Neurodegenerative Disease

· Tau-opathies vs. Synucleinopathies

o Tau

§ Alzheimers Disease

§ Pick's Disease ("3 repeat")

§ PSP ("4 repeat")

§ Corticobasal Degeneration

o alpha-synuclein

§ Parkinsons Disease

§ Lewy Body Disease

§ Multiple System Atrophy (including shy-drager and olivopontocerebellar atrophy)

Disease	Protein	Pathology	Miscellaneous
Alzheimer’s	A-beta, tau	Plaques, tangles	Related to Down’s syndrome
Parkinson’s	alpha synuclein	Lewy bodies
Huntington’s	Huntingin	nuclear inclusions	trinucleotide repeat disorder (ch 4)
ALS	Neurofilament	Neuronal aggregates, bunina bodies (like Lewy bodies but with ubiquitin)	superoxide dysmutase mutation (autosomal dominant) – oxidative stress?
PSP	Tau	tangles

• Alzheimer’s – 7% of elderly population, M=F, often family history
• Mid adult onset of slowly progressive dementia (initially memory, then progresses to other cognitive functions)
• Accounts for 70% of progressive dementia in adults
• Familial form occurs in 10% of patients and is autosomal ominant (chromosome 21)
• Single most important risk factor is age
• Dementia is present in 5% of population > 65 years and 20% of population > 80 years
• Autopsy studies show that 50% with dementia have Alzheimer’s and another 20% have Alzheimer’s plus vascular disease
• Pathology:  Neuronal loss in cerebral cortex, nucleus basalis, locus ceruleus, and Raphe nucleus with neurofibrillary tangles and senile plaques, cerebrovascular amyloid deposition
• Diffuse atrophy with decreased neurons/synapses in neocortex and hippocampus
• Neurofibrillary tangles – intracytoplasmic paired helical fragments immunoreactive for tau
• Neuritic amylolid plaques – core of beta-amyloid
• Hirano bodies – rod-shaped eosinophilic intracytoplasmic inclusions
• Decreased acetylcholine, fewer neurons in basal nucleus of Meynert
• medial temporal lobes shrink faster
• amyloid - diffuse and neuritic plaques
• neurofibrillary tangles - hyperphosphylated, ubiquitinated tau
• progression of neurofibrillary involvement:
• 1-2 (entorhinal cortex, transentorhinal stage) 60% intact, 20% mild impairment, 20% dementia
• 2-3 (limbic stage, in hippocampus) 30% intact, 30% mild impairment, 40% dementia
• 4-5 (neocortical stage) 10% intact, 20% mild impairment, 70% dementia
• Parkinson’s disease (paralysis agitans)
• 40-50 years old, M>F, 1% of elderly population
• Mid to late adult onset of slowly progressive extrapyramidal dysfunction
• Bradykinesia, pill-rolling tremor, rigidity, dementia
• Stooped posture, bradykinesia, rhythmic tremor of limbs which subsides with active movement, masked fascies
• Dementia occurs in one-third of advanced cases
• Pathology:  Neuronal loss in substantia niagra with reactive gliosis and Lewy bodies (eosinophilic cytoplasmic inclusions); decreased dopamine in caudate and putamen
• Decreased neuromelanin and neurons in substantia nigra pars compacta, locus ceruleus, dorsal motor nucleus of vagus – tyrosine hydroxylase is rate-limiting step in dopamine production
• Lewy bodies – eosinophilic intracytoplasmic, neurofilament with laminated core and clear halo
• Can be idiopathic, CO, Mn, MPTP, von Ecomo encephalitis (1930’s) – no lewy bodies
• Drugs causing parkinsonism: Manganese, MPTP, ethanol/methanol, disulfuram, carbon monoxide, cyanide
• affects all catecholaminergic nuclei
• lewy bodies (also parkinson's plus: MSA, PSP, OPCA)
• Medications to treat:
• MAO inhibitors – slows progression early
• Anticholinergics for rest tremor (Artane, benztropine)
• Beta blockers for action tremor (propranolol)
• Amantadine – increases release of dopamine (releases stored dopamine from presynaptic terminals)
• Bromocriptine or pergolide – stimulate dopamine receptors
• Levodopa and carbidopa – peripheral dopadecarboxylase inhibition allows central activity only; for akinesia and postural imbalance; Given in combination with carbidopa to prevent destruction in periphery
• Anti-cholinergics
• Parkinson’s Plus
• PSP (Progressive Supranuclear Palsy) (Stiele-Richardson-Olzenski)
• M>F, onset 50-60 years (sometimes after pneumonia), death 10 years later
