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Dementia – It is a syndrome of acquired global or multifocal impairment of cognitive function involving decline in intellect, memory or personality in the presence of normal consciousness.

  1. Alzheimer’s disease
    It is the most common cause of dementia in the elderly.

Pathogenesis – Risk factors –

  1. Old age                        
  2. Low education                                      
  3. Positive family history          
  4. Female sex                  
  5. Past h/o head trauma with concussion          
  6. Aluminium, Mercury Toxicity
  7. Viruses, Prion                      
  8. Genetic factors – Down’s syndrome, APP gene on chromosome 21
    Presenilis – 1 gene on chromosome 14
    Presenilis – 2 gene on chromosome 1
    Apo E 4 gene on chromosome 19(single most important biological marker)
    Apo E  2 gene on chromosome 14(protective for alzhiemer’s)
  9. Increase blood homocystine level (LQ 2012)

Extra Edge:  Smoking is not a cause of AD
Use of NSAID is associated with decrease risk.Q


Extra Edge: Hippocampus

  1. It belongs to the limbic system and plays important roles in the consolidation of information from short-term memory to long-term memory (LQ 2012) and spatial navigation.
  2. It is located in the medial temporal lobe.
  3. It contains two main interlocking parts: Ammon's horn and the dentate gyrus.
  4. In Alzheimer's disease, the hippocampus is one of the first regions of the brain to suffer damage; memory problems and disorientation appear among the first symptoms.
  5. Damage to the hippocampus can also result from  hypoxia, encephalitis, or medial temporal lobe epilepsy.
  6. People with extensive, bilateral hippocampal damage have anterograde amnesia—the inability to form or retain new memories.

: At autopsy, the most severe pathology is usually found in the hippocampus, temporal cortex, and nucleus basalis of Meynert (lateral septum).

neuritic senile plaques and cytoplasmic neurofibrillary tangles (AIIMS May 09). The neuritic plaque contain Aβ amyloid, proteoglycans, Apo E, α1 antichymotrypsin.

Diffuse atrophy of cerebral cortex with secondary enlargement of ventricular system.

Decrease in cerebral cortical levels of Acetylcholine (LQ 2012), choline acetyltransferase and nicotinic cholinergic receptors. Reduction in norepinephrine levels in brainstem nuclei.


Figure - Mechanism of amyloid generation in Alzheimer disease. Amyloid precursor protein (APP) is a transmembrane protein, with potential cleavage sites for three distinct enzymes (α-, ß- and γ-secretases) as shown in A. The Aß domain extends from the extracellular side of the protein into the transmembrane domain. When APP is cleaved by α-secretase (B), subsequent cleavage by γ-secretase does not yield Aß. In contrast, cleavage by ß-secretase followed by γ-secretase (C) results in production of Aß, which can then aggregate and form fibrils. In either pathway, intramembranous cleavage by γ-secretase follows cleavage at a site located closer to the N-terminus of the protein.

Table -  Genetics of Alzheimer Disease








Amyloid precursor protein (APP)

• Single missense mutations Double missense mutation Trisomy 21 (gene dosage effect)

• Early-onset FAD Increased Aß production


Presenilin-1 (PS1)

• Missense mutations Splice site mutations

• Early-onset FAD Increased Aß production


Presenilin-2 (PS2)

• Missense mutations

• Early-onset FAD Increased Aß production


Apolipoprotein E (ApoE)

• Allele ε4

• Increased risk of development of AD Decreased age at onset of AD

Clinical Features –

Alzheimer’s disease early feature:

  1. Episodic memory loss (It is 1st to be noted)
  2. Nominal aphasia (Patient forgets the name)
  3. Loss of visual spatial skill (LQ 2012)
  4. Anosognosia (Patient is unaware of his problem)
  5. Apraxia
  6. 10% of the patient develop Capgras syndrome. (LQ 2012)
  7. Loss of consciousness is not a feature. (LQ 2012)

Extra Edge: The Capgras delusion is a disorder in which a person holds a delusional belief that a friend, spouse, parent or other close family member, has been replaced by an identical-looking impostor. The Capgras delusion is classed as a delusional misidentification syndrome.

In the end stage

  1. Myoclonic
  2. Primitive reflex – sucking, rooting

Course of disease - Typical disease duration is 8 – 10 years.

Treatment –

  1. Donepezil- drug of choice
  2. Tacrine-(S/E- hepatotoxicity)

MAO – Inhibition of cholinesterase with resulting increase in cerebral levels of acetylcholine


Recent Advances: Newer drugs

  1. Rivastigmine
  2. Galantamine (LQ 2012)
  3. Memantine
  4. Huperizine A


Extra edge: Huperzine A is a naturally occurring alkaloid compound found in the plant Huperzia serrata. It is also an acetylcholinesterase inhibitor, which is a mechanism of action similar to donepezil, rivastigmine, and galantamine.

