A. Definitions [2]

1. Dementia is Global Impairment of Cognitive Function
   1. Loss of memory and one or more other cognitive abilities
   2. Aphasia, apraxia, agnosia, or distrubance inexecutive functioning
   3. Chronic progressive decrease in intellectual capacity
   4. Leading to social or occupational disability (decline from previous functional level)
   5. Occurring in a state of clear consciousness (delirium excluded)
2. Must Rule Out Delirium and Pseudodementia
   1. Delirium is acute, temporary confusional state; waxing and waning attention
   2. Pseudodementia occurs in setting of other diseases such as depression, psychosis
3. Types of Dementia (see below)
   1. Amyloidopathies: Alzheimer's Disease (AD)
   2. Tauopathies: AD, frontotemporal dementia (Pick's Disease), Progressive Supranuclear Palsy, Progressive Subcortical Gliosis, Corticobasal Degeneration
   3. Synucleinopathies: Parksinon's disease, dementia with Lewy bodies, multisystem atrophy
   4. Mixed dementia: coexisting AD and vascular dementia, increasing in prevalence [39]
4. Mild Cognitive Impairment (MCI; see below) [2,3]
   1. Report (by patient or informant) of memory loss
   2. Abnormal performance for age (>1.5 SD below mean) on memory testing
   3. Normal general cognition and activities of daily living (ADL)
   4. Criteria for dementia not met
5. Mental Retardation: lifelong decreased mental capacity
6. Korsakoff's Psychosis: memory loss, confabulation
7. Aphasia: language loss, no other decrease in brain functions (not part of dementia)

B. Epidemiology

1. Prevalence of Dementia
   1. In persons age 65 years old, 1.5%
   2. In persons age 85 years old, 30%
   3. Increases with age ~1% per year after age ~65
   4. Global prevalence 2004 ~24 million
   5. Worldwide incidence of new cases ~4.6 million per year
   6. Expected >80 million cases in 2040
   7. Reduced incidence in people of African or Asian origin
   8. In most series, 65-75% of dementias are due to AD [1]
2. Cost associated with AD alone in USA is nearly $100 billion annually
3. Dementia Screening [5,6]
   1. Unclear if dementia screening is warranted given modest benefits of potential therapy
   2. Screening tests have good sensitivity but only fair specificity
   3. Cholinesterase inhibitors are somewhat effective in slowing cognitive decline in AD by 2-7 months
4. Median Survival after Dementia Diagnosis
   1. About 3 years in >65 year olds [4]
   2. Overall, ~8 years from diagnosis [1]
   3. Age adjusted mortality rates are increased >3 fold in those with dementia
5. Risk Factors
   1. Age
   2. Dementia in close family members
   3. Hypertension (HTN)
   4. Cerebrovascular vascular disease, transient neurological attacks, and stroke [64]
   5. Silent brain infarctions on MRI at baseline are 2X risk for dementia [50]
   6. Other vascular disease, particularly coronary artery disease (CAD)
   7. Alcohol abuse [65]
   8. Poor education
   9. Lack of use of cognitive abilities
   10. AIDS associated dementia
   11. MCI is a risk factor for AD, with ~45% developing AD within 5 years
6. Risk Reduction
   1. Early detection may lead to slight reduction in progression in AD with current agents [6]
   2. Alcohol consumption (see below)
   3. Exercise at least 3 times per week associated with ~40% reduced incidence of dementia in 65 year old persons without baseline dementia [14]
   4. Participation in leisure activities associated with 7% reduced risk of dementia [54]
   5. Folic acid supplementation 800µg/day for 3 years improved domains of cognitive function that tend to decline with age, mainly in patients with low vitamin B12 levels [62]
   6. Non-steroidal antiinflammatory drugs probably do not affect progression [7]
7. Alcohol Consumption [8,38]
   1. Mild to moderate alcohol consumption is generally recommended (1-6 drinks / week)
   2. Associated with 40-70% reduced risk of dementia of any cause in persons >55-65 years
   3. Associated with 70% reduced risk of vascular dementia in persons >55 years
8. Cognitive Impairment Without Frank Dementia [23]
   1. Found in >5.4 million persons in USA in 2002
   2. About 22% of of persons >70 years in USA
   3. Includes prodromal Alzheimer's Disease (8.2%) and cerebrovascular disease (5.7%)

