Spatial test for agricultural pesticide "blow-in" effect on prevalence of Parkinson's disease.

The current study used Department of Veteran's Affairs (VA) clinical records, State of California pesticide application records, spatial maps of distribution of Parkinson's disease patients, and pesticide applications to determine if there was evidence for "blow-in" of pesticides as a factor in explaining the prevalence of Central Valley Parkinson's disease. The results did not support the hypothesis of increasing prevalence of Parkinsonism attributable to wind drift.

Cerebral glucose metabolic patterns in Alzheimer's disease. Effect of gender and age at dementia onset.

No previous study of Alzheimer's disease has, to our knowledge, assessed the effect of both age at dementia onset and gender on cerebral glucose metabolic patterns. To this end, we used positron emission tomography (fludeoxyglucose F 18 method) to study 24 patients with clinical diagnoses of probable Alzheimer's disease. Comparisons of the 13 patients with early-onset dementia (less than 65 years of age) with the 11 patients with late-onset dementia (greater than 65 years of age) revealed significantly lower left parietal metabolic ratios (left posterior parietal region divided by the hemispheric average) in the early-onset group. The metabolic ratio of posterior parietal cortex divided by the relatively disease-stable average of caudate and thalamus also separated patients with early-onset dementia from those with late-onset dementia, but not men from women. Further comparisons between sexes showed that, in all brain regions studied, the 9 postmenopausal women had higher nonweighted mean metabolic rates than the 15 men from the same age group, with hemispheric sex differences of 9% on the right and 7% on the left. These results demonstrate decreased parietal ratios in early-onset dementia of Alzheimer's disease, independent of a gender effect.

Neuropil threads are collinear with MAP2 immunostaining in neuronal dendrites of Alzheimer brain.

Alzheimer disease (AD) neuropathology includes neuropil threads (NTs) and neurofibrillary tangles (NFTs). In tangle-bearing neurons, the normal cytoskeleton is severely disrupted and replaced with paired helical filament (PHF) aggregates of aberrantly phosphorylated microtubule-associated protein tau. In this study, double-label immunocytochemistry was used to clarify the relationship between the appearance of neurofibrillary pathology (NTs and NFTs) and the loss of normal cytoskeletal components, such as microtubule-associated protein 2 (MAP2) in 13 AD cases and 6 nondemented elderly control individuals. Brain areas examined included neocortex (cingulate, motor, and inferior parietal cortices), hippocampus, and entorhinal cortex. In mildly affected neurons, PHF-1 immunostained NTs were found in dendrites, frequently at dendritic branch points, and were adjacent to MAP2 immunostaining. In more severely affected neurons, the PHF-1 immunoreactivity occupied distinct dendritic segments and appeared to displace MAP2. Interspersed MAP2 immunopositive dendritic segments were often beaded in appearance. In all instances where dendrites with NTs could be traced back to the soma, the soma also contained PHF-1 immunostained fibrils in various stages of NFT formation. The results suggest that PHFs gradually displace normal microtubules in dendrites, and cause degeneration of dendritic segments between NTs.

Advances in Alzheimer therapy: cholinesterase inhibitors.

After a decade of intense study of cholinergic therapies for Alzheimer's disease, three conditions in this field are apparent: 1) The potential that cholinergic agents will ameliorate the memory dysfunction of Alzheimer patients (as 1-dopa benefits Parkinson patients) is still a stimulus for research. 2) Cholinergic neuropharmacology and its impact on the therapy of memory disorders associated with cholinergic dysfunction needs to be further characterized and understood. 3) While there is still a search for a symptomatic treatment for AD, the path to find a treatment for the Alzheimer disease process must first pass through a phase of basic research to find the cause of Alzheimer's disease. At the meeting, there was an undercurrent of concern that the cholinergic deficit is too severe to be treated, that the cholinergic systems are too complex to respond to a pharmacologic therapy and that too many other systems are involved in Alzheimer's disease for a cholinergic treatment to be successful. However, this concern was balanced by the evidence of basic scientific experiments which indicate that the central cholinergic system mediating memory can be positively manipulated in animal lesion preparations and Alzheimer tissue. Also there were reports that improved pharmacological approaches and psychological measures are being developed. It appears that Alzheimer therapy is at the stage that cancer chemotherapy was 20 years ago: the promising agents cause nausea without producing clear effects but the basic laboratory studies strongly suggest that substantial benefits are possible and several agents have shown encouraging results. Meanwhile, patients and scientists are becoming increasingly interested in the field.(ABSTRACT TRUNCATED AT 250 WORDS)

Anticonvulsants attenuate amyloid beta-peptide neurotoxicity, Ca2+ deregulation, and cytoskeletal pathology.