MMSE (Mini Mental Status Examination) maximum score-30


Recent Advances: Drugs which reduce progression of AD

  1. Estrogen replacement therapy       
  2. Ginkgo         
  3. NSAID
  4. Selegiline                               
  5. Statin          
  6. Lowering serum homocysteine are underway to slow the progression to dementia. (Ref. Hari. 18th ed., Pg- 3309)
  7. There is now a strong interest in the relationship between diabetes and AD. (Ref. Hari. 18th ed., Pg- 3309)


Recent Advances not given in Harrison 18th edition also !!!

  1. Gantenerumab is a monoclonal antibody being tried for treatment of Alzheimer because it lowers levels of beta-amyloid in the brain.
  2. ß and γ secretase inhibitor reduce production of A ß (Immunotherapy). 


Extra Edge: With ageing a slight decrease in cognitive impairment of seen due to increase in level of homocystine. (AIIMS Nov 2012)

  1. Thiamine (Vit B1) deficiency
    Causes: Wernicke’s encephalopathy
    1. Triad of Global confusion, Ophthalmoplegia, Ataxia   (G.O.A.)
    2. Prolonged untreated thiamine deficiency causes irreversible dementia / amnestic syndrome (Korsakoff’s psychosis)
    3. In Korsakoff’s syndrome, the patient is unable to recall new information despite normal attention span, and level of consciousness.
    4. Memory for new events is seriously impaired whereas memory of knowledge prior to the illness is relatively intact.
    5. There is damage to the medial thalamic nuclei and mammillary bodies.

Korsakoff psychosis –amnesia & confabulation


Thiamine deficiency causes lactic acidosis (AIIMS Nov 10)

  1. Vascular Dementia (Ref. Hari. 18th ed., Pg – 3309)
    Dementia associated with cerebral vascular disease can be divided into two general categories:
    1. Multi-infarct dementia
    2. Diffuse white matter disease (also called leukoaraiosis, subcortical arteriosclerotic encephalopathy or Binswanger's disease).
    3. With normal aging, there is also an accumulation of amyloid in cerebral blood vessels, leading to a condition called cerebral amyloid angiopathy of aging (not associated with dementia), which predisposes older persons to hemorrhagic lobar stroke.
    4. AD patients with amyloid angiopathy may be at increased risk for cerebral infarction.
  2. Huntington’s Disease (HD) (Ref. Hari. 18th ed., Pg- 3330)
    1. Autosomal dominant, degenerative brain disorder Q
    2. The HD gene called IT IS is located on chromosome 4.
    3. It contain CAG triple repeat expansion   
    4. Onset is 4 –5th decade. May be childhood to >75year.
    5. Clinical hallmarks are progressive chorea and emotional disturbance, dementia and death Q
    6. Gait is poorly coordinated and has a dancing quality. Emotional disturbance manifest as irritability in behavior.
    7. Attention, Judgment, awareness and executive functions are seriously deficient at an  early stage.
    8. Depression, social withdrawal, irritability and disinhibitions positive
    9. Seizure are common  which Juvenile HD & rare which Adult HD.
    10. Pathologically there is atrophy of caudate nucleus
    11. Neuro chemically there is marked decrease at GABA anergic and cholinergic neurons in corpus striatum.  
    12. Treatment – Phenothiazine, haloperidol, benzodiazepines, olanzapine.

HD may present as Parkinson (Westpal variant)


Important Points:

Other triple repeat genetic abnormality are dystrophica myotonia (CTG),fragile X syndrome(CGG), Freidrich’s ataxia(GAA)}  

Huntington’s Disease: Inheritance and genetics:
  1. It is inherited as an autosomal dominant disease
  2. Genetic abnormality responsible for Huntington’s disease is a CAG trinucleotide expansion on a gene called 'Huntingtin' which is localized on chromosome 4.
  3. Means age of onset HD : 40 – 50 years

Effect of parental sex in Huntington’s disease

Characteristic manifestations include

1. Gene inherited from father

2. Gene inherited from mother

  1. Individuals who inherit the gene from their father usually have an early onset disease.
  2. Effect of Anticipation is exhibited strongly
  3. ‘Anticipation' means that successive generations develop the disease at an earlier age than their parent.
  4. When gene is inherited from father the phenomenon of Anticipation is exhibited strongly.
  1. Individuals who inherit disease from the mother usually have a late onset disease.
  2. Effect of Anticipation is less characteristic
    When gene is inherited from mother, the phenomenon of 'Anticipation' may be exhibited but this phenomenon is less marked or less characteristic.
  1. Normal Pressure Hydrocephalus
    1. It is a triad of abnormal gait (Ataxic gait), dementia and urinary incontinence.
    2. Papilledema is not a feature.
    3. NPH is caused by obstruction to normal flow of CSF over the cerebral convexity and   delayed absorption into   the venous system.
    4. H/O conditions producing scarring of basilar meninges such as meningitis, SAH and head trauma positive.
    5. Enlarged lateral ventricles (Hydrocephalus) with little or no cortical atrophy. There is communicating hydrocephalus.
    6. CSF – Pressure is in high normal range.
      TLC, DLC, Protein, Sugar are normal.

