a2c00erkjzj.gif"> <bR> </td> <td valign="top" height=458 BGCOLOR="#FFFFFF" TEXT="#080000"> <div> <FONT SIZE="5" COLOR="#336600" FACE="Times New Roman" ><I>NEUROPATHOLOGY</I></FONT><FONT SIZE="1" COLOR="#663399" FACE="Times New Roman" >    </FONT> |    <B> </B><FONT SIZE="2" COLOR="#0000BF" FACE="Times New Roman" ><A HREF="index.htm" TARGET="_top" TITLE="NEUROPATHOLOGY"><U><B>home</B></U></A></FONT></div> <div> <A HREF="id18.htm" TARGET="_top" TITLE="HISTOLOGY REVIEW"><U>HISTOLOGY REVIEW</U></A>   |   <A HREF="id19.htm" TARGET="_top" TITLE="PHYSIOLOGY REVIEW"><U>PHYSIOLOGY REVIEW</U></A>   |   <A HREF="id20.htm" TARGET="_top" TITLE="PATHOLOGY 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DISEASES</B><FONT SIZE="3" COLOR="#000000" FACE="Arial" ><B> </B></FONT></div> <div> <U>DEMENTIA</U><FONT SIZE="2" COLOR="#000000" FACE="Arial" > </FONT></div> <div> <B><U>ALZHEIMER DISEASE</U></B><FONT SIZE="3" COLOR="#000000" FACE="Arial" ><B> </B></FONT></div> <div> <B><U>FRONTOTEMPORAL DEMENTIAS</U></B><FONT SIZE="3" COLOR="#0000FF" FACE="Arial" ><B><U> -</U></B></FONT><B><U>PICK DISEASE</U></B></div> <div> <B><U>TAUOPATHIES</U></B></div> <div> <B><U>HUNTINGTON DISEASE</U></B><FONT SIZE="3" COLOR="#000000" FACE="Arial" ><B> </B></FONT></div> <div> <B><U>PARKINSON DISEASE</U></B><FONT SIZE="3" COLOR="#000000" FACE="Arial" ><B> </B></FONT></div> <div> <B><U><IMG BORDER="0" SRC="Symb075c00b700f0ff000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">DIFFUSE LEWY BODY DISEASE</U></B><FONT SIZE="3" COLOR="#000000" FACE="Arial" ><B> </B></FONT></div> <div> <B><U><IMG BORDER="0" SRC="Symb075c00b700f0ff000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">MPTP PARKINSONISM</U></B></div> <div> <B><U><IMG BORDER="0" SRC="Symb075c00b700f0ff000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">MOTOR NEURON DISEASES</U></B><FONT SIZE="3" COLOR="#000000" FACE="Arial" ><B> </B></FONT></div> <div> <B><U><IMG BORDER="0" SRC="Symb075c00b700f0ff000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">AMYOTROPHIC LATERAL SCLEROSIS</U></B><FONT SIZE="3" COLOR="#000000" FACE="Arial" ><B> </B></FONT></div> <div> <B><U><IMG BORDER="0" SRC="Symb075c00b700f0ff000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">ALS-PARKINSON-DEMENTIA</U></B><FONT SIZE="3" COLOR="#000000" FACE="Arial" ><B> </B></FONT></div> <div> <B><U><IMG BORDER="0" SRC="Symb075c00b700f0ff000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">SPINAL MUSCULAR ATROPHY</U></B></div> <div> <B><U>ATAXIA AND CEREBELLAR DEGENERATIONS</U></B><FONT SIZE="3" COLOR="#000000" FACE="Arial" ><B> </B></FONT></div> <div> <B><U><IMG BORDER="0" SRC="Symb075c00b700f0ff000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">FRIEDREICH ATAXIA</U></B><FONT SIZE="3" COLOR="#000000" FACE="Arial" ><B> </B></FONT></div> <div> <B><U><IMG BORDER="0" SRC="Symb075c00b700f0ff000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">OLIVOPONTOCEREBELLAR ATROPHY</U></B></div> <div> <B><U>THE PATHOLOGY OF SEIZURES</U></B><FONT SIZE="3" COLOR="#000000" FACE="Arial" ><B> </B></FONT></div> <bR> <bR> <bR> <bR> <bR> <bR> <div> <B><U>degenerative diseases</U></B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700c800000000.gif" HEIGHT="13" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Almost all the degenerative diseases are unknown as etiology and causes , stipulation remain , but as brain and cns everyday are discovery , and treatment are discovered.</B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Degenerative diseases are characterized clinically by loss of neurological function (dementia, loss of movement control, paralysis), and pathologically by loss of neurons.</B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> In some of them, loss of neurons is accompanied by specific histopathological findings such as Alzheimer plaques and Lewy bodies.</B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> Others show a gradual neuronal atrophy and loss, without specific pathology.</B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> Some degenerative diseases involve specific anatomical systems or interconnected sets of neurons.</B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> The pathology is either diffuse or, when it is focal, is bilateral and symmetric. </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Degenerative diseases are inexorably progressive.</B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> Most of them are diseases of old age, but some involve young people, including children. </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">The term "degenerative" or "neurodegenerative," is vague. </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">It is now becoming clear that degenerative diseases are essentially biochemical disorders that kill neurons. </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Many degenerative diseases are inherited. </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Their genes are known and DNA-based diagnosis (including prenatal diagnosis) is available for some of them.</B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> More information about the gene products and understanding of pathophysiological mechanisms will open the way to specific treatments. </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">The most common degenerative disease is Alzheimer disease and the second most frequent is Parkinson disease.</B><B> </B></div> <bR> <bR> <bR> <bR> <div> <B><U>DEMENTIA</U></B><FONT SIZE="3" COLOR="#FF0000" FACE="Arial" ><B><U> </U></B></FONT></div> <bR> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Dementia (loss of mental power) is a generic term, not a disease entity. Any pathology that causes significant brain damage, at any age, can cause dementia. </B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">The causes of dementia include:</B><B> </B></div> <div> <TABLE BORDER="2" CELLPADDING="1" CELLSPACING="1" WIDTH="853" BORDERCOLORLIGHT="#C0C0C0" BORDERCOLORDARK="#808080" FRAME="BOX" RULES="ALL" ALIGN="BOTTOM" HSPACE="0" VSPACE="0" BGCOLOR=#FFFF99 > <tR> <tD VALIGN=CENTER BGCOLOR=#FFFF00 HEIGHT= 351 WIDTH="843"><div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Stroke and ischemic encephalopathy</B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> </B>(multi-infarct or vascular dementia)<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Head trauma </B></div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">(subdural hematomas, </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">diffuse axonal injury)<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Hydrocephalus</B><FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">CNS infections </B></div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">(HIV encephalitis, </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Creutzfeldt-Jakob disease)<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Metabolic CNS disorders </B></div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">(lysosomal storage and peroxisomal diseases)<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Demyelinative diseases</B> </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">(multiple sclerosis)<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Neurodegenerative diseases </B></div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">(Alzheimer disease, </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Parkinson disease, </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">diffuse Lewy body dementia, </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Huntington disease)</div> </tD> </tR> </TABLE></div> <bR> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">A history of dementia and its possible genetic implications is one of the most frequent reasons why an autopsy is done today. </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Dementia is easy to diagnose clinically but there are no reliable clinical or laboratory tests for determining if its is caused by Alzheimer disease (AD) or some other neurodegenerative condition.</div> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> In most cases, examination of brain tissue is the only way to answer this question. </div> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">The autopsy is the foundation of our knowledge of Alzheimer disease and other degenerative diseases. As we learn more about the various degenerative dementias, the role of the autopsy has become even more important. </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">The vast majority of patients who come to autopsy with the primary diagnosis of dementia turn out to have a neurodegenerative disease, usually AD. A small proportion have multi-infarct dementia.</div> <bR> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> Some patients have more than one disease contributing to the dementia, e.g. AD, MS and multiple strokes.<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <bR> <bR> <bR> <DIV ALIGN="LEFT"></DIV> <div> <B><U>Alzheimer's Disease</U></B></div> <div> <FONT SIZE="3" COLOR="#000000" FACE="Arial" ><IMG SRC="0f8f44a0.gif" border=0 width="500" height="330" ALIGN="BOTTOM" HSPACE="0" VSPACE="0"><IMG SRC="0faf47e0.gif" border=0 width="500" height="382" ALIGN="BOTTOM" HSPACE="0" VSPACE="0"></FONT><FONT SIZE="3" COLOR="#000000" FACE="System" >Alzheimer plaques. Bielschowsky stain.</FONT><FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT>In their fully developed stage, SPs have a central core of fibrillary<B> amyloid </B>material</div> <bR> <div> <IMG SRC="0fcf4340.gif" border=0 width="500" height="308" ALIGN="BOTTOM" HSPACE="0" VSPACE="0"></div> <div> Senile dementia of the Alzheimer's type (SDAT), or Alzheimer's disease (AD) is becoming more common in developed nations as the population includes more and more older persons. There is no known cause for the disease. It is not known why some people present as early as 30 or 40 years of age with dementia while others do not present until their late 70's or 80's. There are familial cases (5-10%) of Alzheimer's disease. Familial cases tend to have an earlier age at onset. Genetic defects in familial cases have been identified on chromosomes 21, 19, 14, and 12. Defects on chromosome 12 appear to be linked to late-onset Alzheimer's disease. There may be mutations to amyloid precursor protein genes.