Increasing evidence supports the involvement of amyloid beta-peptide (A beta) and an excitotoxic mechanism of neuronal injury in the pathogenesis of Alzheimer's disease. However, approaches aimed at preventing A beta toxicity and neurofibrillary degeneration are undeveloped. We now report that anticonvulsants (carbamazepine, phenytoin, and valproic acid) can protect cultured rat hippocampal neurons against A beta- and glutamate-induced injury. Each of the anticonvulsants attenuated the elevation of intracellular free calcium levels [(Ca2+)i] elicited by A beta or glutamate suggesting that their neuroprotective mechanism of action involved stabilization of [Ca2+]i. These compounds were effective at clinically relevant concentrations (carbamazepine, 100 nM-10 microM; phenytoin, 100 nM-1 microM; valproic acid, 100 nM-100 microM). The anticonvulsants suppressed glutamate-induced alterations in tau and buiquitin immunoreactivities. Compounds that stabilize [Ca2+]i may afford protection against the kinds of insults believed to underlie neuronal injury in Alzheimer's disease.

Comparison of neuropathologic criteria for the diagnosis of Alzheimer's disease.

The National Institute on Aging and Reagan Institute (NIA-RI) criteria, and other neuropathologic criteria for Alzheimer's disease (AD), were compared with the clinical diagnosis of dementia in a well defined population of Catholic sisters. The 47-participant subset examined in this study were college educated and lacked complicating conditions such as brain infarcts or diffuse Lewy body disease. Sixteen participants had a clinical diagnosis of dementia. The NIA-RI criteria imply a perfect correlation between neuritic plaque (NP) density and neurofibrillary tangle distribution. However, NP density often did not coincide with tangle distribution. As a result, it was not possible to categorize many of the participants using the NIA-RI guidelines. The 'high likelihood' category of the NIA-RI criteria for AD research settings (neocortical Braak stage and frequent neocortical NP) had relatively high specificity (90% of nondemented participants did not meet this criteria). However, only half of the demented participants were in this category. Neuropathologic criteria requiring the presence of neocortical tangles (rather than neocortical Braak stage) had relatively high sensitivity, accounting for 87-94% of participants with dementia, but also included 32-35% of nondemented participants. Criteria based on neocortical NP or senile plaques had 100% sensitivity, but a majority of nondemented participants also met these criteria. The results support consideration of both tangles and NP for the neuropathologic diagnosis of AD, but indicate that refinement of the NIA-RI criteria is necessary. A possible refinement is suggested for further consideration.

Are there clinical differences between familial and nonfamilial Alzheimer's disease?

OBJECTIVE: The purpose of the study was to determine whether there are differences in clinical characteristics in two groups of patients with Alzheimer's disease, those reported to have a family history of dementia and those without a family history of dementia. METHOD: Using a data set from an Alzheimer's disease patient registry, funded as part of a National Institute on Aging cooperative agreement, the authors made comparisons of sociodemographic and clinical variables in a group of 462 patients with Alzheimer's disease, 172 reported to have at least one first-degree relative with dementia and 290 classified with no family history. RESULTS: Patients with a presumptive family history differed from those without a family history in two ways: the course of dementia was described as having a fast rather than a slow progression from onset of symptoms to diagnosis, and caregivers reported a higher prevalence of family history of psychiatric disorders. There were no significant differences in age at onset, duration, female gender, aphasia and apraxia, handedness, family history of Down's syndrome, or number of children, brothers, and sisters. CONCLUSIONS: The association of faster course and family history of psychiatric disorders in the patients with a family history of dementia is consistent with the hypothesis of heterogeneity, but the overall results could also be explained by a genetic-environmental model of Alzheimer's disease.

