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ABSTRACT: An association has been observed in several independent data sets between late onset Alzheimer's Disease (AD) and the APOE locus on chromosome 19. We have examined the genotype in family history positive (FHP) and family history negative (FHN) cases and find a distortion of the APOE allele frequencies in accord with previous studies. However, when we examined the allele distribution of the at-risk siblings of the FHP group we found an excess of the epsilon 4 allele which also differs significantly from historic controls but not from the affected siblings. The age distribution of the affected and unaffected siblings was similar, suggesting that the allelic frequency distortion in the unaffected siblings was not due to their being below the mean age of onset. Lod score linkage analysis, with age dependent onset and non-stringent specification of the genetic parameters, did not suggest linkage to the APOE locus. Furthermore, an analysis of variance of the age of disease free survival suggested that APOE genotype contributes a small fraction of the total variance indicating that the APOE locus is a poor predictor of disease free survival age within late onset families. One explanation for the age dependent association reported by other groups, and our results, is that the APOE locus enhances the rate of progression of the disease process in otherwise predisposed individuals and that variation at this locus is not able in and of itself to cause the disease. We suggest this hypothesis is compatible with the current literature regarding APOE and AD.
American Journal of Medical Genetics 03/1995; 60(1):1-6.
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ABSTRACT: There is a paucity of data regarding Alzheimer's disease (AD) patients' longitudinal deterioration in the ability to conduct numerous activities required for daily living. In this study, 52 patients with AD were assessed at baseline and at a 1-year follow-up using the Direct Assessment of Functional Status (DAFS) scale, an objective, well-validated measure of a broad spectrum of functional capacities that is administered within the clinical setting. An important finding was that the level of initial performance on each of the 11 functional tasks measured did not relate to the degree of functional decline in that particular area. Communication skills, such as using the telephone (deterioration among 35.4% of the patients) and preparing a letter for mailing (deterioration among 32.7%), showed the most frequent deterioration among patients upon follow-up. More than half of the AD patients studied demonstrated impairment on one or both of these measures. The pattern of findings indicates that many subtests of the DAFS were sensitive to functional decline after a 1-year period and that the scale has utility in objectively establishing longitudinal patterns of deterioration.
International Psychogeriatrics 02/1995; 7(4):495-503. · 2.24 Impact Factor
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PhD T. Tsuda MD,
R. Lopez BSc,
E. A. Rogaeva PhD,
M. Freedman MD,
E. Rogaev PhD,
D. Drachman MD,
D. Pollen MD,
J. Haines PhD,
Y. Liang,
D. R. Crapper McLachlan MD, [......],
R. Lopez,
E. A. Rogaeva,
M. Freedman,
E. Rogaev,
D. Drachman,
D. Pollen,
J. Haines,
D. R. Crapper McLachlan, R. Duara,
P. St George‐Hyslop
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ABSTRACT: Allele frequencies for polymorphisms in the aplipoprotein E and the apolipoprotein CII genes were determined in subjects of Ashkenazi Jewish origin with lateonset Alzheimer's disease and in unaffected control subjects from the same ethnic group. A significant association was observed between late-onset Alzheimer's disease and the ε4 (112Cys→Arg) allele of apolipoprotein E; however, no association was detected with apolipoprotein CII. These results suggest that the association with ε4 is probably not due to linkage disequilibrium.
Annals of Neurology 06/1994; 36(1):97 - 100. · 11.09 Impact Factor
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ABSTRACT: Neural-network classification methods were applied to studies of FDG-PET images of the brain acquired from a total of 77 "probable" Alzheimer's disease and 124 normal subjects at two different centers.
Classification performances, as determined by relative-operating-characteristic (ROC) analyses of cross-validation experiments, were measured for FDG PET images obtained with either a 15-mm FWHM PETT V or a 6-mm FWHM Scanditronix PC-1024-7B camera for various methods of data representation. Neural networks were trained to distinguish between normal and abnormal subjects on the basis of regional metabolic patterns. For both databases, classification performance could be improved by increasing the "resolution" of the representation (decreasing the region size) and by normalizing the regional metabolic values to the value of a reference region (occipital region).
The optimal classification performance for Scanditronix data (ROC area = 0.95) was higher than that for PETT V data (ROC area = 0.87). Under Bayesian theory, the classification performance with Scanditronix data corresponded to an ability to change a pre-test probability of disease of 50% to a post-test probability of either 90% for a positive classification or 10% for a negative classification.