C. Overview of Symptoms

1. Early
   1. Reducetion in Problem Solving
   2. Poor Grasp of Situation
   3. Decreased Agility of Thought
   4. Neurologic type gait abnormalities predict onset of non-Alzheimer's dementia [51]
   5. Effects on Language (mainly in primary progressive aphasia)
2. Middle
   1. Defect in basic mental functions
   2. Forgetful
   3. Bewilderment in the face of complexity
   4. Cannot understand / interpret a proverb
3. Late
   1. Decreased language ability
   2. Loss of basic everyday functions
   3. Loss of cranial nerve functions
   4. Social behavior usually maintained - probably through habit
4. Endstage
   1. Loss of all mental powers
   2. Cannot perform ADLs
   3. Will not recognize even closest relatives
   4. Bedridden

D. Mild Cognitive Impairment (MCI)

1. Transition stage between cognitive changes of "normal" aging and actual dementia
2. Two main forms: Amnestic and Nonamnestic
   1. Amnestic mainly affects memory, linked to AD
   2. Nonamnestic does not affect memory, may progress to other dementias
3. Affects ~12% of those >70 years
4. Conversion to AD at 10-15% per year
5. Symptoms
   1. Report (by patient or informant) of memory loss
   2. Abnormal performance for age (>1.5 SD below mean) on memory testing
   3. Normal general cognition and activities of daily living (ADL)
   4. Criteria for dementia not met
6. Supported by modern cerebral imaging and electroencephalographic (EEG) studies
   1. Structural and functional changes are distinct from normal aging and true dementia
   2. Hippocampal atrophy is found
   3. High grade stenosis of Left, but not Right, internal carotid artery associated with ~6X increased risk for cognitive deficits and 2.X risk of congnitive decline [35]
7. Prevention / Treatment
   1. Exercise at least 3 times per week associated with ~40% reduced incidence of dementia in 65 year old persons without baseline dementia [14]
   2. Donepezil (Aricept®) but not vitamin E in MCI patients reduces the number of AD cases after 1 year [60] but not after 3 years [65]

E. Specific Symptoms of Dementia Syndromes [1]

1. AD
   1. Mood: apathy, depression, anxiety
   2. Behavior: agitation, disinhibition, eating disorder
   3. Psychotic Features: hallucinations, delusions, euphoria
2. Dementia with Lewy Bodies
   1. Mood: depression
   2. Psychotic Features: hallucinations, delusions
   3. Pathology similar to Parkinson's disease, but dementia precedes movement disorder
3. Vascular Dementia
   1. Mood: depression
   2. Behavior: thoughtlessness, crying
   3. Psychotic Features: hallucinations, delusions
4. Frontotemporal Dementia (FTD)
   1. Mood: euphoria, anxiety, suicidal ideation, apathy
   2. Behavior: inappropriate, disinhibition, agitation, eating disorder, hypersexuality, perseveration
   3. Psychotic Features: none
   4. On autopsy, 15-30% of FTD are AD
5. Parkinson's Disease
   1. Mood: depression, anxiety
   2. Behavior: generally intact
   3. Psychotic Features: hallucinations, delusions
6. Primary Progressive Aphasia [55]
   1. Mood: normal mood in first two years of syndrome
   2. Behavior: impaired word finding, object naming, syntax, or word comprehension
   3. Psychotic Features: none in early and mid stages
   4. All major limitations in ADLs due to language impairment
   5. Rule out stroke, tumor, other causes of aphasia