</div> <div> The diagnosis clinically is made by the finding of progressive memory loss with increasing inability to participate in activities of daily living. Late in the course of the disease, affected persons are not able to recognize family members and may not know who they are. The definitive diagnosis is made pathologically by examination of the brain at autopsy. Grossly, there is cerebral atrophy, mainly in frontal, temporal, and parietal regions. As a consequence, there is ex vacuo ventricular dilation.</div> <div> The pathognomonic microscopic feature of AD is an increased number of neuritic plaques in the cerebral cortex. These neuritic plaques are composed of tortuous neuritic processes surrounding a central amyloid core. Reactive astrocytes and microglia may appear at the periphery of these plaques. Though plaques may easily be found in the hippocampus, their presence in increased numbers in neocortex is necessary for a diagnosis of AD. The amyloid core consists primarily of a small peptide known as Aß which is derived from the larger amyloid precursor protein (APP). Plaques that have the amyloid proteins but lack the neuritic processes are known as diffuse plaques, which do not count toward the diagnosis of AD. Since the number of plaques increases with age, the number needed for diagnosis of AD is age-dependent. Other histologic features of AD include neurofibrillary tangles, amyloid angiopathy, and granolovacuolar degeneration.</div> <div> Pathologically, AD is characterized by two lesions, Senile Plaques (SPs) (also called neuritic plaques or Alzheimer plaques) and Neurofibrillary Tangles (NFTs). Biochemically, both these lesions are due to postranslational modifications of extracellular (SPs) and intracellular (NFTs) proteins. SPs are spherical lesions in the cerebral cortex, measuring up to 100 microns.<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> In their fully developed stage, SPs have a central core of fibrillary<B> amyloid </B>material</div> <div> This is surrounded by degenerating nerve cell processes, reactive astrocytes and microglia. Each SP represents a focus of damage of the neuropil that includes the processes of several neurons and probably thousands of synapses. Thus, SPs cause severe disconnection. The amyloid of SPs <B>(ß amyloid or Aß)</B> is a polymer of a 42 to 43 amino acid peptide which is folded in a way that makes it insoluble and resistant to the action of proteolytic enzymes. It is derived from a larger precursor protein, the <B>Amyloid Precursor Protein (APP). </B>APP is a transmembrane protein, made by neurons and other brain cells. It is also found in extraneural tissues and is especially abundant in platelets. Its function is unknown. The Aß amyloid residue includes part of the transmembrane domain of APP and is thought to result from aberrant cleavage of APP by proteolytic enzymes called secretases.</div> <div> Aß is toxic to neurons. In brain slice preparations, it causes loss of long term potentiation, damages synapses, and kills neurons. Moreover, it shows selective neurotoxicity for the hippocampus and entorrhinal cortex (areas that are severely affected in AD) while sparing cerebellar neurons. There is a poor correlation bertween the amount of Aß that is deposited in the brain and the severity of the neurological dysfunction in AD. In transgenic AD models, severe neurological deficits occur in absence of amyloid deposits. Damage is apparently caused by small Aß oligomers that are soluble and are not deposited in the brian as amyloid.</div> <div> NFTs are abnormal filamentous inclusions in the neuronal body made up of pairs of filaments that are twisted around one another <B>(paired helical filaments).</B><FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <bR> <div> Biochemical evidence points to a loss of the choline acetyltransferase and acetylcholine in the cerebral cortex of patients with Alzheimer's disease. However, the significance of this finding is not clear. There is loss of higher brain functions with AD leading to profound dementia. The course is usually over 5 to 7 years. The immediate cause of death for most persons with Alzheimer's disease is pneumonia, typically an aspiration pneumonia.</div> <div> Chemically, they are composed of insoluble protein polymers, mainly over-phosphorylated <B>microtubule associated protein tau</B>, and MAP2. They displace organelles, and interfere with cellular functions. More important, the abnormalities of MAPs destabilize the cytoskeleton and impair axoplasmic flow, thus affecting nutrition of axon terminals and dendrites. In severe AD, the hippocampus often contains extracellular NFTs embedded in the neuropil, like fossilized skeletons of neurons. Small NFTs are also seen in dendrites (neuropil threads) and are components of SPs. SPs are specific for AD. NFTs, though mainly a lesion of AD, occur also in a few other conditions.The relationship between SPs and NFTs is not known.<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> The lesions of AD can be best appreciated in sections of brain stained with the Bielschowski silver stain and immunostains for Aß. NFTs and neuropil threads stain black with the Bielschowski stain (Figures 9.2 and 9.4). Aß immunostains highlight the amyloid cores of SPs and reveal vascular amyloid deposits in many cases ( Figure 9.3). SPs and NFTs are seen mainly in the hippocampus, neocortex and amygdala. In very severe cases, they may appear in the diencephalon and in the brain stem. There are no such lesions in the white matter. SPs and NFTs are associated with <B>loss of neurons and synapses</B> and <B>brain atrophy.</B><FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <bR> <div> The gene for APP is on chromosome 21. Trisomy 21 (Down syndrome) provides a clear mechanism for Aß deposition. Persons with this condition produce one and a half times as much APP as normal people do and develop AD at a young age, some of them in their 20s. Most AD, however, is not due to overproduction of APP, but to some other mechanism, either an abnormality of the APP molecule that renders it more amyloidogenic, or a defect of processing of normal APP. This appears to be the case in infrequent genetic forms of AD. In these patients, autosomal dominant AD develops before age 65 (presenile dementia) due to mutations of the APP gene and of the presenillin 1 and 2 genes on chromosomes 14 and 1 respectively. The presenillins are thought to be involved in the degradation of Aß.<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> Setting aside Down syndrome and autosomal dominant AD, the vast majority of AD develops in old age and is probably due to an interaction of genetic and other intrinsic and environmental factors. The most important genetic risk factor is the Apolipoprotein E (<B>ApoE</B>) <B>genotype</B>. ApoE occurs in three isoforms: ApoE2, ApoE3 and ApoE4. The gene for ApoE is on chromosome 19. One copy is inherited from each parent. The most common ApoE allele is ApoE3. Persons who are homozygous for the ApoE4 allele develop AD at a mean age 70. Persons with other ApoE phenotypes develop the disease later. According to some models, most people will develop AD if they live long enough. ApoE4 has been detected in NFTs and in SP amyloid. This suggests that ApoE lipoproteins participate in some way in the processing of APP, and play a role in the assembly of the neuronal cytoskeleton.<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> The role of the environment and general state of health in AD is now beginning to be explored. Chronic cellular damage by free radicals and nonenzymatic glycation of proteins is thought to contribute to the loss of neurons and synapses that is associated with old age and to aggravate the pathology of AD. There is also evidence that inflammatory and immune mechanisms are involved in the pathogenesis of AD. Acute-phase proteins are elevated in serum and deposited in SPs; microglial cells accumulate around SPs; and complement components are present in SPs. APP is an acute phase protein which is released in brain tissue following trauma and other insults. Dementia and parkinsonism develops sometimes in boxers (dementia pugilistica or the punch drunk syndrome) and accelerated cognitive decline occurs with advancing age in persons with a history of traumatic brain injury. The brain in dementia pugilistica shows NFTs and amyloid deposits (diffuse plaques) but not the typical neuritic plaques of AD.</div> <div> The risk for developing AD in old age can be assessed partially based on the ApoE genotype. The contribution of general health and the environment is difficult to factor in, and there may be other genetic risk factors that we don't know about. Possibly, whether a person with ApoE4/4 develops AD at 70 vs 75 years depends on general health and the environment. Stroke, CNS infections, traumatic brain lesions, multiple sclerosis and any type of brain damage deplete structural and functional reserves and aggravate the dementia.<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> <B>Old age</B> (without clinical dementia) is associated with some loss of neurons and synapses and an overall reduction of brain weight by 200 gm. The remaining neurons are enough to carry out neurological function. Some compensatory dendritic sprouting is also seen. <B>Neuronal plasticity</B> (the ability to make new synapses) is enhanced by trophic factors (neurotrophins). The best-known neurotrophin, <B>nerve growth factor</B>, is important for growth and maintenance of cholinergic neurons that are depleted in AD. Neuronal activity also enhances plasticity.<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> The brain, in AD, shows a loss of cholinergic neurons in the basal forebrain, decrease in <B>acetylcholine </B>(Ach) levels and decrease in the acetylcholine synthesizing enzyme <B>choline acetyltransferase </B>(CHAT) in the cerebral cortex. Animal models show that Ach plays a crucial role in information processing and memory. Although other neurotransmitter systems (noradrenalin, serotonin, somatostatin and other peptides) are also deficient in AD, the cognitive impairment correlates best with the loss of cholinergic imput. Acetylcholinesterase inhibitors (tacrine) and Ach receptor agonists, including nicotine, have been used to treat AD. The marginal success of this approach suggests that, in addition to Ach deficiency, there is a disruption of the Ach transduction pathway and other profound alterations that contribute to the cognitive dysfunction.