Alzheimer’s Disease

Cortical atrophy of temporoparietal cortex [Ref Robbins 7^thle p 1386] Alzhiemer’s disease

Pathological features

The major pathological features in Alzhiemer’s disease are:-

• Cerebral atrophy
• Neuronal loss
• Amyloid plaques
• Neurofibrillary tangles

These changes are most severe in the following locations in decreasing order:

• Medial temporal lobes

– Including the amygdala, hippocampal formation and entorhinal cortex.

• Basal temporal cortex

– Extending over the lateral posterior temporal cortex, parieto occipital cortex and posterior cingulate gyrus

• Frontal lobes

– An important point is that primary motor, somatosensory, visual and auditory cortices are relatively spared

Ans:B-Recent memory loss

Everyone has occasional memory lapses. It’s normal to lose track of where you put your keys or forget the name of an acquaintance. But the memory loss associated with Alzheimer’s disease persists and worsens, affecting the ability to function at work or at home.

People with Alzheimer’s may:

• Repeat statements and questions over and over
• Forget conversations, appointments or events, and not remember them later
• Routinely misplace possessions, often putting them in illogical locations
• Get lost in familiar places
• Eventually forget the names of family members and everyday objects
• Have trouble finding the right words to identify objects, express thoughts or take part in conversations

• Alzheimer’s disease (AD) is the most common cause of dementia in the elderly (followed by vascular multi-infarct dementia and diffuse Lewy body disease).
• AD often begins insidiously with impairment of memory and progresses to dementia.
• Histologically, AD is characterized by numerous neurofibrillary tangles and senile plaques with a central core of the amyloid alpha protein 

• Silver stains demonstrate tangles and plaques and Congo red shows amyloid deposition in plaques and vascular walls (amyloid angiopathy).
• In AD there are also numerous Hirano bodies, and granulovacuolar degeneration is found in more than 10 of the neurons of the hippocampus. Grossly, brain atrophy (narrowed gyri and widened sulci) is predominant in the frontal and superior temporal lobes

Lewy bodies

Delirium is broadly defined as an acute decline in attention and cognition.

It is characterized by altered sensorium, confusion, stupor, and fluctuations of consciousness.

Several genes play important pathogenic roles in at least some patients with Alzheimer’s disease(AD). One is the APP gene on chromosome 21. Adults with trisomy 21 (Down syndrome) consistently develop the typical neuropathologic hallmarks of AD if they survive beyond age 40. Presenilin-1 (PS-1) is on chromosome 14 and encodes a protein called S182. Mutations in this gene cause an early-onset AD transmitted in an autosomal dominant, highly penetrant fashion. The Apo E gene on chromosome 19 is involved in the pathogenesis of late-onset familial and sporadic forms of AD.

AD most often presents with an insidious onset of memory loss followed by a slowly progressive dementia over several years. Pathologically, atrophy is distributed throughout the medial temporal lobes, lateral and medial parietal lobes and lateral frontal cortex. Microscopically, there are neuritic plaques containing A-beta, neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau filaments, and accumulation of amyloid in blood vessel walls in cortex and leptomeninges.

Clinical Manifestation begins with memory impairment and spreading to language and visuospatial deficits.The management of AD is challenging and gratifying, despite the absence of a cure or a robust pharmacologic treatment. Donepezil (target dose, 10 mg daily), rivastigmine (target dose, 6 mg twice daily or 9.5-mg patch daily), galantamine (target dose 24 mg daily, extended-release), memantine (target dose, 10 mg twice daily), and tacrine are the drugs presently approved by the Food and Drug Administration (FDA) for treatment of AD.

Ref:Harrison’s Internal Medicine, 18th Edition, Pages 3307, 3309, 3049

Lateral geniculate body of the thalamus is resistant to the neurofibrillary tangles of Alzheimer’s disease. So lateral geniculate body is the single best answer of choice.

