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Biomedical subjects

D Galasko

Publications and source records attributed to D Galasko.

At least 37 records · Page 2Linked to original sources
PubMed2001

Biological markers and the treatment of Alzheimer's disease.

Disease-modifying approaches are being developed to treat Alzheimer's Disease (AD). These are expected to slow the clinical progression of AD or delay the onset of AD. Biological markers, measured in cerebrospinal fluid (CSF) or in the periphery, may be useful adjuncts to clinical assessment methods for AD, especilly when applied to these types of treatment approaches. Markers related to beta-amyloid and tau, components of AD lesions, can be quantified in CSF and show a stable and predictable pattern over time in AD. Biomarkers related to oxidation, such as isoprostanes, and to inflammation may provide information regarding mechanisms leading to neuronal damage. Biomarkers could be used during early clinical testing of drugs that affect key pathogenic steps inAD, such as amyloid production or clearance, to assess drug action and dose-responserelationships. In large-scale clinical trials or in clinical practice, biomarkers that are easy to access, such as blood or urine tests, could help in evaluating effects of treatment.

Alzheimer Disease↗
PubMed2001

Rate of cognitive change in Alzheimer's disease: methodological approaches using random effects models.

Subtraction of serial scores, Least Squares Estimators, and Best Linear Unbiased Predictors (BLUPs) were compared for estimating rates of cognitive change for Mini-Mental State Exam (MMSE) and Dementia Rating Scale (DRS) scores for 299 probable Alzheimer's disease patients. The BLUPs provided cleaner group estimates of subjects' intercepts and slopes and are preferred. Regression analysis of the BLUP estimates of rate of change indicated that steeper declines were associated with higher levels of education and older age at onset. These effects were much smaller than those due to estimated initial cognitive test score. Differences in longitudinal metric characteristics of the MMSE and DRS were found, with the DRS yielding more precise change estimates. We discuss modeling these longitudinal data, and discuss use of the estimates of rate of change and intercept as data in their own right.

Aged↗
PubMed2000

Incidence of and risk factors for hallucinations and delusions in patients with probable AD.

OBJECTIVE: To examine the incidence of and risk factors for hallucinations and delusions associated with patients clinically diagnosed with probable AD. BACKGROUND: Estimates of the incidence of psychosis in AD range widely from 10% to 75%. The risk factors for psychosis of AD are not known, although multiple studies indicate that AD patients with psychosis demonstrate greater cognitive and functional impairment. METHODS: The authors conducted psychiatric evaluations of 329 patients with probable AD from the University of California at San Diego Alzheimer's Disease Research Center to determine the incidence of hallucinations and delusions. They examined data from annual clinical and neuropsychological evaluations to determine whether there were specific risk factors for the development of hallucinations and delusions. RESULTS: Using Cox survival analyses, the cumulative incidence of hallucinations and delusions was 20.1% at 1 year, 36.1% at 2, 49.5% at 3, and 51.3% at 4 years. Parkinsonian gait, bradyphrenia, exaggerated general cognitive decline, and exaggerated semantic memory decline were significant predictors. Age, education, and gender were not significant predictors. CONCLUSIONS: The authors found a relatively high incidence of hallucinations and delusions in patients diagnosed with probable AD and suggest that specific neurologic signs, cognitive abilities, and accelerated decline may be predictive markers for their occurrence.

Alzheimer Disease↗
PubMed2000

Better cognitive and psychopathologic response to donepezil in patients prospectively diagnosed as dementia with Lewy bodies: a preliminary study.

