Prediction of deterioration of mild cognitive impairment with CT and SPECT.

BACKGROUND: Mild cognitive impairment (MCI) is a condition referring to persons with significant memory impairment, often accompanied by functional deficits in the attention, language, visuospatial, and psychomotor domains, who do not fulfill the criteria for dementia. Individuals with MCI are at an increased risk of developing dementia. The objective of this study was to examine baseline differences between MCI subjects who did or did not deteriorate at follow-up on measures of cognition and neuroimaging. MATERIAL/METHODS: MCI individuals (n=105) enrolled in a longitudinal study at the Alzheimer's Day Clinic in Warsaw received annual clinical and psychometric examinations for up to a mean of three years. At baseline, all patients received temporal lobe-oriented CT and 99mTc HMPAO SPECT. The diagnosis of MCI according to Mayo Clinic Petersen's Criteria was conducted by a panel of specialists and neuropsychological testing was completed on all subjects. RESULTS: After three years of follow-up, 42 subjects remained stable or had improved (8) and 63 had progressive cognitive disturbances, including 23 who converted to dementia. Compared with stable MCI patients, decliners have significantly higher radial width of the temporal horn bilaterally and width of the lateral part of the transverse fissure on the right, dilated third ventricle, and smaller oblique thickness of the anterior part of the hippocampal formation bilaterally at the baseline. No significant differences in SPECT perfusion were found between the two groups. CONCLUSIONS: The proposed linear measurements of atrophy in CT may constitute a predictor for those MCI patients who are more likely to deteriorate.

CYP46: a risk factor for Alzheimer's disease or a coincidence?

Excess cholesterol is removed from the brain via hydroxylation mediated by cholesterol 24S-hydroxylase (CYP46). Although serum and cerebrospinal fluid (CSF) concentrations of 24S-hydroxycholesterol are altered during the progress of Alzheimer's disease, studies carried out to date in different populations on the association of CYP46 gene polymorphisms and risk of AD have been inconclusive. In this report, we analyzed CYP46 polymorphisms in 215 Polish AD cases and 173 healthy individuals. A fragment of CYP46 intron 2 was amplified by PCR reaction and sequenced. We discovered a new single nucleotide substitution in CYP46 intron 2, but found no difference in particular genotype or allele frequencies between AD patients and controls. However, the GG genotype of the known rs754203 polymorphic site might be a risk factor for AD, especially in APOE varepsilon4 carriers. Interestingly, in AD patients the rs754203 G allele was more frequent in males than in females. However, considering the extreme divergence of results obtained by different authors, a clear connection between the CYP46 gene and AD is questionable.

The E318G substitution in PSEN1 gene is not connected with Alzheimer's disease in a large Polish cohort.

Mutations in the presenilin 1 (PSEN1) gene are known to cause nearly 50% of early-onset, familial Alzheimer's disease (AD) cases. To determine whether E318G mutation is related causally to AD in the Polish population E318G mutation frequency was assessed using PCR-RFLP method in a total of 659 subjects: 256 AD patients, 210 healthy, age-matched control subjects, 100 Parkinson's disease patients and 93 centenarians. When the mutation frequencies were compared to healthy controls, no significant differences between the groups were found. It could be concluded that E318G mutation is not related causally to AD in the Polish population, either as a risk factor or a disease causing mutation.

Strong association between Saitohin gene polymorphism and tau haplotype in the Polish population.

The saitohin (STH) gene is located in intron 9 of the tau protein gene. It has been postulated that the R allele of Q7R polymorphism at the Saitohin gene is over-represented in the homozygous state in sporadic Alzheimer's disease (AD). Tau protein was implicated in AD pathophysiology and the tau gene haplotype is probably connected with sporadic late-onset Parkinson's disease (PD). We analyzed the STH polymorphism and tau gene haplotype in 100 clinically diagnosed AD cases, 100 PD cases and 100 age-matched healthy controls. We found that the R allele of the STH gene is associated with the H2 haplotype of tau in all cases. Additionally we observed no correlation between R allele frequency and AD or PD.

Simultaneous analysis of five genetic risk factors in Polish patients with Alzheimer's disease.

As Alzheimer's disease (AD) is a complex disease, we decided to estimate how previously reported genetic polymorphisms interact to increase the risk for the disease. Five candidate genes were chosen: apolipoprotein E (APOE), alpha 2-macroglobulin, cathepsin D, myeloperoxidase and nitric oxide synthase. Genotyping was performed in 100 cases of late-onset AD and 100 healthy controls. We found a highly significant difference in APOE epsilon 4 distribution between groups (P<0.005). However, no evidence of association for other studied loci was found. Cumulative analysis of five genetic polymorphisms was performed, but it also failed to reveal any synergistic effect of candidate genes greater than that caused by APOE itself. Our results suggest that the APOE epsilon 4 allele is the only known genetic risk factor for late-onset, sporadic AD.

Mutations in presenilin 1, presenilin 2 and amyloid precursor protein genes in patients with early-onset Alzheimer's disease in Poland.

Mutations in three causative genes have been identified in patients with an autosomal-dominant form of early-onset Alzheimer's disease (EOAD). To determine the spectrum of mutations in a group consisting of 40 Polish patients with clinically diagnosed familial EOAD and 1 patient with mild cognitive impairment (MCI) and family history of AD, we performed a screening for mutations in the presenilin 1 (PSEN1), presenilin 2 (PSEN2) and amyloid precursor protein (APP) genes. Four previously recognized pathogenic mutations in PSEN1 gene (H163R, M139V) and APP gene (T714A, V715A), and three novel putative mutations in PSEN1 gene (P117R and I213F) and PSEN2 gene (Q228L) were identified. The 34 patients with no mutations detected were older than the patients with mutations. A frequency of APOE4 allele was higher in this group. Frequency of mutations is relatively low (17%), possibly due to used operational definition of a patient with familial EOAD (a patient having at least one relative with early-onset dementia). It could be concluded that screening for mutations in the three genes could be included in a diagnostic program directed at patients with a positive family history or age of onset before 55 years.