M. Otto
Epidemiology
Alzheimer's disease (senile dementia of the Alzheimer type) is the most common cause of dementia. An important risk factor for Alzheimer's disease is age. The incidence, i. e., the number of newly occurring dementia cases per year, increases from about 0.5% in the 60–70 years age group to about 2–8% in the 85–90 years age group.
Etiology
About 10% of cases of Alzheimer's disease are familial. Mutations are found in significantly fewer patients than that. So far, various mutations in the amyloid precursor protein (APP) gene and in the presenilin genes 1 and 2 have been reported. Several research groups have reported that presence of the ε4 allele of the apolipoprotein E (ApoE) gene predisposes for the disease. The risk of developing Alzheimer's disease is increased by a factor of 2–5 in heterozygous ApoE ε4 carriers, and by a factor of 5–34 in homozygous ApoE ε4 carriers (see also Chap. 8).
Classification and Clinical Features
Alzheimer's disease is subdivided into clinically probable and clinically possible Alzheimer's disease. A definite diagnosis can only be established by neuropathologic examination. It has been demonstrated that only up to 80% of patients with a clinical diagnosis of Alzheimer's disease actually meet the neuropathologic criteria. This should be taken into account particularly when evaluating neurochemical markers from patients with a clinical diagnosis of Alzheimer's disease.
An essential component of the diagnosis of possible or probable Alzheimer's disease is the exclusion of other forms of dementia.
Diagnosis
Neuroimaging. Signs of atrophy or hypoperfusion found by magnetic resonance imaging (MRI) or positron emission tomography (PET) are often considered a diagnostic indicator. MRI and computed tomography (CT) of the brain are not suited to early differential diagnosis of dementia. Currently, only PET seems suitable for early diagnosis of Alzheimer's, since it is the only imaging procedure that provides a three-dimensional representation and quantification of the spatial and temporal distribution of tracers in the brain tissue and, thus, a portrait of the energy metabolism in the brain.
Histopathology. Intracellular senile plaques and extracellular neurofibrillary tangles (NFTs) are diagnostically relevant indicators. Senile plaques consist largely of amyloid beta (Aβ) peptides. These are degradation products of the amyloid precursor protein, which is a component of the cell membrane. The neuropathologic diagnosis is based on the presence of neuritic (senile) plaques, the surroundings of which usually show pronounced activation of microglia. Neurofibrillary tangles consist of hyperphosphorylated tau protein monomers that have combined to form paired helical filaments. The extent of Aβ plaque pathology is classified according to CERAD (Consortium to Establish a Registry of Alzheimer's Disease) and that of tau protein pathology is clue staged according to the Braak classification (Braak and Braak, 1991).
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Table 11.2 Core symptoms of dementia |
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Disease |
Core symptoms |
Supportive diagnosis |
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Alzheimer's disease |
• Neuropsychological deficits • Memory deficit • Perseveration, preserved facade |
• CT, MRI show temporoparietal atrophy • CSF: tau protein increased, Aβ1–42 decreased, ApoE ε4 more frequent |
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Multi-infarct dementia (vascular dementia) |
• Episodic, fluctuating course • Emotional instability • Impaired short-term memory, nocturnal confusion • Focal neurological signs • Vascular risk factors (hypertension!) |
CT (SPECT, MRI, PET): cerebrovascular lesions |
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Subcortical arteriosclerotic encephalopathy (Binswanger's disease) |
• Special form of vascular dementia • Mostly hypertension, gait apraxia, urinary dysfunction |
CT, MRI: demyelination of white matter and/or subcortical lacunar infarcts |
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Lewy body dementia |
• Dementia • Extrapyramidal motor symptoms • Visual hallucinations • Fluctuating cognitive deficits • Hypersensitivity to neuroleptics |
CSF: tau protein may be increased, Aβ1–42 may be decreased |
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Frontotemporal dementia |
• Failure to perform routine activities, aphasia, personality disorder with disinhibition, grasp reflexes, oral tendency • In rare cases, incontinence, motor neuron involvement |
• CT: frontal or temporal lobe atrophy • SPECT: early frontal or temporal hypoperfusion • CSF: tau protein may be slightly increased; S 100B is often increased |
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Multiple system atrophy |
• Parkinsonian symptoms or cerebellar symptoms • Dementia appears only later • Autonomic dysfunction |
MRI: hyperintense border between putamen and external capsule in the T2-weighted image |
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Creutzfeldt-Jakob disease |
• Dementia • Cerebellar and/or visual symptoms • Myoclonia, extrapyramidal and/or pyramidal signs • Rapidly progressing |
• CSF: tau protein, 14–3-3 protein, and S 100B protein dramatically increased • Serum: S 100B increased • EEG: triphasic waves • MRI: hyperintense basal ganglia on T2-weighted imaging; pulvinar hyperintensity in vCJD patients |
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Progressive paralysis (syphilis) |
• Expansiveness, megalomania • Impaired pupil reaction, dysarthria |
Specific antibody production in the CSF |
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AIDS dementia complex |
• Progressive loss of cognitive skills • Apathy, headache • Impaired coordination, tremor |
Specific antibody production in the CSF |
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Communicating (normalpressure) hydrocephalus |
• Urinary dysfunction • Gait apraxia • Paraspasm of the legs |
• CT: hydrocephalus internal > external • Lumbar puncture (40 mL) improves impaired gait |
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Whipple's disease |
• Oculomotor dysfunction, myoclonia • Abdominal symptoms |
• Biopsy of small intestine • CSF: PAS-positive cells, detection of Tropheryma whipplei |
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Toxic encephalopathy |
• Often: polyneuropathy • Changes in skin, mucosae, and appendages |