• Downgaze palsy first, then loss of all eye movements
• Pseudobulbar palsy, Gait ataxia, Parkinsonism, Frontal lobe signs, axial rigidity and mild dementia
• Loss of neurons in midbrain
• vertical ophthalmoplegia, postural instability
• Decreased intellect/vision/speech, gait palsies, vertical gaze palsies, loss of voluntary eye movements, loss of optokinetic nystagmus, decreased oculocephalic reflexes, pseudobulbar palsy, axial rigidity without tremor
• Atrophy in midbrain (superior colliculus and subthalamic nucleus), fewer neurons in globus pallidus/substantia nigra/brainstem nuclei ventriculomegaly
• unlikely to respond to dopamine
• Pathology:  Upper brainstem and basal ganglionic neuronal loss, neurofibrillary tangles, gliosis, and granulovacuoloar degeneration, Neurofibrillary tangles seen (different than those in Alzheimer’s) in GPi and STN, also cortex and cerebellum
• Prognosis:  Median survival is <6 years with respiratory complications being the usual cause of death
• MSA (Multiple System Atrophy)
• early dysautonomia, cerebellar dysfunction
• stiatonigral degeneration
• some initial dopamine response
• synuclein inclusions
• autonomic dysfunction (anhidrosis/impotence/incontinence/orthostasis), poor response to dopamine
• Two Types:
• Shy-Drager – 50 years old, death 7 years, M>F, usually sporadic, loss of cells in putamen and intermediolateral spinal cord
• Progressive autonomic dysfunction
• Symptoms: Orthostatic hypotension, Impaired GI motility, Urinary/sexual dysfunction
• Pathology: Degeneration of sympathetic pregaglionic neurons of the intermediolateral cell column of the thoracic and upper lumbar spinal cord
• Olivopontocerebellar degeneration – 15 years, usually sporadic, ataxia in lower extremities, atrophy in pons/inferior olive/cerebellar cortex
• CBGD (Combined Basal Ganglia Degeneration)
• cortical dysfunction (alian limb)
• no response to dopamine
• may be unilateral
• Lewy Body Disease – Lewy bodies seen in cortex as well (unlike Parkinson’s)
• Can cause cortical dementia
• Parkinsonism, demential with psychotic features, frontal degeneration
• staged 1-3 (brainstem, limbic, cortical)
• cross with degree of AD to determine diagnosis
• Pick’s Disease – younger than Alzheimer’s, F>M, sporadic (occasionally autosomal dominant)
• Similar to Alzheimer’s but more frontal lobe dysfunction, frontotemporal atrophy, no plaques or tangles
• Progressive dementia with prominent dysphasia
• Onset occurs between ages of 40-60 with female predominance
• Accounts for approximately 5% of cases of dementia
• Symptoms:  Apathy and abulia progress to early, prominent dysphasia with palilalia, and impairment of gait
• Pathology:  Focal frontotemporal lobar atrophy and neuronal loss with agyophilic inclusions (Pick bodies)
• Prognosis:  Progresses over 2-5 years
• Pick bodies – intracytoplasmic eosinophilic inclusions – especially in hippocampus
• Gray matter and white matter equally affected
• Death 3-5 years
• frontotemporal degeneration, tau
• inclusions look like another nucleus
• Striatonigral degeneration
• 50 years old
• Rigidity, parkinsonism, akinesia, syncope, atrophic brown putamen, depigmented substantia nigra
• No lewy bodies or neurofibrillary tangles are seen
• Huntington’s – onset 30’s, survive 30 years
• Autosomal dominant, chromosome 4, M=F
• Early to middle adult onset chorea with progressive dementia
• Small percentage present with a Parkinsonian syndrome
• Incidence is 7-10/100,000 population, M=F
• Starts with suspicious personality, then subcortical dementia, then chorea of hand/face
• Pathology:  Atrophy of the caudate nucleus and, to a lesser extent, putamen and globus pallidus; decrease of GABA and Ach
• Caudate atrophy with boxcar ventricles (cortex/putamen/globus pallidus spared), atrophy of striatum, cortical degeneration
• intranuclear accumulation of huntingtin (usu transported to cytoplasm)
• inclusions decrease risk of cell death
• Spiny neurons affected more than aspiny
• Decreased GABA and acetylcholine
• Increased norepinephrine and somatostatin
• onset of disease related to number of repeats
• Rx:  No known treatment

