1. The Dementias William S. Woodfin, M. D
The Dementias William S. Woodfin, M.D. Neurology Specialists of Dallas Clinical Assoc. Prof. of Neurology UT Southwestern Medical School

2. Definition
Dementia:The development of multiple cognitive deficits suffficiently severe to cause impairment in occupational or social functioning
Mild Cognitive Impairment: usually refers to a single cognitive domain

3. Classification Alzheimer’s Disease: Sporadic v. Familial
Parkinson Syndromes
Fronto-Temporal Lobar
Vascular
Infectious
Metabolic
Pseudodementia
Others

4. Differential Diagnosis of Dementia
Keywords: Diagnosis, Incidence
Differential diagnosis of dementia
Alzheimer’s disease (AD) is the most common cause of cognitive decline in the elderly.1 A substantial number of diseases can present with dementia and should be included in the differential diagnosis when evaluating a patient.
Numerous disorders mirror Alzheimer’s-type dementia, and dementia syndrome may have more than 1 etiologic factor in the geriatric patient. It is estimated that within the diagnosis of dementia, approximately 65% of patients present with AD. Vascular dementia (VaD) is the second most common cause of dementia. Other potential causes include Parkinson’s disease, Lewy body disease, and frontal lobe dementia.2,3
AD and VaD are easily confused because many symptoms are similar. One primary difference is that the onset of AD is gradual, while VaD begins abruptly and progresses in a stepwise manner. Also, in AD, deterioration in a broad range of intellectual abilities can occur without affecting motor abilities until advanced stages of the disease. In addition, in AD, focal signs and symptoms are generally absent. On the other hand, while AD may present a normal brain CT, a VaD patient will show evidence of stroke or stroke-related change. VaD patients frequently have an underlying vascular disorder while AD patients do not. In addition, there are a few causes of dementia that are reversible such as depression, effects of medication, vitamin B12 deficiency, and hypothyroidism. These causes need to be ruled out and treated appropriately.2,4
References: 1. Small GW, Rabins PV, Barry PP, et al. Diagnosis and treatment of Alzheimer disease and related disorders: consensus statement of the American Association for Geriatric Psychiatry, the Alzheimer’s Association, and the American Geriatrics Society. JAMA. 1997;278: Morris JC. Differential diagnosis of Alzheimer’s disease. Clin Geriatr Med. 1994;10: Zurad EG. New treatments of Alzheimer’s disease: a review. Drug Benefit Trends. 2001;137: Corey-Bloom J, Thal LJ, Galasko D, et al. Diagnosis and evaluation of dementia. Neurology. 1995;45:

5. Corticobasalganglionic
DEMENTIA SYNDROMES
Normopressure
Hydrocephalus
Vascular
Parkinsonism
Multiple
System Atrophy
FXTAS
Alzheimer’s
Disease
Lewy Body
Parkinson’s
Disease
Supranuclear
Palsy
Diffuse
Lewy Body
Disease
Corticobasalganglionic
Degeneration
Fronto-temporal
Dementia
Amyloid and Tau
α-SYNUCLEINOPATHIES
TAUOPATHIES

6. Alzheimer’s History: Alois Alzheimer 1906
Epidemiology: * 4 million pts.
* A disease of advancing age but not normal aging. Loss vs. shringage of neurons
* Age %
Age %
* Underdiagnosed
* Women more than men
* Cost $110 billion

7. DSM-IV Definition of Alzheimer’s Disease
Development of multiple cognitive deficits manifested by both memory impairment (amnesia) and 1 or more of the following cognitive disturbances: aphasia, apraxia, agnosia, or disturbance in executive functioning (abstractions)
Cognitive deficits cause significant impairment in social functioning and represent a significant decline from a previous level of functioning
Course is gradual in onset with continuing cognitive decline
Deficits are not due to any other CNS disorder, systemic illness, or substance-induced condition
Deficits do not occur exclusively during the course of delirium
Purpose:
To list the DSM-IV criteria for defining AD
Key Points:
The DSM-IV definition of Alzheimer’s disease is listed here.
Memory loss alone is not sufficient—at least 1 other cognitive disturbance such as apraxia or agnosia is required to fulfill the DSM-IV criteria for AD.
Additionally, observed cognitive decline must impair social functioning to a significant degree and be gradual in onset.
Finally, all other potential causes for dementia should be ruled out first.
Source: Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994:85-86.

