The BDNF Val66Met polymorphism is not associated with late onset Alzheimer's disease in three case-control samples.
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Age of Onset↗
Biomedical subjects
L Thal
Publications and source records attributed to L Thal.
Cholinergic deficits in the brains of patients with parkinsonism-dementia complex of Guam.
Patients with parkinsonism-dementia complex (PDC) of Guam showed moderate loss of choline acetyl transferase activity in the midfrontal and inferior parietal cortex, and severe loss in the superior temporal cortex. This deficit was similar to that seen in Alzheimer's disease and less severe than Lewy body disease. Thus, cholinergic deficits in the neocortex might contribute to some of the cognitive alterations in PDC of Guam.
Acetylcholine↗
Current concepts in mild cognitive impairment.
The field of aging and dementia is focusing on the characterization of the earliest stages of cognitive impairment. Recent research has identified a transitional state between the cognitive changes of normal aging and Alzheimer's disease (AD), known as mild cognitive impairment (MCI). Mild cognitive impairment refers to the clinical condition between normal aging and AD in which persons experience memory loss to a greater extent than one would expect for age, yet they do not meet currently accepted criteria for clinically probable AD. When these persons are observed longitudinally, they progress to clinically probable AD at a considerably accelerated rate compared with healthy age-matched individuals. Consequently, this condition has been recognized as suitable for possible therapeutic intervention, and several multicenter international treatment trials are under way. Because this is a topic of intense interest, a group of experts on aging and MCI from around the world in the fields of neurology, psychiatry, geriatrics, neuropsychology, neuroimaging, neuropathology, clinical trials, and ethics was convened to summarize the current state of the field of MCI. Participants reviewed the world scientific literature on aging and MCI and summarized the various topics with respect to available evidence on MCI. Diagnostic criteria and clinical outcomes of these subjects are available in the literature. Mild cognitive impairment is believed to be a high-risk condition for the development of clinically probable AD. Heterogeneity in the use of the term was recognized, and subclassifications were suggested. While no treatments are recommended for MCI currently, clinical trials regarding potential therapies are under way. Recommendations concerning ethical issues in the diagnosis and the management of subjects with MCI were made.
Aged↗
Frequency of behavioral symptoms characterizes agitation in Alzheimer's disease.
This study describes two well-characterized groups of Alzheimer's disease (AD) patients with similar levels of cognitive functioning, but with different overall behavioral disturbance levels. We sought to determine the nature of this difference-whether AD patients with higher levels of behavioral disturbance (n = 148) differ from less disturbed AD patients (n = 235) in terms of (a) the range of symptoms exhibited, (b) the frequency of occurrence of these symptoms, or (c) both of these. We defined and operationalized 'diversity of behaviors' and 'frequency' with respect to the item-level responses on the Cohen-Mansfield agitation inventory (CMAI). We found that, in these two samples of AD patients, differences occurred in the frequency of 10 out of 21 behaviors, rather than in a variety of endorsed behaviors. These 10 behaviors, observed at different frequencies in both groups, may be useful for monitoring change in studies of drugs or behavioral interventions for behavioral disturbance in persons with AD.
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Clinical trial designs for demonstrating disease-course-altering effects in dementia.
Advances in our understanding of the pathogenesis of Alzheimer disease (AD) and vascular dementia (VaD) now permit responsible discussion of therapies that may go beyond relief of cognitive and behavioral symptoms and actually slow progression of disease. The mechanisms of neuronal death and the pathologic role of glia are being elucidated, and epidemiologic studies have suggested potential protective value for anti-inflammatory drugs, estrogen, and free-radical scavengers. However, demonstrating disease-modifying drug effects for progressive conditions such as dementia can be a daunting task, fraught with clinical, statistical, and ethical dilemmas. To evaluate trial designs for demonstrating such effects, the International Working Group on Harmonization of Dementia Drug Guidelines (IWG) conducted a symposium at the Sixth International Congress on Alzheimer's Disease and Related Disorders, held July 1998 in Amsterdam. The presentations at the IWG symposium covered the two basic designs currently being used in clinical trials, survival analysis and staggered-start/withdrawal, in addition to clinical data generated from the National Institute on Aging Alzheimer's Disease Cooperative Study vitamin E/selegiline trial in patients with AD and the phase III clinical studies of propentofylline in patients with AD and VaD. It is hoped that this article will open a dialogue among investigators and regulatory authorities regarding appropriate trial designs to support a regulatory claim for disease-modifying effects.