• Wilson’s disease (hepatolenticular degeneration) – M>F
• Autosomal recessive, chromosome 13
• Onset 10 years, liver disease (cirrhosis)/splenomegaly by 20 years
• Copper accumulates in brain
• Decreased ceruloplasmin, decreased serum copper, increased urine copper
• CT shows hypodense basal ganglia
• Kayser-Fleischer rings in deepest corneal layer around iris
• Alzheimer type II astrocytes seen
• Tremor, dysarthria, rigidity
• Spongy red degeneration in putaman and globus pallidus (opalski cells)
• Atrophy superior, middle, frontal gyri
• Low copper diet helps; also chelate with D-penicillamine

• Fahr’s disease (idiopathic basal ganglia calcification)
• calcified basal ganglia and cerebellar blood vessels especially around dentate; associated with renal disease and decreased PTH

• Paget’s Disease
• Associated with increased alkaline phosphatase
• Associated symptoms:
• CN XII palsy due to involvement of nerve along extramedullary course
• Deafness due to direct involvement of ossicles of middle ear on impingement by bone on CN VIII
• Loss of sight due to compression of CN II
• CN IX/X/XI compression producing dysphagia, dysphonia, or pain at the base of the occiput
• Enlargement of vertebral bodies, pedicles, and laminae produce narrowing of canal with spinal cord compression, especially in thoracic spine
• NPH (rare) – due to involvement at base of skull
• Tangier Disease
• Increased cholesterol, triglycerides producing atherosclerosis
• Asymmetric neuropathy, sensorimotor, fluctuating course
• Entire body pain and temperature sensory loss
• Homocysteinuria
• tall thin frame, arachnodactyly (like Marfan’s)
• mental retardation, strokes
• cystathione synthase deficiency
• Abetalipoproteinemia (Bassen Kornzweig Syndrome) – clinically similar to Friedrich’s ataxia
• Autosomal recessive
• Near absence of beta-lipoprotein and low cholesterol, fatty acids, and chylomicrons
• Retinal (macular) degeneration
• Acanthosis of RBC’s
• Chronic progressive neurologic deficit (cerebellum and peripheral nerves)
• Ataxia of gait, trunk, extremities
• Pes cavus and kyphoscoliosis
• Malabsorption syndrome
• Hartnup’s Disease – intestinal malabsorption of tryptophan; aminoaciduria
• Scaly erythematous rash on face
• Episodic ataxia
• Treatment with PO nicotinamide

• Friedrich’s Ataxia – most frequent hereditary ataxia
• Autosomal recessive, chromosome 9, M=F
• Onset 20 years, wheelchair 5 years after onset, death 10 years after onset
• Spares motor function
• Associated with cardiomyopathy and diabetes
• Degeneration of axons and myelin in posterior columns and spinocerebellar tracts
• Cerebellar purkinje, inferior vermis, inferior olive, brainstem nuclei, dorsal root ganglion, large peripheral myelinated nerves
• Mental status normal
• Starts lower extremities, then upper extremities, then speech

• degeneration of spinocerebellar tracts
• Loss of vibration and position sense, ataxia, dysarthria, decreased position sense
• Hypoactive DTR’s
• Club foot, kyphoscoliosis, vision loss (retinitis pigmentosa)
• Autosomal recessive, chromosome 9
• Normal intellect
• Diabetes and cardiomyopathy
• Dorsal column, spinocerebellar tract

• Familial Myoclonic Epilepsy – autosomal recessive, myoclonic seizures
• Lafora body disease – mid teens, dementia, cerebral atrophy
• Lafora bodies – basophilic intracytoplasmic polyglucosan inclusions; found diffusely in neurons, also heart, muscle, liver
• Baltic myoclonus – onset 1^st decade, purkinje atrophy

• Hallervorden-Spatz
• Onset late childhood, death 20 years later
• Sporadic (occasionally autosomal recessive)
• Extrapyramidal corticospinal dysfunction, dementia
• Basal ganglia hypodense on CT
• Brown atrophic globus pallidus and substantia nigra with iron deposition
• Acquired heptaolenticular degeneration
• Liver disease causes increased ammonia
• Often long-term TPN causing manganese toxicity
• Hypodense basal ganglia on T1
• Pseudolaminar necrosis, changes at gray-white junction
• Hepatic encephalopathy
• asterixis, mental status change, EEG slow waves; ammonia greater than 20; Alzheimer type II cells (large with vesicular nucleoli for increased production of glutamine synthetase to detoxify environment) in basal ganglia, cortex, substantia nigra; increased GABA
• Reye’s syndrome – nonicteric hepatic encephalopathy with influenza or varicella treated with aspirin; brain edema, liver failure, mortality 10%
• Uremic encephalopathy – no edema, peripheral polyneuropathy