8. Alzheimer’s Disease (AD): More Than Just Memory Loss
AD is a progressive, degenerative disease involving:
A Decline in ability to perform activities of daily living
B Changes in personality and behavior
C Loss of memory and other cognitive functions
D Eventual nursing home placement, death
$ Increases in resource utilization
AD affects all aspects of life for both the patient and the caregiver

9. Progression of Alzheimer's Disease
Early Diagnosis Mild-Moderate Severe 30
Cognitive Symptoms 25 20
Loss of ADLs
MMSE score 15
Behavioral Problems 10
Nursing Home Placement 5
Death
0.5 1
1.5 2
2.5 3
3.5 4
4.5 5
5.5 6
6.5 7
7.5 8
8.5 9
Years
Feldman H, Gracon S. In: Clinical Diagnosis and Management of Alzheimer’s Disease. 1996,

10. Risk Factors for Alzheimer’s Disease
Keywords: Risk Factors
Risk factors for Alzheimer’s disease
The greatest risk factor for Alzheimer’s disease (AD) is age.1 It has been noted that after age 65, the prevalence of AD doubles approximately every 5 years until age 84.2
Various genetic patterns play a role in the expression of AD. AD may be inherited on chromosomes 14 and 21.1 History of a first-degree family member with AD increases one’s risk of developing the disease.1,3
Female gender is an additionally known risk factor for AD.4
Other potential risk factors include previous head injury,3,5 history of depression, and hypothyroidism.3
References: 1. Corey-Bloom J, Galasko D, Thal LJ. Is it Alzheimer’s? A strategy for diagnosis. Intern Med. 1995;16: Ritchie K, Kildea D. Is senile dementia “age-related” or “aging-related”?—evidence from meta-analysis of dementia prevalence in the oldest old. Lancet. 1995;346: Henderson AS. Alzheimer’s disease in its epidemiological context. Acta Neurol Scand. 1993;149(suppl): Jorm AF, Korten AE, Henderson AS. The prevalence of dementia: a quantitative integration of the literature. Acta Psychiatr Scand. 1987;76: Small GW, Rabins PV, Barry PP, et al. Diagnosis and treatment of Alzheimer disease and related disorders: consensus statement of the American Association for Geriatric Psychiatry, the Alzheimer’s Association, and the American Geriatrics Society. JAMA. 1997;278:

11. Apolipoprotein E ε 4 allele: a “susceptibility gene” on chromosome 19
single copy→ 2-3 x risk, double copy→ 5 x risk
lowers age of onset
may be assoc. c clearing of Aβ- increased plaques,
but no increase in NFTs
ε 2 allele appears protective
“Not necessary or sufficient”- ½ of AD pts. don’t have
the allele, 10-20% of normal older adults carry one or
two

12. Gross Pathology
Temporal lobes esp. hippocampus & entorhinal cortex. Olfactory bulbs and tracts
Parietal lobes
Subcortical nuclei that project to the cortex:
Nucleus Basalis of Meynert (AcH)
Locus ceruleus (NE)
Raphae nuclei (Serotonin)

13. Neuropathologic Changes Characteristic of Alzheimer’s Disease
Normal AD
NORMAL
ALZHEIMER’S AP
NFT
Gross, diffuse atrophy with resulting enlargement of the ventricular system is seen in brains from AD patients, especially in the late stages of the disease.
It is the neurofibrillary tangles and amyloid plaques that are the most distinctive features of AD. The amyloid plaques begin in a diffuse form and develop into a compact, fibrillar form surrounded by dystrophic neurites and glial cells. In the photomicrograph of the left, two large plaques with light staining cores and dense staining halos are visible in the upper left-hand corner.
The photomicrograph on the right shows neurofibrillary tangles that contain abnormal cytoskeletal elements and appear as dark staining “flames” within the neurons.
Acetylcholine, serotonin, and norepinephrine are neurotransmitters that are decreased as a result of these neurologic changes. Immunoreactivity to substance P is reduced also.
AP = amyloid plaques.
NFT = neurofibrillary tangles.
Courtesy of Albert Enz, PhD, Novartis Pharmaceuticals Corporation.
EXTRACELLULAR
INTRACELLULAR 6