Treatment - Ventricular peritoneal shunt.

Extra Edge: Fronto-temporal dementia (chromosome-17) is characterized by localized or regional atrophy of the temporal and or frontal lobe. 'The distinguishing anatomical hallmark of Frontotemporal dementia is a marked lobar atrophy (regional atrophy) of temporal and/or frontal lobe'



Anatomical Feature

Frontotemporal dementia

Regional (Localized) Atrophy of temporal and/or frontal lobe

Alzheimer’s disease

Diffuse cerebral atrophy


Widespread demyelinating lesions of cerebral cortex

C. J. disease

Widespread neuronal loss and gliosis

Friedreich’s Ataxia

Cerebral cortex is usually not involved.

Involvement is primarily restricted to spinal cord, brainstem and cerebellum.

Differential Diagnosis of Dementia
(Ref. Hari. 18th ed., Pg -3302)


Potentially Reversible dementia

  1. Vitamin deficiencies
    1. Thiamine (B1): Wernicke's encephalopathy  
    2. B12 (pernicious anemia)
    3. Nicotinic acid (pellagra)
  2. Endocrine and other organ failure
    1. Hypothyroidism                           
    2. Adrenal insufficiency and Cushing's syndrome
    3. Hypo-and hyperparathyroidism            
    4. Renal failure
    5. Liver failure                         
    6. Pulmonary failure
  3. Alcoholism
  4. Psychiatric
    1. Depression (pseudodementia)              
    2. Schizophrenia
  5. Chronic Infections
    1. Neurosyphilis                               
    2. Tuberculosis, fungal, protozal               
    3. Whipples disease
  6. Head trauma and diffuse brain damage
    1. Chronic subdural haemorrhage             
    2. Normal pressure hydrocephalus
  7. Toxic disorders
    1. Drug, medication, and narcotic poisoning     
    2. Heavy metal intoxication

Irreversible dementias

  1. Alzheimer’s
  2. Vascular dementia: 
    1. Multi infarct
    2. Diffuse white matter disease (Binswanger's)
  3. Parkinson’s disease
  4. Degenerative
    1. Huntington’s disease
    2. Pick's disease
    3. Dementia with Lewy bodies
    4. Progressive supranuclear palsy
    5. Multisystem degeneration
    6. Frontotemporal dementia
    7. Cortical basal degeneration
    8. Multiple sclerosis

Clinical Differentiation of the Major Dementias (Ref. Hari. 18th ed., Pg-3303)


First Symptom

Mental Status





Memory loss

Episodic memory loss

Initially normal

Initially normal

Entorhinal cortex and hippocampal atrophy


Apathy; poor judgment/insight, speech/language; hyperorality

Frontal/executive, language; spares drawing

Apathy, disinhibition, hyperorality, euphoria, depression

Due to PSP/CBD overlap; vertical gaze palsy, axial rigidity, dystonia, alien hand

Frontal and/or temporal atrophy; spares posterior parietal lobe


Visual hallucinations, REM sleep disorder, delirium, Capgras' syndrome, parkinsonism

Drawing and frontal/executive; spares memory; delirium prone

Visual hallucinations, depression, sleep disorder, delusions


Posterior parietal atrophy; hippocampi larger than in AD


Dementia, mood, anxiety, movement disorders

Variable, frontal/executive, focal cortical, memory

Depression, anxiety

Myoclonus, rigidity, parkinsonism

Cortical ribboning and basal ganglia or thalamus hyperintensity on diffusion/flare MRI


Often but not always sudden; variable; apathy, falls, focal weakness

Frontal/executive, cognitive slowing; can spare memory

Apathy, delusions, anxiety

Usually motor slowing, spasticity; can be normal

Cortical and/or subcortical infarctions, confluent white matter disease

Note: AD - Alzheimer's disease; FTD - frontotemporal dementia; PSP - progressive supranuclear palsy; CBD - cortical basal degeneration; DLB - dementia with Lewy bodies; CJD - Creutzfeldt-Jakob disease.

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