<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> There are no specific clinical findings in AD. However, progressive dementia evolving over a few years without focal neurologic deficits or abnormal imaging findings is probably AD. Elevation of tau protein and decrase of Aß in CSF are useful biomarkers. A definitive diagnosis can only be made by pathological examination of brain tissue. Autopsy studies show that the brains of most people over 65, even without clinical dementia, contain a few SPs and NFTs in the hippocampus and entorhinal cortex. This suggests that formation of SPs and NFTs is part of the aging process. The brains of demented people contain more SPs and NFTs, not only in the limbic cortex but also in the neocortex and other regions. The more numerous and widespread the Sps and NFTs, the more severe the dementia. The distribution of the lesions correlates with the clinical picture. Involvement of the hippocampus explains the impairment of memory. Should cases with a few SPs and NFTs in the hippocampus be diagnosed as AD, even if there is no clinical dementia? Certainly the presence of these lesions indicates that the metabolic abnormalities that cause AD are set in motion. In some individuals, this process advances rapidly and causes severe dementia; in others, it is slow and causes forgetfulness and a mild cognitive impairment. While old age is the most important risk factor for AD, it is worth emphasizing that 90 percent of people over 65 have no clinical dementia. Despite significant advances in the past 20 years, major gaps in our knowledge of AD remain. Knowledge about the neurotransmitter deficiencies, neuronal plasticity, and the role of the environment and body-brain interactions may provide a basis for designing treatment protocols for AD.<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> A novel prevention and treatment method for AD was reported recently in transgenic mice that overexpress a mutant APP and develop AD <FONT SIZE="3" COLOR="#800000" FACE="Verdana" >neuropathology</FONT>. Active immunization of young animals with Aß and passive immunization with Aß antibodies prevented the development of AD; immunization of older animals reduced the extent and severity of AD pathology. This raises the possibility of a vaccine against AD.<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <bR> <div> <B> <A NAME="ftd"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></B><B>FRONTOTEMPORAL DEMENTIAS</B><FONT SIZE="3" COLOR="#000000" FACE="Arial" ><B> -</B></FONT><B>PICK DISEASE</B><FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT>Frontotemporal dementias (FTDs) are a group of progressive neurodegenerative disorders that have an insidious presenile onset and affect higher cortical function causing personality change (apathy or disinhibition), expressive aphasia, and other deficits, but lack the memory loss and visuospatial disorientation that are so characteristic of AD. The following entities are included in the FTDs:</div> <div> <TABLE BORDER="2" CELLPADDING="1" CELLSPACING="1" WIDTH="595" BORDERCOLORLIGHT="#C0C0C0" BORDERCOLORDARK="#808080" FRAME="BOX" RULES="ALL" ALIGN="BOTTOM" HSPACE="0" VSPACE="0" > <tR> <tD VALIGN=CENTER BGCOLOR=#FFFF00 HEIGHT= 94 WIDTH="585"><div> Pick Disease<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> Frontotemporal Dementia with Parkinsonism Linked to Chromosome 17 (FTDP-17)</div> <div> Corticobasal Degeneration</div> <div> Frontotemporal Dementia with Motor Neuron Disea</div> </tD> </tR> </TABLE></div> <DIV ALIGN="LEFT"></DIV> <div> Pathologically, FTDs are characterized by atrophy of the frontal and temporal lobes (lobar atrophy) that contrasts the diffuse cortical atrophy of AD. Microscopic examination shows the following:</div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Neuronal loss and gliosis.<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Spongiosis (a band like vacuolization of the superficial cortex).<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Pick inclusion bodies (spherical silver positive cytoplasmic neuronal inclusions that contain tubular structures with tau protein).<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Tau positive filamentous structure in neurons and glial cells.<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Abnormal neurons with ballooning of their cytoplasm and dissolution of Nissl granules, similar to changes that occur following loss of afferents.<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> This full blown phenotype characterizes <B>Pick disease</B> but many FTDs lack some of these features, especially Pick bodies. To complicate matters, older Pick disease patients may also have AD, simply because AD is very common. </div> <div> Most FTDs are sporadic. FTDP-17 is an autosomal dominant FTD with Parkinsonian manifestations that is caused by mutations of the tau protein gene on 17q. This discovery is an important clue about the pathogenesis of FTDs and other degenerative diseases in which abnormal tau proteins are deposited in neurons and glial cells (tauopathies). </div> <div> Though degeneration in FTDs is primarily cortical, there are pathological changes in the substantia nigra and other subcortical structures. Conversely, subcortical degenerative disease such as Parkinson Disease, Progressive Supranuclear Palsy, and Motor Neuron Disease may affect the frontal and temporal lobes. Our concept of FTDs is still in a state of flux but significant progress has been made in the late 90s in sorting out the FTDs and other non AD dementias and getting insights into their pathogenesis and genetics.</div> <bR> <div> <FONT SIZE="3" COLOR="#000000" FACE="Arial" ></FONT><B>TAU AND TAUOPATHIES</B><FONT SIZE="2" COLOR="#000000" FACE="Arial" > <A NAME="tau_and_tauopathies_1"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></FONT><FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT><B>Tau</B> (the Greek letter t): a microtubule associated protein, coded by a gene on 19q21. Normally, tau is phosphorylated and is present mainly in axons where it binds and stabilizes microtubules.</div> <div> <B>Tauopathies</B>: neurodegenerative diseases characterized by abnormal deposits of tau in the form of paired helical or straight filaments. The tauopathies include:</div> <div> <TABLE BORDER="2" CELLPADDING="1" CELLSPACING="1" WIDTH="595" BORDERCOLORLIGHT="#C0C0C0" BORDERCOLORDARK="#808080" FRAME="BOX" RULES="ALL" ALIGN="BOTTOM" HSPACE="0" VSPACE="0" > <tR> <tD VALIGN=CENTER BGCOLOR=#FFFF00 HEIGHT= 113 WIDTH="585"><div> Alzheimer Disease<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> Pick Disease</div> <div> Frontotemporal Dementia with Parkinsonism Linked to Chromosome 17 (FTDP-17)</div> <div> Corticobasal Degeneration</div> <div> Progressive Supranuclear Palsy</div> </tD> </tR> </TABLE></div> <DIV ALIGN="LEFT"></DIV> <div> In AD, the tau deposits (NFTs and neuropil threads) are present in the neuronal body and dendrites and consist of hyperphosphorylated tau. Overphosphorylation may be due to exposure of tau to high concentrations of heparan sulfate in the neuronal cytoplasm. In other tauopathies, both, neurons and glial cells are affected. It is not clear if the deposits themselves damage neurons or if neurodegeneration is caused by cytoskeletal abnormalities or other lesions. FTDP-17 is due to mutations of the tau gene. This discovery suggests that other tauopahties may also be caused by tau mutations. </div> <bR> <div> <B> <A NAME="hd"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></B><B>HUNTINGTON DISEASE (HD)</B><FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> Huntington Disease (HD) is a fatal <B>autosomal dominant</B> condition that begins usually in the fourth decade of life and is characterized by behavioral changes, chorea and dementia. Gross examination of the brain reveals <B>atrophy of the caudate nucleus and putamen, cortical atrophy</B> and dilatation (ex vacuo) of the anterior horns of the lateral ventricles.<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> <B><IMG SRC="0feeb3f0.gif" border=0 width="491" height="319" ALIGN="BOTTOM" HSPACE="0" VSPACE="0"></B><FONT SIZE="3" COLOR="#000000" FACE="Arial" >. Huntington disease. Atrophy of the caudate nucleus and putamen and hydrocephalus ex vacuo</FONT></div> <div> Microscopically, there is loss of medium size spiny internuncial neurons in the caudate and putamen, loss of cortical neurons and gliosis.<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> The molecular abnormality of HD is CAG trinucleotide expansion of the huntingtin gene on chromosome 4p. This adds a polyglutamine segment to the huntingtin protein. This protein is widely expressed throughout the brain. Its function is unknown. The expanded huntingtin conjugated with ubiquitin forms aggregates (inclusions) in the nuclei of affected neurons. These inclusions can be detected by immunohistochemistry using antibodies to huntingtin. These findings sugggest that there is an error in the proteolytic degradation of of the expanded huntingtin. This degradation takes place in chambers called proteasomes and involves conjugation of huntingtin with ubiquitin. Impairment of this process apparently causes huntingtin-ubiquitin complexes to be translocated into the nuclei. CAG repeats on other genes are also seen in spinobulbar muscular atrophy (Kennedy disease), Machado-Joseph disease, an autosomal dominant ataxia seen mainly in Portugese of Azorean descent and cerebellar degenerations. As in all genetic disorders with trinucleotide repeats, HD shows the phenomenon of anticipation, i.e. the number of repeats increases in successive generations, resulting in earlier onset and more severe disease. Biochemical analysis of the striatum shows loss of neurotransmitters, including GABA, acetylcholine and glutamate, which correlates with the loss of small neurons. Decrease of GABA and unbalanced dopamine activity result in chorea.