In several retrospective post-mortem studies, patients meeting clinical criteria for Alzheimer's disease (AD) who gained the greatest cognitive benefit from treatment with an acetylcholinesterase (AChE) inhibitor were found to have neocortical Lewy bodies accompanying classical AD neuropathology. This 'dementia with Lewy bodies' (DLB) subtype manifests both parkinsonian and psychopathologic features that set it apart from 'pure' AD (hereafter called AD). In the present preliminary study, 16 dementia patients were prospectively categorized as having DLB versus AD. Subjects were also categorized according to their profile on surface electromyographic (EMG) measures demonstrated in prior work to be analogues of clinically observed parkinsonian extrapyramidal signs (EPS). All patients were prescribed the AChE inhibitor donepezil (5 mg per day). At baseline and at 6 months, patients underwent cognitive testing with the Mini-Mental State Examination (MMSE) while caregivers assessed their psychopathologic status using the Behavioral Symptoms in Alzheimer's Disease (BEHAVE-AD) scale. The tester was blinded to the AD versus DLB classification of the patients. AD cases (N=12) had only a slight increase in cognitive scores, while DLB patients' (N=4) mean MMSE scores increased to a significantly greater degree. Furthermore, patients categorized by EMG as EPS positive (N=8) attained an increase in their mean MMSE score from baseline to 6 months that differed significantly from a decline in MMSE observed among their EPS negative (N=4) counterparts. For all subjects, an increase in MMSE scores across 6 months of treatment correlated with a decline in BEHAVE-AD scores.

Aged↗
PubMed2000

Psychopathology at initial diagnosis in dementia with Lewy bodies versus Alzheimer disease: comparison of matched groups with autopsy-confirmed diagnoses.

Dementia with Lewy bodies (DLB) is believed to be the second most common form of dementia, after Alzheimer disease (AD). DLB has been reported to be associated with an increase in psychopathology; however, antemortem diagnosis of DLB cannot always be made with certainty. We searched the database of University of California, San Diego SOCARE (Seniors Only Care) outpatient program. There were 26 autopsy-confirmed cases of DLB. We matched them individually with 26 autopsy-confirmed cases of 'pure' AD on gender, ethnicity, and Mini-Mental State Examination score at the baseline evaluation. We compared the two groups on psychopathologic measures and possible risk factors for psychopathology based on the data obtained at the time of the initial diagnosis of dementia. Five psychiatric symptoms: hallucinations, delusions, anxiety, anhedonia, and loss of energy were significantly more common in DLB patients than in AD patients. DLB patients were younger at initial evaluation and death as compared to AD patients, but there was no difference in age of onset of dementia, level of education, or family or past history of any major neuropsychiatric disorder, prescription of psychotropic medications, or sensory impairment. Psychiatric symptoms were more common at time of initial diagnosis of dementia in DLB than in AD patients. This difference could not be attributed to any known risk factors for psychopathology examined. Psychopathology should be considered an integral part of DLB, and should be taken into account in the initial diagnosis of the type of dementia.

Age of Onset↗
PubMed2000

Amyloid-beta and treatment opportunities for Alzheimer's disease.

Proposed treatments of Alzheimer's disease (AD) are most likely to succeed if they are based on an understanding of the complex biology of AD and its effects on cognition. Treatments may target a single or multiple components of the complex pathology of AD with the hope that by affecting an individual component of AD pathology, the disease course can be affected. One such component is amyloid-beta (Abeta), a feature of the senile plaque. Abeta may be critical for inducing the pathology seen in AD. Accumulation of Abeta may result in a cascade of biochemical events leading to neuronal dysfunction, which may present opportunities for intervention at multiple different points to slow disease progression. Treatment may be directed towards decreasing Abeta production, increasing Abeta removal, and decreasing Abeta aggregation. Alternatively, treatment may be directed at more distal pathways by: modulating downstream events possibly due to Abeta such as free radical toxicity, decreasing inflammation, preventing cell membrane damage, restoring calcium homeostasis, preventing excitotoxicity, and blocking the cellular response to injury by inhibiting neuronal apoptosis. This review underscores the complex biology of Abeta specifically looking at the potential targets of therapeutics based on emerging knowledge of this biology.

Journal Article↗
PubMed1999

Longitudinal stability of CSF tau levels in Alzheimer patients.

