Transcript Hemorrhage
L10-L11 CNS TUMORS Gliomas Gliomas – most common primary brain tumors Astrocytomas: Infiltrating astrocytomas (80%) – typically located within the cerebrum in individuals ages 40-70, causing seizures, headaches, and focal neurological deficits (dependent on the location and growth rate of the tumor) Lower grade? Mutations in p53 or overexpression of PDGF-α/PDGF-α receptor Higher grade? Mutations in tumor suppressors RB and p16/CDKNaA or an unknown tumor suppressor on CHR19q Grade II: Well-differentiated Diffuse astrocytoma – poorly defined, infiltrative tumor that expands and distorts the brain (ranging in firmness and size) with the ability to remain static or slowly progress over years Morphology: ↑ glial cellularity; Variable nuclear pleomorphism; Feltwork of fine astrocytic processes (GFAPpositive); Indistinct transition between neoplastic and normal tissue Survival – 5+ years: Eventually, deterioration with more rapid growth transforms into a higher grade, impacting the mass and adjacent tissues Grade III: Anaplastic astrocytoma Morphology: More densely cellular with More nuclear pleomorphism (than Grade II) with Mitotic figures Gliomas Grade IV: Glioblastoma (or glioblastoma multiforme) – variation in gross appearance (with firmness and color) Non-infiltrating astrocytomas: Grade I: Pilocytic astrocytomas – most common non-infiltrating astrocytoma in children and young adults within the cerebellum, very slowly growing and appearing well-circumscribed or infiltrative and cystic Morphology: Most densely cellular with Most nuclear pleomorphism; Necrosis; Vascular or endothelial cell proliferation Poor prognosis: 15 months with surgical resection followed by radiation therapy and chemotherapy Morphology: Bipolar cells with Meshwork of long, thin “hairlike” processes (GFAP-positive) Causes: NF1 (loss of neurofibromin); p53 (RARELY); Spontaneous Treatment: Surgical resection Oligodendrogliomas (5-15%) – located in the white matter of the cerebrum in individuals ages 40-60, causing neurologic complaints and seizures (for years) Morphology: Well-circumscribed, gelatinous, grey masses with cysts, focal hemorrhaging, and calcification Sheets of cells with spherical nuclei (containing granular chromatin) surrounded by clear cytoplasm, containing Delicate meshwork of anastomosing capillaries; Calcification (90%) Causes: Loss of heterozygosity of CHR1p and CHR19q (80%) Better prognosis: 5-10 years with surgery, chemotherapy, or radiation therapy (and progression to higher grades within 6 years) Gliomas Ependymomas – arise next to the ventricular system (e.g., fourth ventricle in individuals ages 1-20; spinal cord in adults) Causes: NF2 on CHR 22 in the spinal cord; mutations in CHR9 in supratentorial lesions Morphology: Solid or papillary masses extending from the ventricular floor Cells with spherical nuclei (containing granular chromatin), forming glandlike round or elongated rosettes/canals with long processes extending into a lumen Perivascular pseudorosettes – arrangement of tumor cells around vessels with an intervening zone of thin ependymal processes directed toward the vessel wall Treatment: Surgical ependymomas Poor resection with supratentorial and spinal prognosis: 5 years (50%) with Posterior fossa ependymomas are associated with hydrocephalus Impossibility of excision from the brainstem Other Brain Tumors Subependymomas – asymptomatic and solid (possibly calcified), slowgrowing nodules attached to the ventricular lining Morphology: Clumps of ependymal-appearing nuclei scattered in a dense, fine, glial fibrillar background Choroid plexus papillomas – located along the choroid plexus in children (commonly in association with the lateral ventricles), causing hydrocephalus Colloid cyst of the third ventricle – non-neoplastic cystic lesion attached to the roof of the third ventricle in young adults, obstructing the foramina of Monro (and causing noncommunicating hydrocephalus with headaches) Fatal Morphology: Thin, fibrous capsule with low to flat cuboidal epithelial lining, containing gelatinous proteinaceous materal Neuronal Tumors Ganglioglioma – most common CNS tumor of mature-appearing ganglion cells with admixed glial neoplasm, appearing in the temporal lobe Seizures Slow growing until anaplastic Rapid progression Morphology: Irregularly clustered ganglion cells with random orientation of neurites Treatment: Surgical resection Dysembryoplastic neuroepithelial tumor – a rare, low-grade temporal lobe tumor