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R Katzman

Publications and source records attributed to R Katzman.

At least 19 recordsLinked to original sources
PubMed2005

Anosmia is very common in the Lewy body variant of Alzheimer's disease.

BACKGROUND: Olfactory abnormalities are reported in Alzheimer's disease and Parkinson's disease. Anosmia appears to be common in dementia with Lewy bodies but not in pure Alzheimer's disease. OBJECTIVE: To determine whether anosmia improves discrimination between the Lewy body variant (LBV) of Alzheimer's disease and "pure" Alzheimer's disease. METHODS: 106 cases of necropsy confirmed pure Alzheimer's disease (n = 89) or LBV (n = 17) were reviewed. All had received butanol odour threshold testing. Anosmia was defined as a score < or = 1.0 on a 0-9 point scale. Logistic regression analysis was used to model potential predictors (for example, parkinsonism, smoking, hallucinations) of neuropathological diagnosis and anosmia. RESULTS: LBV cases had an increased prevalence of anosmia (65%) compared with Alzheimer's disease (23%; odds ratio (OR) = 6.3, p = 0.00045), or normal elderly people (6.7%). Within the dementia cases, the negative predictive value (92%) and specificity (78%) of anosmia were both good; sensitivity for detecting LBV was 65%, but the positive predictive value (PPV) was only 35%. Logistic regression models showed anosmia (OR = 5.4, p = 0.005) and visual hallucinations (OR = 7.3, p = 0.007) were strong independent predictors of Lewy body pathology. When anosmia was added as a core feature to consensus diagnostic criteria for probable Lewy body dementia, five additional cases of LBV were detected (29% increased sensitivity), but with four additional false positives (1% increased discrimination, 4% decreased specificity, 33% decreased PPV). CONCLUSIONS: Anosmia is very common in LBV. Adding anosmia as a core feature improved sensitivity for detecting LBV, but did not improve discrimination between Alzheimer's disease and LBV owing to a concomitant increase in false positives.

1-Butanol↗
PubMed2002

Alzheimer's disease can be accurately diagnosed in very mildly impaired individuals.

BACKGROUND: The growing propensity to diagnose AD in individuals with very mild cognitive impairment increases the danger of false-positive diagnostic errors. Unfortunately, there is little systematically acquired information about the accuracy of the AD diagnosis in very mildly impaired patients. OBJECTIVE: To determine the accuracy of the diagnosis of AD in very mildly impaired patients and to identify objective measures that effectively distinguish these patients from elderly normal controls (NC). METHODS: Consecutive patients with Mini-Mental State Examination scores of > or = 24 who received a clinical diagnosis of AD were evaluated annually for at least 3 years. The initial diagnosis was verified or refuted by autopsy or by information obtained in subsequent evaluations. Initial neuropsychological test scores of verified AD patients were compared with those of NC subjects to identify effective diagnostic measures. RESULTS: The diagnosis of AD was confirmed in 98 of 110 (89%) very mildly impaired patients (33/36 by autopsy, 65/74 by disease progression). The diagnosis was inaccurate in 12 patients (11%): Seven were subsequently diagnosed with other neurologic disorders, and five were ultimately found to be normal. Neuropsychological measures of delayed recall, verbal fluency, and global cognitive status (i.e., Mattis Dementia Rating Scale) provided excellent sensitivity (> or = 96%) and specificity (> or = 93%) for differentiating between very mildly impaired AD patients and NC subjects. CONCLUSIONS: When comprehensive assessment procedures are employed, AD can be diagnosed with reasonably high accuracy in very mildly impaired individuals. However, the dementia evaluation should be repeated after approximately 1 year to ensure the accuracy of the initial diagnosis.

Aged↗
PubMed2000

Association between severe cerebral amyloid angiopathy and cerebrovascular lesions in Alzheimer disease is not a spurious one attributable to apolipoprotein E4.