<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> A rare form of chorea, beginning in adolescence or early adult life, is associated with an erythrocyte abnormality (<B>chorea with acanthocytosis</B>). Pathologically, this entity is similar to Huntington disease but is caused by a different gene defect. <B>Sydenham Chorea</B> is a transient disorder in rheumatic fever caused by antibodies that react with neuronal antigens in the basal ganglia.<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <bR> <bR> <div> <B><U>Multi-infarct Dementia</U></B></div> <div> Multi-infarct dementia (MID) can cause a dementia similar to Alzheimer's disease (AD). However, no pathologic findings are present characteristic of AD. Instead, there are multiple ischemic lesions in the cerebral cortex that cumulatively result in loss of enough neurons to produce dementia. Most patients with MID have an abrupt onset of cognitive symptoms along with an incremental loss of mental function. Focal neurologic deficits can be present, depending upon the size and location of the infarcts. In some cases, though, there is gradual loss of mental function. Pathologically, marked cerebral arterial atherosclerosis and/or thromboembolic disease can account for the appearance of many infarcts, typically small and scattered</div> <bR> <div> <B><U>Pick's Disease</U></B></div> <div> This is an uncommon cause for dementia, but it appear similar to Alzheimer's disease. The cerebral atrophy with Pick's disease is lobar and typically involves the frontal and temporal lobes. This atrophy is so striking that it is "knife-like" in appearance. This atrophy may be asymmetrical. Microscopically, there is marked loss of cortical neurons with gliosis. Pick bodies, cytoplasmic inclusions that are highlighted by silver stain, are seen in the cortex</div> <bR> <div> <B><U>Huntington's Disease</U></B></div> <div> This is autosomal dominant in inheritance and the patient's usually present between the ages of 20 and 50 years, with a course that averages 15 years to death. Patients may either present with choreiform movements, character change, or psychotic behavior. The genetic defect is localized to chromosome 4. The abnormal gene on chromosome 4 codes for a protein containing increased trinucleotide repeat sequences. The greater the number of repeats, the earlier the onset of the disease. Spontanenous new mutations are uncommon.</div> <div> Pathologically there is severe loss of small neurons in the caudate and putamen with subsequent astrocytosis. With the loss of cells, the head of the caudate becomes shrunken and there is "ex vacuo" dilatation of the anterior horns of the lateral ventricles. There is a loss of gamma aminobutyric acid (GABA), acetylcholine and substance P.</div> <bR> <div> <B><U>Parkinson's Disease</U></B></div> <div> This syndrome covers several diseases of different etiologies which affect primarily the pigmented neuronal groups including the substantia nigra, locus ceruleus, dorsal motor nucleus of X and the substantia innominata. Patients usually present with movement problems such as a festinating gait, cogwheel rigidity of the limbs, poverty of voluntary movement, and a pill rolling type of tremor at rest. In time the patient's facies will become mask-like. Usually mental deterioration does not occur but some patients may become demented as the disease progresses. Idiopathic Parkinson's disease commonly begins in late middle age and the course is slowly progressive. The pigmented neurons are slowly lost as the disease progresses and melanin pigment can be seen within the background neuropil or within macrophages. Astrocytosis occurs secondary to neuronal loss.</div> <div> Some patients with Parkinsonian symptoms also have dementia, and in these patients there are Lewy bodies in the cerebral cortex, as well as the substantia nigra. This can be termed diffuse Lewy body disease (DLBD), and it is in the differential diagnosis for Alzheimer's disease. Pathologically, Lewy bodies in association with Parkinson's disease are found within the cytoplasm of pigmented neurons. These are homogeneous pink bodies on H&E stains with a surrounding halo. They represent filaments of unknown etiology.</div> <div> Parkinson disease (PD) is the most frequent subcortical degenerative disease. It begins most frequently in the sixth decade and is characterized by rigidity, tremor at rest, slowness of voluntary movement, an expressionless (mask-like) face, stooped posture, and a shuffling, small-step gait. PD probably has a multifactorial etiology that includes genetic and environmental factors. The vast majority of cases are sporadic. Rare autosomal dominant forms have been described recently. These have a mutation in the gene of a synaptic protein a synuclein, on chromosome 4q. The pathology of PD is degeneration of the nigrostriatal dopamine pathway. Grossly, there is depigmentation of the substantia nigra and locus ceruleus.</div> <div> <B><IMG SRC="100d5040.gif" border=0 width="725" height="260" ALIGN="BOTTOM" HSPACE="0" VSPACE="0"></B><FONT SIZE="3" COLOR="#000000" FACE="Arial" >Parkinson disease. Depigmentation of the substantia nigra (left) compared to normal (right</FONT></div> <div> Microscopic examination reveals <B>loss of substantia nigra neurons</B>. Their pigment (neuromelanin) is discharged into the neuropil where it is taken up by macrophages. Affected neurons have characteristic round lamellated eosinophilic cytoplasmic inclusions, <B>Lewy bodies</B></div> <div> <B><IMG SRC="10290240.gif" border=0 width="400" height="292" ALIGN="BOTTOM" HSPACE="0" VSPACE="0"></B><FONT SIZE="3" COLOR="#000000" FACE="System" >Lewy body in substantia nigra neuron.</FONT><FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> Lewy bodies are composed of degenerated neurofilaments and contain wild type a -synuclein and ubiquitin. Ubiquitin binds abnormal proteins and helps in their degradation. Ubiquitinated intracellular products are present in other neurodegenerative disorders including Alzheimer disease. In addition to the substantia nigra and the locus ceruleus, degeneration involves the dorsal motor nucleus of the vagus nerve, other brain stem nuclei, the hypothalamus, basal forebrain, and sympathetic ganglia. Dementia with senile plaques and neurofibrillary tangles develops in about 20 to 30 percent of patients with PD. Conversely, patients with AD may have PD pathology.<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> Some patients with parkinsonism and dementia have  <A NAME="diffuse_lewy_body_disease"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A><B>diffuse Lewy body disease (DLBD)</B>. DLBD shows small, inconspicuous Lewy bodies in cortical neurons, in addition to the characteristic pathology of the substantia nigra. Patients with DLBD may also have AD. The biochemical substrate of PD is <B>dopamine depletion</B> in the striatum. Dopamine is produced by substantia nigra neurons from DOPA (also a precursor of melanin) and transported along the axons of these neurons to the striatum.<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> The pyridine analogue <B>MPTP</B> (1-methyl-1-4-phenyl-1,2,3,6-tetrahydropyridine) is taken up selectively by dopaminergic neurons.Its active compound, MPP (1-methyl-4-phenylpyridinium) inhibits mitochondrial function and induces cell death. Toxic damage of dopaminergic neurons causes parkinsonian symptoms . This was discovered when a drug addict accidentally injected himself with MPTP (a by-product of meperidine synthesis) made by himself.  <A NAME="mptp_parkinsonism"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A><B>MPTP parkinsonism </B>in humans and experimental animals resembles PD. The MPTP model and the ALS- Parkinson-Dementia cases from Guam (see below) suggests that PD can be caused by environmental neurotoxins.<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> Treatment of PD consists mainly of L-dopa. Unilateral tremor and rigidity may respond to stereotactic ablation of the contralateral globus pallidus and ventrolateral thalamus. A recent experimental therapy of PD involves implanting fetal substantia nigra into the striatum. Grafts obtained from seven to nine week fetuses survive, innervate the striatum, and supply missing dopamine. Immunosuppression with cyclosporin A prevents rejection. Some patients show significant clinical improvement.<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> Parkinsonian syndromes may appear in the course of other conditions that damage the substantia nigra, e.g., striatonigral degeneration, postencephalitic parkinsonism, manganese poisoning, carbon monoxide poisoning, hypoxic-ischemic encephalopathy and stroke.<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <bR> <div> <B> <A NAME="mnd"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></B><B>MOTOR NEURON DISEASES</B><FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> <FONT SIZE="3" COLOR="#000000" FACE="Arial" > <A NAME="amyotrophic_lateral_sclerosis"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></FONT><B>Amyotrophic Lateral Sclerosis (ALS)[SEE ALSO IN MY USMLE2 WEB PAGE]</B> is a fatal degenerative disorder of upper and lower motor neurons.Lower motor neuron loss causes muscle weakness and atrophy; upper motor neuron involvement causes corticospinal tract signs (spasticity, hyperactive tendon reflexes, Babinski signs). The etiology of ALS is unknown. About 10 percent of cases are familial, autosomal dominant. Twenty percent of patients with familial ALS have a mutation of a gene on chromosome 21q that codes for <B>superoxide dismutase (SOD1)</B>. This enzyme protects cells from toxic oxygen radicals. This suggests that oxidative injury plays a role in the degeneration of motor neurons in ALS. However, it turns out that the disease in these cases is due to toxic properties of the mutant SOD1.<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> The pathology of ALS is degeneration and <B>loss of motor neurons</B> of the anterior horns and motor nuclei of brain stem.<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> Degenerating anterior horn neurons develop proximal axonal swellings filled with 10 nm neurofilaments. Because of loss of lower motor neurons, muscles undergo <B>denervation atrophy.