of childhood that causes seizures Good prognosis: Surgical resection Attenuation of the overlying skull? Longterm presence of tumor Central neurocytoma – a low-grade neuronal neoplasm in the ventricular system (e.g., third and fourth ventricles) with evenly spaced, round, uniform nuclei and islands of neuropil Poorly Differentiated Neoplasms Neuroectodermal-originating tumors are often poorly differentiated, retaining primitive and undifferentiated cells Medulloblastoma (20%) – most common undifferentiated, highly malignant neoplasm in the cerebellar midline of children, leading to hydrocephalus Morphology: Well-circumscribed, grey, friable tumor, extending to the cerebellar folia (to involve the leptomeninges) Sheets of anaplastic cells: Small tumor cells with minimal cytoplasm and elongated, crescentshaped, hyperchromatic nuclei; Mitoses with markers of cellular proliferation (e.g., Ki-67); Possible presence of Homer Wright rosettes or GFAP-positive phenotypes Poor prognosis: 5 years + Total excision and Irradiation (75%) with Loss of CHR17p Iso-CHR17q; MYC amplification Atypical teratoid/Rhabdoid tumor – highly malignant posterior fossa or supratentorial tumor of young children Morphology: Large tumors with softer consistency, spreading to the brain surface Rhabdoid cells with immunoreactive eosinophilic cytoplasm (containing intermediate filaments), sharp cell borders, and eccentrically-located nuclei; Mitoses Poor prognosis: <1 year with Deletions of hSNF5/INI1 (chromatin remodeling) in CHR22 (90%) Other Parenchymal Tumors Primary CNS lymphomas – most common aggressive multifocal CNS neoplasm within the brain parenchyma of the immunosuppressed, originating from B-cells (with latent Epstein-Barr viral infection) Late complication (rare): Nodal, bone marrow, or extra-nodal involvement outside of the CNS Poor prognosis: Chemotherapy Morphology: Expression of BCL-6 by diffuse large, B-cells Germ cell tumors – located at the midline of the pineal and suprasellar regions in children (90%) Epidemiology: Japanese (10%); European (0.2-1%) Histological classification of brain cell tumors exhibits metastasis of gonadal germ cell origins Pineal parenchymal tumors – lesions arising from pineocytes of the pineal gland Pineocytomas – low-grade, well-differentiated lesions with neuropil islands and cells with small, spherical nuclei in adults Pineoblastomas – high-grade, poorly differentiated tumors of densely packed small cells, exhibiting necrosis and mitoses, in children Meningiomas Meningiomas – slow-growing benign tumors attached to the dura mater, arising from the arachnoid meningothelial cells, or within the ventricular system, arising from the stromal arachnoid cells of the choroid plexus, in female adults Causes: Loss of NF2 (merlin) on CHR22q12 Associated with tumor presence at multiple sites (with acoustic neuromas or glial tumors) Risk: Prior radiation therapy (with reduced risk of recurrence) Express progesterone receptors, growing rapidly during pregnancy Histologic patterns: Syncytial; Fibroblastic; Psammomatous; Secretory; Microcystic Symptoms: Vague nonlocalizing symptoms with focal compressive findings Morphology: Round masses with well-defined dural bases, compressing the underlying brain, extending into the overlying bone (but easily separable); Encapsulated surface with thin, fibrous tissue and a bosselated/polypoid appearance; Presence of calcified psammoma bodies L12-L13 CEREBROVASCULAR DISEASES Cerebrovascular Disease Cerebrovascular disease – injury to the brain due to altered bloodflow due to ischemia or hemorrhaging Stroke 3rd leading cause of death in the U.S. (following heart disease and cancer) and most prevalent neurologic disorder The brain is a highly aerobic tissue, requiring a constant supply of oxygen and glucose through the blood Hypoxia – impaired oxygenation to the tissues by lowered PO2, impairment of the blood’s oxygencarrying capacity, or inhibition of O2 use by the tissues Ischemia – transient or permanent interruption of normal circulatory bloodflow due to a reduction in perfusion pressure (e.g., hypotension) or small-/large-vessel obstruction Global cerebral ischemia – a generalized reduction of cerebral perfusion (e.g., hypotension) Focal cerebral ischemia – follows a reduction or cessation of bloodflow to a localized area due to a smallvessel disease (e.g., vasculitis; occlusion secondary to arteriosclerotic lesions with hypertension) or large-vessel disease (e.g., embolic or thrombotic arterial