A. Classification

1. Classified by primary central nervous system (CNS) area affected
2. Cerebral Cortex
   1. Alzheimer's Disease - USA prevalence >4 million
   2. Pick's Disease - USA prevalence ~5,000
   3. Diffuse Lewy Body Disease (Lewy Body Dementia)
   4. Frontotemportal Dementia - USA prevalence 40,000
   5. Spongiform Encephalophathies - prion related diseases (~400 cases per year)
3. Basal Ganglia
   1. Parkinson's Disease - USA prevalence >1 million (see below)
   2. Huntington's Disease (autosomal dominant) - USA prevalence 30,000
   3. Fahr's Disease - rare disorder of symmetric basal ganglia calcifications [9]
4. Brainstem and Cerebellum
   1. Spinocerebellar Ataxias - USA prevalence ~12,000
   2. Multiple System Atrophy (MSA: 3 subtypes)
   3. Friedrich's Ataxia
   4. Denatorubropallidouysian Atrophy
5. Motor System
   1. Amyotrophic Lateral Sclerosis - USA prevalence 20,000
   2. Spinal and Bulbar Muscular Atrophy
   3. Spinal Muscular Atrophy (SMA) [16]
   4. Familial Spastic Paraparesis (autosomal and recessive variants described)
   5. Familial Encephalopathy with Neuroserpin Inclusion Bodies [10]
6. Idiopathic inflammatory Diseases - including multiple sclerosis

B. Pathophysiology [3,11]

1. Nearly all neurodegenerative diseases involve abnormal processing of neuronal proteins
   1. Misfolded proteins
   2. Altered post-translational modifications
   3. Abnormal proteolytic cleavage
   4. Anomolous gene splicing
   5. Improper expression of proteins
   6. Diminished clearance of degraded proteins
2. The particular protein that is improperly processed determines which neurons affected
   1. These proteins cause apoptotic cell death of affected neurons
   2. This in turn leads to specific clinical manifestations (syndromes)
3. Positron Emission Tomography (PET) [8]
   1. PET scans with 18F-flurodeoxyglucose can be used to assess regional brain metabolism
   2. Brain metabolism is typically reduced or compromised in neurodegenerative disease
   3. PET scanning of patients presenting with dementia symptoms provides >90% sensitivity and ~75% specificity for neurodenegerative diseases
   4. PET scanning should be considered in patients with cognitive symptoms of dementia

C. Alzheimer's Disease (AD) [12]

1. Prevalence is >4 million people in USA
2. 100,000 deaths per year attributable to AD
3. Neuropathological Hallmarks
   1. Neurofibrillary Tangles
   2. Senile Plaques
   3. Unclear which of these initiates the other, or if they are independent
   4. Acetylcholine based neurons are primarily affected
4. Neurofibrillary Tangles
   1. Aggregations of microtubule associated protein tau (see below)
   2. The tau in these aggregates is hyperphosphorylated
5. Senile Plaques
   1. Also called neuritic plaques
   2. Accumulation of several proteins with inflammation around ß-amyloid deposits
   3. Nerve terminals degenerate around these areas
   4. These terminals also contain tau
   5. ß-amyloid also inhibits mitochondrial oxidative phosphorylation [15]
6. Progressive neuronal loss in specific brain regions
   1. Hippocampus
   2. Entorhinal cortex
   3. Association areas of neocortex
7. Tau Protein
   1. Tau is a microtuble associated protein
   2. Normally promotes assembly and stability of microtubule
   3. Protein is involved in many of the pathological features of AD
   4. Mutations in tau also clearly associated with secondary parkinsonism
8. Apolipoprotein E and Progression of AD
   1. Apolipoprotein E (ApoE) is produced mainly in astrocytes
   2. ApoE is carried by the low-density lipoprotein (LDL) receptor into neurons
   3. ApoE binds to neurofibrillary tangles
   4. There are 3 different variants in the ApoE gene and protein: Apo E2, Apo E3, and Apo E4
   5. Apo E4 high an increased affinity for the tangles, and increases ß-amyloid deposition
   6. Apo E4 is neither necessary or sufficient for AD development
   7. However, presence of the Apo E4 variant increases progression of AD
   8. Apo E4 is also synergistic with other causes of dementia in promoting mental decline [4]
9. Familial Early Onset AD
   1. Familial early onset AD syndromes are well known
   2. Mutations in presenilin 1 on chromosome (chr) 14q account for ~50% of early AD
   3. Mutations in presenilin 2 on chr 1 accounts for <1% of early AD
   4. Seven different mutations in ß-amyloid gene on chr 21 linked to early AD
   5. However, ß-amyloid (amyloid precursor protein) mutations account for <1% of early AD
   6. Presence of Apo E4 variant is synergistic with early onset AD mutations