</B><FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <bR> <div> There is also <B>degeneration</B> <B>of the corticospinal tracts</B>. As the name of the disease indicates, this is most evident in the lateral corticospinal tracts which lose axons and myelin, shrink and become gliotic</div> <div> Involvement of the internal capsule and motor cortex is usually mild or inapparent, but in severe cases there is loss of Betz cells. Degeneration may also infrequently involve sensory tracts</div> <bR> <div> ALS (also known as Lou Gehrig's disease after the famous first baseman who had this disease) results from loss of motor neurons which is most striking in the anterior horn cells of spinal cord but may involve cranial motor nuclei and Betz cells. The loss of anterior horn cells leads to muscle atrophy. Astrocytosis is seen in response to the loss of motor neurons. Because of the loss of upper motor neurons, there is lateral column degeneration with gliosis, the so-called "sclerosis" of the lateral columns of spinal cord. Males are affected more commonly than females. The patients present in middle age with weakness of the extremities and may go on to develop bulbar signs and symptoms. The course is usually 2 to 6 years after diagnosis, but patients presenting with bulbar signs and symptoms have a shorter life span because of swallowing difficulties and aspiration. The etiology is unknown.</div> <bR> <div> <IMG SRC="104f4250.gif" border=0 width="500" height="293" ALIGN="BOTTOM" HSPACE="0" VSPACE="0"><FONT SIZE="3" COLOR="#000000" FACE="System" >Denervation. End-stage atrophy. Clusters of sarcolemmal nuclei.</FONT> </div> <div> <IMG SRC="106f4600.gif" border=0 width="500" height="352" ALIGN="BOTTOM" HSPACE="0" VSPACE="0"><FONT SIZE="3" COLOR="#000000" FACE="System" >Denervation. Group atrophy.</FONT> </div> <bR> <bR> <bR> <div> <B>ALS-Parkinson-Dementia. </B>A combination of ALS, PD and AD, known locally as Lytico-Bodig disease, is frequent among the Chamorro people of Guam. The appearance of this disease in successive generations strongly implicates genetic factors. Indeed, each of the components of Lytico-Bodig can be genetic. However, in recent years, the incidence of ALS-P-D in Guam has declined dramatically. Epidemiological work and animal experiments support the hypothesis that ALS-P-D of Guam is caused by a <B>neurotoxin</B> in the seed of the plant cycas circinalis. This has been a staple in the local diet, used in bread and other foods. Another hypothesis implicates other environmental factors leading to deficiencies of calcium and magnesium, and high concentrations of aluminum and other minerals in drinking water, with <B>aluminum</B> deposition in neurons. Aluminum can disrupt the neuronal cytoskeleton and cause neurofibrillary pathology. The drastic decline of ALS-P-D in recent years has been attributed to changes in diet and improved nutrition. ALS-P-D of Guam underlines the important role of genetics and environmental neurotoxins in the pathogenesis of neurodegenerative diseases.<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <bR> <bR> <bR> <div> <FONT SIZE="3" COLOR="#000000" FACE="Arial" > <A NAME="spinal_muscular_atrophy"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></FONT><B>Spinal Muscular atrophy. </B>This very important group of genetic disorders, characterized by degeneration and loss of spinal and brain stem motor neurons. This group includes several distinct clinical and genetic syndromes. Most are autosomal recessive, but there are X-linked and autosomal dominant forms. SMA is the most common fatal recessive disorder in children after cystic fibrosis. Autosomal recessive SMA has been mapped to a gene on chromosome 5q that codes for a protein called survival motor neuron (SMN) protein. Deletions in this gene cause motor neuron loss. Autosomal recessive SMAs cover a wide clinical spectrum. They are crippling and most are ultimately fatal diseases. The most important entity in this group is <B>Infantile Spinal Muscular Atrophy (Werdning-Hoffman Disease)</B> which begins in utero or in infancy. Loss of lower motor neurons causes denervation atrophy of muscle, manifested by severe hypotonia, weakness and inability to breathe. Brain stem and spinal motor neurons shrink, become pyknotic, and die. Activated microglial cells often surround and ingest degenerated neurons (neuronophagia). In advanced cases, there is gliosis. In some cases, other neuronal groups besides motor neurons are affected. Juvenile Spinal Muscular Atrophy (Kugelberg-Welander Disease) begins in adolescence and has a slow progression, compatible with long survival (in a wheelchair). It tends to cause proximal weakness and may be confused with myopathy. An adult onset, X-linked spinal and bulbar muscular atrophy (Kennedy disease) is associated with CAG trinucleotide repeats.</div> <bR> <bR> <bR> <div> <B> <A NAME="ataxia"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></B><B>ATAXIA AND CEREBELLAR DEGENERATION</B><FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> Ataxia can be caused either by lesions that interrupt the sensory input to the cerebellum (spinal ataxia and peripheral neuropathy) or by intrinsic lesions of the cerebellar cortex (cerebellar ataxia). The main spinal ataxia and most frequent inherited ataxia overall is Friedreich ataxia. The cerebellar ataxias can be divided into cerebellar cortical degeneration and pontocerebellar atrophy. Friedreich ataxia is a disease entity. Cerebellar cortical degeneration and pontocerebellar atrophy should be regarded as patterns or phenotypes, not disease entities. Each of them inludes multiple clinically overlapping familial and sporadic disorders. The familial ones among them are most often autosomal dominant and are characterized by expanded CAG repeats in diverse chromosomal loci. Loss of Purkinje cells for whatever reason causes transsynaptic degeneration of the inferior olives. Hence, cerebello-olivary or olivopontocerebellar degeneration means primary cerebellar degenereration with secondary loss of inferior olivary neurons. In addition to the inherited ataxias, cerebellar degeneration is caused by a variety of acquired conditions including prion disease, HIE, nutritional deficiency and inherited metabolic diseases.<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <bR> <bR> <bR> <bR> <div> <FONT SIZE="3" COLOR="#000000" FACE="Arial" > <A NAME="friedreich_ataxia"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></FONT><B>Friedreich ataxia (FA)</B> is an autosomal recessive spinal ataxia which begins usually before age 20 with ataxia of gait. Foot deformity (pes cavus), scoliosis, and cardiomyopathy are also common and there is an increased incidence of blindness, deafness and diabetes. FA is essentially a sensory neuropathy. Loss of sensory ganglion cells and degeneration of their axons in peripheral nerves, dorsal roots and posterior columns<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> <IMG SRC="108f40e0.gif" border=0 width="500" height="270" ALIGN="BOTTOM" HSPACE="0" VSPACE="0">. Friedreich ataxia. Degeneration of the posterior and lateral columns</div> <div> deprives the cerebellum of sensory input that is necessary to coordinate movement. There is also degeneration of the spinocerebellar and pyramical tracts, dentate nuclei and superior cerebellar peduncles. The spinal cord pathology is evident in myelin stains. The cerebellar cortex is normal. DNA analysis in FA shows GAA trinucleotide repeats of a gene on chromosome 9q that codes for a protein called frataxin which is localized in mitochondria. This suggests that FA is due to mitochondrial dysfunction and oxidative stress. Deficiency of the antioxidant vitamin E causes similar spinal cord lesions.<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> <B> <A NAME="opca"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></B><B>Olivopontocerebellar degeneration. </B>The pathology in <B>cerebellar cortical degeneration </B>consists of loss of Purkinje cells and inferior olivary neurons. In <B>Olivopontocerebellar atrophy (OPCA)</B> there is, in addition, loss of neurons in the pontine nuclei, and atrophy of the transverse fibers of the pons and middle cerebellar peduncles.<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> Atrophy of the pons and cerebellum can be detected by MRI. Some inherited OPCA cases show also a variety of additional neurologic deficits. Sporadic OPCA is frequently combined with <B>striatonigral degeneration</B> which causes parkinsonian symptoms, and degeneration of sympathetic neurons of the spinal cord (Shy-Drager syndrome) which causes orthostatic hypotension and other autonomic dysfunction. The combined neurodegeneration is called <B>multiple system atrophy</B>. In addition to loss of neurons in the affected nuclei, multiple system atrophy shows glial and neuronal inclusions containing the protein ubiquitin which is involved in the degradation of proteins in proteasomes. An autosomal recessive OPCA in infants and children is associated with a defect in glycosylation of proteins (<B>carbohydrate deficient glycoprotein syndrome</B>).<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> <B>Ataxia-telangiectasia</B> (A-T) is a childhood disease characterized by ataxia, a variety of other neurologic deficits, vascular ectasia and immunodeficiency. It is due to mutations of a gene that regulates the cell cycle. These mutations result in defective DNA repair. There is loss of Purkinje and granular neurons and degeneration of other neuronal groups, A-T patients frequently develop opportunistic infections and lymphomas. </div> <bR> <div> <B><U>Creutzfeldt-Jakob Disease</U></B></div> <div> Creutzfeldt-Jakob disease (CJD) is rare, affecting less than one person in a million per year. Though it has been reported to occur at a variety of ages, the median age of onset is in the seventh decade, and the course of the illness can be from a few weeks to eight years. However, the average length of survival from onset of the disease is six months. CJD is a uniformly fatal rapidly progressive dementia.</div> <div> There are no characteristic gross pathologic features of CJD. In fact, because of the typical short course of the disease, no gross changes are seen at all. Persons living beyond 6 months to a year may have some degree of generalized cerebral atrophy.