A i.e. Apo E gene

A i.e. Acetyl choline

D i.e.Cerebral infarcts

A i.e. Cerebellar atrophy

Ans. All the above

All 4 A’s are seen early in Alzheimer’s disease.4 A’s are:

• Amnesia-Memory disturbances
• Aphasia-Disturbances in language function
• Apraxia-Difficulty in performing learned motor movements
• Agnosia-Difficulty to interpret a sensory stimulus

D i.e. Extracellular inclusions (lesions) can occur in the absence of intracellular inclusions to make pathological diagnosis of AD

Characteristic cognitive impairments in Alzheimer’s disease include amnesia, aphasia, agnosia, and apraxia (the 4 As)Q. These four impairments are also included in DSM-IV TR diagnostic criteria of Alzheimer’s disease. However, there appears no cognitive functions that are truely preserved in AD. Visuo-spatial difficulties commonly occur in the middle stages of the disorder and may result in topographical disorientation, wandering and becoming lost. Difficulties with calculation (acalculia), attention and cognitive planning all occur.

–  For neuropathological diagnosis of AD, h/o dementia, extracellular neuritic senile (amyloid) plaques and intracellular NFTs all are required. Number of senile plaque increases with age, number of NFTs correlates with severity of dementia and presence of tau (r) protein suggest neurodegenerationQ.

It is the most common cause of dementiaQ. It causes gradually progressive cortical (parieto-temporal) dementiaQ beginning with memory impairment and spreading to language and visuospatial deficits over a prolonged courseQ.

C i.e. Lateral geniculate body

Alzheimer’s disease, a type of cortical dementia, does not involved sub cortical areas such as lateral geniculate body (nucleus)- a part of thalamusQ. Earliest and most severe degeneration is usually found in medial temporal lobe (entorhinal/ perirhinal cortex & hippocampus), lateral temporal cortex and nucleus basalis of MeynertQ. Area of visual association and cuneal gyrus (VI) are also cortical areas.

A. i.e. Initial loss of long term memory B. i.e. Delayed loss of short term memory C. i.e. Step ladder pattern

B i.e. Abrupt onset acute exacerbation

C i.e. Alzheimer’s disease

• Duration of 1 month only, is enough to rule out schizophrenia, in which duration should be at least 6 months
• In psychiatric disorders like schizophrenia & psychosis, there may never be organic symptoms like increased tendon reflexes.
• Features of Alzheimer dementia are

1. Memory impairment without impairment of consciousness
2. Anosognosia (Unaware of his problem) Prosopagnosia (difficulty in identifying known faces)
3. Focal neurological signs (ex asymmetrical hyperreflexia or weakness)
4. Primitive reflexes (ex grasp, snout, suck, Palmo-mental, & tonic foot reflexes)
5. Frontal lobe signs
6. Aphasia (language disturbance)
7. Apraxia (impaired ability to carry out motor activities despite intact motor function)
8. Agnosia (failure to recognize or identify objects despite intact sensory function)
9. Disturbance in executive functioning (i.e. planning, organizing, sequencing, abstracting)

C i.e. Acetyl choline

Ans. is ‘a’ i.e., Neurofibrillary tangles; ‘b’ i.e.,Neuritic plaques

Ans. is ‘a’ i.e., Atrophy of parietal and temporal lobes

Gross pathology in Alzhiemer’s disease:

o Diffuse cerebral atrophy of the hippocampus, amygdala and entorhinal cortex.

o Enlargement of the ventricles caused by neuronal loss.

• Grossly the brain shows a variable degree of cortical atrophy marked by widening of the cerebral sulci.
• These changes are most pronounced in the temporal and parietal lobes:

 Frontal lobes can also be involved.

Ans. is ‘a’ 10% buffered neutral formalin

Ans. is ‘d’ i.e., Alzheimer disease

o Donepezil is a cerebroactive drug. It is used in Alzheimer’s disease (AD).

Ans. is ‘a’ i.e., Alzheimer’s diseaes

Ans. is ‘a’ i.e., TCAs

o Cholinergic transmission is diminished in Alzheimer’s disease.

o All agents that benefit the conduction act to enhance acetyhcholine activity by inhibition of the acetylcholinesterase which metabolises and inactivates acetylcholine.

o Consequently acetylcholine remains usable for longer.

o Rivastigmine acts in similar way.

o Tricyclic antidepressants (TCAs) have anticholinergic property, therefore they counteract that cholinergic effect of rivastigmine.

