Alzheimer’s disease (AD), also referred to simply as Alzheimer’s, is a chronic The term senile dementia of the Alzheimer type (SDAT) was used for a time to describe This audio file was created from a revision of the article “Alzheimer’s . – ALZHEIMER DISEASE; AD – PRESENILE AND SENILE or ‘senile’ dementia, and suggested the term ‘senile dementia of the Alzheimer type’ (SDAT) . With Alzheimer’s disease there is great individual variability as to the nature of symptoms experienced and the speed at which deterioration occurs. The types of .
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A homozygous mutation in the APP gene with a dominant-negative effect on amyloidogenesis was found in a patient with an early-onset progressive dementia and his affected younger sister See also APP-related cerebral amyloid angiopathy CAA;which shows overlapping clinical and neuropathologic features.
Alzheimer disease is the most common form of progressive dementia in the elderly. It is a neurodegenerative disorder characterized by the neuropathologic findings of intracellular neurofibrillary tangles NFT and extracellular amyloid plaques that accumulate in vulnerable brain regions Sennvik et al.
Terry and Davies pointed out that the ‘presenile’ form, with onset before age 65, is identical to the most common form of late-onset or ‘senile’ dementia, and suggested the term ‘senile dementia of alzheimerdiseasee Alzheimer type’ SDAT. Haines reviewed the genetics of AD. Selkoe reviewed the pathophysiology, chromosomal loci, and pathogenetic mechanisms of Alzheimerdiseasee disease. Theuns and Van Broeckhoven reviewed the transcriptional regulation of the genes involved in Alzheimer disease.
Alzheimer disease is a genetically heterogeneous disorder. Evidence also suggests that mitochondrial DNA polymorphisms may be risk factors in Alzheimer disease Finally, there have been associations between AD and various polymorphisms in other genes, including alphamacroglobulin A2M; Schottky described a familial form of presenile dementia in 4 generations. The diagnosis was confirmed at typeifle in a patient in the fourth generation. Lowenberg and Waggoner reported a family with unusually early onset of dementia in the father and 4 of 5 children.
Postmortem findings in 1 case were consistent with dementia of the Alzheimer type. Dementia was zlzheimerdisease with conspicuous parkinsonism and long tract signs. Two patients had neuropathologic changes of spongiform encephalopathy of the Creutzfeldt-Jakob type CJD; at autopsy, but the long clinical course was unusual for CJD.
There was no increased incidence of Down syndrome or hematologic malignancy. These families also demonstrated an increase in the frequency of Down syndrome 3.
No excess of hematologic malignancy was found in relatives. In a study of the families of Down syndrome children and controls, Berr et al. In a large multicenter study of first-degree relatives of AD alzheiemrdisease and nondemented spouse controls, Silverman et al. Axonal defects consisted of swellings that accumulated abnormal amounts of microtubule-associated and molecular motor proteins, organelles, and vesicles.
Impairing axonal transport by reducing the dosage of a kinesin molecular motor protein enhanced the frequency of axonal defects and increased amyloid-beta peptide levels and amyloid deposition. Subjects underwent baseline clinical and cognitive assessments, brain imaging, and cerebrospinal fluid and blood tests. They then conducted cross-sectional analyses of baseline data in relation to estimated years from expected symptom onset in order to determine the relative order and magnitude of pathophysiologic changes.
Concentrations of amyloid-beta in the CSF appeared to decline 25 years before expected symptom onset.
Amyloid-beta deposition, as measured by positron-emission tomography with the use of Pittsburgh compound B, was detected 15 years before expected symptom onset. Increased concentrations of tau protein in the CSF and an increase in brain atrophy were detected 15 years before expected symptom onset.
Cerebral hypometabolism and impaired episodic memory were observed 10 years before expected symptom onset. Global cognitive impairment, as measured by Mini-Mental State Examination and the Clinical Dementia Rating scale, was detected 5 years before expected symptom onset, and patients met diagnostic criteria for dementia at an average of 3 years after expected symptom onset.
The disorder was characterized by early onset of memory deficits, decreased speed of cognitive processing, and impaired attention to complex cognitive sets. The family immigrated to Canada from the British Isles in the 18th century.
The mean age of onset of dementia was 43 years. The earliest cognitive functions affected were recent memory, information-processing speed, sequential tracking, and conceptual reasoning. Language and visuoperceptual skills were largely spared early in the course of the disease. Later, there were progressive cognitive deficits and inability to perform the activities of daily living. Death occurred, on average, 6 years after onset. The family was Romanian, many of its members having migrated to Indiana.
At age 52 years, the proband developed progressive cognitive decline with memory loss and visuospatial troubles, as well as stroke-like episodes characterized by monoparesis and language disturbances detectable for a few days. MRI showed T2-weighted signal hyperintensities in subcortical and periventricular white matter without bleeding. Neuropathologic examination showed neurofibrillary tangles and A-beta and A-betaimmunoreactive deposits in the neuropil.
Alzheimer’s disease – causes, symptoms, prevention – Southern Cross NZ
The vessel walls showed only A-beta deposits, consistent with amyloid angiopathy. There were also multiple white matter infarcts along the long penetrating arteries. Other affected family members had a similar clinical picture. Alzheimerdieease unaffected family members carried the mutation, and all but 1 were under 65 years of age.
The distinctive clinical features in this family were a rapidly progressive dementia starting in the fourth decade, seizures, myoclonus, parkinsonism, and spasticity. Variable features included aggressiveness, visual disturbances, and pathologic laughter.
