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1

Why are cases of dementia increasing?

2

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)

3

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

4

What is delirium?

- Clouding of consciousness: altered clarity or awareness of the environment 

- Reduced capacity to shift, focus, and sustain attention to environmental stimuli 

5

What are the DSM-IV diagnostic criteria for dementia?

6

What are the DSM-IV criteria for delirium?

7

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 

8

What are the key features that distinguish dementia from depression?

9

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 

10

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

11

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 

12

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 

13

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 

14

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

15

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 

16

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 

17

What are these?

- Neuritic plaques in cortex on left 

- Neurofibrillatory tangles in hippocampus on right 

18

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 

19

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 

20

What are the risk factors for AD?

- STRONG: age, genetics, Down's

- WEAK: education level, mental inactivity, female gender, head injury, hypercholesterolemia, smoking 

21

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 

22

What does this image show?

- INC amyloid on PET imaging, characteristic of AD 

23

What does this image show?

- DEC glu utilization of FDG-PET imaging, characteristic of AD 

 

24

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 

25

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 

26

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 

27

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 

28

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 

29

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 

30

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)