occlusion associated with artherosclerosis) Infarction – necrosis caused by impaired oxygenation from an obstruction to bloodflow Hemorrhage – results from ruptured blood vessels due to hypertension or aneurysms Global Cerebral Ischemia Mild cases of a severe hypotensive episode – a transient post-ischemic confusional state followed by complete recovery and no irreversible damage May have regions of selective vulnerability (e.g., neurons) based on cerebral bloodflow and metabolic requirements Severe cases – widespread neuronal death independent of regional vulnerability (in which survivors remain in a persistent vegetative state or become “brain dead”) “Brain death” – irreversible diffuse cortical injury and brainstem damage and absent cerebral perfusion Morphology: Edematous and swollen brain, producing widened gyri and narrowed sulci Irreversible ischemic injury (i.e., infarction): Early changes (12-24 hrs): Acute neuronal changes (i.e., red neurons) with microvacuolization followed by eosinophilia of the cystoplasm and subsequent nuclear pyknosis and karyorrhexis Infiltration of neutrophils Subacute changes (24 hrs-2 wks): Tissue necrosis; Influx of MOs; Vascular proliferation; Reactive gliosis Repair (2+ wks): Removal of necrotic tissue; Loss of normally organized CNS structure; Gliosis Focal Cerebral Ischemia Cerebral arterial occlusion Focal ischemia Infarction (if sustained) of a specific region Extent of tissue damage depends on the duration of the ischemia and the adequacy of collateral flow (e.g., Circle of Willis) Causes: Embolization from a distant source Branches of the middle cerebral artery Thrombosis associated with artherosclerosis Bifucation of the carotid artery, Origination of the middle cerebral artery, or Ends of the basilar artery Sources: Cardiac mural thrombi; Thromboemboli arising from arteries (e.g., plaques within the carotid arteries) Predisposing factors: Myocardial infarct; Valvular disease; Atrial fibrillation “Shower embolization” – fat embolism that occurs after fractures, causing generalized cerebral dysfunction in higher cortical areas and unconsciousness Embolization of bone marrow following trauma Widespread hemorrhagic lesions Morphology: Narrowing of the lumen with anterograde extension (and possible fragmentation and distal embolization) Predisposing factors: Hypertension; Diabetes Vasculitides: Infectious vasculitis – associated with immunosuppression and opportunistic infections of Aspergillosis and CMV encephalitis) Polyarteritis nodosa (and other non-infectious vasculitides) – involve the cerebral vessels, causing infarcts throughout the brain Primary angiitis – an inflammatory disorder of the small-/medium-sized parenchymal and subarachnoid vessels, causing chronic inflammation, multinucleated giant cells, and destruction of vessel walls Infarcts Red hemorrhagic infarction (A) – characterized by multiple (and confluent) petechial hemorrhages associated with embolisms (secondary to reperfusion of damaged vessels and tissues) Pale, anemic nonhemorrhagic infarction (B) – associated with thrombosis Deficits are determined by the anatomic distribution of the resultant damage (and not underlying pathologic process) Hypertensive Cerebrovascular Disease Effects of hypertension (on the brain): Lacunar infarcts – single or multiple, small, cavitary infarcts as a result of occlusion of the deep penetrating arteries that supply the basal ganglia and white matter from arteriolar sclerosis Slit hemorrhages – slitlike cavities surrounded by brown discoloration as a result of the resorption of small hemorrhages caused by ruptured small penetrating vessels Hypertensive encephalopathy – acute syndrome arising from malignant hypertension, causing diffuse cerebral dysfunction (e.g., headaches, confusion, vomiting, convulsions) Coma Requires a reduction in intracranial pressure Hypertensive Cerebrovascular Disease Massive hypertensive intracerebral hemorrhage – rupture of a small intraparenchymal vessel that causes a hemorrhage and the sudden onset of neurologic symptoms (e.g., stroke) Causes: Spontaneous in middle to older adults; Hypertension; Cerebral amyloid angiopathy (CAA) Hypertension (50%) – most common underlying cause of primary brain parenchymal hemorrhage (causing death in 15% of individuals with chronic hypertension), causing accelerated artherosclerosis in larger arteries and hyaline arteriosclerosis in smaller vessels (and proliferative changes and necrosis of arterioles in severe cases) Cerebral