BACKGROUND: We have previously reported an association between severe cerebral amyloid angiopathy (CAA) and cerebrovascular lesions in Alzheimer disease (AD), which is particularly strong for microinfarcts, hemorrhages, and multiple lesion types. Cerebral amyloid angiopathy has also been associated with the apolipoprotein E4 (APOE4) genotype, which is in turn associated with premature coronary artery disease and atherosclerosis. OBJECTIVE: To test whether severe CAA would be more strongly associated with cerebrovascular lesions than would APOE4 genotype. METHODS: We reviewed 306 cases of autopsy-confirmed AD (from the University of California, San Diego, brain autopsy series) to assess whether APOE genotype and other clinical risk factors were predictive of vascular lesions (VLs) in AD. Cerebral amyloid angiopathy severity was assessed using a semiquantitative scale in 4 brain regions (ie, hippocampus, midfrontal cortex, inferior parietal cortex, and superior temporal cortex) and an average score was computed for each case. RESULTS: We found that severe CAA was associated with an increased frequency of VLs (33% of the cases of severe CAA had VLs vs 19% of the cases of mild or absent CAA; P=.02). While the APOE4/4 genotype was associated with an increased severity of CAA, there was no significant relationship between APOE genotype and frequency of VLs. Logistic regression models showed that severe CAA, advanced age, atherosclerosis, and Hachinski Ischemia Scale score of 7 or more were all significantly associated with VLs, but the number of APOE4 alleles, history of hypertension, coronary artery disease, sex, and serum cholesterol levels had nonsignificant effects. Within strata of APOE genotype, the presence of severe CAA was associated with increased frequency of VLs (eg, within APOE4/4 homozygotes, VLs were present within 47% of the cases of severe CAA vs 9.5% of the cases of mild or absent CAA; P=.01). CONCLUSIONS: Severe CAA confers a greater risk of VLs in AD, even within strata of APOE genotype. Therefore, the association between severe CAA and VLs in AD is not a spurious one owing to APOE4. Overall, our cases of AD with APOE4 do not seem to be a more "vasculopathic" subtype of AD. The mechanisms by which CAA produces VLs of various types need to be further elucidated, as these are probably important in producing the common entity of "mixed" AD/vascular dementia. Arch Neurol. 2000.

Aged↗
PubMed2000

Relationship between severe amyloid angiopathy, apolipoprotein E genotype, and vascular lesions in Alzheimer's disease.

In this brief review, we aim to describe the complex relationship between cerebral amyloid angiopathy (CAA), apolipoprotein E (ApoE), and cerebrovascular lesions in Alzheimer's disease (AD). First, we review the evidence that CAA is associated with, and may cause, specific types of vascular lesions (VLs). In addition to being a leading cause of lobar hemorrhages in the elderly, CAA has been implicated as a likely cause of small infarcts, microinfarcts, and incomplete infarctions in the deep white matter. We also review the role that ApoE4 (the major genetic risk factor for AD) has in predisposing toward CAA, coronary artery disease, and possibly toward cerebrovascular disease. Last, we provide evidence that the association between CAA and VLs is not a spurious one due to an increase in the ApoE4 genotype. Even within patient groups with the same ApoE genotype (specifically, E4/4 homozygotes and E3/3 homozygotes), our recent analyses have found significant increases in VLs in association with severe CAA. We discuss the implications of this finding as advancing a pathogenic role for severe CAA in producing many of the VLs commonly found in AD cases.

Aged↗
PubMed2000

Modulation of amyloid beta-protein clearance and Alzheimer's disease susceptibility by the LDL receptor-related protein pathway.