Screening for solvents, alcohol, lead, psychopharmaceuticals |
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Metabolic causes and endocrinopathy |
Systemic symptoms (e. g., hypothyroidism, hyperparathyroidism, funicular myelosis, carcinoid syndrome, uremia) |
• Hashimoto's encephalopathy: detection of antibodies. Note: Patients may have normal thyroid function • CSF: increasing barrier dysfunction may be the only |
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Table 11.3 Examination protocols for evaluating dementia syndromes (adapted from Hüll and Bauer, 1999) |
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Diagnostic test |
Importance for differential diagnosis |
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CT |
• Exclusions: tumor, hemorrhage, cerebral infarction, hematoma, hydrocephalus • Atrophy in Alzheimer's disease |
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MRI |
• Atrophy in Alzheimer's disease • Typical vascular lesions in SAE • Hyperintense basal ganglia in sporadic CJD • Hyperintense pulvinar in variant CJD • Hyperintense margin between putamen and external capsule in MSA |
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EEG |
• Exclusion: nonconvulsive state • Periodic triphasic complexes in CJD |
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CSF analysis |
• Typical patterns of tau protein and Aβ1–42 in Alzheimer's disease • Dramatic increase of tau protein, 14–3-3 protein, and S 100B protein in CJD • Specific antibodies in encephalitis, HIV infection, syphilis, borreliosis |
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T3, T4, TSH |
• Hypothyroidism • Thyrotoxicosis |
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Thyroid autoantibodies |
Evidence of Hashimoto's encephalopathy |
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Vitamins B1, B6, B12, C, folic acid |
• Funicular myelosis • Wernicke-Korsakow syndrome |
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ESR, electrophoresis, rheumatologic serology |
Lupus erythematosus |
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TPHA test |
Syphilis |
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HIV test |
AIDS |
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Lipid electrophoresis, lactate |
Mitochondropathy |
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Electrolytes |
• Hyponatremia • Hyperparathyroidism |
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Liver enzymes |
• Hepatic encephalopathy • Alcoholism |
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Creatinine, urea |
Chronic renal insufficiency |
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Glucose |
Severe diabetes mellitus |
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Genetic tests |
• ApoE ε4 carrier status in Alzheimer's disease • PrP mutation in genetic CJD • APP mutation in genetic Alzheimer's disease |
The histopathological changes, particularly the development of NFTs, occur in a characteristic sequence in various regions of the brain. The first alterations appear in the transentorhinal cortex (Braak stages 1 and 2); later the limbic regions become involved (Braak stages 3 and 4). In the late stages of the disease, isocortical regions of the brain are also affected by neurofibrillary changes (Braak stages 5 and 6). Histopathological studies on many brains have shown that the entire course of the disease may take up to 50 years. About 30 years may pass between the first changes in the transentorhinal region and the first clinical symptoms.
CSF analysis. Until recently, CSF analysis has only been carried out to exclude acute or chronic inflammation. It has now been established by many studies that the CSF of patients with Alzheimer's disease contains:
• Decreased levels of Aβ peptide1–42 (< 450 pg/mL).
• Elevated levels of total tau protein (> 450 pg/mL).
Pitfalls of CSF analysis in Alzheimer's disease
Decreased levels of Aβ peptide1–42 and elevated levels of tau protein may also occur in other forms of dementia. Furthermore, about 20% of patients with Alzheimer's disease have normal levels of Aβ peptide1–42 and tau protein. The interpretation of Aβ1–42 levels is further hampered by the fact that in some studies the levels depended on the ApoE ε4 gene dose. These studies revealed that lower Aβ1–42levels are already found in nondemented persons carrying one ApoE ε4 allele. Interestingly, higher Aβ1–42 levels have been reported in test persons taking insulin. Whether we will have to work with ApoE ε4-specific and medication-specific reference levels in the future is currently under debate.
Fig. 11.1 Separation of Aβ peptides in urea-based SDS-PAGE/immunoblot according to Wiltfang (Lewczuk et al., 2004; Maler et al. 2007) (top); this procedure permits quantitative detection of Aβ peptides in the CSF. For comparison, total Aβ fraction in a conventional SDS immunoblot (bottom).
Recent studies suggest that calculating the ratio Aβ1–42/Aβ1–40 is more important for differential diagnosis than determining only Aβ1–42. This has been confirmed for the Aβ1–42/Aβ1–39 ratio in our own investigations into distinguishing Alzheimer's disease from Creutzfeldt-Jakob disease. In that study, we used a special urea gel electrophoresis in contrast to the conventional ELISA procedures which can only measure Aβ1–42 and Aβ1–40 (Fig. 11.1). However, further studies are still needed before this ratio can be recommended for general use. Determination of phosphorylated isoforms of tau protein should also increase the diagnostic sensitivity for Alzheimer's disease versus other forms of dementia, although here, too, further studies are needed before generalized use of this marker can be recommended.
References
Braak H, Braak E. Neuropathological staging of Alzheimer-related changes. Acta Neuropathol 1991;82:239–259
Hüll H, Bauer J. Demenzen. In: Berlit P, ed. Klinische Neurologie. Heidelberg: Springer; 1999:829–856
Lewczuk P, Esselmann H, Bibl M, et al. Electrophoretic separation on amyloid beta peptides in plasma. Electrophoresis 2004;25:3336–3343
Maler JM, Klafki HW, Paul S, et al. Urea-based two-dimensional electrophoresis of beta-amyloid peptides in human plasma: evidence for novel Abeta species. Proteomics 2007;7:3815–3820
Further Reading
Kretzschmar HA, Neumann M. Neuropathological diagnosis of neurodegenerative and dementia diseases. Pathologe 2000;21:364–374
Mirra SS, Heyman A, McKeel D, et al. The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer's disease. Neurology 1991;41:479–486