14. βaptists v Tauists

15. Microscopic Pathology
Amyloid (Senile) Plaques: Extraneuronal Aβ
Dystrophic axons and dendrites
Astrocytes
Microglia
Neurofibrillary Tangles: Intraneuronal- predominantly
axonal, longer axons
Hyperphosphorylated tau protein
Neuronal loss
Vascular change: Cerebral Amyloid Angiopathy
Aβ 40

16. Etiology: Amyloid Hypothesis
Cleavage of transmembranous APP by secretases
Aβ 40 & Aβ 42
Insoluble oligomers
Insoluble fibrils
Diffuse plaque
Mature plaque- due to inflammatory reaction with astrocytes and microglia
Neuronal and synaptic injury
NFTs and Neuronal death
Loss of neurotransmitters

17. Evidence for the Amyloid Hypothesis
Aβ neurotoxic in vitro
Overexpression of APP in transgenic mice=disease
Mutations in APP = early onset disease
All known mutations= increased Aβ
Downs Syndrome with 3 copies of APP gene
Apolipoprotein E € 4 accelerated Amyloid deposition
Amyloid antibodies in mice and men slows disease

18. Familial Alzheimer’s Chromosome 14 c presenilin 1 gene
Both code for a portion of γ-secretase
Chromosome 21 c APP mutations
Onset of sxs. In 40s & 50s

19. PET Imaging of Amyloid

20. Tau Association With Microtubules
Hyperphosphorylated tau subunits
Tau bound to microtubule
Microtubule
PHF composed of tau subunits
PHF = paired helical filaments.

22. Prevention Anti-Inflammatories Hormones Vitamins and Herbs
Diet and Antioxidants
Alcohol and Smoking
Exercise
Basic Medical Care
Blood Pressure
Lipids
Homocystine
Specific Agents
Cholinesterase Inhibitors
NMDA Receptor Blockers

23. Anti-Inflammatories Dutch study, NEJM 2001: RR 0.95 < 1 month
months
0.20 > 2 years
No benefit with trials of: Prednisone
Diclofenac
Rofecoxib
Naproxen

24. Estrogens Mechanisms: Estrogen receptors associated with NGF receptors
May enhance neurotransmitter function, esp. Ach
May diminish excitatory effect of Aβ
May alter APP resulting in less Aβ
PET shows increased blood flow and glucose metabolism in hippocampus
Early studies mixed: Prior to 1999, 4 impairment, 7 improvement
WHIMS: Estrogen & Progesterone: Mild increase in stroke and dementia
Estrogen alone: stopped this year, risk of dementia about the same
Would earlier institution of estrogens or longer duration of treatment be useful? Cache Co. Utah study

25. Vitamins and Herbs Vitamin E- No help
Potential toxicity: bleeding, HA,N,V,diarrhea, bone pain, hair loss
Vitamin C- No compelling evidence
Folic Acid- Increasing evidence for protection for AD and VaD
Would use more than 400 mcgm/day
Ginko Biloba- several studies suggest some improvement
St. Johns Wort- caution

26. Diet & Antioxidants
Fats: Diets high in unsaturated, unhydrogenated fats and low in saturated/transunsaturated fats may protect against dementia and coronary disease.
Cholesterol: Mixed findings. Dietary cholesterol has less impact on serum cholesterol than does saturated fat intake.
Dietary Flavinoids: May diminish risk
Caloric Intake: Animal studies show all degenerative diseases associated with aging diminish with reduced caloric intake.
Increased oxidative stress and accumulation of free radicals.

27. Alcohol & Smoking Red Wine: 250-500 ml/day may protect
May be due to flavanoids, also found in tea,fruit, and vegetables.
Beer: May worsen odds with low intake of thiamine and other B vitamins
Dangers in the elderly: Lean body mass
Trauma
Interactions with medications
Smoking: Accelerates microvascular cerebral disease

28. Exercise Physical: Decreases glucose and LDL levels, raises HDL
Aerobic vs. anaerobic and frontal lobe function
Mental: Educational attainment
Ongoing cognitive efforts: Nun study- Top 10% were % less likely than bottom 10% to become demented.
Sensory support: eyeglasses, hearing aids

29. Basic Medical Care Control of blood pressure and glucose
Statins: Inhibit activity of β and γ secretase
May limit effects of APO € 4 allele
Endothelial remodeling
Increase e NOS
Decrease endothelin-1
PROSPER study (Pravastatin)
HPS study (Simvastatin)
Atorvastatin

30. Specific Pharmaceutical Intervention
Cholinesterase Inhibitors: Donepezil (Aricept)
Rivistigmine (Exelon)
Galantamine (Reminyl→Razadyne))
NMDA Inhibitors: Memantine (Namenda)
Considerations in their use: Cognition
Behavior
Activities of Daily Living
Efficacy, Safety, Side Effects and Cost (~$140/mo.)

