Clinical Presentation Alzheimer Disease

Clinical case Alzheimer disease

A 72-year-old man is brought to the office by his wife because of increasing forgetfulness. His wife states that during the past several years her husband has had trouble keeping up with his bills and recalling where he placed things. He often has difficulty remembering words when he speaks, forgets the names of his 2 grandsons, and asks the same questions repeatedly. He’s also begun to have difficulty dressing himself. Yesterday he got lost on his way home from the supermarket, despite having lived in the area most of his life. The man admits that his memory is “not what it used to be,” but other than showing some irritation at the physician’s questions he does not appear to be greatly concerned. His past medical history is not significant, and he denies having urinary incontinence, fever, or recent trauma. Vital signs are within normal limits. He is oriented to person and place, but cannot recall the date. Physical exam reveals a normal gait and the absence of focal neurologic deficits. His complete blood count, electrolytes, liver enzymes, and blood glucose levels are normal. Levels of vitamin B-12 (cobalamin), vitamin D, and TSH are normal. An RPR is negative.

Significant findings:
- Progressive memory loss
- Language alteration
- Apraxia
- No focal neurologic deficits
- Normal gait
What will most likely be found on this patient's brain CT or MRI?(Required)
Choose one answer:
- A. Previous multiple small cerebral infarcts
- B. Focal atrophy of the frontal and temporal lobes on brain
- C. T2-hyperintense lesions (≥3 mm in long axis) periventricular, cortical or juxtacortical
- D. Enlarged cerebral ventricles
- E. Diffuse corticocerebral atrophy

Learning Objectives:

1. Discuss the differential diagnoses of dementia
2. Identify the clinical manifestations of Alzheimer disease
3. Discuss the diagnosis of Alzheimer disease
4. Describe the pathologic features of Alzheimer disease
5. Review the mechanism of action of drugs used in the management of Alzheimer disease

Dementia – the loss of cognitive ability severe enough to represent a decline from a previous level of functioning.

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1. Differential diagnoses of dementia

Vascular Dementia

Cognitive decline in the setting of cerebrovascular disease
Second leading cause of dementia
Suspected in the presence of long-standing hypertension or diabetes mellitus
Multiple small cerebral infarcts can result in the loss of cognitive function
CT and MRI show previous cerebral infarcts

Frontotemporal Dementia (Pick Disease)

Focal atrophy of the frontal and temporal lobes on brain CT or MRI
Deposition of tau protein in the brain (Pick bodies)
Most commonly affects males over 60 years old
Language and behavior become abnormal first
Memory is preserved until later stages

Lewy Body Dementia

Dementia in the presence of parkinsonian signs:
Resting tremor
Shuffling gait
Fluctuations in cognitive function with periods of alertness and attention
Visual hallucinations in more than 75% of cases

Huntington Disease

Autosomal dominant degenerative disorder of adult onset
Movement disorders, neuropsychiatriс manifestations, and dementia

Creutzfeldt-Jakob Disease

A spongiform encephalopathy
Rapidly progressive dementia following infection with prion proteins

Other causes of dementia are those known as reversible causes these can be related to alcohol and medication intake or metabolic disorders such as vitamin B-12 deficiency, thyroid disease, hyponatremia, hypercalcemia and hepatic and renal dysfunction.

Detection and subsequent correction of these conditions may lead to reversal of dementia symptoms making their early diagnosis critically important another cause of reversible dementia is normal pressure hydrocephalus.

