Codon 129 polymorphism of prion protein gene in sporadic Alzheimer's disease.

Codon 129 polymorphism of the prion protein gene represents a major genetic risk factor for Creutzfeldt-Jakob disease (CJD). Both CJD and Alzheimer's disease (AD) are brain amyloidoses and it would be possible that codon 129 polymorphism plays a role in the susceptibility to AD. In order to investigate this polymorphism in AD the distribution of polymorphic codon 129 of the PRNP gene in 194 probable AD and 124 controls selected in Italy and 109 neuropathologically verified AD and 58 matched controls recruited in the USA was studied. No significant association was found for the PRNP polymorphism in AD compared to controls either in Probable or in Definite AD series even after stratification for APOE polymorphism. This study does not support a role of PRNP polymorphism as a susceptibility factor for AD.

Brain structural alterations before mild cognitive impairment.

OBJECTIVE: To determine whether alterations of brain structure in normal aged individuals precede the development of mild cognitive impairment (MCI) or Alzheimer disease (AD). BACKGROUND: Persons with MCI and AD demonstrate cortical volume losses vs asymptomatic aged individuals, particularly in the hippocampus, amygdala, and entorhinal cortex. It is unknown whether these losses or other volumetric changes are present, and to what degree, in cognitively normal individuals before the clinical diagnosis of MCI. METHODS: Structural MRI was performed on a cross-section of 136 longitudinally examined normal aged subjects. All subjects were cognitively normal at the time of their scan, but 23 later developed MCI, and 9 of these 23 went on to an AD diagnosis. Extracted volumes from voxel-based morphometric analysis were combined with clinical data to compare the 23 subjects who eventually developed MCI to 113 subjects who remained cognitively normal over an average follow-up of 5.4 years. RESULTS: Initially normal subjects who eventually developed MCI demonstrated decreased gray matter volumes in the anteromedial temporal lobes bilaterally and left angular gyrus while still cognitively normal. CONCLUSION: Structural brain changes in anatomic areas involved in higher cognitive processes precede clinical signs and symptoms in longitudinally followed normal subjects destined to develop mild cognitive impairment.

Alzheimer disease risk associated with APOE4 is modified by STH gene polymorphism.

The association of the STH gene polymorphism with Alzheimer disease (AD) is debated. In the analysis of two genetically and diagnostically distinct groups of Alzheimer patients from the USA and Italy, the authors did not find an association with the STH polymorphism. However, the APOE-4-associated risk of AD greatly increased if the STH-G allele was also present. The STH-G allele appears to be a risk modifier for AD.

Brain donation in normal aging: procedures, motivations, and donor characteristics from the Biologically Resilient Adults in Neurological Studies (BRAiNS) Project.

Medical autopsy rates have been declining for the past several decades, yet, for more than a decade, the University of Kentucky Alzheimer's Disease Research Center has been recruiting healthy older adults into a program involving annual assessments of mental status, biannual medical and neurological exams, and prearranged postmortem brain examination. The present article focuses on the characteristics of these donors to explore potential factors that contribute to the decision to donate. The motivations of this unique group of individuals could serve to inform physicians who request autopsies for medical and research purposes. Over 500 volunteers who have enrolled in this program are well-educated community-dwelling adults over the age of 60. They are generally motivated by personal experiences with Alzheimer's disease, referral by someone already enrolled, and a desire to promote scientific knowledge. These volunteers' reasons suggest that rates of tissue donation or autopsy for basic research and investigations of causes of death might be increased by providing individuals and families with information concerning the medical and scientific value of the procedure. Within research settings, encouraging participant recruitment of friends or family members would likely increase tissue acquisition rates.

"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.

Critical decline in fine motor hand movements in human aging.

BACKGROUND: Slowing of motor movements in human aging is a well-known occurrence, but its biologic basis is poorly understood. Reliable quantitation may refine observations of this phenomenon to better aid research on this entity. METHODS: A panel equipped with timing sensors under computer control was used to measure upper extremity movement times in two groups of healthy individuals: adults younger than 60 years of age (n = 56; range, 18-58 years) and adults older than 60 years of age (n = 38; range, 61-94 years). RESULTS: Fine motor performance was better in the dominant hand (p = 0.0007) regardless of age. Adult and aged groups differed on two basic timing measures, which reflect coarse motor and fine motor performance (p < 0.0001). There were no gender differences on either measure. There was a strong effect of task difficulty with age on coarse motor (p < 0.01) and fine motor (p < 0.0001) measures. The fine motor measure of hand performance in healthy individuals correlated in a nonlinear fashion with age for more difficult tasks (r2 = 0.63) but showed a simple linear relation for less-demanding tasks (r2 = 0.5). CONCLUSION: This technique sensitively detects age-related motor performance decline in humans. There may be a critical period in late midlife when fine motor performance decline either begins or abruptly worsens.

Alzheimer neuropathologic alterations in aged cognitively normal subjects.