</div> <div> The spongiform encephalopathy of CJD is seen microscopically to exhibit many round to oval vacuoles varying in size from one to 50 microns in size in the neuropil of cortical gray matter. These vacuoles may be single or multiloculated. The vacuoles may coalesce to microcysts. Most cases of CJD also demonstrate neuronal loss and gliosis. In general, the longer the course of the disease, the more pronounced the microscopic changes will be.</div> <div> The agent associated with CJD appears to be a prion protein (PrP), a neuronal cell surface sialoglycoprotein that is encoded by a gene on chromosome 20. It is thought that the PrP is converted via a conformational change to an abnormal form of PrP that is protease-resistant and can accumulate in the central nervous system of affected persons. This accumulation of abnormal protein accounts for the degenerative changes in the cerebral cortex.</div> <div> These abnormal PrP's can be transmitted from a person with spongiform encephalopathy to another person, at least by the evidence from transmission via pituitary extracts, corneal transplants, dural grafts, and contaminated electrodes. Transmission via close personal contact or via transfusion of blood products does not appear to occur. How transmission occurs naturally is not clear, though an acquired mutation of the gene encoding for PrP may account for the appearance of sporadic cases. The abnormal PrP can catalyze the conversion of normal to abnormal PrP. Further evidence for genetic mutation comes from the appearance of familial cases of CJD. About 15% of CJD cases are familial, with clusters reported in Chile, Slovakia, and Italy. Transmission in familial cases appears to be autosomal dominant, and the onset is earlier in life than for sporadic cases.</div> <div> CJD is one form of spongiform encephalopathy, other forms of which can affect mammalian species besides humans. The spongiform encephalopathy known as scrapie that is seen in sheep is poorly transmissible to other species. However, bovine spongiform encephalopathy (BSE), also called "mad cow disease", can be transmitted more readily to animals other than cattle. The relationship of human spongiform encephalopathy with animal forms of this disease is not entirely clear. An outbreak of BSE among cattle in England in the 1980's was followed by the appearance of rare cases of a CJD-like illness that were characterized by younger age of onset and more extensive spongiform change with plaques in the brains of affected persons. These cases are known as variant Creutzfeldt-Jakob disease (vCJD). This suggests the possibility of a relationship, but the rarity of vCJD cases, similar to the rarity of standard CJD cases, precludes compelling epidemiologic evidence. Cases of vCJD continue to appear in regions were BSE was prevalent.</div> <bR> <div> <B><U>Other Degenerative Diseases</U></B></div> <div> Frontal lobe degeneration (FLD), also called frontotemporal dementia or non-specific frontal lobe dementia, has a slow, insidious onset marked in the early stages by personality changes, then progressive loss of speech, disinhibition, apathy, personal neglect, and finally mutism. The mean age of onset is in the 6th decade. The gross pathologic findings are similar to Pick's disease, with marked atrophy in a frontal lobe and sometimes temporal lobe distribution. Microscopically, there is a spongy vacuolization of layer 2 of the frontal and temporal cortex, along with loss of neurons and gliosis, but no Pick bodies and no increase in neuritic plaques.</div> <div> Corticobasal degeneration (CBD) is marked by extrapyramidal signs and apraxia. Memory loss may be present. Neuropathologic features may overlap Alzheimer's disease, progressive supranuclear palsy, and parkinson's disease. Microscopically, CBD is characterized by neuronal loss, gliosis of cortex, particularly rostral frontal cortex, and nigral degeneration.</div> <div> Multiple system atrophy (MSA) has features that overlap striatonigral degeneration, olivopontocerebellar atrophy, and Shy-Drager syndrome. Most patients with MSA exhibit symptoms similar to Parkinson's disease. MSA is characterized microscopically by the appearance of glial cytoplasmic inclusions.</div> <div> Progressive supranuclear palsy (PSP) is classically marked by a supranuclear gaze palsy along with rigidity, but patients with this disorder may present with dementia that appears similar to Alzheimer's disease. The diagnosis is made by the microscopic findings of globose neurofibrillary tangles and variable neuron loss with gliosis of the globus pallidus, subthalamic nucleus, periaqueductal grey matter, and substantia nigra.</div> <bR> <div> <B>THE PATHOLOGY OF SEIZURES</B><FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> Seizures are caused by paroxysmal discharges from groups of neurons that arise as a result of excessive excitation or loss of inhibition. This loss of balance between excitatory and inhibitory neurotransmission may result from biochemical derangements such as HIE, hypoglycemia, hypocalcemia, fluid-electrolyte imbalance, endocrine-metabolic disorders, intoxications, or from structural lesions. The latter may be diffuse such as Creutzfeldt-Jakob disease and neuronal storage disease or focal such as a brain tumor or scar. Most seizures, however, especially generalized seizures, occur without a known predisposing factor (idiopathic epilepsy). Some forms of idiopathic epilepsy are probably caused by ion channel abnormalities.</div> <div> Based on the pattern of the attack, seizures are divided into generalized tonic-clonic (grand mal), partial or focal, and several special epileptic syndromes. Structural lesions that cause seizures are frequently detected in focal seizures. The most common such lesions are cerebral changes resulting from perinatal brain damage, malformations, cerebral infarcts, trauma, brain tumors and infections. These lesions involve the cerebral cortex and are characterized by <B>neuron loss</B> and <B>gliosis</B>. Residual neurons in <B>epileptogenic foci</B>, show loss of dendritic spines, possibly due to loss of afferents. The sources of these afferents have been presumably destroyed by a tumor, trauma, stroke, or other lesion. Even minute lesions of the cerebral cortex may destroy, out of proportion, small, inhibitory (GABAergic) interneurons, thus reducing the inhibition that controls large pyramidal cells.In most generalized seizures, no primary lesions are detected by imaging or neuropathological examination, possibly because they are very small, perhaps even submicroscopic. The most logical sites of such epileptogenic foci are the neuronal synapses. Synapses are in a state of flux during childhood and adolescence; first they proliferate excessively and then they are reduced to adult levels. The dynamic state of synapses explains why most seizures arise (and often stop) for no apparent reason during childhood. </div> <div> The most common seizures in children and adults are partial complex seizures originating from the temporal lobe (<B>temporal lobe epilepsy </B>[TLE] or psychomotor epilepsy). These seizures begin with a visceral sensation or other aura and are followed by a state of impaired consciousness, automatic motor activities or convulsions. The EEG localizes the epileptogenic focus in the medial portion of the temporal lobe. Because TLE is refractory to drugs, it is often treated by resection of the temporal lobe including the hippocampus and surrounding area and the amygdala. Examination of temporal lobectomy specimens reveals pathology in most cases. The most common lesions are hippocampal sclerosis, tumors (gangliogliomas, gliomas), cortical dysplasias and hamartomas, vascular malformations, ischemic and traumatic lesions, and infectious-inflammatory lesions. In many cases, no pathology is found.<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> <B>Hippocampal sclerosis</B> ( HS or Ammon’s horn sclerosis) consists of loss of neurons in the dentate nucleus, and the CA4 (end folium) and CA1 sectors of the hippocampus with variable gliosis. These lesions cause shrinkage of the hippocampus that can be detected by MRI.<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> The pathogenesis of this lesion has been the subject of a "chicken or the egg" argument for almost 100 years. Some authors propose that HS is the cause of seizures and others that it is the result of seizures. Proponents of the first view argue that the hippocampus is damaged early in life by birth injury, complicated febrile seizures and other events and this damage makes it prone to seizures. Unlike the neocortex, the hippocampus continues to develop after birth and is more vulnerable to such insults. In some cases of TLE there is a history of febrile seizures and other insults but in most cases no such history can be elicited. On the other hand, there is also strong support for the idea that HS is secondary to seizures. Animal experiments and observations in humans show that even a single seizure can cause neuronal damage and that this damage may occur without convulsions, it is cumulative, and correlates with the duration and severity of electrical abnormaliry. The presumed mechanism of damage is discharge of glutamate during the epileptic attack and the most frequent site of damage is the CA1 sector of the hippocampus. This area is also especially vulnerable to hypoxia which also initiates an excitotoxic cascade. This circular argument about HS underlines the rich connectivity and excitatory neurotransmission of certain fields of the hippocampus. However, epileptic brain damage is not limited to the hippocampus. Intractable epilepsy and status epilepticus cause also neuronal loss in the cerebral cortex, thalamus and cerebellum (Purkinje cells). In addition, patients with epilepsy suffer brain damage from falls and have a high frequency of unexpected death. </div> <bR> <DIV ALIGN="LEFT"></DIV> <div> <B>DEMYELINATIVE DISEASES</B><FONT SIZE="3" COLOR="#000000" FACE="Arial" ><B> </B></FONT></div> <bR> <div> <B><U>MULTIPLE SCLEROSIS AND VARIANTS</U></B><FONT SIZE="3" COLOR="#000000" FACE="Arial" ><B> </B></FONT></div> <div> <B><U><IMG BORDER="0" SRC="Symb075c00b700f0ff000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">SCHILDER DISEASE</U></B></div> <div> <B><U><IMG BORDER="0" SRC="Symb075c00b700f0ff000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">NEUROMYELITIS