This classification can be used to either strongly confirm or rule out the presence of abnormalities.
Journal of Nuclear Medicine 02/1994; 35(1):7-15. · 6.38 Impact Factor
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E I Rogaev,
W J Lukiw,
G Vaula,
J L Haines,
E A Rogaeva,
T Tsuda,
N Alexandrova,
Y Liang,
M Mortilla,
L Amaducci, [......],
R J Polinsky,
P Frommelt, R Duara,
R Lopez,
D Pollen,
J F Gusella,
R Tanzi,
D MacLachlan,
D Crapper,
P H St George-Hyslop
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ABSTRACT: The c-FOS gene product, a putative transacting transcriptional regulator of the amyloid precursor protein (APP) gene, is a candidate locus for the familial Alzheimer's disease (FAD) mutation on chromosome 14 (FAD14). In light of this functional relationship, we investigated the nucleotide sequence and segregation of c-FOS and the nucleotide sequence of the 5' APP promoter. Single-stranded conformational polymorphisms (SSCPs) in the c-FOS gene revealed that c-FOS closely cosegregates with the FAD14 gene but does not show allelic association with FAD. A conservative third-position T-->C mutation was demonstrated in exon 2 (codon 84) of c-FOS, and a C-->G substitution was detected at -209 bp in the 5' promoter of APP. Neither were unique to FAD and are unlikely to be pathogenic or secondary modifiers of the FAD phenotype. We conclude that the c-FOS open reading frame is probably not the site of the FAD14 locus, but we cannot exclude the existence of modifier loci on chromosome 21.
Neurology 12/1993; 43(11):2275-9. · 8.31 Impact Factor
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ABSTRACT: In a neuroanatomical study of dyslexia, measurements were made of the superior surface of the temporal lobe (SSTL) on MRI scans in a sample of 17 dyslexics and 21 non-dyslexic subjects. Both anterior and posterior halves of the SSTL area showed significant leftward asymmetry in non-dyslexics, but showed symmetry in dyslexics. The total SSTL area showed greater leftward asymmetry in non-dyslexics than in dyslexics. The dyslexics also revealed a significant correlation (r = 0.69, P = 0.005) between Woodcock-Johnson Passage Comprehension scores and posterior SSTL asymmetry, such that those with higher scores had more leftward asymmetry. This suggests that among dyslexics the direction of SSTL asymmetry may serve as a risk factor and/or a marker for the severity of reading comprehension problems.
Neuropsychologia 09/1993; 31(8):811-21. · 3.64 Impact Factor
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ABSTRACT: Using a liberal criterion, a conservative probability-based criterion, and a criterion for autosomal dominant inheritance, we classified 36%, 13.5%, and 6.4% of 311 patients, respectively, as having familial Alzheimer's disease (FAD). The mean age of onset was over 70 years for all three categories of FAD. FAD and sporadic Alzheimer's disease (SAD) cases did not differ in clinical features, incidence of risk factors for dementia, or MRI or PET features. We observed earlier age of onset of AD to be related positively to longer duration of disease. Except for the autosomal dominant AD group, there was an earlier age of onset in FAD probands. The inheritance of AD from mothers was from 1.7 to 3.6 times more frequent than from fathers. Among SAD patients only, we found a preponderance of women, who were more frequently affected than would be expected from the male/female ratio in the general population of the same average age. Language performance tended to be less affected in FAD than in SAD patients, contrary to some previous reports.
Neurology 08/1993; 43(7):1377-84. · 8.31 Impact Factor
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The Lancet 08/1993; 342(8864):178. · 38.28 Impact Factor
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ABSTRACT: Because the diagnosis of dementia is highly dependent on the identification of neuropsychological deficits, there have been increasing concerns regarding cultural bias in tests designed to measure cognitive and intellectual function in English-speaking and Spanish-speaking adults. Despite their widespread clinical use, the effects of potential cultural bias on these measures among these two groups are largely unknown. We assembled a group of 76 females who received an NINCDS-ADRDA clinical diagnosis of Alzheimer's disease (AD). Half of these subjects were primary Spanish speakers, and the other half reported English as their primary language. All subjects were matched on chronological age and severity of memory impairment. Factors such as educational attainment and depression were entered into the analyses as covariates. The two groups were compared with respect to their performance on a battery of neuropsychological tests that are representative of what is typically used to diagnose the presence and severity of dementia. The finding that Spanish-speaking AD patients scored lower on specific neuropsychological measures is discussed in terms of inherent language biases and the possible lack of saliency of a number of these tests. The results obtained further suggest the need to modify certain neuropsychological indices so that they will better serve diverse ethnic and cultural groups.