Susceptibility to Alzheimer's disease (AD) is governed by multiple genetic factors. Remarkably, the LDL receptor-related protein (LRP) and its ligands, apoE and alpha2M, are all genetically associated with AD. In this study, we provide evidence for the involvement of the LRP pathway in amyloid deposition through sequestration and removal of soluble amyloid beta-protein (Abeta). We demonstrate in vitro that LRP mediates the clearance of both Abeta40 and Abeta42 through a bona fide receptor-mediated uptake mechanism. In vivo, reduced LRP expression is associated with LRP genotypes and is correlated with enhanced soluble Abeta levels and amyloid deposition. Although LRP has been proposed to be a clearance pathway for Abeta, this work provides the first in vivo evidence that the LRP pathway may modulate Abeta deposition and AD susceptibility by regulating the removal of soluble Abeta.

Adult↗
PubMed1998

Differences in a dinucleotide repeat polymorphism in the tau gene between Caucasian and Japanese populations: implication for progressive supranuclear palsy.

Previous studies of a tau polymorphism in Caucasian subjects with progressive supranuclear palsy (PSP) showed an over-representation of one genotype, A0/A0, versus normal control subjects. This result suggested that tau may be playing a genetic role in the progression of PSP. This study examines whether the over-representation of A0/A0 is Caucasian-specific or universal to PSP. Unfortunately, we found this dinucleotide repeat was relatively non-polymorphic in Japanese subjects. As a result, the genotypes were virtually the same, A0/A0, between Japanese PSP and control subjects. However, this outcome, albeit negative, does suggest two possible roles of the tau gene in PSP pathogenesis: (1) the role of this dinucleotide repeat in PSP may be different between Caucasian and Japanese populations or (2) this repeat may not be causal for PSP but represents a marker for other molecular genetic risk factors within or close to the tau gene on chromosome 17.

Alzheimer Disease↗
PubMed1998

Self-perceived health and 5-year mortality risks among the elderly in Shanghai, China.

Studies of the elderly worldwide over the last 3 decades have reported that a self-rating of "poor" compared with "excellent/good" health increases the relative risk of dying. The authors tested the strength of this association by performing age-stratified Cox regression analyses on a 5-year longitudinal study of a representative sample of noninstitutionalized elderly aged 65 years and older (n=3,094) in a district of Shanghai, China. More than 20 potential confounders that were only partially controlled in other studies and threats to response validity due to cognitive impairment or diagnosed dementia that were not considered in previous studies were taken into account in this analysis. The results showed that among those aged 65-74 years, "poor" perceived health increases the adjusted relative risk of death by 1.93 (95% confidence interval 1.20-3.11) compared with "excellent/good" health. The adjusted relative risk of a "fair" rating of health is 2.16 (95% confidence interval 1.44-3.25). In the older age group, mortality risks for the ratings of fair as well as poor compared with excellent/good health were not statistically significant. The authors posit that several mechanisms related to host vulnerability markers and greater-than-expected utilization of health services may explain the association between self-assessed health and mortality risks. Future research should strive to develop more precise measures of these and related variables.

Aged↗
PubMed1998

Neurobiology of autism.

Autism is a behaviorally defined, life-long static developmental disorder of the brain that is poised for neurobiological investigation. It affects at least 1 or 2 in 1000 persons and has a broad range of severity. It has multiple causes, with genetics playing a major role. According to the DSM-IV, defining features are impaired sociability, language and communication, and range of interests and activities. Mental deficiency is frequent but by no means universal. The cognitive profile is characteristic, occasionally with a superior but narrow talent. Perseveration, concreteness, affective blunting, and lack of insight into other persons' thinking may be conspicuous. The neurological basis of autism's many sensorimotor features, including stereotypies, is unknown. Attention and sleep are affected, and one third of individuals experience epilepsy by adulthood. Whether subclinical epilepsy plays a role in the developmental regression of the one third of the toddlers who lose their language skills and become autistic remains to be determined. Clinical neuroimaging and biochemical investigations are generally unremarkable. Fewer than 35 brains have been examined pathologically, none with modern techniques. The findings thus far suggest subtle prenatal neuronal maldevelopment in the cerebellum and certain limbic structures. Abnormalities in distributed networks involving serotonin and perhaps other neurotransmitters require further documentation.