OPTICA</U></B><FONT SIZE="3" COLOR="#000000" FACE="Arial" ><B> </B></FONT></div> <div> <B><U><IMG BORDER="0" SRC="Symb075c00b700f0ff000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">CSF FINDINGS</U></B><FONT SIZE="3" COLOR="#000000" FACE="Arial" ><B> </B></FONT></div> <div> <B><U><IMG BORDER="0" SRC="Symb075c00b700f0ff000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">PATHOGENESIS OF MS</U></B><FONT SIZE="3" COLOR="#000000" FACE="Arial" ><B> </B></FONT></div> <div> <B><U><IMG BORDER="0" SRC="Symb075c00b700f0ff000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">PATHOPHYSIOLOGY OF MS</U></B></div> <div> <B><U>EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS</U></B><FONT SIZE="3" COLOR="#000000" FACE="Arial" ><B> </B></FONT></div> <div> <B><U>ACUTE DISSEMINATED ENCEPHALOMYELITIS</U></B><FONT SIZE="3" COLOR="#000000" FACE="Arial" ><B> </B></FONT></div> <div> <B><U>PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY</U></B><FONT SIZE="3" COLOR="#000000" FACE="Arial" ><B> </B></FONT></div> <div> <B><U>CENTRAL PONTINE MYELINOLYSIS</U></B><FONT SIZE="3" COLOR="#000000" FACE="Arial" ><B> </B></FONT></div> <bR> <div> Demyelinative diseases of the central nervous system are characterized by loss of myelin with relative sparing of axons. In contrast, infarcts, contusions, encephalitis and other conditions destroy myelin and axons equally. The main demyelinative disease of the CNS is <B>multiple sclerosis (MS)</B> and its variants. Its counterpart in the peripheral nervous system is inflammatory demyelinative polyradiculoneuropathy (<B>Guillain-Barré syndrome-GBS</B>) and its chronic variants. Both these are autoimmune inflammatory diseases. There are also virus-induced demyelinative diseases. Demyelinative diseases should be distinguished from leukodystrophies, which are inherited metabolic disorders of myelin lipids.<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <bR> <div> <B> <A NAME="ms"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></B><B>MULTIPLE SCLEROSIS AND VARIANTS</B><FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> MS affects one in every 500 persons. It is more frequent in young adults and causes a variety of neurological deficits (visual loss, paralysis, sensory loss, ataxia, nystagmus, psychiatric disorders, dementia). Most cases have a long course (20-30 years), with remissions and exacerbations. Some cases are progressive from the start or go into a progressive phase later. The pathology of MS develops around blood vessels. Acute lesions (<B>MS plaques</B>) show perivascular mononuclear cells,<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT>stripping and fragmentation of myelin, and variable loss of oligodendrocytes. In most cases, the inflammatory reaction subsides only to appear at another location or at another time. Some lesions expand at their periphery while activity in their center subsides. The pathological process may be arrested at any time, sometimes after partial demyelination. Macrophages remove damaged myelin. A tangle of astrocytic processes fills the gaps of lost tissue. Remaining oligodendrocytes attempt to make new myelin, but this process is ineffective because gliosis creates a barrier between the myelin producing cells and their axonal targets. With time, plaques reach a burned-out stage consisting of demyelinated axons traversing glial scar tissue. Although myelin is preferentially affected, axon loss may be significant. In H&E stains, plaques appear pale compared to normal white matter. Active lesions are cellular because of inflammatory cells, macrophages, and reactive astrocytes. Activity is often confined to the borders of plaques. Myelin stains reveal the lesions unequivocally</div> <div> Grossly, MS plaques appear as irregular, sharply demarcated, gray areas in the white matter. They are usually multiple. Long-standing plaques are firm (sclerosis) because of gliosis. Plaques are randomly distributed. They have a predilection </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">for the <B>periventricular white matter</B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">optic nerves,</B></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0"> and spinal cord</B></div> <bR> <div> but spare no part of the CNS. They may involve gray matter such as cerebral cortex, deep nuclei and brainstem. In these locations, they involve selectively myelinated axons while sparing the neuronal bodies.<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> The pathology of MS is highly variable and its clinical course unpredictable. Some patients have a few lesions that do not progress. In others, new crops of lesions or expansion of already existing ones develop with each exacerbation. Some patients have a relentless progression, leading to extensive confluent demyelination. This variant of MS is called  <A NAME="schilder_disease"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A><B>Schilder disease</B><FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <bR> <div> <IMG SRC="1095dbb0.gif" border=0 width="349" height="443" ALIGN="BOTTOM" HSPACE="0" VSPACE="0">Schilder disease, MRI. Large confluent plaques</div> <bR> <div> and has been confused in the past with <B>X-linked adrenoleukodystrophy. </B>Because of the predilection of plaques for the optic nerves and the spinal cord, some patients present with visual loss or transverse myelitis (paralysis, sensory loss).  <A NAME="neuromyelitis_optica"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A><B>Neuromyelitis optica (Devic disease)</B> is a form of MS that combines optic nerve and spinal cord lesions. Usually, these patients have plaques elsewhere in the brain or develop them later. These other plaques may be clinically silent, whereas the optic and spinal lesions always cause symptoms. Perivascular inflammation, in the acute phase, damages the blood-brain barrier. Fluid (and contrast) leak into the lesions, accounting for their low density on T1 MRI images, bright signal on T2, and contrast enhancing quality. Unlike brain tumors, acute MS lesions cause little or no mass effect. However, a subacute onset of neurological symptoms with a single contrast-enhancing lesion may mimic a neoplasm. Schilder disease, in particular, tends to cause bilateral lesions that join across the corpus callosum, which is also seen in some glioblastomas. Biopsy diagnosis of acute MS, especially with stereotactic needle biopsies, may be tricky because cellularity and reactive astrocytes in the lesions may be misinterpreted as a neoplasm.<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> <FONT SIZE="3" COLOR="#000000" FACE="Arial" > <A NAME="csf_findings"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></FONT><B><U>CSF FINDINGS.</U></B> CSF protein is moderately elevated, and there is mild mononuclear pleocytosis. The latter is a measure of the activity of the disease. Total protein exceeding 110 mg/dl and cell counts higher than 50/cubic mm make the diagnosis of MS unlikely. The IgG fraction is elevated above 11 percent of total CSF protein, especially in chronic MS. The IgG/albumin index in CSF is elevated in 90 percent of MS patients, including some who have normal total protein. Elevation of IgG/albumin index in CSF but not in serum means that IgG is produced intrathecally. Oligoclonal IgG bands are detected on agarose electrophoresis in 90 percent of patients. This pattern may be present even when the total amount of IgG is normal. Oligoclonal bands indicate that IgG represents antibodies to specific antigens. About 70 percent of MS patients and only 5 percent of controls have antibodies to measles. A smaller number have antibodies to rubella, mumps, and herpes simplex. Similar CSF changes are seen in some chronic CNS infections such as chronic measles encephalitis and syphilis. Myelin proteins such as myelin basic protein leak from plaques into the CSF and can be detected by radioimmunoassay.<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> <FONT SIZE="3" COLOR="#000000" FACE="Arial" > <A NAME="etiology_pathogenesis"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></FONT><B><U>ETIOLOGY-PATHOGENESIS OF MS.</U></B><B> </B>MS is probably an autoimmune disorder. Genetic susceptibility and environmental factors play important roles in its pathogenesis.<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> <B>Genetic factors:</B> The risk of MS in relatives of patients is 7 times higher than in the general population. Monozygotic twins are 25.9 percent concordant for MS; dizygotic twins are only 2.3 percent concordant. Genetic susceptibility is probably conferred by MHC molecules that modulate the immune response (particularly autoimmunity) and cell-cell interactions. MS patients express with high frequency certain class I and II HLA antigens, particularly DW2 and DR2.<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> <B>Environmental factors:</B>The incidence of MS is higher in high latitude zones. Prevalence in the northern US is 4-6 times higher than in the South. Individuals who grow up in high prevalence areas retain the high risk even if they subsequently migrate to low-risk regions. These findings suggest that an unknown predisposing factor is acquired by prolonged exposure to some environments. Viruses, particularly measles and HTLV-1, have been suspected but there is no proof that they are involved in the pathogenesis of MS.<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> There are several <B>immunological abnormalities</B> apparent in MS, but how these damage myelin is unclear. The immune phenomena include perivascular lymphocytes and monocytes, T-cell abnormalities (alterations of T4 and T8 cells, activated T-cells), B-cell changes (intrathecal plasma cells and intrathecal immunoglobulin production), and the presence of cytokines in the plaques. Pregnancy, which causes a diffuse immunosuppression, suppresses MS activity. The disease flares up postpartum. Interferon (INF) gamma, which enhances the immune response, provokes MS attacks. Infections such as URIs stimulate secretion of INF gamma by immune cells and exacerbate MS. On the other hand, INF beta, which suppresses the immune response, decreases the frequency of attacks.