Journal of Gerontology 06/1993; 48(3):P142-9.
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P St George-Hyslop,
J Haines,
E Rogaev,
M Mortilla,
G Vaula,
M Pericak-Vance,
J F Foncin,
M Montesi,
A Bruni,
S Sorbi, [......],
R Tanzi,
T Tsuda,
L Farrer,
J M Cantu, R Duara,
L Amaducci,
L Bergamini,
J Gusella,
A Roses,
D Crapper McLachlan
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ABSTRACT: Familial Alzheimer's disease (FAD) has been shown to be genetically heterogeneous, with a very small proportion of early onset pedigrees being associated with mutations in the amyloid precursor protein (APP) gene on chromosome 21, and some late onset pedigrees showing associations with markers on chromosome 19. We now provide evidence for a major early onset FAD locus on the long arm of chromosome 14 near the markers D14S43 and D14S53 (multipoint lod score z = 23.4) and suggest that the inheritance of FAD may be more complex than had initially been suspected.
Nature Genetics 01/1993; 2(4):330-4. · 35.53 Impact Factor
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ABSTRACT: Twenty subjects with mildly to moderately severe Alzheimer disease (AD) and 14 normal elderly control subjects were studied using [18F]fluorodeoxyglucose and positron emission tomography (PET) to investigate regional cerebral glucose metabolism during both a resting state and a behavioral activation state, utilizing a reading memory task (RMT). The RMT produced significant global metabolic activation of 15 +/- 15% in normal subjects and 11 +/- 13% in AD subjects. The occipital regions were preferentially activated, but all regions in both groups were also significantly activated. The RMT did not allow a better discrimination of AD patients from normal controls on the basis of regional metabolic deficits. Regions in the AD group that were individually classified as hypometabolic during rest also exhibited metabolic activation. The apparent viability of hypometabolic regions in AD patients challenges current hypotheses regarding the cause of abnormal metabolism in AD.
Journal of Cerebral Blood Flow & Metabolism 12/1992; 12(6):927-34. · 5.01 Impact Factor
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ABSTRACT: The assessment of functional capacity is regarded as an important part of a comprehensive diagnostic work-up for dementia. However, there is a paucity of data regarding comparative functional performance among different ethnic/cultural groups. In this study, we compared Spanish- and English-speaking dementia patients and normal controls on a comprehensive functional assessment battery administered within the clinical setting. Despite equivalent levels of cognitive impairment, Spanish-speaking dementia patients evidenced more difficulties on certain functional tasks relative to their English-speaking counterparts. On the other hand, Spanish- and English-speaking controls did not differ with regards to their functional performance. Results suggest that the extent of deterioration in specific functional subskills may be related to the degree to which they have been overlearned and practiced. Further, they indicate the potential utility of direct functional assessment in both Spanish- and English-speaking populations.
Journal of Gerontology 12/1992; 47(6):P389-94.
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ABSTRACT: The value of PET as an objective diagnostic tool for dementia may depend on the degree to which abnormal metabolic patterns can be detected by quantitative classification methods. In these studies, a neural-network classifier based on coarse region of interest analyses was used to classify normal and abnormal FDG-PET scans. The performance of neural networks and of an expert reader were evaluated by cross-validation testing. When the "abnormal" class was represented by subjects with clinical diagnoses of "Probable Alzheimer's," the areas under the relative-operating-characteristic (ROC) curves were 0.85 and 0.89 for the neural network and the expert reader, respectively. When testing with abnormal subjects represented by "Possible AD" cases, ROC areas for both the network and the expert were 0.81. The neural network out-performed discriminant analysis. It is concluded that PET has potential for the detection of abnormal brain function in dementing diseases, and that the combination of neural networks and PET is a useful diagnostic tool. Despite the low-resolution "view" afforded the neural network, its performance was nearly equivalent to that of an expert reader.