amyloid angiopathy (CAA) – deposition of amyloidogenic peptides in the walls of small-/medium-sized meningeal and cortical vessels, weakening the vessel walls Charcot-Bouchard microaneurysms – development of minute aneurysms associated with chronic hypertension Acute hemorrhages – characterized by the extravasation of blood with compression of the adjacent parenchyma Chronic hemorrhages – exhibit an area of cavitary destruction of the brain with a rim of brown discoloration Cerebral autosomal dominant anteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) – a rare hereditary form of stroke caused by mutations in the gene for Notch3 receptor, causing recurrent strokes and dementia Ganglionic hemorrhages – hemorrhage occurs in the basal ganglia and thalamus Lobar hemorrhages – hemorrhage occurs in the lobes of the cerebral hemispheres May appear asymptomatic if smaller regions are affected or be clinically devastating if larger portions of the brain and ventricular system are affected Possible gradual resolution of the hematoma Subarachnoid Hemorrhage Subarachnoid hemorrhage – result of a ruptured saccular (berry) aneurysm (or extension of a traumatic hematoma, rupture of a hypertensive intracerebral hemorrhage in the ventricular system, vascular malformation, or tumors) Saccular aneurysm (2%) – most common type of intracranial aneurysm commonly located near major arterial branch points in the anterior circulation (90%) with a bright red, shiny surface and thin, translucent walls Causes: Spontaneous; Genetic and Mendelian disorders (e.g., Polycystic kidney disease, Ehlers-Danlos syndrome Type IV, NF1, Marfan syndrome) Develop over time due to an underlying defect in the vessel Unruptured saccular aneurysm – a thin-walled outpouching at an arterial branch point of the Circle of Willis (or other major vessel) Rupture commonly occurs in females ages 50+ due to acute increases in intracranial pressure, causing blood to fill the subarachnoid space and a sudden, excruciating headache before losing consciousness Death (25-50%) or Improved symptoms with continual bleeding Early phase: Increased risk of ischemic injury from vasospasm Healing phase: Meningeal fibrosis and scarring Obstruction of CSF flow and Interruption of CSF resorption Other aneurysm types: Fusiform atherosclerotic of the basilar artery, Mycotic, Traumatic, and Dissecting Cerebral infarction L14 DEMYELINATING DISORDERS AND SPONGIFORM ENCEPHALOPATHIES Demyelinating Diseases Demyelinating diseases – acquired conditions characterized by damage to myelin with relative preservation of the axons, impacting the transmission of electrical impulses along the axons Limited by the capacity to regenerate myelin and the degree of secondary damage to axons Types: Immunological reactions Infections (e.g., Progressive (e.g., Multiple sclerosis) multifocal leukoencephalopathy from JC polyoma virus) that damages myelin Inherited disorders (e.g., Leukodystrophies) that affect the synthesis or turnover of myelin Demyelinating Diseases Multiple sclerosis (MS) – the most common autoimmune demyelinating disorder characterized by relapsing and remitting episodes of neurologic deficits caused by an immune response to myelin sheaths, creating white matter lesions in female adults (1 in 1,000) Causes (genetic and environmental): MHC isDR2 extended haplotype Initiated by CD4+ TH1 and TH17 cells that react to self-myelin Ags, secreting IFN-γ to activate MOs and promote the recruitment of neutrophils, respectively (possibly due to EBV) Morphology: Multiple, well-circumscribed, depressed, glassy, grey-tan, irregularly-shaped plaques that are firmer than the surrounding white matter (and occur adjacent to the lateral ventricles, optic nerves and chiasm, brainstem, ascending/descending fiber tracts, and cerebellum) Ongoing myelin breakdown with excess MOs containing lipid-rich, PAS-positive debris (as perivascular cuffs along the outer lesion edge) Relative preservation of axons and depletion of oligodendrocytes with each plaque (with prominent gliosis and astrocytic proliferation) Symptoms: Unilateral vision impairment (due to CN II), causing optic neuritis and retrobulbar neuritis; Brainstem dysfunction (e.g., ataxia, nystagmus, internuclear ophthalmoplegia); Spinal cord lesions causing motor and sensory impairment, spasticity, and loss of bladder function Diagnosis: CSF: Mildly elevated protein and moderate pleocytosis; ↑ IgG levels Immunoelectrophoresis: Oligoclonal IgG bands – signify the presence