• Acquired broad and persistent impairment of intellect /behavior
• Sufficiently severe to impair competence in daily living, occupation or social interaction
• May be static or progressive

Primary

Without other neurological signs

With neurological symptoms
Secondary

Metabolic, Nutritional, Infections,
Medications

S pace O ccupying L esions , Trauma

Depression, N ormal P ressure H ydrocephalus


Alzheimer Disease (pure ~40%, + mixed~70%)

Vascular Disease, MID (5-20%)

Diffuse Lewy Body-15%

Fronto Temporal Dementia-5%

Movement disorders ( Parkinson, CBGD,
Huntington, Wilson..) 6%

Psychiatric (Depression..) 5%

Toxic Metabolic- 4%-15% (Drugs, Ethanol,
Toxins Endocrine (thyroid, diabetes), Ears,
Eyes, Environmental

Infectious-3%

NPH-2.5%

Tumor

Trauma

• Thyroid dysfunction
– Hypothyoidism – elevated TSH
• Compensated hypothyroidism may have normal T4, FTI
– Hyperthyroidism
• Apathetic, with anorexia, fatigue, weight loss, increased
T4
• Diabetes
• Hypoglycemia
(loss of recent memory since episode)
• Hyperglycemia
• Hypercalcemia
• Nephropathy, Uremia
• Hepatic dysfunction (Wilson’s disease)
• Vitamin Deficiency (B12, thiamine, niacin)
– Pernicious anemia – B12 deficiency,
?homocysteine

Sensory deficits might contribute to the appearance of the patient being demented
• Central Auditory Processing Deficits
• Hearing problems are socially isolating
• Visual problems are difficult to accommodate by a demented patient
• Environmental stress factors can predispose to a variety of conditions
• Nutritional deficiencies

– Concussion, Contusion
• Occult head trauma if recent fall
– Subdural hematoma
– Hydrocephalus:
• Normal pressure (late effect of bleed)
– Dementia pugilistica
– Possible contributor to Alzheimer’s disease initiation and progression (? 4% of cases)
– Concern re: physical abuse by caretakers

– HIV
– Neurosyphilis
– Viral encephalitis (herpes)
– Bacterial meningitis
– Fungal (cryptococcus)
– Prion (Creutzfeldt-Jakob disease); (mad cow disease)

Age-Associated Memory Impairment vs
Mild Cognitive Impairment
• Memory declines with age
• Age - related memory decline corresponds with atrophy of the hippocampus
• Older individuals remember more complex items and relationships
• Older individuals are slower to respond
• Memory problems predispose to development of Alzheimer’s disease

Mini Mental Status Examination
) תודוקנ 10 ( םוקמ ןמז : תואצמתה
) תודוקנ 3 ( ץע , לגד , רודכ : םילימ 3 : הריכז
ןחלוש הלימה לש רוחאל תויא /) תודוקנ 5 ( 100-7
) תודוקנ 3 ( תיהשומ הריכז
) תודוקנ 2 ( םויש
) תודוקנ 1 ( אוה בהז ץצונה לכ אל : הרזח
) תודוקנ 3 ( תודוקפ תנבה
) הדוקנ 1 ( םייניעה תא םוצע ארקנה תנבה
) הדוקנ 1 ( טפשמ תביתכ
) הדוקנ 1 ( םינוגטנפ תקתעה












Cognitive decline grater than expected for an individuals age and education, but does not interfere notably with ADLs

Prevalence (in population based epidemiological studies in adults >65):3-
19%

Natural HX:>50% progress to dementia in
5 years

Peterson et al 1999
Conference: International Psychogeriatric Association in
Bethesda USA, Jan 21-23,2005

A subjective memory complaint
(preferable corroborated by an informer)

Preserved general intellectual functioning
(estimated on vocabulary tests)

Memory impairment on cognitive tests(<1.5 SD mean of normal). relative to age and education matched

Intact ability to perform ADL.

Absence of dementia

Exclude specific medical/psychiatric causes of memory diff

Course :

10-15% year deteriorate to dementia (memory clinic population)

50% develop dementia ultimately

40% improve
Predictors of progression to dementia

Enthorhinal /hippocampal atrophy

Older age, Lower MMSE

Cerebro vascular disease/white matter lesions
 apoE4 allele

Parkinsonism

Impaired episodic memory/recall, anxiety, depression, loss of insight

• Memory impairment
• At least one :
• Impairment of abstract thinking
• Impaired judgment
• Aphasia, Apraxia,
• Constructional difficulties
• Personality change
• Impairment in the ability to interfere with social activities and relationship with others
• No delirium , Depression or Organic condition

%
Affected
+
Age

Natural History of Alzheimer’s Disease
20
15
10
5
0
30
25
Early diagnosis
Symptoms
Mild-to-moderate Severe
Diagnosis
Loss of functional independence behavioral problems
Nursing home placement
Death
1 2 3 4 5
Time (years)
6 7 8 9
Reproduced with permission from Feldman and Gracon, 1996.