Journal of Nuclear Medicine 09/1992; 33(8):1459-67. · 6.38 Impact Factor
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ABSTRACT: Fifteen male homosexual subjects (mean age 31.6 +/- 7.2 yr) who were asymptomatic, but HIV-1 seropositive (HIV+) were compared to 15 male age-matched HIV-1 seronegative (HIV-) subjects using resting PET/FDG studies and MR scans. Mean cerebral metabolic rates for glucose (mg/100 g/min) in the HIV+ and HIV- subjects were 7.7 +/- 1.7 and 7.0 +/- 2.1, (p = 0.44), respectively. An index of regional metabolic asymmetry for the whole brain was 5.8% +/- 3.2% in the HIV+ and 2.7% +/- 2.3% in the HIV- (p = 0.002), and the difference was most prominent in the prefrontal area. Significant asymmetries were found in 10/15 HIV+ subjects, primarily in prefrontal (7/15) and premotor (4/15) regions. MRI scans showed no abnormalities on clinical or quantitative evaluation in HIV+ subjects. Upon follow-up of HIV+ subjects over 18-40 mo, seven became symptomatic, of which two died. There was no relationship between the presence of PET scan abnormalities and earlier onset of symptomatic disease.
Journal of Nuclear Medicine 10/1991; 32(9):1725-9. · 6.38 Impact Factor
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ABSTRACT: Positron-emission tomography (PET) was used to study regional cerebral metabolic activity during oral reading in right-handed adult males with, and without a childhood and family history of developmental dyslexia. Significant group differences in normalized regional metabolic values were revealed in prefrontal cortex and in the lingual (inferior) region of the occipital lobe. Lingual values were bilaterally higher for dyslexic than normal readers. In contrast to the asymmetry observed in prefrontal and lingual regions in nondyslexic subjects during reading, the dyslexic pattern was more symmetric. These results demonstrate that individuals who suffered from familial developmental dyslexia as children, activate different brain regions during reading as adults, as compared to individuals without such childhood history.
Journal of Clinical and Experimental Neuropsychology 08/1991; 13(4):531-44. · 2.13 Impact Factor
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ABSTRACT: Recent evidence suggests that specific types of intrusive errors may occur more often in the protocols of Alzheimer's disease (AD) patients than in those of patients diagnosed with other types of dementia. Using the FULD Object Memory Evaluation, we documented the occurrence of five qualitatively different types of intrusive errors for mildly and moderately impaired patients with AD and multiple cerebral infarctions (MCI). Depressed and normal elderly controls were also studied. Despite an equivalent degree of impairment on a broad array of neuropsychological measures, mildly impaired AD patients evidenced greater deficits on a measure tapping retrieval from semantic memory and demonstrated a higher occurrence of specific types of intrusive errors relative to their mildly impaired MCI counterparts. Further, both of these measures were highly correlated, suggesting that these indices may be particularly sensitive to semantic dysfunction associated with early AD.
Brain and Cognition 06/1991; 16(1):104-17. · 3.17 Impact Factor
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ABSTRACT: The areas of six bilateral brain segments in the right and left hemispheres, on a horizontal brain section, and the area of subdivisions of the corpus callosum, on a midsagittal brain section, were measured on magnetic resonance images obtained from 21 dyslexic and 29 control subjects. In the entire group, the frontal half of the horizontal brain section showed asymmetry, with the right side being larger, whereas posteriorly only the occipital polar segment was asymmetrical, with the left side being larger. Dyslexic subjects exhibited asymmetry, with the right side greater than the left side, in contrast to the relatively symmetrical pattern that is normally observed in the midposterior segment that corresponds to the angular gyrus. In the corpus callosum, dyslexic subjects were found to have a larger splenium than nondyslexic subjects, and dyslexic female subjects were found to have a larger splenium than dyslexic male subjects. Because transcallosal pathways connecting the left and right angular gyrus regions traverse through the splenium of the corpus callosum, the above findings in dyslexic subjects suggest an anatomic abnormality in the angular gyrus region.