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Molecular analysis of glycopeptide-resistant Enterococcus faecium isolates collected from Michigan hospitals over a 6-year period.
The purpose of this study was to evaluate the molecular relatedness of clinical isolates of glycopeptide-resistant Enterococcus faecium isolates collected from hospitals in Michigan. A total of 379 isolates used in this study were all vancomycin-resistant E. faecium isolates collected from 28 hospitals and three extended-care facilities over a 6-year period from 1991 to 1996. For the 379 isolates, there were 73 pulsed-field gel electrophoresis (PFGE) strain types. Within strain types, there were as many as six restriction fragment differences. Most isolates (70%) belonged to six strain types, which were designated M1 (36%), M2 (3%), M3 (18%), M4 (6%), M10 (4%), and M11 (3%). PFGE strain M1 was cultured from 135 patients in 13 hospitals during the period 1993 to 1996. Strain type M2 was cultured from 11 patients in two hospitals during the period 1991 to 1992 and was not observed after 1992. Strain type M3 was cultured from 70 patients in 10 hospitals during the period of 1994 to 1996. Both M4 and M10 were cultured from 23 patients in three hospitals and from 15 patients in two hospitals, respectively, during 1995 to 1996. M11 was cultured from 13 patients in four hospitals during 1996. A total of 23 of 28 hospitals had evidence of clonal dissemination of some isolates. Plasmid content and hybridization analysis done on 103 isolates from one hospital and two affiliated extended-care facilities indicated that the strains contained from one to eight plasmids. Mating experiments indicated transfer of vancomycin resistance from 94 of these isolates into plasmid-free E. faecium GE-1 at transfer frequencies of <10(-9) to 10(-4). Gentamicin resistance and erythromycin resistance were cotransferred at various frequencies. A probe for the vanA gene hybridized to the plasmids of 23 isolates and to the chromosomes of 72 isolates. A probe for the vanB gene hybridized to the chromosomes of 8 isolates. The results of this study suggest inter- and intrahospital dissemination of vancomycin-resistant E. faecium strains over a 6-year period in southeastern Michigan. The majority of isolates studied belonged to the same few PFGE strains, indicating that clonal dissemination was responsible for most of the spread of resistance that occurred.
Anti-Bacterial Agents↗
Neuropsychological assessment of severely demeted elderly: the severe cognitive impairment profile.
BACKGROUND: Although the assessment of cognitive functioning in the late stages of Alzheimer's Disease (AD) is important for identifying abilities that may improve communication and interactions with severely impaired patients in clinical and institutional settings and for assessing the efficacy of pharmacologic agents and behavioral interventions for the treatment of AD, few adequate instruments exist for measuring the cognitive capacities of these severely demented individuals. OBJECTIVES: To evaluate the reliability and validity of the Severe Cognitive Impairment Profile (SCIP), a measure of neuropsychological functioning in severely demented patients, and compare it with other available instruments. DESIGN AND METHODS: We administered the Mattis Dementia Rating Scale (DRS), Mini-Mental State Examination (MMSE), SCIP, and Severe Impairment Battery (SIB) to 41 severely demented patients with AD participating in an AD research center. We used (1) Spearman rank correlation coefficients to assess interrater and test-retest reliability and construct validity of the SCIP; (2) one-way analysis of variance with post hoc comparisons to examine performance on the SCIP and the SIB at different levels of dementia severity; and (3) descriptive statistics to establish the sensitivity of the SCIP to cognitive functioning in a subgroup of very severely demented patients. RESULTS: Interrater and test-retest reliability correlation coefficients were highly significant for total SCIP score (r=0.99 and r=0.96, respectively) as well as for all SCIP subscales. High correlations were also found between SCIP scores and two widely used tests of global cognitive functioning, the DRS (r=0.91) and the MMSE (r=0.84), suggesting good construct validity. The SCIP was able to significantly differentiate between four groups of severely impaired patients divided by level of dementia severity, while the SIB was unable to differentiate between the less severely demented groups. A subgroup of 16 very severely demented patients (DRS score, <50 points) obtained an average of 45% of total possible points on the SCIP, compared with an average of 1% and 21% of total possible points on the MMSE and DRS, respectively. After approximately 1 year of decline, 12 severely demented patients with AD were able to correctly answer an average of more than 58% of the items on the SCIP, compared with only 30% on the DRS and 20% on the MMSE. CONCLUSIONS: The SCIP is a reliable, valid measure of neuropsychological functioning in severely demented patients with AD with the ability to avoid both floor and ceiling effects and to evaluate a wider range of cognitive abilities than other tests used with severely impaired individuals.