An empirical evaluation of the Global Deterioration Scale for staging Alzheimer's disease.

OBJECTIVE: Although the Global Deterioration Scale has been widely used since its publication in 1982, its stages are based on implicit assumptions about the linearity, temporality, and interdependence of cognitive, functional, and behavioral impairment in Alzheimer's disease. The authors evaluated the validity of these assumptions and tested the hypothesis that psychopathology and functional impairment would occur in earlier stages than the Global Deterioration Scale predicts. METHOD: The analyses were based on data on 324 patients with Alzheimer's disease who were selected from a registry of such patients. Data analyses included 1) descriptive statistics on the frequency of psychiatric symptoms and difficulties with activities of daily living and 2) logistic regression, with symptoms and functional impairment as independent variables, to test for significant changes in patients' status between stages of the Global Deterioration Scale. RESULTS: More than 50% of the patients at stage 2 displayed psychopathology, and 32% had two or more symptoms. The significant increase in psychiatric symptoms occurred between stages 3 and 4, not between stages 5 and 6 as predicted by the Global Deterioration Scale. Impairment in functional status was observed at all stages, and significant increases occurred between stages 3 and 4 as well as between stages 5 and 6. CONCLUSIONS: Psychiatric symptoms and functional impairment occur earlier than predicted by the Global Deterioration Scale, and the rate of change is also different from that specified in the scale. Separate scales to describe cognitive, clinical, and functional status may be the best way to describe the illness until better multidimensional instruments are developed.

Violent automatism in a partial complex seizure. Report of a case.

We describe a patient who had a violent automatism that occurred during a partial complex seizure. The initial spike wave activity was recorded from nasopharyngeal leads that were lost as the patient began his vigorous, violent activity. This activity included nondirected, automatic, stereotyped behavior with physical assaults on objects in his path.

"Preclinical" AD revisited: neuropathology of cognitively normal older adults.

OBJECTIVE: To classify neuropathologic alterations in the brains of nondemented older adults using current sets of criteria for AD. BACKGROUND: AD neuropathologic alterations are found in the brains of some nondemented elderly subjects and suggest the possibility of presymptomatic AD. Three sets of guidelines have been developed to classify AD using senile plaques, neuritic plaques, and neurofibrillary tangles (NFT). METHODS: Neuropathologic changes in 59 older adults followed longitudinally with a standard battery of mental status measures were investigated using Khachaturian, Consortium to Establish a Registry for Alzheimer's Disease (CERAD), and National Institute on Aging-Reagan Institute (NIA-RI) guidelines. AD neuropathologic markers were evaluated in neocortical and allocortical regions. Cases were categorized as neuropathologically "normal" or "AD-like" and compared for possible mental status differences. RESULTS: Between 11 and 49% of cases met one or more of the three classifications of AD. With adjustments for multiple comparisons, only NFT in hippocampal CA1 region were associated with autopsy age, suggesting that this may represent a pathologic process associated with normal brain aging. Using the NIA-RI guidelines, subjects in the AD-like group performed less well on the immediate paragraph recall and word-list delayed recall than their counterparts who did not meet these guidelines. CONCLUSIONS: These data indicate that the prevalence of "preclinical" AD in our population is relatively low based on the NIA-RI classification. Although many subjects had AD-like changes based on CERAD and Khachaturian guidelines, they exhibited no differences in mental performance, suggesting that the aging brain may be able to withstand such structural changes without meaningful impact on mental functioning.

Single SPECT measures of cerebral cortical perfusion reflect time-index estimation of dementia severity in Alzheimer's disease.

