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Biomedical subjects

F J Huff

Publications and source records attributed to F J Huff.

At least 19 recordsLinked to original sources
PubMed1999

Prospective study of risk factors for Alzheimer's disease: results at 7.5 years.

OBJECTIVE: The primary goal of this study was to evaluate increased platelet membrane fluidity as a putative risk factor for Alzheimer's disease and its relationship to the APOE epsilon4 genotype. METHOD: This report describes the results of a prospective, longitudinal study of 330 initially asymptomatic, first-degree relatives of probands with Alzheimer's disease. RESULTS: Nine incident cases of Alzheimer's disease were detected during the first 2,220 subject-years of the follow-up period. Age, increased platelet membrane fluidity, and the APOE epsilon4 allele made significant independent contributions to the risk of developing Alzheimer's disease, while sex and years of education did not. Increased platelet membrane fluidity was associated with incident Alzheimer's disease cases between the ages of 64 and 71, while the epsilon4 allele was associated with incident Alzheimer's disease cases from age 64 until at least age 80. CONCLUSIONS: These results indicate that increased platelet membrane fluidity is not produced by the APOE epsilon4 allele. Instead, increased platelet membrane fluidity and the epsilon4 allele appear to make significant independent contributions to the risk of developing Alzheimer's disease among the first-degree relatives of patients with this disorder. Moreover, the age ranges over which these risk factors operate appear to be different.

Adult↗
PubMed1996

Preliminary evaluation of besipirdine for the treatment of Alzheimer's disease. Besipirdine Study Group.

Besipirdine hydrochloride (HP 749) is an indole-substituted analog of 4-aminopyridine. Besipirdine enhances both cholinergic and adrenergic neurotransmission in the central nervous system, and may have greater efficacy than purely cholinergic agents in treating dementia due to Alzheimer's disease. The present study examined the efficacy and tolerability of two doses of besipirdine (5 and 20 mg BID) in 275 patients with Alzheimer's disease during 3 months of treatment and during 3 months after withdrawal of treatment. Besipiridine was generally well tolerated. The level of performance on a cognitive test was sustained during 3 months of treatment with besipirdine, whereas the performance of patients treated with placebo deteriorated over the same time period. The results suggest a dose-response relationship, with greater efficacy after 3 months of treatment and longer persistence after treatment withdrawal for besipiridine 20 mg BID than for 5 mg BID. A clinical global rating did not detect a besipirdine treatment effect. The full efficacy after 3 months of treatment did not persist after withdrawal of treatment, suggesting that the benefit is primarily symptomatic. Treatment with higher doses and for longer periods may enhance efficacy on both cognitive and clinical global assessments.

Alzheimer Disease↗
PubMed1996

A treatment and withdrawal trial of besipirdine in Alzheimer disease.

Besipirdine hydrochloride (HP 749) is an indole-substituted analog of 4-aminopyridine. Besipirdine enhances both cholinergic and adrenergic neurotransmission in the central nervous system. The present study examined the efficacy and tolerability of two doses of besipirdine (5 and 20 mg b.i.d.) in 275 patients with Alzheimer disease during 3 months of treatment and for 3 months after withdrawal of treatment. Assessment after withdrawal of treatment was used in an effort to distinguish persistent efficacy attributable to a neuroprotective mechanism from reversible symptomatic efficacy. Besipirdine was generally well tolerated. The level of performance on the cognitive subscale of the Alzheimer Disease Assessment Scale (ADAS-Cog) was sustained during 3 months of treatment with besipirdine, whereas some deterioration in the performance of patients treated with placebo was observed over the same period. The small difference between active and placebo treatment groups approached, but did not reach statistical significance in the primary intent-to-treat analysis (p = 0.067); analysis of patients who completed all assessments was supportive (p = 0.031). Global ratings using the Clinician Interview-Based Impression of Change did not detect a besipirdine treatment benefit, possibly because of an adverse effect on mood and behavior in some patients. A high ratio of adrenergic to cholinergic potency may have resulted in the adverse effects of besipirdine and hence its failure to support the hypothesis that multiple neurotransmitter treatment may be more efficacious than monotherapy. The efficacy apparent on the ADAS-Cog after 3 months of treatment did not persist 3 months after withdrawal of treatment, suggesting that the benefit was symptomatic. This study provides a practical example of the use of treatment withdrawal assessment to distinguish neuroprotective from symptomatic efficacy.

Aged↗
PubMed1996

Prospective study of increased platelet membrane fluidity as a risk factor for Alzheimer's disease: results at 5 years.