31. Parkinson Syndromes Idiopathic PD: Up to 40% c dementia; 65% by age 85
3rd leading cause overall
Increases c age at dx., early hallucinosis & advanced motor signs, presence of depression

32. Pathological changes are those of Alzheimer’s dis
Pathological changes are those of Alzheimer’s dis. In addition to the typical pathology of Lewy bodies and neuronal loss in the substantia nigra.
Lewy bodies- intraneuronal, eosinophilic inclusions containing misfolded α-synuclein

33. 2) Diffuse Lewy Body Disease
Motor sxs, dementia c often striking fluctuation and prominent haullucinosis
Lewy bodies are diffusely distributede in the cerebral cortex

34. Fronto-Temporal Lobar
Fronto-Temporal Dementia: Characterized by behavioral & executive function changes % is familial % of all dementias. Earlier age of onset. Atrophy of frontal & temporal poles. Pick bodies- argyrophilic round intraneuronal inclusions composed mainly of abnormal tau proteins. Unresponsive to AChI- tret c SSRIs & ? Memantine.

35. 2) Primary Progressive Aphasia
Predominantly expressive
Other cognitive domains essentially intact
Focal atrophy seen on imaging
Eventual dementia

36. 3) Semantic Aphasia Predominantly a receptive aphasia
Atrophy seen more in parietal and posterior temporal regions

37. 4) Other Tauopathies
Progressive Supranuclear Palsy (Steele-Richardson-Olsewski Syn.)
Corticobasal ganglionic degeneration

39. Vascular 2nd leading cause of dementia
Subtypes: Cortical- large vessel & embolic stroke. Stepwise progression. More severe aphasia. Sensoro-motor abnormalities.
Subcortical- small vessel. Pseudobulbar palsy, gait impairment ( marche à petit pas), urinary incontinence

40. Treatment of Vascular Dementia
Attempt to limit progression: Hypertension, diabetes, homocysteine, lipids, cardiac
Cognitive: possibly AChIs & memantine
Behavioral: above + SSRIs

41. Visuospatial Impairment
Typical Differential Points of Common Dementias at Initial Presentation
Memory Loss
Impaired Language
Visuospatial Impairment
Motor
Signs
Abnormal
Behavior
Vascular
Event _ _
Alzheimer’s Disease
FTD
Dementia with Lewy Bodies
Ischemic vascular dementia
NPH + _ ++ – + – _ _ + + _ ++ + + ++ + _ _

43. Infectious Cruetzfeldt-Jacob Disease Familial Sporadic New Variant
Fatal familial insomnia
Gerstmann-Sträussler-Scheinker

44. Other Infectious
HIV
GPI
Lyme disease
Fungal
Tuberculous
PML

45. Metabolic
Thyroid
B 12
Folate
Thiamine
Hepatic

46. Other
Huntington’s disease: irritability, apathy, impulsive behavior, poor personal hygeine, psychosis. Etiol. unclear until chorea appears esp. c spontaneous mutation.
HD gene on chrom. 4 contains trinucleotide repeats,CAG, encoding for glutamine preventing normal turnover of protein, huntingtin, in cytoplasm and nuclei. Abn. aggregation of this protein may→ pathology, cortical 7 subcortical

47. Other continued
Tumor
Subdural hematoma
Hydrocephalus
Demyelinating

48. Pseudodementia
Probably the most common etiology in the patient population
Stress
Depressive disorders
Anxiety disorders

49. Clinical Evaluation History Neurological Exam N-P testing Blood work
Imaging & EEG

50. Counseling for Patients & Families
Prognosis re. rate of decline & life expectancy
Patient & family goals for treatment
Review of finances & power of attorney
Medical advance directives
Driving
Home safety
Wandering (
Long term care
Resources for family and caregiver includ. Alz. Assoc. & ABA Commission on Legal problems for the Elderly