BACKGROUND: Antemortem levels of tau in the cerebrospinal fluid (CSF) of Alzheimer's disease (AD) patients have repeatedly been demonstrated to be elevated when compared to controls. Although CSF tau has been reported to be elevated even in very mild AD, it is unknown how tau levels change during the course of the disease. METHODS: We have followed 29 mild-to-moderately affected AD subjects over 2 years with repeated CSF taps. Clinical measures of dementia severity (Clinical Dementia Rating Scale, Global Deterioration Scale and Mini-Mental Status Examination) were obtained at the start and conclusion of the observation period, and CSF tau was measured with a standard enzyme-linked immunoabsorbent assay (ELISA) using two monoclonal antibodies. RESULTS: Despite significant changes in the clinical measures consistent with progression of the disease, no significant overall change in CSF tau levels (548 +/- 355 vs. 557 +/- 275 pg/mL, NS) was observed. None of the clinical variables was significantly correlated with either baseline measures of CSF tau or delta CSF tau (last-first). Similarly, CSF tau at baseline and changes over time were not significantly related to Apolipoprotein E (APO E) phenotype. CONCLUSIONS: These data suggest that CSF tau levels are stable over extended periods of time in a group of mild-to-moderately demented AD subjects and that CSF tau levels do not predict the severity or rate of progression of AD, at least not during the middle stages of the illness.

Aged↗
PubMed1999

Variability in annual Mini-Mental State Examination score in patients with probable Alzheimer disease: a clinical perspective of data from the Consortium to Establish a Registry for Alzheimer's Disease.

OBJECTIVE: To determine the variability in annual Mini-Mental State Examination scores of patients with Alzheimer disease enrolled in the Consortium to Establish a Registry for Alzheimer's Disease (CERAD). PATIENTS: A total of 372 patients with probable Alzheimer disease with 1 or more years of follow-up. SETTING: Twenty-one CERAD clinical sites throughout the United States. RESULTS: An average annual decline of 3.4 points in CERAD patients returning for longitudinal reassessments was close to the SD of the measurement error of 2.8 points for the Mini-Mental State Examination. There was wide variability in individual rates of decline. Even with 4 years of follow-up, 15.8% of the patients had no clinically meaningful decline in Mini-Mental State Examination score (defined as a change in initial score >3, ie, 1 SD of measurement error). Validity of measurements of the rate of change in Mini-Mental State Examination scores improved with longer observation intervals and was reliable for most patients when observations were separated by 3 or more years. CONCLUSIONS: Although the Mini-Mental State Examination is a useful screening instrument to assess level of cognitive function, it has limited value in measuring the progression of Alzheimer disease in individual patients for periods less than 3 years because of a large measurement error and substantial variation in change in annual score.

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PubMed1999

Neuropsychological function and apolipoprotein E genotype in the preclinical detection of Alzheimer's disease.

Nondemented older adults genotyped for the Apolipoprotein E (ApoE) epsilon4 allele (n = 43) were neuropsychologically compared to participants without a copy of the epsilon4 allele (n = 90). At baseline, the groups did not differ on age, education, gender, or global cognitive status. ApoE-epsilon4 participants demonstrated significantly poorer mean performances on delayed recall, but no significant group differences emerged on attention, language, constructional skills, psychomotor speed, or executive function. Significantly more ApoE-epsilon4 participants developed probable or questionable Alzheimer's disease (AD) compared with non-epsilon4 participants, suggesting that the group differences resulted from a preponderance of preclinical AD cases within the epsilon4 group and not from a direct influence of ApoE genotype on cognition. Cox proportional hazards analysis, adjusting for age, years of education, and global cognitive status, revealed that ApoE-epsilon4 allele status and measures of recall performance were significant and independent predictors of conversion to AD. Results support the importance of specific episodic memory changes and possession of the ApoE-epsilon4 allele in the preclinical detection of AD.

Aged↗
PubMed1999

Human apolipoprotein E isoform-specific differences in neuronal sprouting in organotypic hippocampal culture.

The apolipoprotein E (ApoE) epsilon4 allele is a major risk factor for neurodegenerative conditions, including Alzheimer's disease. A role for ApoE is implicated in regeneration of synaptic circuitry after neural injury. In the in vitro mouse organotypic hippocampal slice culture system, we previously showed that cultures derived from ApoE-knockout mice are defective in mossy fiber sprouting into the dentate gyrus molecular layer. This sprouting defect was rescued in cultures from transgenic mice expressing ApoE3 under the control of the human promoter and in ApoE-knockout cultures treated with ApoE3-conditioned media. Although the ApoE3 transgene fully restored sprouting, ApoE4 restored sprouting to only 58% of ApoE3 levels. These data indicate that ApoE isoform-specific effects on neuroregeneration may contribute to its genetic risk for Alzheimer's disease.