OBJECTIVE: The primary goal of this study was to evaluate increased platelet membrane fluidity as a putative risk factor for Alzheimer's disease. METHOD: This report describes the initial results of a prospective, longitudinal study of 330 initially asymptomatic, first-degree relatives of probands with Alzheimer's disease. RESULTS: Five incident cases of Alzheimer's disease were detected during the first 1,582 subject-years of the follow-up period. The age-specific incidence of Alzheimer's disease was several-fold higher than corresponding figures that were obtained in two prospective community studies. Most important, both age and increased platelet membrane fluidity made significant independent contributions to the risk of developing Alzheimer's disease. CONCLUSIONS: These results validate age and a family history of Alzheimer's disease as risk factors for this disorder and provide the first prospective evidence of increased platelet membrane fluidity as a biological risk factor for Alzheimer's disease.

Adult↗
PubMed1995

A "bridging" (safety/tolerance) study of besipirdine hydrochloride in patients with Alzheimer's disease.

Besipirdine hydrochloride is a novel compound with cholinergic and adrenergic activity being investigated as a treatment for Alzheimer's disease (AD). The pharmacodynamics of some anti-dementia drugs are known to differ in patients with AD as compared with elderly normals. The present study was designed to determine the maximum tolerated dose (MTD) of multiple oral doses of besipirdine in AD patients. Twelve AD patients (NINCDS/ADRDA criteria; 7M, 5F, ages 58-75, mean age 65) were randomized to besipirdine (n = 9) or placebo (n = 3) in a double-blind, parallel-group, rising-dose design. Doses were 10, 20, 30, and 40 mg bid for 2 days each, followed by 50 and 60 mg bid for 5 days each. The most common adverse events were asymptomatic postural hypotension and asymptomatic bradycardia. Two patients on active drug developed severe adverse events: 1 after 3 days at 50 mg bid (nausea and vomiting); 1 after 3 days at 60 mg bid (angina). Due to the anginal episode, the study was terminated on Day 17. Plasma concentrations increased linearly with dose for besipirdine and its major metabolite. The two patients who developed severe adverse events had the highest plasma concentrations measured. Besipirdine 50 mg bid was considered the maximum tolerated dose (MTD).

Aged↗
PubMed1993

Sensitivity and specificity for dementia of population-based criteria for cognitive impairment: the MoVIES project.

BACKGROUND: Few norms exist for the elderly on the cognitive tests commonly used to screen for dementia; conventional cutpoints used in clinical settings may be of limited value in population screening. A particular problem is posed by elderly populations with low educational levels, as performance on most cognitive tests is affected by education. Thus, a healthy but poorly educated population may obtain test scores in the range considered impaired in the clinical setting. METHODS: A random sample of 1,367 subjects aged 65+ years was screened for dementia in a rural community in Southwestern Pennsylvania. Two sets of cognitive measures were used: a global cognitive scale (the MMSE) and a brief battery of tests tapping a variety of cognitive domains. Rather than using a priori cutoff scores, we examined the specificity and sensitivity for dementia of two operationally defined levels of cognitive impairment, at the 5th and 10th percentiles of the study sample on each set of measures. RESULTS: Results suggest that the screening of multiple cognitive domains at the 10th percentile had significantly greater sensitivity but not lower specificity for definite dementia than did the use of the single global scale. CONCLUSION: Our data support the use of population-based cutpoints over standard cutoff scores, in that the global scale at the conventional cutoff was less sensitive than the battery at the same percentile, and because adequate norms do not exist for tests such as those in the battery.

Aged↗
PubMed1992

Time dependency of cognitive recovery with cobalamin replacement: report of a pilot study.

OBJECTIVE: To examine the effects of cobalamin repletion on cognition in elderly subjects with low serum cobalamin and evidence of cognitive dysfunction. DESIGN: Time series data collected in an open trial of parenteral cobalamin therapy. SETTINGS: Outpatient geriatric assessment centers, inpatient geropsychiatry unit, and tertiary care university hospital. PARTICIPANTS: Twenty-two subjects with low serum cobalamin (less than 150 pmol/L) and evidence of cognitive dysfunction were entered consecutively over an 8-month period of time. Eighteen subjects completed the study. INTERVENTIONS: Subjects received 1000 micrograms of cyanocobalamin intramuscularly daily for 1 week, then weekly for 1 month, then monthly thereafter for a minimum of six months. OUTPATIENT MEASURE: The Mattis Dementia Rating Scale (DRS) was administered both before and at least 6 months after full cobalamin replacement therapy. The hypothesis that cognitive improvement was dependent on the duration of cognitive symptoms was formulated a posteriori. RESULTS: After a minimum of 6 months of cobalamin therapy, 11 of 18 patients showed cognitive improvement. There was a striking correlation between duration of cognitive symptoms and response to therapy. Patients symptomatic for less than 12 months gained an average of twenty points on the DRS (paired t test P = 0.0076), whereas patients symptomatic greater than 12 months lost an average of three points (paired t test P = .34). Two patients symptomatic for only 3 months normalized their DRS scores, gaining 31 and 28 points, respectively. CONCLUSION: There may be a time-limited window of opportunity for effective intervention in patients with cognitive dysfunction and low serum cobalamin.