To test this hypothesis, they analyzed APP using quantitative multiplex PCR of short fluorescent fragments, a sensitive method for detecting duplications that is based on the alzueimerdisease amplification of multiple short genomic sequences using dye-labeled primers under quantitative conditions.
Alzheimer’s disease – Symptoms and causes – Mayo Clinic
In the 5 index cases with the combination of early-onset Alzheimer disease and CAA, they found evidence for a duplication of the APP locus In the corresponding families, the APP locus duplication was present in affected subjects but not in healthy subjects over the age of 60 years. The phenotypes of the affected subjects in the 5 families were similar. None had mental retardation before the onset of dementia. None had clinical features suggestive of Down syndrome.
Neuropathologic examination of the brains of 5 individuals from 3 kindreds showed abundant amyloid deposits, present both as dense-cored plaques and as diffuse deposits, in all regions analyzed. Neurofibrillary tangles were noted in a distribution consistent with the diagnosis of definite Alzheimer disease.
However, the most prominent feature was severe CAA. However, there was little decline in underlying gray matter volume in these patients. In a comparison of 59 unrelated patients with AD and over 1, controls, Borenstein Graves et al. The authors suggested that the clinical expression of AD may occur when degeneration in specific brain regions falls below a critical threshold of ‘brain reserve,’ beyond which normal cognitive function cannot be maintained. In a study of sibs of probands diagnosed with AD, Sweet et al.
However, patients with familial AD had a more severe reduction in glucose metabolism in all these areas, suggesting that genetic predisposition further strains the degenerative process. They concluded that increased platelet membrane fluidity see characterized a subgroup of patients with early age of symptomatic onset and rapidly progressive course. Zubenko and Ferrell described monozygotic twins concordant for probable AD and for increased platelet membrane fluid. Birchall and Chappell suggested that individual vulnerability of genetic factors influencing intake, transport or excretion of aluminum may be a mechanism for familial AD.
They noted that expression of RAGE was particularly increased in neurons close to deposits of amyloid beta peptide and to neurofibrillary tangles. Cholinergic projection neurons of the basal forebrain nucleus basalis express nerve growth factor NGF receptors p75 NTR and TrkAwhich promote cell survival.
These same cells undergo extensive degeneration in AD. By contrast, cortical p75 NTR levels were stable across the diagnostic groups. The Framingham Massachusetts Study cohort has been evaluated biennially since In a sample of 1, subjects mean age, 76 years from this cohort, Seshadri et al. They used multivariable proportional-hazards regression to adjust for age, sex, apoE genotype, vascular risk factors other than homocysteine, and plasma levels of folate and vitamins B12 and B6.
Over a median follow-up period of 8 years, dementia developed in subjects, including 83 given a diagnosis of Alzheimer disease. The multivariable-adjusted relative risk of dementia was 1. The relative risk of Alzheimer disease was 1. With a plasma homocysteine level greater than 14 micromol per liter, the risk of Alzheimer disease nearly doubled.
Among AD patients and controls, Prince et al. In a retrospective study of AD patients, Evans et al. The effect was not seen in patients with the APOE4 allele and high cholesterol. Reelin was not increased in plasma samples, suggesting distinct cellular origins.
The reelin kD fragment was also increased in CSF samples of other neurodegenerative disorders, including frontotemporal dementiaprogressive supranuclear palsy PSP;and Parkinson disease PD; Similar decreases were not seen in brain extracts from patients with other forms of dementia.
In a mouse model of AD, reduced neuronal TGFBR2 signaling resulted in accelerated age-dependent neurodegeneration and promoted beta-amyloid accumulation and dendritic loss. In a study of the families of Alzheimer disease patients, Heston found an excess of Down syndrome and of myeloproliferative disorders, including lymphoma and leukemia.
Neurons of Alzheimer patients show a neurofibrillary tangle that is made up of disordered microtubules. An identical lesion occurs in the neurons of Down syndrome, at an earlier age than in Alzheimer disease. Leukemia and accelerated aging are also features of Down syndrome. Heston and Heston and Mastri speculated a disorder of microtubules as a common pathomechanism. Heston and White further speculated defective organization of microfilaments and microtubules in AD. Using immunoprecipitation techniques, Grundke-Iqbal et al.
Gajdusek suggested that the amyloid in Alzheimer disease and Down syndrome is formed from a precursor synthesized in neurons as well as in microglial cells and brain macrophages. He further suggested that the precursor synthesized in neurons produces intracellular neurofibrillary tangles, and that the precursor synthesized in microglial cells and brain macrophages is exuded from the cell, forming the extracellular amyloid plaques and vascular amyloid deposits.
Dying neurons may also contribute to extracellular deposits. The findings suggested that cerebral amyloid angiopathy is an integral component of AD.
Using immunocytochemistry, Wolozin et al. The number of reactive neurons decreased sharply after age 2 years, but reappeared in older individuals with Down alzhrimerdisease and in patients with Alzheimer disease. Carrell speculated that plaque formation in AD was a consequence of proteolysis of a precursor protein; self-aggregation of the cleaved A4 peptides explained the precipitated amyloid, while release of a trophic inhibitory domain explained the interwoven neuritic development.
Using computer-enhanced typffile of immunocytochemical stains of Alzheimer disease prefrontal cortex, Majocha et al. These brains also showed a significantly higher frequency of hemorrhages or ischemic lesions compared to those with little or no amyloid angiopathy