Autistic Disorder↗
PubMed1998

Interaction of apolipoprotein E epsilon 4 with other genetic and non-genetic risk factors in late onset Alzheimer disease: problems facing the investigator.

The Apolipoprotein E4 allele (Apo-epsilon4) is the major susceptibility gene for late onset Alzheimer Disease (AD) but epidemiological data suggest that the effect of this allele is modified in different individuals by genetic or environmental factors. Age and head injury are major non-genetic factors modifying the Apo-epsilon4 risk. There is conflicting data as to whether alleles of other chaperon proteins (such as alpha-1-antichymotrypsin (ACT)) or Apo-epsilon4 receptors (such as the VDRL receptor) modify the Apo-epsilon4 risk for AD. We analyze problems posed by genetic association studies including those of multiple comparisons and selection of controls, the latter problem exacerbated by the wide variations in Apolipoprotein E allele frequencies observed in different groups and localities.

Alzheimer Disease↗
PubMed1998

A preliminary analysis of incidence of dementia in Shanghai, China.

The incidence of dementia based on DSM-III criteria and the impact of age and education on the development of dementia using the data of a longitudinal community population survey is discussed. Study subjects were randomly sampled from the community and were assessed by a two-stage procedure twice during a 5-year period. The screening instrument was the Mini-Mental State Examination and the second stage measures include a medical history and physical examination, a neurological examination and an intensive neuropsychiatric interview and testings (i.e. Blessed Dementia Scale, Activity of Daily Living, Fuld Object Memory Test and Block Design Test. All identified cases from the second stage interview were further verified by computed tomographic scan and laboratory tests. A total of 1970 subjects of non-dementia aged 65 or older in 1987 were re-surveyed after 5 years, of whom 114 new cases of dementia were identified. The incidence of dementia in total was 1.15% annually, 0.98% for males and 1.27% for females. The incidence for Alzheimer's disease, vascular dementia and dementia by other causes was 0.74, 0.33 and 0.08%, respectively. The highest rate (2.02%) was found in illiterate individuals. The incidence of dementia in the Shanghai cohort is similar to that from other countries. Age and education are closely related to the occurrence of dementia. While age increases by each 5 years for those aged 65 and over the likelihood of developing dementia increases nearly one-fold (74%). Education shows great protective effect on the development of dementia. The non-educated has a higher risk of suffering from dementia than does the educated.

Aged↗
PubMed1998

Association of CYP2D microsatellite polymorphism with Lewy body variant of Alzheimer's disease.

OBJECTIVE: To examine the genetic association of CYP2D6 locus with Lewy body variant (LBV) and Parkinson's disease (PD). METHODS: Allelic association was studied in patients with pure AD, LBV, and PD by using the CYP2D microsatellite, the (dG-dT)n dinucleotide repeat (n=16 to 27) located between CYP2D8P and CYP2D7 genes, and the CYP2D6 B and D mutations. RESULTS: We found overrepresentation of the alleles longer than 21 repeat (the long-type alleles) in LBV (allele frequency, 0.313) (odds ratio=1.99, p=0.019 by chi2 test) and in PD (0.298) (odds ratio=1.86, p=0.037), but not in pure AD (0.196), compared with the age-matched control (0.186). Strong association was noted of the long-type alleles with the CYP2D6 B mutation (odds ratio=88.50, p < 0.001 by Fisher's exact test), but not with the D mutation or the deletion of CYP2D6 gene. CONCLUSIONS: The CYP2D locus is closely associated with LBV and PD. The CYP2D6 B mutation may be involved in pathogenesis of LBV and PD in a dominant-negative manner, or in the linkage disequilibrium of the CYP2D microsatellite to another pathogenic gene locus.

Aged↗
PubMed1998

Cognitive decline is faster in Lewy body variant than in Alzheimer's disease.