Ans. is ‘b’ i.e., Tricyclic antidepressant

Rivastigmine (cholinesterase inhibitor) should not be used with drugs that have cholinergic antagonistic activity like tricyclic antidepressants (TCA) as the combination is counter productive.

Answer is C (Trisomy 21) :

Several genetic factors are known to play important roles in pathogenesis of at least some cases of Alzheimers disease. Trisomy 21 is one of them.

Adults with trisomy 21 (Down’s) consistently develop the Neuropathologic hallmark’s of Alzheimer’s disease if they survive beyond age 40.

Answer is B (Temporo-Parietal cortex):

Alzheimer’s disease predominantly affects the temporoparietal cortex although frontal lobe is also frequently involved

Alzheimer’s disease predominantly affects the temporo-parietal cortex’ – Alzheimer’s Disease by Terry Regional deficits are most prominent in the temporo-parietal cortex’ – Alzheimer’s Disease by Terry

Answer is C (Smoking):

Smoking has not been mentioned as a risk factor_, for Alzheimer’s disease.

Answer is D (Dopamine):

Dopamine deficiency is not a feature of Alzheimer’s disease.

Answer is A (Acetylcholine):

The most important biochemical abnormality in Alzheimer’s disease is the decrease in cortical levels of Acetylcholine

Biochemically Alzheimer’s disease is associated with a decrease in the cortical levels of several proteins and neurotransmitters especially acetylcholine, its synthetic enzyme choline-acetyl-transferase, and nicotinic cholinergic receptors. Reduction of acetylcholine is related in part to degeneration of cholinergic neurons in the nucleus basalis of Meynert (NBM) that projects through the cortex. There is also noradrenergic and serotonergic depletion due to degeneration of brainstem nuclei such as the locus ceruleus and dorsal raphe’ – Harrison’s

Answer is C (Dementia):

Alzheimer’s Disease is the most common cause of Dementia in elderly.

Clinically, AD most often presents with subtle onset of memory loss followed by slowly progressive dementia that has a course of several years.

Answer is None (All are seen) > Agnosia

Aphasia, Apraxia, Acalculia and Agnosias may all be seen in Alzheimer’s Dementia.

`Agnosia’ in Alzheimer’s disease usually presents late in the disease and is not included in the ICD-10 Diagnostic criteria for dementia in Alzheimer’s disease with early onset and hence may be selected as the single best answer by exclusion.

Dementia in Alzheimer’s Disease with Early Onset (ICD-10 criterion)

1. The criteria for dementia in Alzheimer’s Disease must be met, and the age at onset must be less than 65 years.
2. In addition atleast one of the following requirements must be met:

a)     evidence of relatively rapid onset and progression

b)     in addition to memory impairment there must be:

– Aphasia (Amnesia or sensory)

– Agraphia

–  Alexia (indicating the presence of temporal, parietal or frontal lobe involvement)

–  Acalculia or

–  Apraxia

Answer is C (NFTs appear extracellularly before intracellular appearance):

NFTs are typically seen intracellularly within the soma and proximal dendrites of neurons.

Neurofibrillary Tangles (NFTs) are intracellular accumulations of hyperphosphorylated ‘tau’ proteins.

Neurofibrillary Tangles are Intracellular Accumulations

• Neurofibrillary Tangles are intracellular accumulations of hyperphosphorylated microtubule binding protein ‘tau’.
• Paired helical filaments of tau protein (NFTs) form intracellularly within the soma and proximal dendrites of neurons.
• These cytoskeletal protein tangles (NFTs), initially impede cellular metabolism and axosplasmic transport leading to impaired synaptic function and eventually to neuronal death.
• These neurofibrillaty tangles may be seen as extracellular tangles after degeneration of the neuron as evidence of the neuronal cell’s demise
• Neurofibrillary Tangles are intracellular accumulations that may appear extracellularly alter degeneration of neuron (neuronal death)

Histopathological Hallmarks of Alzheimer’s Disease

Amyloid Plaques (Extracellular)

• Amyloid Neuritic Plaques are formed by extracellular accumulation of beta amyloid deposits within the neutropil
• ‘Neuritic’ or ‘Senile’ I3-amyloid plaques are an early histopathological sign of Alzheimer’s disease (that occur rarely in healthy subjects)
• The amyloid 13-protein accumulated in single neuritic plaques is toxic to surrounding structures and adjacent neurons.
• Clinicopathological studies have shown that amy/aid burden does not directly correlate with severity or duration of dementia.