Normal Pressure Hydrocephalus

Most commonly affects elderly males
Clinical triad:
- Dementia
- Gait disturbances
- Urinary incontinence = “Wacky, Wobbly and Wet”
CT and MRI show enlarged cerebral ventricles

Alzheimer Disease

Neurodegenerative disorder of unknown cause
Primarily presents in patients over 65 years of age
Most common cause of dementia (70% of cases)

2. Clinical manifestations of Alzheimer disease

Memory Impairment

First clinical manifestation is memory impairment in the form of anterograde episodic amnesia
Characteristic pattern of memory impairment:
- Early loss of recent memory (hippocampus)
- Immediate, distant, and procedural memory are preserved until later stages of disease
Other forms of cognitive impairment:
- Language and visuospatial skills are affected first
- Behavioral and executive dysfunction appear later
- Apraxia manifests as the inability to perform learned motor tasks

Executive Dysfunction

Poor judgment, poor planning, or poor insight
- Anosognosia, or loss of insight into one’s own disorder, is characteristic of Alzheimer disease
- Patients trivialize severity of their condition

Later Stages

Neuropsychiatrie manifestations:
- Changes in personality
- Aggression
- Agitation
- Psychosis
30% of patients suffer from depression
Focal neurologic deficits may appear

3. Diagnosis of Alzheimer disease

There is no diagnostic test for Alzheimer disease
Diagnosis must be made clinically once all other causes of dementia have been excluded
Exclusion tests include:
- Complete blood count
- Electrolyte panel
- Levels of thyroid hormone, liver enzymes, vitamin B-12
- RPR (rapid plasma reagin) is a screening test for syphilis
- HIV ELISA
- Brain CT, MRI
Usually confirmed postmortem, following autopsy and histopathologic examination of the patient’s brain tissue

4. Pathologic features of Alzheimer disease

The pathogenesis of Alzheimer disease is unknown
Microscopic findings characteristic of Alzheimer disease are not pathognomonic for it:
- Neurofibrillary tangles
- Senile plaques
- Granulovacuolar degeneration
- Amyloid angiopathy of small to medium-sized brain vessels
Macroscopic findings:
- Diffuse cerebral and/or cortical atrophy
- Hippocampal atrophy

Neurofibrillary Tangles

Made of phosphoryiated tau protein:
- A stabilizer of microtubules found in neurons
- When phosphoryiated, forms insoluble intraneuronal inclusions:
  - Interfere with proper functioning
  - Lead to neuronal degeneration
Most prominent in the hippocampal region
Neurofibrillary tangle count strongly correlates with disease severity

Senile Plaques

Composed of beta-amyloid deposits in the extracellular brain matter
A small number of plaques can be a physiologic finding as a result of the normal aging process
A large number of plaques is consistent with Alzheimer disease
Mutations in certain genes could be responsible for the increased deposition of amyloid protein:
- Amyloid precursor protein (APP) gene (chromosome 21)
- Presenilin 1 gene (chromosome 14)
- Presenilin 2 gene (chromosome 1)

Alzheimer Disease in Down Syndrome

The role of chromosome 21 in the production of amyloid precursor protein has been speculated to contribute to the high prevalence of Alzheimer disease in people with trisomy 21
Down syndrome patients are known to develop Alzheimer disease in their forties, 15-20 years before the general population

5. Treatment of Alzheimer disease

No cure for Alzheimer disease, but early treatment has been shown to slow progression.

Cholinesterase Inhibitors

Cholinestrase inhibitors (donepezil) are indirect-acting cholinomimetics:
- Prevent the breakdown of acetylcholine in the synaptic cleft
Acetylcholine is a neurotransmitter involved in synaptic plasticity:
- Allows for synapses to change, thereby allowing for learning and memory
Patients have a marked reduction in the activity of choline acetyltransferase in the cerebral cortex and hippocampus
By increasing the amount of acetylcholine available in neural junctions, cholinesterase inhibitors are thought to slow the progression of neuronal degeneration

NMDA Receptor Antagonist (Memantine)

The N-methyl-D-aspartate (NMDA) receptor:
- Involved in learning and memory
- Found abundantly within hippocampal and cortical neurons
Glutamate:
- The main excitatory neurotransmitter acting on these neurons
- Activates the NMDA receptor by increasing the flow of cations through non-selective channels
- Excessive stimulation of the NMDA receptor by glutamate can result in neurotoxicity
Memantine:
- Thought to block excessive activity of the NMDA receptor while preserving its normal functions (neuroprotective effect)
- Used in combination with cholinesterase inhibitors