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Oral physostigmine in Alzheimer's disease: effects on norepinephrine and vasopressin in cerebrospinal fluid and plasma.
Physostigmine is a cholinesterase inhibitor which enhances central and peripheral cholinergic activity. In this study, we explored in persons with Alzheimer's disease (AD) the effects of an acute dose of physostigmine in patients receiving chronic physostigmine treatment on the activity of the cholinergically regulated noradrenergic and arginine vasopressin (AVP) systems. Specifically, we estimated the effects of sustained release oral physostigmine on central and peripheral noradrenergic and AVP systems by measuring norepinephrine (NE) and AVP in cerebrospinal fluid (CSF) and plasma. Lumbar punctures were performed in both physostigmine and no drug treatment conditions. In some subjects the effects of physostigmine on the plasma AVP response to the osmolar stimulus of a hypertonic saline infusion also were measured. NE concentrations in both CSF and plasma were significantly lower in the physostigmine than in the no drug condition. AVP concentrations did not differ between conditions in either compartment, nor did physostigmine affect the AVP response to hypertonic saline. Physostigmine appears to decrease both central and peripheral noradrenergic activity in AD.
Administration, Oral↗
The CYP2D6B allele is associated with a milder synaptic pathology in Alzheimer's disease.
Both genetic and environmental factors affect the progression of Alzheimer's disease (AD). The presence of cortical Lewy bodies in AD patients is associated with an altered presentation of AD pathology suggestive of an interaction between the pathogenesis of Lewy bodies and AD lesions. Since the CYP2D6B mutant allele is often present in patients with Lewy body diseases (Parkinson's disease and Lewy body variant of AD), we extended these prior observations by studying the neuropathology associated with the presence of the CYP2D6B mutant allele in a pure AD population without Lewy bodies. AD patients who possessed the CYP2D6B mutant allele, in comparison with those without the CYP2D6B allele, were found to have a smaller decline in two synaptic markers, choline acetyltransferase and synaptophysin, in the frontal cortex relative to normal control values. On the other hand, senile plaques and neurofibrillary tangles were not significantly affected by the presence of the CYP2D6B mutant allele in the frontal cortex of AD patients. Association of the CYP2D6B mutant allele with Lewy body formation in both Parkinson's disease and the Lewy body variant of AD and with the milder synaptic pathology in pure AD without Lewy bodies suggest that depending on the contribution of other genetic and environmental factors, this mutant allele may be involved with different aspects of neurodegeneration.
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HIV-associated psychosis: a study of 20 cases. San Diego HIV Neurobehavioral Research Center Group.
OBJECTIVE: Psychosis is an uncommon but serious complication of infection with HIV. This article presents the results of a study of HIV-infected individuals with psychosis. METHOD: The authors evaluated 20 HIV-infected men who had noniatrogenic new-onset psychosis without delirium, current substance abuse, or previous psychotic episodes. Clinical, neuropsychological, CSF, magnetic resonance imaging, and neuropathologic assessments were made. A comparison group consisting of 20 nonpsychotic HIV-infected men matched to the psychotic subjects with respect to age, race, years of education, and Centers for Disease Control HIV stage was also evaluated. RESULTS: The psychotic patients differed from the nonpsychotic comparison subjects in having significantly higher rates of past stimulant and sedative/hypnotic abuse or dependence and, at follow-up, a significantly higher rate of mortality. They also showed a trend toward greater global neuropsychological impairment. CONCLUSIONS: New-onset psychosis may be, at least in part, a manifestation of an HIV-associated encephalopathy.