UNLABELLED: To determine the relationship between cerebral cortical blood flow loss and the temporal development of the dementia in Alzheimer's disease (AD), SPECT was studied in a cross section of AD patients with a broad range of impairment. METHODS: Thirty patients with a diagnosis of probable AD had their mini-mental state examination scores transformed into time-index values to give an estimation of dementia severity relative to the developmental time course. SPECT images were obtained using 99mTc-ethyl cysteinate dimer and a 3-head camera. Cortical surface perfusion was analyzed, including modified Talairach standardization, to obtain cortical elements from the convexity (each representing about 0.25 cm2 at the surface, 6.6-mm cortical depth) referenced to the mean perfusion of the full greater cerebellar hemisphere. These element ratios were analyzed (individually and by averages of estimated Brodmann's areas and brain regions) using linear regression with the time-index value. RESULTS: For individual posterotemporal and inferoparietal Brodmann's areas (21, 22 and 39, 40, respectively) the correlation coefficients between cortical perfusion ratios and dementia severity ranged between -0.67 and -0.78 (P < 0.001). Perfusion ratios from these regions declined 2.5%-4.2% for each estimated year of progression. Prefrontal area perfusion showed less association with severity. Perfusion in primary cortical regions had no significant association with dementia severity. CONCLUSION: Cerebral cortical perfusion loss is temporally related to development of dementia. The spatial pattern of high, significant correlations between cortical perfusion and dementia severity shows a regional distribution that corresponds closely to the distribution of AD pathology described in autopsy studies.

Age, education, and changes in the Mini-Mental State Exam scores of older women: findings from the Nun Study.

OBJECTIVE: To describe the relationship of Mini-Mental State Exam (MMSE) scores and changes over time in MMSE scores to age and education in a population of older women. DESIGN: A prospective study of a defined population. SETTING: Various motherhouses and church-run health care facilities in the Eastern, Midwestern, and Southern regions of the United States. PARTICIPANTS: Catholic sisters (nuns) participating in the Nun Study, a study of aging and Alzheimer's Disease. The 678 participants were 75 to 102 years old (mean 83.3, standard deviation 5.5, median 82.3) at the time of the first functional assessment. Second assessments were obtained an average of 1.6 years later on 575 survivors. MEASUREMENTS: The outcome variables were MMSE scores at the first assessment (Time-one), and MMSE scores at the second assessment (Time-two). The independent variables were age at Time-one, and education (bachelor's degree or no bachelor's degree). RESULTS: Time-one MMSE scores decreased with age at Time-one. The decrease in MMSE scores with age was less in sisters with bachelor's degrees than in sisters without bachelor's degrees. The changes in MMSE scores had a "U-shaped" relationship with Time-one score, where the greatest declines occurred in sisters with intermediate Time-one scores. Stratified analysis by age, education, and Time-one MMSE scores of 20 or greater because of the small numbers of sisters with Time-one scores less than 20. In sisters with Time-one MMSE scores in the categories 20 to 23, 24 to 26, or 27 to 30, older ages at Time-one were associated with greater decline in those with bachelor's degrees, but not in those without bachelor's degrees. Also, lower education was associated with greater decline in sisters aged 75 to 84 years at Time-one, but this education effect disappeared or reversed in sisters who were 85 years of age or older at Time-one. CONCLUSIONS: Cognitive function as measured by the MMSE decreased with age at Time-one, most steeply as a function of age in those without bachelor's degrees. Cognitive function declined over 1.6 years within individuals, and the extent of decline increased with age in the sisters with bachelor's degrees. The extent of decline varied with age and education in an interactive manner, which may have been attributable to a hardy survivor effect in lower educated sisters. It may be necessary to consider such interactions whenever changes in function are studied, particularly when analyses are stratified by the initial level of function.

Sex differences in the psychiatric manifestations of Alzheimer's disease.

OBJECTIVE: To test the null hypothesis, ie, that there are no gender differences in psychiatric problems manifest in patients with Alzheimer's disease. DESIGN: Survey. SETTING: Patients living in the community and evaluated at Alzheimer's disease and geriatric outpatient programs. PATIENTS: Three hundred twenty-eight women and 186 men clinically diagnosed with Alzheimer's disease using NINCDS/ADRDA or DSM-III-R criteria. MEASUREMENTS: Psychiatric signs and symptoms recorded following a psychiatric interview, including the Hamilton Depression Rating Scale. RESULTS: Approximately two-thirds of both men and women had psychiatric problems, but women had significantly more multiple symptoms. When pairs of symptoms were analyzed for independence, agitation was only significantly associated with paranoia in men, whereas in women agitation was significantly associated with most other psychiatric problems. CONCLUSION: The higher prevalence of multiple psychiatric problems in women may be due to many factors, including sociodemographic influences, physician bias, and/or other differences between men and women. The finding of a different pattern of association of symptoms with agitation in men and women deserves replication.

