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ABSTRACT: The mild cognitive impairment (MCI) stage of dementia with Lewy bodies (MCI-DLB) has not yet been defined, but is likely to differ in the MCI stage of Alzheimer's disease (MCI-AD). To determine whether clinical features distinguish MCI-DLB and MCI-AD, 9 cases of neuropathologically confirmed MCI-DLB and 12 cases of MCI-AD were compared. No significant differences were found between MCI-DLB and MCI-AD cases in age at death, gender, ApoE status, education, time followed while clinically normal, or duration of MCI. MCI-DLB and MCI-AD cases differed clinically in the expression of Parkinsonism (P=0.012), provoked hallucinations or delirium (P=0.042), or the presence of any of these noncognitive symptoms of DLB (P<0.0001). Letter fluency (P=0.007) was significantly lower and Wechsler Logical Memory I (P=0.019) was significantly higher in MCI-DLB compared to MCI-AD cases. These data demonstrate the feasibility of differentiating underlying pathologic processes responsible for cognitive decline in the preclinical disease state and suggest that further refinement in diagnostic criteria may allow more accurate early detection of prodromal DLB and AD.
Neurobiology of aging 12/2008; 31(10):1805-13. · 5.94 Impact Factor
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ABSTRACT: Comparative analysis of subjects with mild cognitive impairment (MCI) diagnosed in a primary research setting and those seen in a tertiary care memory disorders clinic.
Subjects who received a diagnosis of MCI between July 1, 2005, and December 31, 2006, in a longitudinal research study of normal cognition (n = 48) and patients diagnosed in a tertiary care referral clinic (n = 34) were evaluated using similar methodologies. Comparative analyses of detailed medical, neurological and neuropsychological data are presented.
The diagnosis of MCI was not accepted by 13 of 48 subjects (27%) classified as MCI in the primary research setting. Nondegenerative, potentially treatable causes of cognitive decline were found in 3 of 34 subjects (9%) seen in the tertiary referral clinic and in 11 of 35 subjects (31%) identified as MCI in the primary research setting (p = 0.02, Fisher's exact test). MCI subjects identified in the primary research setting were older than those referred to the memory clinic (mean +/- SD, 79.7 +/- 7.0 vs. 71.5 +/- 9.0 years, p < 0.0001, t test) and had more years of education (16.0 +/- 3.2 vs. 13.6 +/- 4.2 years, p < 0.01, t test). MCI subjects in the primary research setting appeared to be in a milder stage of disease, characterized by higher Mini-Mental State Examination scores (28.2 +/- 1.8 vs. 25.7 +/- 1.8, p < 0.0001), and a tendency towards single domain involvement, predominantly memory (mean number of domains involved, 1.0 vs. 2.5, p < 0.0001). More advanced stages of MCI, seen in the tertiary referral population, had additional involvement of attention (p < 0.0001, Fisher's exact test) and visuospatial domains (p < 0.0002, Fisher's exact test). Semiquantitative grading of hippocampal and medial temporal lobe atrophy did not differ between groups (p = 0.81, Mann-Whitney U test).
The diagnosis of MCI may be unwelcome in naïve persons. Remedial causes of MCI should be actively investigated. Demographic and clinical characteristics of MCI differ between research subjects and patients referred to a tertiary care clinic.
Dementia and Geriatric Cognitive Disorders 09/2008; 26(2):187-92. · 2.14 Impact Factor
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Advances in experimental medicine and biology 02/1994; 370:647-52. · 1.09 Impact Factor
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ABSTRACT: A series of clones displaying a high-frequency "switching" phenotype for expression of the adenine phosphoribosyltransferase (aprt) gene was previously isolated from the P19 mouse embryonal carcinoma stem cell line. In a subset of these clones, loss of aprt expression was correlated with increased DNA methylation, a nuclease-resistant chromatin conformation, and loss of RNA transcription; reactivation was associated with a reversal of these parameters. In this report, the role of DNA methylation in transcriptional inactivation was studied in the H22D3 clone. The cells of this clone contain a single inactive aprt allele that is methylated. Mass cultures of H22D3 were treated with 2-deoxy-5'-azacytidine (5aCdr) and found to reactivate aprt at frequencies ranging from 60 to 90%. Treated cultures were then assayed over time for aprt mRNA, chromatin conformation, and DNA methylation of the aprt gene. These studies demonstrated that 5aCdr treatment resulted in promoter region-specific hemidemethylation and chromatin relaxation starting at 12 h. This was followed by the appearance of RNA transcripts at 18 h and increasing levels of APRT enzymatic activity at 36 h after treatment. Complete demethylation occurred significantly later. Experiments in which cells were treated with 5aCdr for varying periods of time demonstrated that a single round of analog incorporation was sufficient for transcriptional reactivation of aprt in H22D3.
Somatic Cell and Molecular Genetics 06/1993; 19(3):221-9.