F. Etiology [11]

1. Treatable Causes of Dementia [65]
   1. Deficiency of cobalamin (vitamin B6), thiamine (vitamin B1), or niacin (vitamin B3)'
   2. Thyroid disorders: hypothyroidism, hyperthyroidism
   3. Adrenal disroders: hypoadrenalism or hyperadrenalism
   4. Calcium disturbances: hypocalcemia or hypercalcemia
   5. Waste Product Accumulation: Renal failure, Liver failure, Pulmonary failure
   6. Intoxication including alcoholism
   7. Chronic subdural hematoma
   8. Normal pressure hydrocephalus - ataxia, incontinence, cognitive decline
   9. Chronic CNS infection (syphilis, neuroborreliosis, others)
   10. Brain tumor
   11. Nonconvulsive seizures
   12. Major depression
   13. Isolated angiitis (vasculits) of the CNS [27]
2. Neurodegenerative Diseases
   1. Nearly all involve abnormal processing of neuronal proteins
   2. Classified as amyloidopathies, tauopathies, synucleinopathies
   3. Misfolded proteins
   4. Altered post-translational modifications
   5. Abnormal proteolytic cleavage
   6. Anomolous gene splicing
   7. Improper expression of proteins
   8. Diminished clearance of degraded proteins
   9. The particular protein that is improperly processed determines which neurons affected
   10. This in turn leads to specific clinical manifestations (syndromes)
3. AD
   1. Apolipoprotein E4 (Apo E4) genotype associated with 3-4X increased risk of AD
   2. Tumor necrosis factor alpha (TNFa) promoter polymorphism (CT or TT) associated with
4. 7X increase risk of AD in patients with Apo E4 [13]
   1. Increasing incidence of AD coexistent with vascular dementia; likely synergy [39]
   2. About 25% of patients with Parkinson's Disease have AD-like dementia
   3. Dementia rate in relatives of black AD patients higher than for white AD patients [15]
   4. Participation in cognitively stimulating activities reduces incidence of AD by >30% [16]
   5. Currently, this is diagnosis of exclusion
   6. Positron emission tomography (PET) with amyloid- plaque/tangle specific agent FDDNP may differentiate between mild cognitive impairment (MCI), AD, and normal brain [12]
5. Vascular Dementia
   1. Involved in ~25% of cases of dementia; clear criteria are not yet available
   2. Formerly called multi-infarct dementia
   3. Most commonly associated with severe atherosclerotic disease
   4. Usually recognized after a clinically obvious cerebrovascular event
   5. Hypertension (HTN) increases risk
   6. HTN, atherosclerosis and diabetes can contribute to cognitive decline, particularly in the presence of Apo E4 [17]
   7. Treatment of systolic HTN in elderly reduces dementia incidence
   8. LDL cholesterol levels correlate with development of dementia in the setting of stroke
   9. Presence of Apo E4 genotype may be synergistic for vascular dementia [20,21]
   10. TNFa promoter polymorism (C to T) associated with 2.5X increased risk of vascular dementia [22]
   11. Metabolic (insulin resistance) syndromes with high vascular inflammation (elevated C reactive protein) contributes to cognitive decline [59]
   12. Increasing AD+vascular ("mixed") dementia [5]
   13. Aggressive treatment of HTN and hyperlipidemia strongly advocated
6. Other Central Nervous System Vascular Dementia
   1. Several less common causes of vascular dementia have been documented:
   2. Central nervous sytem autoimmune disease: systemic lupus, granulomatous angiitis of the CNS
   3. Hereditary multi-infarct dementia (CADASIL)
   4. Subacute arteriosclerotic encephalopthy (Bindswanger's Disease) more insidious
7. Subcortical Dementias [21]
   1. Huntington's Chorea
   2. Parkinson's Disease
   3. Corticobasal Ganglionic Degeneration
   4. Progressive Supranuclear Palsy
   5. Olivopontocerebellar Atrophy (autosomal dominant or recessive)
   6. Hemochromatosis
   7. Subacute sclerosing panencephalitis (SSPE)
   8. Herediatry leukodystrophies
8. Abnormal Tau Proteins
   1. Tau proteins are normally associated in an ordered fashion with microtubules
   2. In disease, tau protein containing inclusions are found in neurons and glial cells
   3. Mutations in tau and/or hyperphosphorylation lead to aggregation of tau into inclusions
9. Trauma / Injury
   1. Primary brain damage
   2. Hypoxemia - contributes to cognitive decline
   3. Hypotension - contributes to cognitive decline
   4. Dementia associated with repeated head trauma, boxing (Dementia Pugilistica) [24]
10. Coronary Artery Bypass Surgery [25]
    1. About 50% of patients have at least 20% decline in neurocognitive function at discharge
    2. Over 5 years, ~40% of patients will have reduced neurocognitive function
    3. Unclear if bypass surgery increases risk for AD or other dementias
11. Spongiform Encephalopathy
    1. Kuru
    2. Creutzfeld-Jacob Disease (CJD) - rapidly progressive (death 1-2 years)
    3. Gerstmann-Straussler-Scheinker Disease
    4. Variant CJD can be detected by antibody staining of PrP(sc) Type 4 in tonsils [22]
12. Neuroserpin Mutations [26]
    1. Collins bodies are neuronal inclusion bodies associated with neurodegeneration
    2. Collins bodies are eosinophilic inclusion bodies formed by neuroserpin aggregation
    3. Mutations in neuroserpin associated with inclusion body formation
    4. Neuroserpin mutations associated with progressive myoclonic epilepsy
    5. Specific neuroserpin mutations cause early versus late onset neurodegeneration
13. Other Conditions Associated with Dementia
    1. Mild cognitive impairment may be prodromal phase of dementia [2]
    2. Dementia with Lewy Bodies (see below)
    3. General Paresis
    4. CNS Tumor
    5. Hepatolenticular Degeneration
    6. Toxic Leukoencephalopathy [28]