Aged↗
PubMed1992

Serum autoantibodies in patients with Alzheimer's disease and vascular dementia and in nondemented control subjects.

BACKGROUND AND PURPOSE: In this study we sought to evaluate the clinical significance of serum autoantibodies to dementing processes. METHODS: We assessed 40 age-matched subjects: 10 patients with probable Alzheimer's disease, 10 with possible Alzheimer's disease with cerebrovascular disease, 10 with vascular dementia, and 10 nondemented control subjects. Serum from each subject was tested for the presence of antithyroglobulin antibody, thyroid antimicrosomal antibody, gastric anti-parietal cell antibody, anti-smooth muscle antibody, antinuclear antibody, rheumatoid factor, antineuronal antibody, and anticardiolipin antibody. In addition, we investigated the sera of these patients for the presence of an antivascular antibody directed against the vascular basement membrane proteoglycan antigen and for circulating immune complexes. RESULTS: Autoantibodies were present in 100% of the patients with possible Alzheimer's disease with cerebrovascular disease, 80% of those with vascular dementia, 40% of those with probable Alzheimer's disease, and 30% of the nondemented control subjects. The highest number of autoantibodies was observed in patients with vascular dementia and possible Alzheimer's disease with cerebrovascular disease. Antinuclear antibody was present in 60% of vascular dementia patients and antineuronal antibody in 50% of these patients. However, no individual autoantibody could differentiate Alzheimer's disease from cerebrovascular disorders. Immune complexes were detected in the serum of 20-30% of each patient group. Neither the patient nor the control sera was found to contain antiendothelial antibody. CONCLUSIONS: Despite the relatively small number of individuals examined in each category, the elevated number of autoantibodies associated with possible Alzheimer's disease with cerebrovascular disease and vascular dementia indicates a possible link between the presence of autoantibodies and cerebrovascular disorders in dementia.

Aged↗
PubMed1991

Serum auto-antibodies in Alzheimer's disease.

The prevalence and clinical significance of non-CNS auto-antibodies in the serum of patients with probable and possible Alzheimer's disease (AD) was determined. Serum was obtained from 88 patients and 55 normal controls. Serum from each subject was tested for the presence of seven different auto-antibodies. Auto-antibodies were detected in 44% of the subjects with probable AD, 70% with possible AD with cerebrovascular disease (CVD), 45% with possible AD and other disease and 42% of normal controls. Although a subpopulation of AD patients with CVD showed a trend to an increased predisposition to develop autoimmune disease, these results do not support the relationship of AD and serum auto-antibodies or autoimmune disease.

Aged↗
PubMed1991

Evaluation of HP 029 (velnacrine maleate) in Alzheimer's disease.

HP 029 (1,2,3,4-tetrahydro-9-aminoacridin-1-ol-maleate) is a cholinesterase inhibitor and one of a series of compounds synthesized at Hoechst-Roussel Pharmaceuticals Inc. (HRPI) as a potential therapeutic agent for senile dementia of the Alzheimer type (SDAT). An ongoing clinical development program for HP 029 (velnacrine maleate) reflects a rational, traditional progression from therapeutic concept through clinical evaluation. Prior to the initiation of outpatient studies, sufficient data had been obtained from normal volunteers and hospitalized patients to support the following conclusions: the pharmacokinetic profile of HP 029 in young and elderly normal men is predictable; tolerance and safety data for HP 029 using normal volunteers poorly correlates with experience in patients with SDAT; patients with SDAT exhibit marked intersubject variability in tolerance within a suspected therapeutic dose range; mandatory endpoints for drug discontinuation for outpatients can be reliably established in an inpatient environment. Subsequently, Protocol 201 was initiated as a multicenter, multistage investigation of HP 029 in patients with probable SDAT (NINCDS-ADRDA criteria). A dose-ranging component determined patient eligibility for a subsequent dose-replication phase based upon explicit safety and efficacy criteria defined within protocol. One a priori specified interim analysis was conducted by the sponsor (HRPI) for administrative purposes after completing approximately 50% of the planned sample (September 1989). Results suggested that (1) beneficial effects of HP 029 existed on key and secondary measures for the approximately 30% of enrolled patients; (2) interim results would provide an accurate reflection of the results at the conclusion of the study (1991); (3) HP 029-induced hepatocellular injury appeared to be a reversible, predominantly dose-related event; and (4) cholinergically mediated adverse events are infrequent and clinically inconsequential at dosages less than or equal to 225 mg/day. Post hoc hypotheses based on the interim dataset suggest that: (1) carry-over effects of HP 029 exist within a dose-ranging/dose-replication paradigm that militate against the utility of an "enriched population" design; (2) beneficial effects are more robust on initial exposure to HP 029 with effects discerned on both memory and arousal; (3) patient characteristics associated with toxicity or response are not identified; (4) dosage reduction in subsequent efficacy trials may reduce hepatocellular injury and yield clinically unimportant differences in overall efficacy results.