D. Parkinson's Disease (PD) [12,13]

1. Second most common neurodegenerative disease (after AD)
   1. Sporadic forms are most common
   2. Familial forms are described
   3. PD has overlap syndromes (secondary parkinsonism) including:
   4. Progressive supranuclear palsy and frontotemporal dementia with parkinsonism
2. Common PD
   1. Affects ~2% of persons over age 65
   2. >500,000 people with PD in US
   3. Multiple genetic loci implicated in etiology of common PD [6]
   4. Common forms associated with mutations in tau genes [7]
3. Familial PD
   1. Most common familial PD due to mutations in parkin gene (autosomal recessive)
   2. Parkin is a ubiquitin carboxy-terminal hydrolase
   3. Very uncommon autosomal dominant form also reported
   4. Autosomal dominant form due to mutations in gene for alpha-synuclein
   5. Alpha-synuclein is a synaptic protein, coded on chromsome 4q21-23
   6. Many of these anomalies affect mitochondrial function [15]
4. Characteristic Symptoms
   1. Rigidity
   2. Bradykinesia (slow movements)
   3. Tremor
5. Pathology
   1. Due initially to loss of cells in substrantia nigra
   2. Depeltion of dopamine in the striatum
   3. Lewy bodies, large intracytoplasmic inclusions, are hallmarks of PD
   4. Lewy bodies occur primarily in melanin-containing neurons of substantia nigra
   5. Lewy bodies contain alpha-synuclein, ubiquitin, and proteasomal subunits
6. Pathophysiology
   1. Not well understood
   2. Current hypothesis is that mutations in protein degradation machinery lead to PD
   3. Abnormal proteolytic pathways lead to aggregations of proteins into Lewy bodies
   4. Related to diffuse Lewy body disease, a form of dementia
   5. May explain dementia symptoms ~25% of patients with PD (similar to AD)
   6. Alpha-synuclein inclusions are also found in patients with multiple system atrophy

E. Diffuse Lewy Body Disease [13,14]

1. Dementia with Lewy Bodies - may be second most common cause of dementia
2. Lewy Bodies
   1. Commonly found in PD and Lewy Body Disease
   2. Lewy Bodies are Eosinophilic neuronal bodies
   3. Lewy neurites are ubiquitin-positive neuronal processes
   4. Lewy bodies found in different areas of the brain in pure Lewy Body dementia versus PD
3. Patients have dementia and early movement disorders
   1. Progressive parkinsonism and early dementia
   2. Little or no resting tremor
   3. Early congnitive and psychiatric features
   4. Hallucinations, psychosis, behavior disorder may be present
4. Relatively common and may coexist with PD
5. Dopamine exacerbates psychiatric symptoms and motor symptoms do not improve
6. Striking deterioration with neuroleptics
7. Cognitive function can improve with central cholinesterase inhibitors

F. Spinocerebellar Ataxias (SCA) [1]

1. Autosomal dominant and recessive forms have been described
   1. Autosomal Dominant SCA Types 1, 2, 3, 6, 7, and 8
   2. Autosomal dominant forms have abnormal CAG repeats similar to Huntington's Disease
2. Type 1 SCA
   1. Linked to chr 6p23, ataxin 1 mutations
   2. Type 1: ataxia, dysarthria, dysphagoia
   3. Ataxia, dysarthria, dysphagia, amyotrophy, pyramidal signs
3. Type 2 SCA
   1. Linked to chr 12q24, ataxin 2 mutations
   2. Ataxia, dysarthria, slow saccades, sensorimotor neuropathy
   3. Extrapyramidal signs
   4. Rare dementia
4. Type 3 SCA
   1. Linked to chr 14q24.3-q31, ataxin 3 mutations
   2. Ataxia, cranial nerve deficits, exophthalmos
   3. Pyramidal and extrapyramidal signs
5. Type 6 SCA
   1. Linked to chr 19p13
   2. Mutations in the alpha-1a voltage dependent calcium channel
   3. Slowly progressive ataxia, dysarthria, nystagmus
   4. Hyporeflexia and loss of proprioception
6. Type 7 SCA
   1. Linked to chr 3p14-21.1, ataxin 7 mutations
   2. Ataxia, retinal degeneration, and blindness
7. Type 8 SCA
   1. Linked to chr 13q21, gene not identified
   2. Ataxia, dysarthria, nystagmus, spasticity
   3. Diminished vibration perception
8. Function of the ataxin proteins is not yet known
9. There are no disease modifying therapies at this time

G. Friedreich's Ataxia [1,5,15]

1. Autosomal recessive ataxia
2. Most common of the hereditary ataxias, ~1 per 50,000 persons
3. Linked to mutations in the frataxin gene on chromosome 9
   1. Frataxin is 210 amino acid protein found in the mitochondria
   2. Appears to be important for cellular energy metabolism
   3. Likely role in iron handling in mitochondria
   4. Found in all tissues studied to date
   5. Particularly prevalent in cardiac and skeletal muscle
   6. Also prevalent in dorsal root ganglia, cerebellar cortex and cerebral cortex
4. Mutations
   1. Variable length inserts of repeated GAA in the first intron of frataxin gene
   2. GAA insertions reduce expression of frataxin gene
   3. Larger GAA insertions correlate with earlier age of onset and more rapid progression
5. Onset of symptoms by age 20 with relentless progression
6. Symptoms and Signs
   1. Ataxia of all four limbs
   2. Cerebellar dysarthria
   3. Absent reflexes in lower limbs
   4. Sensory loss
   5. Pyramidal signs
   6. Skeletal abnormalities and hypertrophic cardiomyopathy common
   7. Pes cavus
7. Spinocerebellar ataxias may have similar symptoms

H. Familial Encephalopathy with Neuroserpin Inclusion Bodies [10]

1. Collins Bodies
   1. Neuronal inclusion bodies associated with neurodegeneration
   2. Eosinophilic inclusion bodies formed by neuroserpin aggregation
2. Mutations in neuroserpin associated with inclusion body formation
   1. These mutations destablize normal neuroserpin protein folding
   2. Specific neuroserpin mutations cause early versus late onset neurodegeneration
3. Symptoms
   1. Progressive myoclonic epilepsy
   2. Dementia
   3. Tremor
   4. Status epilepticus
   5. Dysarthria

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