G. Dementia with Lewy Bodies [20]

1. Also called Lewy Body Disease
2. Accounts for 15-35% of cases of dementia in autopsy series [29]
3. Lewy Bodies
   1. Large, intracytoplasmic, spherical, eosinophilic neuronal inclusion bodies
   2. These inclusions are also found in Parkinson's Disease
   3. Lewy bodies stain brightly with ubiquitin antibodies and for neurofilaments
   4. Alpha-synuclein, a synaptic protein, is also prominant and can bind ß-amyloid
   5. Cells with Lewy bodies are dying
   6. Alpha-synuclein prominant inclusions found in mutlisystem atropha (MSA)
4. 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
5. Symptoms
   1. Fluctuating cognitive impairment with episodic delirium
   2. Prominant psychiatric symptoms including depression
   3. Psychotic symptoms with and visual hallucinations and delusions
   4. Extrapyramidal symptoms - parkinsonism, exacerbated by dopamine antagonists
   5. Generally greater impairment of short term over long term memory
6. Diagnosis
   1. International consensus criteria have been established
   2. International diagnostic criteria have sensitivity of ~40-80% and specificity of ~80% [29]
   3. Premortem diagnostic methods are not currently in routine use
   4. Single-photon emission computerized tomographic scanning using presynaptic dopaminergic specific agents shows early dopamine pathway degeneration [30]
   5. Contrast with cholinergic degeneration seen in patients with AD
7. Treatment
   1. Classical neuroleptics (phenothiazines, butyrphenones) are contraindicated
   2. Atypical neuroleptics such as olanzepine or clozapine may be considered but can worsen symptoms
   3. Cholinesterase inhibitors such as rivastigmine may have some benefit
   4. Rivastigmine provided clinically significant, modest improvement in mood and cognition [31]

H. Frontotemporal Dementia (FTD) and Pick's Disease [34]

1. Selective loss and atrophy of neurons in frontal and temporal lobes
2. ~90% of cases are sporadic, ~10% are familial
3. Initially abnormal behavior without memory loss
   1. Inappropriate behavior and disinhibition
   2. Agitation
   3. Hyperorality
   4. Eating disorder
   5. Perseveration
   6. Hypersexuality
4. Progressive dementia occurs over time
5. Parkinson-like rigidity may also occur
6. Pathogenesis
   1. Familial form caused by various mutations in tau genes
   2. Sporadic forms show uncommon aggregations of tau proteins
7. Pathology
   1. ~15% of frontotemporal dementia have Pick Bodies (true Pick's Disease)
   2. Pick bodies are intracellular collections of partially degraded, ubiquitinated tau fibrils
   3. Amyloid (neuritic) plaques are not seen in this disease