 Advanced age
 Gender
 High cholesterol
 Hypertension
 Stroke( fam hx)
 Diabetes Mellitus
 Smoking
 Homocysteine
 ETOH
 Cardiac disease
 Micro-vessel pathology
 High viscosity
 Trombogenic Factors
 Hypotension
 Head injury/LOC
 Menopause (High
 Low education
 Genetics (
Early onset
APP, Presenillins (5%) Late onset: Apo
4> 50%).
 Gait abnormality

1
14
Genetic Linkages
19 21
PS 1
(FAD 3)
APLP 1
(FAD 2)
ApoE
APP
(FAD 1)
PS 2
(FAD 4)

A genetic susceptibility risk factor
Possible allels
ε2-rare
ε3-most frequent
ε4-
ε4/ ε4 probability>90% AD by age 85
10 years earlier compared to carriers of ε2 or
ε3
Up to 50% of late onset AD do not possess an ε4 allele

• Clinical
• Biomarkers
– CSF (Aß, Tau)
– Imaging
• Structural: MRI
• Functional: PET, SPECT, fMRI
• Molecular: amyloid

SP
NFT
Amyloid angiopathy

Coronal MRI sections from individual subjects (Control, MCI, and
AD), illustrating mild degree of atrophy in MCI and greater atrophy in mild AD compared with age-matched control

Proton magnetic resonance spectroscopic imaging (MRS)
1
H spectra from posterior cingulate from individual subjects
(Control, MCI, and AD), illustrating increased mI peak in MCI and decreased NAA peak in AD.
Figure courtesy of Kejal Kantarci, M.D. (Mayo Clinic, Rochester, MN

Brain metabolism and perfusion at rest: FDG-PET and single-photon emission computed tomography reduction at rest of metabolism and perfusion in
• posterior temporoparietal
• posterior cingulate
• frontal regions

Task-related brain hemodynamics and metabolism:
Decreased medial temporal lobe activation can be detected during the performance of memory tasks in mild AD patients compared with nondemented older individuals, as measured by fMRI. Group statistical comparison showing regions with decreased activation in AD patients compared to age-matched normal controls

IMAGING BIOMARKERS OF AD-RELATED BRAIN
PATHOLOGY
.
FIG. 5
In vivo PET-based detection of β amyloid. Increased retention of
Pittsburgh compound-B (PIB) is found in frontal and temporo-parietal regions in patients with clinical AD.
Figure courtesy of William E. Klunk, M.D., Ph.D.
(University of Pittsburgh Medical Center, Pittsburgh, PA .

•
Styrylbenzoxazole Derivatives for In Vivo Imaging of Amyloid
Plaques in the Brain , Nobuyuki et al, JNEUROSCI.4456-
03.2004

Pathophysiology of AD
The amyloid cascade

• ACEI
• Donepezil, Rivastigmin, Galantamine
• NMDA antagonists
• Memantine

Reduce production of amyloid
• ß-secretase and γ-secretase inhibitors
Increase the clearance of Aß
42
• Immunization

• Assumption:
• A-beta accumulation and toxicity are influenced by zinc and copper-
Cliocuinol (Iodochlorhydroxyquin)
Ritchie CW et al, Arch Neurol. 2003;60:1678-1679
.
• Iron-

• Non Pharmacological therapies
– Music, light, exercise, relaxation
• Pharmacological therapies
– Anxiolitics
– Cholinomimetics
– Antidepresants
– Antipsychotics

(Roman et al, 1993)

Dementia

Evidence of cerebrovascular disease

The two disorders must be reasonably related (within 3 months following a recognized stroke)

Subtypes of VaD
Macrovascularthromboembolic
(multi-infarct dementia)
Multiple subcortical lacunar strokes
(Lacunar state)
Extensive WML or
Binswanger’s dis
Mechanisms of VaD
Thrombosis or emboli involving large or medium arteries
Single strategic stroke Single ischemic lesions in behavioral critical area
Arteriosclerosis of the deep penetrating endarterioles
Arteriosclerosis of the deep penetrating endarterioles
Structures involved
Cerebral cortex: ACA,
MCA, PCA, borderzone
Thalamic, Caudate,l angular gyrus,ant cingulated, basal forebrain, genu of int capsule
BG, Thalamus, frontalsubcortical circuits
Mixture odf 1,2,3,4,
Post-ischemic dementia
Hemorhagic dementia
Genetic cerebrovascular disorders
Vascular -AD
Vasculitides
Decreased BP , impaired perfusion
CADASIL, Fabry
Combination od AD and vasc
Variable mechanisms and locations
Periventricular and deep white matter , frontal sub cortical curcuits
Frontal and other cortical laminar necrosis, loss of cells in the striatum, hippocampus, pyramidal cells in cerebellum
Tend to involve deep white matter
Frontal subcortical circuits

•
Slowing of information processing
•
Memory deficits
•
Impaired executive functions
•
Personality and mood alterations
•
Gait dysfunction

•
Course:gradual/steady/fluctuating
•
Cog/behav deterioration (+ additional inf)
•
New vascular episode increases the magnitude of mean deterioration
•
Low MMSE, steeper deterioration
•
Rate of deterioration is determined by the severity of cognitive impairment

Scheltens, 2001.

• LB occur in in paralimbic, basal forebrain and mesial frontal regions.
• Usually also in sub-cortical structures
• Marked cholinergic deficiency

Consensus Criteria for the Clinical dx of DLB
Report of the Consortium on DLB .Neurology 1996;47(5)

Fronto-temporal Dementia a consensus on clinical diagnostic criteria
Neurology 1998;51:1546-1554
• Insidious onset and gradual deterioration
• Insight-absent
• Personality: alteration, blunted emotions, reduced empathy
• Exec/functions: inertia, loss of volition distractibility, disinhibition, abstraction, planning, problem solving
• Language: economical-mutism, press
• Memory: inefficient, rec > recall
• Motor: repetitive/stereotyped behaviors, gluttony

FTD
Age younger than AD
Usually asymetric ( in frontal and temporal atrophy)
Family history in 50%
Tau deposits in neurons, glia, white matter-Tauopathies
Different phenotypes within same genotype and between different entities

Pick synd
(Frontotemporal lobar degeneration)
20% of patients at memory clinics
• Frontal Variant fvFTD: 40%
• Semantic Dementia : 40%
• Progrssive Aphasia: 20%
• FTD-with mutation of tau gene on ch 17
• Each may present with motor neuron disease
• May present with asymmetric clinical features and pathology