OBJECTIVES: To quantify the rate of cognitive decline on the Mini-Mental State Examination (MMSE) in autopsy-diagnosed Lewy body variant (LBV) of Alzheimer's disease (AD) cases. We hypothesized that LBV patients would have a faster cognitive decline and shorter survival compared with patients with pure AD. BACKGROUND: Prior reports have shown extrapyramidal signs to be associated with a poorer prognosis in AD. It has been suggested that LBV is often characterized by a rapidly progressive course. Few data are available regarding the rate of cognitive decline in autopsy-confirmed LBV dementia cases. METHODS: We searched the databases of the University of California-San Diego Alzheimer's Disease Research Center and the Consortium to Establish a Registry in Alzheimer's Disease (CERAD) for dementia cases with 1) an autopsy diagnosis of definite or probable AD (CERAD criteria) with concomitant Lewy bodies and 2) longitudinal MMSE assessments. This resulted in a series of 40 LBV cases and 148 AD cases without Lewy bodies, with comparable baseline MMSE scores, age, and education. The rate of cognitive decline was calculated as the baseline MMSE -- final MMSE. Methods were devised to reduce floor effects on the MMSE. RESULTS: The average rate of cognitive decline was -5.8 +/- 4.5 points/y in LBV and -4.1 +/- 3.0 points/y in AD (t-test, p < 0.01). The LBV group declined a similar amount on the MMSE (means, -10.0 versus -9.6 points) over a significantly shorter time interval (1.9 versus 2.7 years; p = 0.005) than did AD patients. At baseline, the mean MMSE scores were nearly identical (18.2 in LBV; 17.8 in AD), but on follow-up examinations approximately 1, 2, and 3 years later, there were intergroup mean differences of 1.8 points (two-tailed p = 0.19), 4.2 points (p = 0.04), and 5.6 points (p = 0.03), respectively. The LBV cases had shorter survival time from the onset of cognitive symptoms (7.7 +/- 3.0 years versus 9.3 +/- 3.5 years; p = 0.007) and a shorter mean survival after entry/baseline, which was of marginal significance (3.6 versus 4.1 years; p = 0.11). CONCLUSIONS: This study demonstrates that LBV is characterized by a faster cognitive decline and accelerated mortality compared with AD.

Aged↗
PubMed1997

Genetic evidence for the involvement of tau in progressive supranuclear palsy.

A dinucleotide repeat polymorphism in a tau intron was identified and used in a case-control study to analyze the genetic association of tau with several neurodegenerative diseases with tau pathology. Subjects with the homozygous tau AO alleles were excessively represented in the progressive supranuclear palsy (PSP) group, compared with the age-matched healthy control group. Consequently, this allele is more frequently found in PSP than in a group of healthy subjects. This trend was not found in Alzheimer's disease or parkinsonism-dementia complex of Guam, both of which are accompanied by major tau pathology. The result suggests a possible involvement of tau in the pathogenesis of PSP.

Base Sequence↗
PubMed1997

Genetic association of the low-density lipoprotein receptor-related protein gene (LRP), an apolipoprotein E receptor, with late-onset Alzheimer's disease.

The presence of the APOE epsilon 4 allele encoding apolipoprotein E4 (apoE4) is the major genetic risk factor for late-onset Alzheimer's disease (AD). However, the molecular and cellular mechanisms by which APOE epsilon 4 renders AD risk are unclear. In this report, we present genetic evidence that an apoE receptor, LRP, may be associated with the expression of late-onset AD. Using a biallelic genetic marker in exon 3 of LRP, late-onset AD cases markedly differed from the control subjects in the distribution of LRP genotypes, and this difference was highly accentuated among AD cases with positive family history of senile dementia. Furthermore, the numbers of neutritic plaques were significantly altered as a consequence of different LRP genotypes in postmortem AD cases. Taken together, our results implicate the pathophysiology of LRP in the expression of late-onset AD.

Age of Onset↗