Aged↗
PubMed1991

Potential clinical use of an adrenergic/cholinergic agent (HP 128) in the treatment of Alzheimer's disease.

A novel compound designated HP 128, which manifests adrenergic and cholinergic properties, was administered for 10 days to patients with Alzheimer's disease in a double-blind, placebo-controlled trial. All patients who entered the trial had previously failed to respond to a structurally related cholinesterase inhibitor without adrenergic properties (HP 029). The primary purpose of the study was to assess the safety and tolerance of HP 128. Efficacy measures were obtained to generate hypotheses for possible future studies. In the dosage range examined, HP 128 was safe and well tolerated. Effects on clinical measures of dementia severity were equivocal.

Aged↗
PubMed1991

Effects of age, gender, and education on cognitive tests in a rural elderly community sample: norms from the Monongahela Valley Independent Elders Survey.

A random sample of 1,350 persons aged 65 years and older in a rural community underwent cognitive screening as part of a survey to establish a population-based registry of dementing disorders. The screening battery included the neuropsychological tests of the assessment protocol used in the National Institute on Aging multicenter Consortium to Establish a Registry for Alzheimer's Disease (CERAD). This paper reports a large body of normative neuropsychological data from this sample with members of relatively low socioeconomic status. Age, sex, and educational level were found to have statistically significant effects on test scores. The implications of these findings for the establishment of screening cutoff scores are discussed.

Aged↗
PubMed1990

Brain imaging abnormalities in mental disorders of late life.

Psychiatric inpatients with dementia (N = 61) or depression (N = 67) in late life were 2.6 times more likely to manifest magnetic resonance imaging abnormalities of the brain than were elderly controls (N = 44). Controlling for the effects of age and gender, demented patients were distinguishable from controls by an increased prevalence of cortical atrophy and infarction, while depressed patients exhibited an increased prevalence of cortical infarctions and leukoencephalopathy. Patients with dementia were distinguishable from those with major depression by an increased prevalence of cortical atrophy. These results indicate that major depression in late life, like dementia, is associated with a remarkable increase in overt pathologic changes in the brain.

Adolescent↗
PubMed1989

The ratio of acetylcholinesterase to butyrylcholinesterase influences the specificity of assays for each enzyme in human brain.

A single-vial extraction radiometric assay was used to measure acetylcholinesterase and butyrylcholinesterase in human post-mortem brain tissue. Data are presented regarding the differential inhibition of acetylcholinesterase and butyrylcholinesterase in several brain areas from a case of Alzheimer's disease and a case without neuropsychiatric disease. The results indicate that neither enzyme is entirely specific for its substrate, and the necessity for using inhibitors depends upon the ratio of acetylcholinesterase to butyrylcholinesterase in a particular sample.

Acetylcholinesterase↗
PubMed1989

Activities and kinetic properties of lumbar cerebrospinal fluid cholinesterases in relation to clinical diagnosis, severity, and progression of Alzheimer's disease.

Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activities of lumbar cerebrospinal fluid (CSF) have been measured in seventeen patients with a clinical diagnosis of probable Alzheimer's disease (Prob AD), possible Alzheimer's disease (Poss AD), or dementia of non-Alzheimer aetiology (Non-AD). The three diagnostic groups did not differ with regard to the Km or saturation kinetic properties of AChE and BChE. The CSF AChE activity was significantly higher in Prob AD than in Non-AD patients. The groups did not differ significantly in BChE activity. The ratio of AChE to BChE activity was significantly higher in both the Prob AD and Poss AD groups than in the Non-AD group, and the ranges of values in the Prob AD and Non-AD groups did not overlap. Among patients in the Prob AD group, severity of dementia was correlated with both AChE activity and the AChE/BChE ratio, and progression of dementia over time was also correlated with AChE/BChE. The AChE/BChE ratio correlated more strongly than AChE with severity and progression of dementia in Prob AD patients, and also better distinguished them from Non-AD patients, suggesting that AChE/BChE may be the more useful marker for diagnosis of AD. It is not clear from the results whether AChE/BChE is useful for diagnosis of the complex dementia cases in the Poss AD group.

Acetylcholinesterase↗