Neurofibrillary Tangles (Intracellular)

• Neurofibrillary tangles arc formed by intracellular accumulation of hyperphosphorylated microtubule binding protein ‘tau’.
• NFT’s occur in many neurodegenerative diseases and /or a group of diseases called laupathies’.
• These include Frontotemporal dementia, Pick’s disease etc. The cooccurance of fi-amyloid plaques with NFT’s suggests a diagnosis of AD.
• The NFT’s are toxic to the neurons and neurons with NFT’s eventually die and degenerate leaving a residual `ghost tangle’, in the extracellular space reminding of the pyramidal cell body in which it was initially formed.
• Clinicopathological studies have shown that dementia correlates more strongly with NFT’s than with senile plaques (3-amyloid)

Answer is C (Lateral Geniculate Body):

`Lateral geniculate body’ is the least commonly affected area amongst the options provided.

Weurofibrillaiy tangles are region specific occuring predominantly in the Hippocampus, Entorhinal cortex and association areas of the Neocortex

‘The Neuropathology of Dementia’ (Cambridge) 1997/7

`Not even a single neuron with Neurofibrillary Tangles (NFT) was seen in the Lateral Geniculate Bodies’

— Distribution of Alzheimer’s Neurofibrillary tangles (Taken from ‘Alzheimer’s Disease’ by George Parry (2006)/55)

Neuro fibrillary Tangles (NFT): Density distribution in Alzheimer’s disease

• Entorhinal cortex — Hippocampus — Amygdala interconnections (most vulnerable)
• Limbic and Temporal cortical areas (next most severely involved)
• Association areas of the neocortex

Topographical Distribution of NFTs in Alzheimer’s disease

Answer is D (Lewy bodies):

Lew)^, bodies’ are characteristically seen in idiopathic parkinsons disease (and not in Alzheimer’s disease).

Alzheimer’s disease is the most common cause of dementia in the Western world and is characterized by the following clinical, pathological and biochemical triad.

Ans. D i.e. Alzheimer’s disease

Ans. B: Alzheimer’s Disease

Neurofibrillary tangles are pathological protein aggregates found within neurons in cases of Alzheimer’s disease. Tangles are formed by hyperphosphorylation of a microtubule-associated protein known as tau, causing it to aggregate in an insoluble form. (These aggregations of hyperphosphorylated tau protein are also referred to as PHF, or “Paired Helical Filaments”).

It is also believed that neurofibrillary tangles are seen in Creutzfeldt-Jakob disease.

Neurofibrillary tangles are also found in Supranuclear palsy.

It’s also related to frontotemporal dementia however without detectable (beta}-amyloid plaques.

Ans. is ‘d’ i.e., Lewy body

Important pathological findings in Alzheimer’s disease :‑

• Cortical atrophy with sidening of the cerebral sulci
• Compensatory ventricular enlargement       Hydrocephalus exvacuo.
• Neuritic (senile) plaques                              —> Made up of A f3₉₀ & Al342.
• Diffuse plaques                                      Contain Ab42.
• Neurofibrillary tangles                         —> Contain tau protein
• Cerebral amyloid angiopathy.

Granulovascular degeneration

Ans. is ‘c’ i.e., Acetylcholine

Neurotransmitters in Alzheimer’s disease

• Acetylcholine has a major role in memory functions and deficiency in cholinergic functioning is associatedwith memory disturbances particularly short term memory. In Alzheimer’s disease there loss of cells in the nucleus basalis of meyernet results in marked reduction in choline acetyltransferase (CHAT), an enzymeinvolved in the synthesis of acetylcholine —> Decreased Acetylcholine.
• The other important neurotransmitter involved is norepinephrine —> There is decrease in nor-epinephrine containing neurons in the locus ceruleus.
• Two other neuroactive peptides have been implicated in AD —> Somatostatin and corticotropin, both of which have decreased concentration.