Drug use patterns of persons with Alzheimer's disease and related disorders living in the community.

OBJECTIVE: To describe drug use patterns by persons with Alzheimer's disease, multi-infarct dementia, and mixed Alzheimer's disease and multi-infarct dementia. DESIGN: Multicenter, patient registry. SETTING: Community-living persons evaluated in primary care, geriatric, and Alzheimer ambulatory settings. PARTICIPANTS: Of the 930 persons in three diagnostic categories, there were 671 with probable or possible Alzheimer's disease by NINCDS/ADRDA criteria or Alzheimer's disease by DSM-III-R criteria, 162 multi-infarct cases by DSM-III-R criteria, and 97 mixed cases by DSM-III-R criteria. In each diagnostic category, 65% were women, and the majority were 70 years or older. MEASUREMENTS: The average number of all prescription and non-prescription drugs and selected therapeutic categories by age, sex, diagnosis, and mini-mental status score at the time of diagnosis or evaluation. RESULTS: Alzheimer patients average 2.3 drugs compared with multi-infarct (4.3; P < 0.0001) and mixed (3.7; P = 0.002) patients, and their pattern of drug use was different when stratified by therapeutic categories and drug classes. Drug use increased with age, and women used significantly more drugs than men in all three diagnostic categories. Women with Alzheimer's disease used significantly more cardiovascular drugs than men with Alzheimer's disease (P < 0.05). The lower the mini-mental status score in patients with any dementia, the greater the mean number of central nervous system agents used. The higher the mini-mental status score in a patient with multi-infarct or mixed dementia, the greater the use of cardiovascular drugs. CONCLUSION: Drug use by Alzheimer patients was lower than in multi-infarct and mixed patients, primarily due to a lower prevalence of cardiovascular drugs.

Visual response latencies in temporal lobe structures as a function of stimulus information load.

In a monkey performing a visual delayed matching-to-sample task, units and visual evoked potentials (VEPs) were sampled from the inferior bank of the superior temporal sulcus (STS; Areas TEa and IPa), the hippocampus, and the presubiculum. VEP latencies indicated that flash information--signaling the imminent presentation of a color sample to be retained--reached the presubiculum and the hippocampus substantially earlier than the STS. In contrast, color sample VEP latencies did not differ between sites, arriving at all sites appreciably later than flash VEPs. Unit data indicated generally excitatory responses to both stimuli at all sites and net inhibition during the interstimulus interval separating flash from sample. As with VEPs, unit latencies to flash were shorter than to sample stimuli. The alerting flash data imply activation of the hippocampus occurring before activation of the STS cortex, whereas the coincident arrival of color sample information suggests temporal synchronization between these structures.

Pharmacokinetics, pharmacodynamics, and safety of metrifonate in patients with Alzheimer's disease.

Metrifonate is converted nonenzymatically to 2.2, dimethyl dichlorovinyl phosphate (DDVP), an inhibitor of acetylcholinesterase (AChE). This 21-day, randomized, double-blind, placebo-controlled trial of metrifonate in patients with Alzheimer's disease (n = 27) evaluated four doses, each administered orally once daily. All patients received a loading dose (LD) for 6 days followed by a maintenance dose (MD) for 15 days. The treatment groups were: panel 1, LD = 1.5 mg/kg (75-135 mg), MD = 0.25 mg/kg (12.5-25 mg); panel 2, LD = 2.5 mg/kg (125-225 mg), MD = 0.40 mg/kg (20-35 mg); panel 3, LD = 4.0 mg/kg (200-335 mg), MD = 0.65 mg/kg (30-60 mg); and panel 4, LD = 4.0 mg/kg (200-335 mg), MD = 1.0 mg/kg (50-90 mg). All metrifonate doses were well tolerated. Most adverse events were mild to moderate in intensity, gastrointestinal in nature, and transient. Mean area under the concentration-time curve (AUC) and maximum concentration (Cmax) for both metrifonate and DDVP increased in relation to dose. Metrifonate and DDVP had similar, largely dose-independent mean values for time to Cmax (tmax) and half-life (t1/2). There was little or no accumulation of either metrifonate or DDVP with long-term administration. After 21 days of treatment, mean percent erythrocyte AChE inhibition was 14%, 35%, 66%, 77%, and 82% for placebo and panels 1 through 4, respectively. Cognitive improvement was observed with the two highest metrifonate doses. These results reflect favorable safety and pharmacokinetic profiles for the use of metrifonate in the treatment of Alzheimer's disease.