of activated self-reactive B-cell clones MRI with contrast: Gadolinium-enhancing lesions to assess disease progression Demyelinating Diseases Neuromyelitis optica – synchronous bilateral optic neuritis and spinal cord demyelination, causing necrosis of white matter and vascular deposition of immunoglobulin and complement (through humoral-mediated immunity) CSF: Excess wbcs (e.g., neutrophils) Express antibodies to aquaporins (responsible for the maintenance of astrocytic foot processes and BBB) Acute disseminated encephalomyelitis (ADEM)/Perivenous encephalomyelitis – a rapidly progressive, diffuse, monophasic demyelinating autoimmune disease that follows a viral infection or immunization, causing a headache, lethargy, and coma Complete recovery (80%) Acute necrotizing hemorrhagic encephalomyelitis (ANHE)/Acute hemorrhagic leukoencephalitis of Weston Hurst – a sudden, hyperacute syndrome of demyelination in children and young adults following an upper respiratory tract infection Fatal (with deficits in most survivors) Central pontine myelinolysis – characterized by symmetric demyelination (with relative preservation of the axons and no inflammation) of the basis pontis and pontine tegmentum (associated with hyponatremia), causing rapidly progressive quadriplegia Spongiform Encephalopathies Prion diseases – transmissible neurodegenerative disorders due to the spreading of misfolded prion protein (PrP), causing “spongiform change” (i.e., intracellular vacuoles in neurons and glia) that incite progressive dementia Misfolding: α-helix containing isoform (PrPC) Abnormal β-pleated sheet isoform (PrPX) Acquires resistance to digestive proteases (e.g., proteinase K) Facilitates the conversion of other PrPC proteins Accumulation in neuronal tissue Creutzfeldt-Jakob disease (CJD) – most common prion disease that manifests as early subtle changes in memory and behavior followed by rapidly progressive dementia in individuals ages 70+ Uniformly fatal (7 months from onset) Causes: Sporadic (85%); Familial mutation in PRNP gene Startle myoclonus – pronounced involuntary jerking contractions on sudden stimulation Morphology: Spongiform transformation of the cerebral cortex and deep grey matter (e.g., caudate, putamen) Uneven, microscopic vacuoles with the neuropil (and stained proteinase K-resistant tissue) Variant Creutzfeldt-Jakob disease (vCJD) – CJD-like illness in young adults, causing behavioral disorders with slowly progressive neurological dysfunction (transferred through blood products) Fatal familial insomnia – neuronal loss and reactive gliosis in the anterior ventral and dorsomedial nuclei of the thalamus, leading to sleep disturbances and ataxia, autonomic disturbances, stupid, and coma (within 3 years) Iatrogenic transmission through corneal transmission, deep implantation electrodes, and contaminated preparations of human GH Cause: Familial mutation in PRNP gene (without spongiform transformation) Others types: Gerstmann-Sträussler-Scheinker syndrome (GSS), Fatal familial insomnia, and Kuru (in humans); Scrapie (in sheep and goats); Mink-transmissible encephalopathy; Chronic wasting disease (of deer and elk); Bovine spongiform encephalopathy L15 NEURODEGENERATIVE DISEASES Neurodegenerative Diseases Neurodegenerative diseases – diseases of grey matter characterized by the progressive selective loss of neurons with secondary changes in white matter tracts Histology: Inclusions of protein aggregates resistant to degradation (through the ubiquitin-proteasome system) Cerebral Cortex Alzheimer’s disease – major cortical degenerative disease characterized by insidious impairment of higher intellectual function (with changes in mood and behavior), presenting with dementia (through the progressive loss of cognitive function, memory, and aphasia) Epidemiology: Incidence of symptoms increases with age (peaking at age 50) Cause: Duplications (and point mutations) on the APP locus of CHR21 Risk: ApoE locus of CHR19 ε4 allele increases the risk, lowering the age of onset Process: Extracellular domain cleavage followed by intramembranous γ-secretase complex cleavage Inclusion: Aβ peptides derived through APP (cell surface receptor with a transmembrane Aβ domain) processing Non-amyloidogenic pathway: Cleavage by α-secretase generates a soluble component –not Aβ Amyloidogenic pathway: Cleavage by β-secretase at the N-terminal domain generates Aβ, allowing it to aggregate into small oligomers and eventually into large aggregates and fibrils Initial