AIDS Dementia Complex↗
Comparison of the effects of single and combined neurotoxic lesions of the nucleus basalis magnocellularis and dorsal noradrenergic bundle on learning and memory in the rat.
Groups of rats received bilateral destruction of either the nucleus basalis magnocellularis (NBM) by infusion of ibotenic acid, the dorsal noradrenergic bundle (DNB) by infusion of 6-hydroxydopamine, or both NBM + DNB (COMB). These lesion groups along with sham operated controls were trained on a food reinforced spatial delayed conditional discrimination task in a T-maze. All four groups were able to attain a criterion of 85% correct responses despite significant group differences in the number of trials to criterion and number of correct responses during training. Performance of the DNB and NBM groups on acquisition trials was significantly lower than controls, significantly higher than the COMB group, but not significantly different from each other. When tested at delays of 30-300 s, all groups demonstrated parallel rates of decline in performance. On reversal learning trials, the NBM and COMB groups were significantly impaired, whereas the performance of the DNB group was better than controls. No significant interaction between the DNB and NBM lesions was observed on any of the behavioral measures. Biochemical analyses demonstrated significant reductions of choline acetyltransferase (ChAT) activity in cortex but not hippocampus of the NBM and COMB groups, and a significant reduction of norepinephrine (NE) in cortex and hippocampus of the DNB and COMB but not the NBM group. The concentration of other monoamine and amino acid neurotransmitters in the lesion groups were unchanged from controls. These results suggest that DNB and NBM lesions produce separate and independent cognitive impairments that do not severely disrupt retention of trial independent (reference memory) and trial dependent (working memory) information on this T-maze task.
Amino Acids↗
In vivo production and release of acetylcholine from primary fibroblasts genetically modified to express choline acetyltransferase.
Primary rat fibroblasts genetically modified to express Drosophila choline acetyltransferase (dChAT) synthesize and release acetylcholine (ACh) in vitro. The ACh produced from the transduced fibroblasts was found to be enhanced by increasing amounts of choline chloride in the culture media. These dChAT-expressing cells were then implanted into the intact hippocampus of adult rats and in vivo microdialysis was performed 7-10 days after grafting to assess the ability of the cells to produce ACh and respond to exogenous choline in vivo. Samples collected from anesthetized rats revealed fourfold higher levels of ACh around dChAT grafts than from either non-grafted or control-grafted hippocampi. Localized choline infusion (200 microM) through the dialysis probes was found to induce a selective twofold increase in ACh release only from the dChAT-expressing fibroblasts. These results indicate not only that dChAT-expressing fibroblasts continue to synthesize and secrete ACh for at least 10 days after intracerebral grafting, but that the levels of ACh can be manipulated in vivo. The ability to regulate products within genetically modified cells in vivo may provide a powerful avenue for exploring the role of discrete substances within the CNS.
Acetylcholine↗
Neurotransmitters in basal ganglia and cortex of Alzheimer's disease with and without Lewy bodies.
We measured the concentrations of the monoamines, their precursors, and their metabolites, and the activity of choline acetyltransferase (ChAT) in basal ganglia and cortical regions of postmortem brains from cases with histologically verified pure Alzheimer's disease (AD), AD with diffusely distributed Lewy bodies (Lewy body variant [LBV]), and normal controls. Dopamine and homovanillic acid (HVA) were severely depleted in basal ganglia of the LBV cases but were not significantly altered in pure AD cases; tyrosine hydroxylase levels in putamen were also significantly reduced in LBV but not AD cases. These reductions in basal ganglia dopamine and HVA suggest that LBV cases have a level of dopamine depletion similar to Parkinson's disease (PD). Additionally, ChAT activity in caudate and norepinephrine concentration in putamen were significantly reduced in the LBV group, which may have contributed to the absence of resting tremor and the milder presentation of parkinsonian features in this group compared with classic PD. In frontal, parietal, and temporal cortex, activity of ChAT in the LBV group was significantly reduced compared with controls and lower than in pure AD.
3,4-Dihydroxyphenylacetic Acid↗
Types of optometric testing emphasized in different practice modes.
