Why are cases of dementia increasing?
What are the 4 common dementia syndromes?
- Alzheimer's (50-60%)
- Vascular dementia (10-20%)
- Dementia with Lewy bodies (10-15%)
- Frontotemporal dementia (Pick's disease)
What is dementia?
- Impairment of intellectual/cognitive function of sufficient severity to interfere with social or occupational activities
- NOTE: neither dementia or delirium are diseases -> they are symptoms
What is delirium?
- Clouding of consciousness: altered clarity or awareness of the environment
- Reduced capacity to shift, focus, and sustain attention to environmental stimuli
What are the DSM-IV diagnostic criteria for dementia?
What are the DSM-IV criteria for delirium?
What are the key features that distinguish dementia from delirium?
- DEMENTIA: cognitive deficit in multiple domains, usually, but not always incl memory
1. Progressive deterioration over mos to yrs
2. Cognitive impairment interferes w/activities of daily life
3. No disorder of alertness
- DELIRIUM: acute disorder usually associated with medical illness, drugs, metabolic, disorders, etc.
1. Deterioration over days to weeks; fluctuating course
2. Altered level of consciousness, excitable, delusions, hallucinations
What are the key features that distinguish dementia from depression?
What is Alzheimer's?
- Progressive neurodegenerative dementing disorder characterized by neuropathological findings of:
1. Loss of cerebral cortical neurons
2. Neuritic plaques containing beta-amyloid
3. Neurofibrillatory tangles
What are the essential criteria for a dx of Alzheimer's?
- Dementia confirmed by neuropsych tests
- Deficits + progressive worsening in memory + 1 or more areas of cognition
- No disturbances of consciousness
- Onset bt ages 40 and 90; most after 65
- Absence of other brain disease to explain dementia
What are some of the supporting/consistent criteria for an Alzheimer's diagnosis?
- Progressive deterioration of single cognitive area
- Impaired activities of daily living, altered behavior
- Family history of dementia
- Labs showing normal CSF, non-specific EEG, and atrophy on CT or MRI
- CONSISTENT: plateaus in course, associated depression, insomnia, incontinence, delusions, non-specific neuro findings later in disease, and CT or MRI normal for age
What are some inconsistent findings for Alzheimer's?
- Sudden or acute onset
- Focal neuro findings, e.g., hemiparesis
- Seizures or gait disorder at onset, or early in disease
What is the clinical presentation of Alzheimer's?
- Insidious onset after age 65 of deficits in recent memory, followed by deficits in attention, language, visual-spatial orientation, abstract thinking, judgment, and eventually personality
- Memory decline is the hallmark of cognitive change in AD (storage deficit) -> begins with recent events, but long-term memories affected as disease progresses
- These impairments should constitute a decline from the previous level of cognitive function, interfering with daily activities
- Motor signs and behavioral changes are typically typically appear later in the course of disease
What is the pathogenesis of Alzheimer's?
- Thought to be production and accumulation of beta-amyloid peptide, leading to formation of neurofibrillary tangles, oxidation & lipid peroxidation, glutamatergic excitotoxicity, inflammation, and activation of the cascade of apoptotic cell death
- Less favored, but still tenable hypothesis stresses tau-protein accumulation, heavy metals, vascular factors, and viral infections
- Natural course of AD averages 10 years
How is Alzheimer's diagnosed?
- PREMORBID: purely clinical, i.e., no definitive lab test
- POSTMORTEM: based on presence of histo evidence of 1) neuritic plaques, 2) neurofibrillatory tangles, and 3) neuron loss
1. Note the gross pathology attached here -> atrophy manifested by narrowing of gyri, and widening of sulci
What do you see here?
- NEURITIC PLAQUES: dystrophic neurites (synapses) containing tau aggregates in straight filament form, surrounding core of extra-cellular beta-amyloid
- NEUROFIBRILLATORY TANGLES: pyramidal cells filled with paired helical and straight filaments of aggregations of hyper-phosphorylated tau protein
What are these?
- Neuritic plaques in cortex on left
- Neurofibrillatory tangles in hippocampus on right
What are the genetics of Alzheimer's?
- EARLY ONSET: auto dom linked to chroms 21 (amyloid precursor protein; AD1 -> also tracks with Down's), 14 (presenilin 1; AD3), & 1 (presenelin 2; AD4)
1. Typically begins before age 65, and progresses more rapidly -> 5-10% of AD pts
- LATE ONSET: sporadic; 90-95% of AD pts
1. 3 risk factor genes (non-mendelian): chroms 19 (ApoE4; AD2), 12, and 10
How is ApoE implicated in AD?