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ABSTRACT: We have sequenced homologous DNA fragments of 2.7 and 2.8 kbp derived from the closely related mouse species Mus musculus domesticus (M. domesticus) and Mus musculus musculus (M. musculus), respectively. These two species diverged approximately 1 million years ago. Each DNA fragment contains 1.35 kbp of the 3' end of the constitutively expressed 2.2-kbp aprt (adenine phosphoribosyltransferase) gene and a similarly sized nontranscribed region downstream of the aprt gene. The aprt gene region contains protein coding sequences (0.35 kbp), intronic sequences (0.75 kbp), and a 3' nontranslated sequence (0.25 kbp). Both the M. domesticus and M. musculus downstream regions share three partial copies of the B1 repetitive element with the M. musculus downstream region containing an additional complete copy of this element. A comparison of the 2.7- and 2.8-kbp DNA fragments revealed a total of 63 molecular alterations (i.e., mutations) that were approximately fourfold more abundant in the nontranscribed downstream region than in the transcribed aprt gene. Of the 11 mutations observed in the transcribed region, 7 were found in introns, 3 in the 3' untranslated sequence, and 1 was a synonymous change in an exon. A comparison of the human and M. domesticus aprt genes has previously revealed no homology in either the intronic or 3' nontranslated regions with the exception of a 26-bp sequence in intron 3 and sequences at the exon/intron boundaries necessary for correct mRNA splicing (Broderick et al., Proc. Natl. Acad. Sci. USA, 84:3349, 1987). Therefore, there does not appear to be selective pressure for sequences within these regions. We conclude that there is a lower rate of accumulation of "silent" mutations in the transcribed mouse aprt gene than in a contiguous nontranscribed downstream region. A possible molecular mechanism involving preferential DNA repair for the transcribed region is discussed.
Journal of Molecular Evolution 02/1993; 36(1):31-40. · 2.27 Impact Factor
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ABSTRACT: A mouse embryonal carcinoma cell line isolated for resistance to the adenine analogue 2,6-diaminopurine (DAP) was found to have near-wild-type levels of adenine phosphoribosyltransferase (APRT) activity in a cell-free assay. This DAP-resistant (DAPr) cell line, termed H29D1, also exhibited near-wild-type levels of adenine accumulation and the ability to grow in medium containing azaserine and adenine. Growth in this medium requires high levels of intracellular APRT activity. Using the polymerase chain reaction (PCR) and the dideoxy chain termination sequencing technique, an A-->G transition was discovered in exon 3 of the aprt gene in H29D1. This mutation resulted in an Arg-to-Gln change at amino acid 87 of the APRT protein that, in turn, resulted in a decreased affinity for adenine. An increased sensitivity of APRT to inhibition by AMP was observed when comparing H29D1 to P19, the parental cell line. Using a transgene containing the A-->G mutation, we demonstrated that this mutation is responsible for the biochemical and cellular phenotypes observed for the H29D1 cell line. The approach used in this study provides a definitive method for linking a mutation to a specific cellular phenotype.
Biochemical Genetics 12/1992; 30(11-12):635-48. · 0.86 Impact Factor
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ABSTRACT: A series of clones displaying high frequency "switching" phenotypes for expression of the adenine phosphoribosyltransferase (aprt) gene were previously isolated from the P19 mouse embryonal carcinoma stem cell line. Most clones contained only one aprt allele. We report here the characterization of each of these clones with regards to enzymatic activity, mRNA steady state levels, DNA methylation, and chromatin conformation. When clones were selected for resistance to the purine analog 2,6-diaminopurine, which requires markedly reduced levels of APRT enzymatic activity, two distinct classes were observed. The first class was associated with reduced or undetectable levels of aprt mRNA, hypermethylation of the 5' CpG island, and a closed chromatin conformation within this region. When clones of this class were selected for reacquisition of APRT enzymatic activity they were found to have increased mRNA levels, a hypomethylated CpG island, and an open chromatin conformation. In contrast, the second class of clones displayed wild-type levels of mRNA, CpG island hypomethylation, and an open chromatin conformation regardless of whether they were selected for the presence or absence of APRT enzymatic activity. The implications of these results for general mechanisms of epigenetic change in somatic cells and the possibility that expression of the mouse aprt gene may be developmentally regulated are discussed.
Somatic Cell and Molecular Genetics 06/1992; 18(3):215-25.
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ABSTRACT: We have used four gene probes specific for mouse chromosome 8, including adenine phosphoribosyltransferase (aprt), to demonstrate that the P19 teratocarcinoma stem cell line contains two distinct chromosome 8 homologs. One represents the common laboratory mouse C3H (Mus musculus domesticus) homolog while the second homolog was presumably contributed by a feral Mus musculus musculus animal. Six cell lines with APRT heterozygous deficiencies were isolated from P19 subclones. A molecular analysis of these heterozygotes demonstrated that three arose by deletion of the Mus musculus musculus aprt allele and three arose by aprt gene inactivation. APRT homozygous deficient cell lines were isolated from both classes of heterozygote; most contained little or no detectable APRT activity. When the heterozygous deficiency was due to deletion of the Mus musculus musculus aprt allele, the most frequent event yielding homozygous deficient cell lines was associated with loss of heterozygosity for all tested markers on the Mus musculus domesticus homolog indicating chromosome loss. In contrast, when the initial event resulting in APRT heterozygous deficiency was gene inactivation, homozygotes arose predominantly from gene deletion or a second inactivation event. These results suggest a potential relationship between the first- and second-step events resulting in APRT deficiencies.
Somatic Cell and Molecular Genetics 04/1991; 17(2):105-16.