Alzheimer Disease↗
PubMed1999

Effects of time and cholinesterase inhibitor treatment on multiple cerebrospinal fluid parameters in Alzheimer's disease.

Development of neuropathology in Alzheimer's disease (AD) cannot be studied directly in living patients. Therefore, concentrations in cerebrospinal fluid (CSF) of the proteins tau, A beta 42, alpha 1-ACT, apoE and other molecules have been analyzed to elucidate their possible role in degeneration and as biomarkers of the disease. To date, however, studies have not analyzed multiple markers in the same patients over time and as a function of pharmacological interventions. In the present investigation we measured CSF tau, A beta 42, alpha 1-ACT, apoE, total protein and electrophoretic fractions, and leukocytes, as well as MMSE, in 12 AD patients of known APOE phenotype. Two or three CSF examinations were performed during periods of up to 2 1/2 years, while subjects were on and off treatment with the cholinesterase inhibitor (ChEI) metrifonate (MTF). CSF A beta 42 and tau levels were in agreement with clinical diagnosis of AD in all patients. Abnormally high proportions of monocytes were found in CSF at baseline, and these proportions correlated positively with plasma alpha 1-ACT and MMSE scores. A small but significant increase in CSF alpha 1-ACT, which correlated with peripheral alpha 1-ACT, was associated with 6 months' MTF treatment, though alpha 1-ACT levels did not change further when treatment continued for 2 years. Monocyte proportions in CSF declined over time in both treated and untreated patients. Among 5 of 6 patients treated for 2 years or more with MTF, CSF measures remained relatively stable. One patient had changes in CSF parameters apparently associated with a transient ischemic attack. Our findings did not indicate that slowed cognitive decline with MTF treatment is associated with systematic change in any CSF marker analyzed. The results suggest that further investigations of the relationship of tau, A beta 42 and cellular abnormalities in CSF early in the course of AD are warranted.

Aged↗
PubMed1998

Retraction.

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Journal Article↗
PubMed1998

Cerebrospinal fluid tau protein is not elevated in HIV-associated neurologic disease in humans. HIV Neurobehavioral Research Center Group (HNRC).

We measured the concentrations of the neuron-specific protein, tau, in the cerebrospinal fluid (CSF) of 32 neurologically characterized HIV-infected (HIVpos) subjects and nine matched seronegative (HIVneg) controls using a sensitive ELISA assay. Of 32 HIVpos subjects, nine had HIV-associated neurocognitive disorders, and nine had clinically diagnosed peripheral neuropathies. CSF tau levels in subjects with HIV-associated neurocognitive disorders were similar to those in HIVneg subjects (185 +/- 83 vs. 223 +/- 106 pg/ml; P = 57). CSF tau levels in HIVpos subjects with peripheral neuropathies did not differ from those without neuropathies (320 +/- 190 vs. 251 +/- 185; P = 23). In summary, CSF tau levels were not elevated in patients with HIV-associated neurologic disease.

AIDS Dementia Complex↗
PubMed1998

Prostaglandin E2 induced polymerization of human alpha-1-antichymotrypsin and suppressed its protease inhibitory activity: implications for Alzheimer's disease.

Different molecular forms of alpha-1-antichymotrypsin (ACT) in sera and cerebrospinal fluids from patients with Alzheimer's disease (AD) were detected. Monomeric and polymeric ACT were observed by polyacrylamide gel electrophoresis of both sera and cerebrospinal fluids. ACT polymers were increased in AD patients with the apolipoprotein E (APOE) 4 allele. Increased levels of inactive ACT molecules were also detected in brain homogenates of patients with the APOE 4 allele. Experimental conditions promoting in vitro polymerization of ACT and the effect of polymerization on the biological activity of this serpin were also explored. Incubation of this serpin with prostaglandins of E series (PGE 2) induced ACT polymerization and decreased its activity. Amyloid beta-peptide1-42 did not significantly affected the biological activity of ACT. Inactivation of protease inhibitors by inflammatory molecules such as PGE 2 released from activated microglia in AD brains may promote amyloid deposition and neurodegeneration.

Alzheimer Disease↗