Archives of Neurology 05/1991; 48(4):410-6. · 7.58 Impact Factor
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ABSTRACT: The effect of behavioral activation on cerebral and cerebellar glucose metabolism was studied in normal subjects when performing either a verbal memory task or a tactile somatosensory task. Each subject was also studied in a resting state control condition, either 1 h earlier or later than the activation task. Compared to the resting state, both tasks produced asymmetrical metabolic activation, which was opposite in direction within the cerebral and cerebellar hemispheres. In both tasks, the difference of activation of CMRglc in the right and left hemispheres in the cerebellum was negatively correlated with that in the sensory-motor region. This apparently coupled metabolic activation of one cerebellum and areas within the opposite cerebral hemisphere represents the inverse of the crossed cerebellar diaschisis phenomenon commonly observed when a vascular lesion affects one cerebral hemisphere and hypometabolism occurs in the opposite cerebellum. Because these correlations were selective and concordant with known anatomical connections, and were found in two different tasks, they suggest strong functional connections between these specific brain regions.
Journal of Cerebral Blood Flow & Metabolism 02/1991; 11(1):48-54. · 5.01 Impact Factor
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ABSTRACT: MR imaging of the brain, performed in 86 normal subjects and 113 patients with objective memory disorder or dementia, demonstrated white- and gray-matter areas of high signal intensity on long TR images (short and long TE). Hyperintensities were analyzed with respect to size (on a scale of 0-3) and location: lesions were periventricular, subcortical, or cortical. The patients with memory disorder and dementia were categorized as having probable/possible Alzheimer disease, a combination of Alzheimer disease and multiinfarct cognitive disorder, or multiinfarct cognitive disorder alone on the basis of clinically determined Hachinski ischemic scores. Significant correlations were found between age and scores for periventricular lesions (r = .40, p less than .0005) and subcortical lesions (r = .39, p less than .0005) in normal subjects. Correlations were also found between the Hachinski ischemic score and scores for periventricular lesions (r = .21, p less than .01), subcortical lesions (r = .27, p less than .0002), and cortical lesions (r = .32, p less than .0005) in subjects with memory disorder/dementia. Comparing multiinfarct cognitive disorder, Alzheimer disease, and normal groups, the mean scores for periventricular lesions were 12.0 +/- 4.6, 7.6 +/- 4.8, and 3.4 +/- 2.6, while mean scores for subcortical lesions were 10.8 +/- 12.2, 4.1 +/- 6.4, and 0.8 +/- 1.2, respectively. Periventricular lesions were present in 99-100% of patients with Alzheimer disease and multiinfarct cognitive disorder. On the other hand, subcortical lesions, which were identified in 100% of patients with multiinfarct cognitive disorder, were present in only about half of the patients with Alzheimer disease. Thus, scores for both periventricular and subcortical lesions are positively correlated with age and risk factors for cerebrovascular disease and also are significantly increased in the presence of objective memory disorder or dementia. These results imply that in the subject groups considered here, elderly patients with vascular dementia are most likely to have severe white-matter abnormalities on MR scans. The score for subcortical lesions appears to be more helpful than the score for periventricular lesions in distinguishing vascular dementia from Alzheimer disease and normal aging, so that a patient with prominent subcortical white-matter abnormalities is more likely to have a diagnosis of vascular than degenerative dementia.
American Journal of Roentgenology 07/1990; 154(6):1285-92. · 2.78 Impact Factor
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ABSTRACT: The widths of the anterior white matter bundle (AWM) and the interhemispheric (AWM-TER) and intrahemispheric (AWM-TRA) bundles at the level of the foramen of Monro on horizontal inversion recovery MRI scans were measured in 17 patients with dementia of Alzheimer type (DAT), 16 patients with multi-infarct dementia (MID) and 47 age-matched normal subjects (NOR). The area of the corpus callosum (CC) on midsagittal spin-echo MRI scans was also measured in 12 DAT, 11 MID and 36 NOR. The Mini-mental score in patients with DAT was 20.8 +/- 5.9, which was not significantly different from that of 22.9 +/- 5.4 in patients with MID. The width of AWM was not significantly decreased in either DAT or MID compared with NOR. However, the width of AWM-TER in DAT and MID showed a significant decrease from that in NOR. The width of AWM-TRA was decreased significantly only in DAT. Compared with NOR, the area of the CC in DAT and MID was decreased by 7.0% (p less than 0.05) and 6.5%, respectively. The white matter bundle has an important role in the connectivity of the brain. Although loss of white matter occurs in both DAT and MID, the change appears more diffuse in DAT than MID.
Rinsho shinkeigaku = Clinical neurology 02/1990; 30(1):110-2.