- 3 alleles: 2, 3, 4 that participate in cholesterol transport
- ApoE4 is a risk factor for AD, contributing to about 50% of late-onset AD (carry 1 or 2 copies)
- Homozygosity for ApoE4 "virtually" assures that by age 80, pts will devo AD
1. E3/E4 combo next most likely to get AD, while E2/E3 least likely to devo disease (although they still can)
- NOTE: testing for this gene can't predict occurrence of AD in any individual pt (non-mendelian inheritance); it is simply a risk factor
What are the risk factors for AD?
- STRONG: age, genetics, Down's
- WEAK: education level, mental inactivity, female gender, head injury, hypercholesterolemia, smoking
What are the biomarkers for AD?
- Low CSF amyloid beta-42
- Elevated CSF tau protein
- Parietal-temporal and hippocampal atrophy on MRI (see attached image)
- INC amyloid on PET imaging
- DEC glu utilization of FDG-PET imaging
What does this image show?
- INC amyloid on PET imaging, characteristic of AD
What does this image show?
- DEC glu utilization of FDG-PET imaging, characteristic of AD
How is Ach implicated in AD?
- Nucleus basalis (of Meynert) atrophies in AD pts; this nucleus harbors neurons that heavily innervate neocortex using Ach
- Levels of Ach are significantly DEC in the neocortex of ppl w/AD -> this observation led to first successsful AD tx
- NOTE: attached image shows cholinergic distribution from NB to neocortex as blue arrows
What 2 enzymes have been targeted by drug companies to address the Ach problem in AD?
- Acetylcholine esterase (AchE)
1. Sample Rx's: Donepezil, Galantamine, Rivastigmine
- Butyrylcholinesterase (BuChE) made by astrocytes: also cleaves Ach
- Pharma companies have developed antagonists to both of these enzymes to be used in the tx of AD
What is the theory behind AD immunotherapy?
- To produce active immunization against beta-amyloid, or to produce passive immunization by giving synthetic Ab's to pts with AD
What are Lewy bodies?
- Eosinophilic, spherical inclusions w/halo appearance in cytoplasm of neurons of substantia nigra in pts w/PD
- Comprised of neurofilament proteins, alpha-synuclein, and ubiquitin
What is dementia with Lewy bodies?
- Dementing disease w/clinical characteristics of PD + early presenting dementia characterized frequently by hallucinations, delusions, and cognitive fluctuations
1. Similar or identical to PD, w/identifying difference being early onset of dementia, i.e., dementia presenting before or simultaneously with parkinsonian symptoms
- Lewy bodies are present in neocortex of DLB pts
- These pts don't respond as well to L-dopa
- Extremely sensitive to neuroleptic agents (anti-psychotics, which may be prescribed for hallucinations), which should be avoided in pts with DLB
What do you see here?
- Lewy bodies in neocortex
- Right image has immunoperoxidase stain for ubiquitin, which helps show Lewy bodies more readily by brown rxn product of neurofilaments, alpha-synuclein, and ubiquitin
- Additional images attached here
What are frontotemporal dementias? Describe their clinical features, physical exam, 3 principal varieties, and the 4 "tauopathies."
- Grouped of dementing disorders based on:
1. Anatomic distribution: atrophy of frontal and/or temporal lobes preferentially
2. Underlying molecular biology: ubiquitin and hyperphosphorylated tau protein in neurons, aka Pick bodies (+/- neurofibrillatory tangles)
- CLINICAL FEATURES: prominent personality and behavior changes w/less prominent memory loss early
1. Frequently misdiagnosed as personality disorders or late-onset psychiatric disorders
- PHYSICAL EXAM: usually reveals early prominent primitive or frontal reflexes (i.e., palmar grasp/glabellar reflex)
- 1/2 of pts have family hx of dementia in 1st-degree relative
- 3 principal varieties: 1) frontal varian FTD, 2) semantic dementia, 3) non-fluent aphasia (latter 2 commonly misdiagnosed bc no prominent behavioral/personality disturbances)
- TAUOPATHIES include: 1) Pick's disease w/or w/o Pick bodies, 2) FTD w/parkinsonism (FTDP-17), 3) Cortico-basal ganglionic degeneration (CBD), 4) Progressive supranuclear palsy (PSP)