<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> In order for MS to develop, there have to be antigens in the brain that elicit a T-cell mediated reaction. These antigens are unknown. They may be components of bacteria and viruses or myelin proteins. Antigens are presented to T4 cells by MHC class II molecules on macrophages and astrocytes. Interaction of the T-cell receptor with the MHC-antigen complex stimulates T-cells which proliferate, release cytokines and activate B-cells and macrophages. The perivascular lymphocytes in acute MS plaques are T-cells. Cytokines damage the blood-brain barrier causing efflux of fluid, humoral factors, and cells. Oligodendrocytes are either directly attacked by cytotoxic T-cells or damaged by cytokines, such as tumor necrosis factor, produced by activated T-cells. Antibody-complement action can also cause demyelination. Macrophages ingest myelin debris.<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> <FONT SIZE="3" COLOR="#000000" FACE="Arial" > <A NAME="pathophysiology"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></FONT><B><U>PATHOPHYSIOLOGY OF MS.</U></B> Demyelination causes <B>loss of</B> <B>saltatory conduction.</B> Linear conduction along demyelinated axons is slow because the internodal axon membrane has few ion channels. In addition, lack of insulation of axons allows impulses to disperse laterally to adjacent demyelinated axons. The abnormal physiology of demyelinated axons results in <B>inefficient conduction or conduction block.</B> This is reflected by <B>abnormal evoked response potentials,</B> an electrodiagnostic test that measures conduction velocity in the CNS. While loss of function is easy to explain, clinical recovery is not. As we saw, remyelination is inefficient because it is blocked by glial scar. Therefore, remyelination does not explain the remissions. The neurological deficit from an acute MS plaque is caused not only by myelin (and partial axon) loss, but also by inflammation, cytokines and edema that involve a wide area around the lesion. Even without remyelination, neurological function returns to some extent when the inflammatory reaction subsides and homeostasis is restored. In tracts that are partially involved by MS lesions, remaining axons carry out the function. New ion channels may develop in the demyelinated axon membrane, helping it to conduct more efficiently. Conductivity in demyelinated areas is also influenced by electrolyte and other chemical changes in the extracellular fluid and by physical factors such as body temperature. These factors explain why deficits get better or worse. Recovery probably depends on structural and functional reserves and on a potential for regeneration that we do not fully understand. Anatomical observations alone do not adequately explain the recovery seen in some MS patients. The autopsy is like a snapshot and is not ideally suited to follow the changes of an evolving disease. MRI imaging is better for this purpose.<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <bR> <div> <B> <A NAME="eae"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></B><B>EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS</B><FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> <B>Experimental allergic encephalomyelitis (EAE)</B> can be induced in mice, rats and guinea pigs by intradermal injection of whole CNS tissue or myelin basic protein (MBP) and complete Freund’s adjuvant. Two weeks after the injection, the experimental animals develop ascending paralysis. The injection of MBP triggers a cell- mediated immune reaction against the recipient's own myelin. MBP-specific T-cells traverse brain capillaries. Interaction of these cells with MBP activates them and results in secretion of cytokines, damage of the blood-brain barrier, and recruitment of macrophages. Microscopical examination shows perivenular lymphocytes, similar to acute MS, but little or no demyelination. EAE can be induced by injection of MBP-specific T-cells. Classic EAE is a monophasic reaction. A chronic relapsing EAE can be produced in guinea pigs. EAE can also be induced by other myelin proteins that are chemically different from MBP and by nonmyelin proteins such as S100 protein. Injection of MOG (myelin oligodendrocyte glycoprotein) along with transfer of anti-MOG lymphocytes can cause demyelination. EAE has been used for years as an experimental model of MS. While it proves that an autoimmune reaction can cause inflammation in the white matter, the analogy stops there. The immunology and pathology of MS are far more complex than EAE.<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <bR> <div> <B> <A NAME="ade"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></B><B>ACUTE DISSEMINATED ENCEPHALOMYELITIS</B><FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> Acute disseminated encephalomyelitis (ADE), also known as postinfectious, postvaccinal, or allergic encephalomyelitis, is an acute demyelinative disease that usually develops a few days to two weeks following a respiratory illness due to Epstein-Barr virus, cytomegalovirus, or mycoplasma pneumoniae. It may also follow a variety of other viral and nonviral infections or vaccinations. Sometimes it appears without a preceding infection. It is a monophasic disease that usually runs a mild course with recovery but sometimes may be severe or fatal. Clinically, it presents with drowsiness, headache, stiff neck, focal deficits, paraplegia and sensory loss. ADE following varicella often presents with ataxia. Severe ADE with confluent lesions causes cerebral edema and herniations. Pathologically, ADE is characterized by microscopic perivenous demyelination and mononuclear cells in the brain and spinal cord. ADE is not an infection. It is thought to be an immune reaction triggered by the preceding viral infection or vaccination. Old rabies vaccines were prepared from brains of inoculated rabbits. ADE following such vaccination was due to sensitization against myelin antigens that were present in the vaccines. Similarity between viral and myelin proteins (molecular mimickry) probably causes ADE following infections. The pathogenesis of ADE is not clear in all cases. Acute hemorrhagic leukoencephalitis is a fulminant, frequently fatal form of ADE with extensive, confluent white matter lesions characterized by vascular necrosis, acute inflammation, hemorrhage, and edema.<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <bR> <div> <B> <A NAME="pml"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></B><B>PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY</B><FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> Progressive multifocal leukoencephalopathy (PML) is a selective <B>infection of oligodendroglia</B> by an ubiquitous opportunistic <B>polyoma virus, JC virus </B>(not to be confused with CJD). It occurs in a setting of <B>immunodeficiency</B> and is common in <B>AIDS.</B> Clinically, PML is characterized by a variety of neurologic deficits (visual loss, paralysis, dementia) evolving rapidly and causing death in a few months. Neuroimaging shows multiple hypodense white matter lesions. The CSF is either normal or shows a few lymphocytes.<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> Pathologically, PML begins with small demyelinative foci at the cortex-white matter junction</div> <div> Confluence of these foci results in large irregular white matter lesions that involve the cerebrum, cerebellum, and brainstem</div> <div> Myelin is destroyed; axons are relatively spared. The nuclei of infected oligodendrocytes are packed with viral particles<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT>that cause them to enlarge and develop a ground glass appearance.<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <bR> <div> PML is a lytic infection leading to oligodendrocyte destruction. Polyoma viruses can also become incorporated into the host genome and cause neoplastic transformation. In PML, astrocytes are also infected by JC virus in a non-lytic manner and show pronounced atypia, suggesting neoplastic change.<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <bR> <div> Inflammation is usually minimal. There is no peripheral nerve demyelination or disease in any other organ system. In addition to its clinical significance, PML is interesting as a model of demyelination due to a lytic infection of myelin-producing cells. Neurotrophic mouse hepatitis virus and canine distemper virus are animal models of virus-induced demyelination, similar to PML.<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <bR> <div> <B> <A NAME="cpm"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></B><B>CENTRAL PONTINE MYELINOLYSIS (CPM)</B><FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> CPM is a degeneration of a symmetrical midline patch of the basis pontis.<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> There is loss of myelin and less severe loss of axons. Neurons of the nuclei pontis are relatively spared. No inflammation is seen. There is no selective involvement of fiber systems. In severe cases, the lesion becomes necrotic and extends to the cerebral hemispheres (extrapontine myelinolysis). CPM is usually an incidental autopsy finding. It may be suspected in life if spastic bulbar paralysis and quadriplegia develop in the appropriate clinical setting. Similar but rare lesions occur in the corpus callosum (Marchiafava-Bignami Disease) and in the spinal cord. Initially, CPM was thought to be a complication of alcoholism and malnutrition but has now been proven to be caused by osmotic disturbances. In some cases, it follows rapid correction of hyponatremia. It has been reported in nonalcoholic patients with rapid shifts in osmolality, e.g. in extensive burns. An experimental model has been produced in dogs.<FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> <B><IMG SRC="10bf4240.gif" border=0 width="500" height="292" ALIGN="BOTTOM" HSPACE="0" VSPACE="0"></B><FONT SIZE="3" COLOR="#000000" FACE="System" >PML. Oligodendrocyte with intranuclear inclusion.</FONT><FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> <B><IMG SRC="10df41f0.gif" border=0 width="500" height="287" ALIGN="BOTTOM" HSPACE="0" VSPACE="0"></B><FONT SIZE="3" COLOR="#000000" FACE="System" >PML. Atypical astrocytes.</FONT><FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <bR> </td> </tr></table></body>