The elgiloy microelectrode: fabrication techniques and characteristics.

A glass-insulated microelectrode made from elgiloy orthodontic wire, a stainless cobalt-chromium alloy containing 15% iron, was described by Suzuki and Azuma (1976). Here, we detail a set of modified electrode fabrication procedures, including techniques for hardening and etching the wire, specifying the size, geometry and exposure of the tip, and adjusting tip impedance over a wide range. Accurate insulation of the tip with molten solder glass produces microelectrodes suitable for extracellular recording from single or multiple units and simultaneous recording of evoked potentials. The finished electrode is tough enough to withstand multiple penetrations of the thickened, fibrous dura of the chronic monkey preparation. The iron content allows Prussian blue staining of marking lesions for histological verification of recording sites.

Seizures in patients receiving concomitant antimuscarinics and acetylcholinesterase inhibitor.

Seizures occurred in two patients with probable Alzheimer's disease who were receiving long-term treatment with metrifonate, an irreversible acetylcholinesterase inhibitor. In both patients seizures were associated with discontinuation of short-term agents with high antimuscarinic properties. Hence, abrupt discontinuation of antimuscarinics or anticholinergics with high antimuscarinic properties in patients receiving long-term acetylcholinesterase inhibition therapy may be associated with a reduction of seizure threshold. With increasing administration of acetylcholinesterase inhibitors for patients with Alzheimer's disease, practitioners should be aware of the potential for drug-drug interactions and other complications. In general, it is good medical practice to avoid concomitant administration with centrally acting anticholinergic agents.

Psychotropic drug use in relation to psychiatric symptoms in community-living persons with Alzheimer's disease.

We attempted to determine the relationship between psychiatric symptoms and psychotropic drug use in persons with Alzheimer's disease based on a multicenter patient registry of 671 community-living persons diagnosed with the disease by published criteria. Logistic regression was performed to determine which symptoms were associated psychotropic use after controlling for age, sex, and Mini-Mental Status Examination (MMSE) score. At least one psychotropic drug was reported by 31% of patients, and 66% had at least one psychiatric symptom. Antipsychotics were associated with a lower MMSE score (odds ratio = 0.92, 95% confidence interval 0.88-0.97), emotional lability (OR = 4.52, 95% CI 1.69-11.94), and hallucinations (OR = 6.54, 95% CI 2.99-14.26). Antidepressants were associated with depressive symptoms (OR = 5.8, 95% CI 2.61-13.46), and benzodiazepines with a lower MMSE score (OR = 0.93, 95% CI 0.90-0.97). Community-living persons with Alzheimer's disease are frequently prescribed psychotropic drugs; however, more than 50% of patients with a psychiatric symptom did not report taking one of these agents. This suggests that alternative therapies and no treatment are also prevalent.

Measuring cognition in advanced Alzheimer's disease for clinical trials.

Measurement of cognitive dysfunction and treatment response in the early stages of Alzheimer's disease (AD) has used such scales as the Mini-Mental State Examination (MMSE) and the AD Assessment Scale (ADAS). With the exception of clinical rating scales, however, there are only a few objective measures of cognition for tracking progression in advanced AD. Given renewed interest in potential therapies for advanced AD, objective measures of cognition are important for the adequate evaluation of change due to AD progression or therapy. Several cognitive measures for advanced AD are reviewed. One measure, the Severe Impairment Battery (SIB) is reviewed in detail. Preliminary analyses from a trial of memantine show significant change on the SIB in memory (p < 0.001) and visuospatial functions (p < 0.02) over six-months with a trend for language and praxis. Data from a donepezil trial also highlight the importance of accurate assessment in advanced AD.