I. Subcortical Dementia

1. Disturbances of
   1. Motivation
   2. Mood - often mistaken for depression
   3. Attention
   4. Arousal
2. Symptoms
   1. Psychomotor slowing
   2. Memory Impairment
   3. Affective and Emotional Disorders
   4. Often associated with stroke
3. Differentiating Dementias
   1. Language problems arise first in subcortical dementia
   2. Alzheimer's patients have spacial impairment early
   3. CADASIL: Notch3 mutations, early onset subcortical multi-infarct dementia
   4. With encephalitis, likely subacute sclerosing panencephalitis [21]
4. Subcortical Dementia Treatment in setting of stroke
   1. Low dose stimulants may be effective
   2. Methylphenidate has been used

J. Related Syndromes

1. Leukoaeriosis
   1. Loss (rarefaction) of central nervous system White mater
   2. Epidemiology: 4.5% of pathological examinations (endemic); ~15% of asymptomatic persons
   3. Neurological dysfunction - usually dementia (Bindswanger's Disease)
   4. Alzheimer's Disease, Multi-Infarct Dementia most common clinical correlates
   5. Focal Neurologic Findings
   6. White mater (Lacunar) Infarctions
2. Korsakoff's Syndrome
   1. Due to thiamine deficiency
   2. Fail test of recent memory
   3. Disorientation to time and place
   4. Can name objects, follow commands, abstract reasoning
3. Aphasia
   1. Cannot name objects or comprehend words
   2. Language specifically impaired; able to match objects (without naming them)
   3. Usually secondary to stroke but primary progressive aphasia also described
   4. Primary progressive aphasia is a form of dementia with language loss, memory intact [55]
4. Failure to Thrive [63]
   1. Generally in older persons
   2. Indicates declining ability to function independently in community
   3. Multifactorial etiology (one or more may be present)
   4. Declining physical function
      1. Cognitive Impairment
      2. Eating difficulties (mechanical and psychological)
      3. Malnutrition
   5. Depression
      1. Concurrent medical illness(es)
      2. History of hypoxemia and/or hypotension
   6. Major issue is how aggressive evaluation and/or therapy should be
   7. Serum albumin level may be useful overall predictor of survival
5. Depression
   1. May be mistaken for dementia ("pseudodementia")
   2. In general, patients with depression are apathetic
   3. Patients with dementia will often try to cover up their declining mental status

K. Diagnosis

1. History
   1. Family and/or friends relate decline in function
   2. Family History of Dementia is often found
2. Intellect Testing [36]
   1. Mini-Cog (3 item recall + clock drawing test; 4 points) is a good screening test [37]
   2. Mini-Mental Status Examination (MMSE)
   3. Memory Impairment Screen (MIS)
   4. Formal Cognitive Testing
3. MMSSE and MIS Screening for Dementia [19]
   1. MMSE: Likelihood ratio (LR) for positive result: 6.3; negative result 0.19
   2. MIS: LR for positive result 33; negative result 0.08
4. Full Mental Status Examination (essential)
   1. Orientation - time, place, person
   2. Language Skills - expression (naming) and comprehending (commands)
   3. Fund of Knowledge - presidents, capital cities
   4. Recent Memory - usually try 5 minutes, thirty minutes (or 1 hour)
   5. Attention Span - serial 7's or spell "world" backwards
   6. Abstract Reasoning - definition of proverbs
   7. Constructional Capacity (praxia) - copy a design (this is often lost in Alzheimer's)
5. Laboratory Evaluation
   1. Reversible causes, though relatively rare, must be ruled out
   2. CT Scan without contrast is recommended intially
   3. Addition of contrast or use of MRI Scan may be used in followup
   4. Spinal Fluid Analysis (Lumbar Puncture) - VDRL for syphilis, protein 14-3-3 for CJD
   5. Blood Tests - syphilis serology (RPR/VDRL/FTA), Vit B12 level, TSH ± Thyroxine (T4)
   6. Consider HIV Testing
   7. Consider EEG to rule out delirium; focal activity usually corresponds to CT
   8. Characteristic EEG changes in CJD
6. Imaging
   1. CT scans are not generally helpful
   2. MRI may show white lesions consistent with vascular dementia
   3. Functional MRI with dynamic susceptibility contrast shows blood flow
   4. Positron emission tomography (PET) with 18F-flurodeoxyglucose can be used to assess regional brain metabolism
   5. PET scanning of patients presenting with dementia symptoms provides >90% sensitivity and ~75% specificity for Alzheimer's disease and other neurodenegerative diseases [40]
   6. PET scanning should be considered in patients with cognitive symptoms of dementia
7. Level of testing and attempts at treatment should be carefully tailored to each patient