symptoms (dependent on the density of tangles >> plaques) of forgetfulness followed by language deficits and the loss of computational skills and learned motor skills Profound disability with incontinence, muteness, and immobilization (within 5-10 years) Secondary intercurrent disease (e.g., pneumonia) leads to mortality Cerebral Cortex Morphology: Cortical atrophy with widened cerebral sulci; Ventricular enlargement (i.e., hydrocephalus ex vacuo) Neurofibrillary tangles and Neuritic (senile) plaques Severe neuronal loss and Reactive gliosis Neurofibrillary tangles – bundles of paired helical and straight filaments in the cytoplasm that displace or encircle the nucleus (visible with silver Bielschosky staining) Helical filaments – composed of abnormally hyperphosphorylated forms of protein tau (an enhancer of microtubule assembly) Neuritic plaques – focal, spherical clusters of dilated, twisted, neuritic processes centered around a central Aβ amyloid core (and clear halo) from a larger APP Diffuse plaques – deposit Aβ peptides in the absence of the surrounding neuritic reaction (as an early stage of plaque development) Cerebral amyloid angiopathy (CAA) Granulovacuolar degeneration – the formation of small, clear intraneuronal cytoplasmic vacuoles, containing argyrophilic granules Hirano bodies – elongated, glassy, eosinophilic bodies consisting of paracrystalline arrays of beaded actin filaments Cerebral Cortex Frontotemporal dementias (FTDs) – a group of disorders that undergo atrophy of the temporal (language) and frontal (personality) lobes, causing progressive deterioration of language and changes in personality, due to the accumulation of tau-containing deposits FTD with Parkinsonism – genetic disorder with the clinical syndrome of FTD accompanied with Parkinson’s-like symptoms Pick disease – rare, progressive atrophic dementia characterized by early behavioral changes with associated personality and language disturbances Progressive supranuclear palsy – illness characterized by truncal rigidity with disequilibrium and nuchal dystonia; pseudobulbar palsy and abnormal speech; ocular disturbances (e.g., vertical gaze and eye movement difficulties); and progressive dementia in males age 50-80 Fatal (within 5-7 years after onset) Corticobasal degeneration – a disease characterized by heterogeneous extrapyramidal symptoms in the elderly FTD without tau pathology – possess ubiquitin-containing inclusions in the cortical layers of the temporal and frontal lobes and dentate gyrus Vascular dementia – irreversible and progressive cognitive disorder associated with vascular injury to the brain, causing widespread infarction and diffuse white matter injury Strategic infarcts – embolic infarcts at the hippocampus, dorsomedial thalamus, or cingulate gyrus Basal Ganglia and Brainstem Parkinson’s disease (PD) – characterized by the triad of bradykinesia, “pill-rolling” tremors, and rigidity and associated autonomic and cognitive dysfunction (e.g., dementia) due to a striatal dopamine deficiency Causes: Autosomal dominant - α-synuclein gene; Autosomal recessive - DJ-1, PINK1, and parkan genes; Sporadic - Mutation in LRRK2 (i.e., cytoplasmic kinase) gene Treatment: Replacement therapy with Levodopa (L-dopa) (with tolerance) Morphology: Diminished pallor (due to a loss of pigmented catecholaminergic neurons) of the substantia nigra and locus ceruleus (with associated gliosis); Lewy bodies within the remaining neurons Lewy bodies – single or multiple cytoplasmic, eosinophilic, ovoid inclusions composed of α-synuclein filaments with a dense core and surrounding halo Parkinsonism – a syndrome with similar symptomology to PD, causing diminished facial expression (e.g., masked facies), stooped posture, bradykinesia, shuffling gait, “pill-rolling” tremors Causes: Drug-induced (e.g., dopamine antagonists, toxins) Basal Ganglia and Brainstem Huntington disease (HD) – relentlessly progressive autosomal dominant disease characterized by jerky, hyperkinetic movements of the entire body (i.e., chorea) and dementia in individuals ages 40-60 Death (within 15 years) Cause: Polyglutamine (CAG) repeat expansion >36 (huntingtin) on CHR4p16.3 Morphology: Atrophy of the caudate nucleus (and putamen), globus pallidus, and frontal lobe; Dilation of the lateral and third ventricles Severe loss of striatal neurons in the tail of the caudate nucleus (with later degeneration in the putamen) Dysregulation of the basal ganglia modulation of motor output, causing choreoathetosis