BACKGROUND: In order to determine if tests performed in an examination vary with practice settings, we surveyed all 5,200 California licensed optometrists and asked them to identify their primary mode of practice and the percentage of time and/or frequency that certain test procedures were done in an eye examination. METHODS: We restricted our analysis to three practice modes: private, corporate, and nonprofit/health maintenance organization (NP/HMO). We received a 66.4 percent response rate. To determine any trends in emphasis of testing by the three practice modes and to establish relationships between the three, we compared each mode of practice to the other. The combinations were private vs. corporate, corporate vs. NP/HMO, and private vs. NP/HMO. The three combinations were compared to the frequency of performing case history, stereo acuity testing, binocular vision testing, biomicroscopy, dilated fundus examination, tonometry and perimetry. RESULTS AND CONCLUSIONS: We found the following relationships in the frequency/emphasis of testing as statistically significant: 1) For stereopsis testing: private practices performed it more often than corporate; 2) For binocular vision testing: private practices performed it more than did either corporate or NP/HMO, corporate performed it more than NP/HMO; 3) For tonometry: corporate performed it slightly more than NP/HMO; 4) For dilation: NP/HMO performed it more than both private and corporate; and 5) For perimetry: private performed it more than both corporate and NP/HMO.
Data Collection↗
The Lewy body variant of Alzheimer's disease: a clinical and pathologic entity.
Thirty-six clinically diagnosed and pathologically confirmed Alzheimer's disease (AD) patients included 13 with cortical and subcortical Lewy bodies (LBs). The patients with LBs appeared to constitute a distinct neuropathologic and clinical subset of AD, the Lewy body variant (LBV). The LBV group showed gross pallor of the substantia nigra, greater neuron loss in the locus ceruleus, substantia nigra, and substantia innominata, lower neocortical ChAT levels, and fewer midfrontal tangles than did the pure AD group, along with a high incidence of medial temporal lobe spongiform vacuolization. Analysis of neuropsychological tests from 9 LBV subjects and 9 AD patients matched for age and degree of dementia revealed greater deficits in attention, fluency, and visuospatial processing in the LBV group. Similar comparisons of neurologic examinations showed a significant increase in masked facies; in addition there was an increase in essential tremor, bradykinesia, mild neck rigidity, and slowing of rapid alternating movements in the LBV group. Extremity rigidity, flexed posture, resting tremor, or other classic parkinsonian features were not characteristic of the LBV patient. In some cases, it may be possible to diagnose LBV premortem on the basis of the clinical and neuropsychological features.
Aged↗
Intracranial mass lesions associated with late-onset psychosis and depression.
Tumors and other mass lesions of the brain may present with symptoms resembling psychosis or depression or with features of delusions, hallucinations, mania, or catatonia. There is an over-representation of tumors affecting the frontal lobe, temporal lobe, and diencephalon in patients with these manifestations. Neurologic symptoms and signs may be helpful in making an early diagnosis of the tumor. Patients with late-onset psychosis, unusual histories of depression, and those with focal neurologic findings associated with psychotic disorders should undergo computerized tomographic (CT) scanning to exclude a focal brain lesion.
Brain Diseases↗
Effects of aging and cholinergic deafferentation on putative muscarinic cholinergic receptor subtypes in rat cerebral cortex.
Despite a 34% decrease in the activity of choline acetyltransferase (ChAT) in the rat cerebral cortex following lesions of the nucleus basalis, there were no changes in the Bmax of the antagonist ligands [3H]quinuclidinyl benzilate ((-)-[3H]QNB) or (-)-[3H]N-methylscopolamine ((-)-[3H]NMS). Furthermore, this treatment produced no significant change in the proportions or affinities of muscarinic receptors having high and low affinity for pirenzepine or (-)-NMS. These data indicate that putative M2 muscarinic receptors are not restricted to ChAT-containing neurons in rat cerebral cortex. In senescent compared to mature rats there was no significant loss of ChAT activity although a significant reduction in the Bmax of both (-)-[3H]QNB and (-)-[3H]NMS binding was observed. However, no changes in the competition of pirenzepine or (-)-NMS for the remaining (-)-[3H]QNB binding sites were observed. Therefore, there is no evidence for any differential regulation of either putative muscarinic receptor subtype in response to cholinergic deafferentation or as a function of the natural aging process.
Acetylcholine↗
Significance of neurotransmitter abnormalities in Alzheimer's disease.
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Alzheimer Disease↗