L. Treatment

1. Reversible forms of dementia (usually toxic / metabolic) are treatable (see above) [65]
2. Statin anticholesterol agents associated with 50-70% reduction in dementia risk [47]
3. Early Cognitive Decline
   1. Physical activity including walking improves cognitive function and reduces decline in older women [58]
   2. Long-term cognitive training in older adults prevents loss of everyday functions, fosters improvements in activities of daily living [18]
   3. Estrogen replacement therapy (ERT) acutely improved perimenopausal cognitive symptoms [6]
   4. ERT did not improve cognitive function after 4 years in postmenopausal women with cardiovascular disease [41]
   5. In prospective randomized studies, ERT/HRT associated with increased incidence of dementia [51,56] and small (~1.5X) increase in cognitive decline [52,56,57]
   6. ERT for one year did not affect progression of mild/moderate Alzheimer's Disease [42]
4. To date, no agents available for reversing progression of chronic dementias:
   1. Alzheimer Disease
   2. Vascular Dementia
   3. Lewy Body Disease
   4. Dementia associated with Parkinson's Disease
   5. Cholinesterase inhibitors and/or memantine should be considered for any patient with dementia, though clinically meaningful responses occur in <25% of patients [66,67]
5. Non-Steroidal Antiinflammatory Drugs (NSAIDs) [53]
   1. Prostaglandin mediated inflammation implicated in progression of disease
   2. Nonspecific or COX2 selective NSAIDs showed no reduction in progression of mild to moderate Alzheimer's Disease
   3. No effect of NSAIDs on risk of developing vascular dementia
6. Specific Treatment of AD
   1. Cholinesterase inhibitors show efficacy in mild to moderate AD
   2. There is no clearly superior cholinesterase inhibitors though tacrine is least effective [66,67]
   3. NMDA antagonist mementine (Nemanda®) is approved for moderate to severe AD
7. Galantamine (Reminyl®) is effective (24mg qd) in patients with probable vascular dementia or AD combined with cerebrovascular disease [44]
8. Neuropsychiatric Symptoms [45]
   1. Atypical antipsychotics olanzapine or respiridone () for aggressive and/or psychotic patients with dementia [43]
   2. Atypical antipsychotics associated with increased risk of stroke in severe dementia
   3. Atypical antipsychotics associated with 1.5X increased risk of death in demented patients [61]
   4. Antidepressants such as sertraline or citalopram improve only depressive symptoms
   5. Cholinesterase inhibitors may have some benefit on psychotic behaviors in AD
9. Ginkgo Biloba [46]
   1. Extracts are typically ~25% flavenoids and ~6% terpenoids
   2. These are antioxidants which scavenge free oxygen radicals
   3. Ginkgolide B, a terpenoid, also inhibits platelet activating factor
   4. Safely and modestly improves dementia, about equal to tacrine
   5. Unclear quality control and consistency of extraction protocols
10. Eating Disorders [63]
    1. Most patients with advanced dementia have or develop eating problems
    2. Decisions to continue feeding shoud focus on the patient's preferences
    3. Main goal of continued oral feeding is provide food and drink to extent that it is enjoyable to the patient; the focus is therefore on comfort rather than life prolongation [63]
    4. Feeding options include hand feeding (45-90 minutes per day) or placement of feeding tube
    5. Long term feeding tube has been placed in ~30% of advanced dementia patients
    6. Tube feeding may prolong life, improve nutrition, prevent aspiration, provide comfort
    7. However, tube feeding is not beneficial overall for patients with advanced dementia [48,49]
    8. Focus must be on the comfort of the patient

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