The histopathologic changes distinguishing early Alzheimer disease (AD) from normal or pathologic aging are not clearly defined. This report describes the autopsy findings of 59 elderly, well-educated, volunteers. They were examined longitudinally with mental status testing, some for up to 8 years, as part of our normal aging study. This study reveals that (1) the brains of many subjects who did not show cognitive impairment on neuropsychologic testing contain abundant senile plaques (SP) and/or neurofibrillary tangles (NFT); (2) 29 subjects met Khachaturian criteria for AD, 15 met CERAD and 7 met National Institute on Aging-Reagan Institute guidelines; (3) Braak and Braak staging method included 9 in stage IV subjects, 4 in stage V, and 1 in stage VI; (4) there was a progression of NFT from entorhinal cortex to hippocampus and amygdala as a function of age; (5) 2 subjects met criteria for a diagnosis of dementia with Lewy bodies but were not demented; (6) cerebral amyloid angiopathy was present in leptomeningeal vessels in 75% of subjects and in parenchymal vessels in 62% of subjects; (7) only 10 of 59 subjects (17%) had no or few degenerative brain changes. Our study demonstrates that the brains of a large percentage of cognitively normal, relatively well-educated individuals contain numerous degenerative changes and only a small percentage are relatively free of these changes.

Alzheimer's disease, dental amalgam and mercury.

BACKGROUND: Mercury, or Hg, is a neurotoxin that has been speculated to play a role in the pathogenesis of Alzheimer's disease, or AD. Dental amalgam releases low levels of Hg vapor and is a potential source of Hg for a large segment of the adult population. METHODS: The authors studied 68 subjects with AD and 33 control subjects without AD to determine Hg levels in multiple brain regions at autopsy and to ascertain the subjects' dental amalgam status and history. The subjects were from central Kentucky and Elm Grove, Wis. The authors conducted dental amalgam assessments during the lives of the majority of subjects and in some subjects at the time of autopsy only. The authors also determined three dental amalgam index scores--Event (placement, repair or removal of amalgam), Location and Time In Mouth--in addition to the numbers of and surface area of occlusal amalgam restorations. The authors determined Hg levels in multiple brain regions and performed full neuropathologic evaluations to confirm the normal status of the brain or the presence of AD. RESULTS: The authors found no significant association of AD with the number, surface area or history of having dental amalgam restorations. They also found no statistically significant differences in brain Hg level between subjects with AD and control subjects. CONCLUSIONS: Hg in dental amalgam restorations does not appear to be a neurotoxic factor in the pathogenesis of AD. The authors found that brain Hg levels are not associated with dental amalgam, either from existing amalgam restorations or according to subjects' dental amalgam restoration history. CLINICAL IMPLICATIONS: Dental amalgam restorations, regardless of number, occlusal surface area or time, do not relate to brain Hg levels.

Trace elements in Alzheimer's disease pituitary glands.

Levels of mercury (Hg), selenium (Se), iron (Fe), rubidium (Rb), and zinc (Zn) were measured in the pituitary gland to assess the possibility of a potential difference in the environmental Hg exposure of Alzheimer's disease (AD) patients and control subjects and levels of other elements of interest in AD. The pituitary gland has been established as a good predictor of environmental Hg exposure. Neutron activation analysis was utilized to determine levels of these elements in pituitary glands of 43 AD subjects and 15 control subjects. No significant differences were observed between the AD and control means for these five elements. The sole significant Pearson's correlation involving Hg was the established correlation with Se, indicative of the detoxification of Hg. The absence of a statistical difference between AD and control pituitary gland Hg levels suggests AD patients do not have an excessive environmental exposure to Hg compared to controls.

N-terminal heterogeneity of parenchymal and cerebrovascular Abeta deposits.

The goals of this study were twofold: to determine whether species differences in Abeta N-terminal heterogeneity explain the absence of neuritic plaques in the aged dog and aged bear in contrast to the human; and to compare Abeta N-terminal isoforms in parenchymal vs cerebrovascular Abeta (CVA) deposits in each of the species, and in individuals with Alzheimer disease (AD) vs nondemented individuals. N-terminal heterogeneity can affect the aggregation, toxicity, and stability of Abeta. The human, polar bear, and dog brain share an identical Abeta amino acid sequence. Tissues were immunostained using affinity-purified polyclonal antibodies specific for the L-aspartate residue of Abeta at position one (AbetaN1[D]), D-aspartate at N1 (AbetaN1[rD]), and pyroglutamate at N3 (AbetaN3[pE]) and p3, a peptide beginning with leucine at N17 (AbetaN17[L]). The results demonstrate that each Abeta N-terminal isoform can be present in diffuse plaques and CVA deposits in AD brain, nondemented human, and the examined aged animal models. Though each Abeta N-terminal isoform was present in diffuse plaques, the average amyloid burden of each isoform was highest in AD vs polar bear and dog (beagle) brain. Moreover, the ratio of AbetaN3(pE) (an isoform that is resistant to degradation by most aminopeptidases) vs AbetaN17(L)-x (the potentially nonamyloidogenic p3 fragment) was greatest in the human brain when compared with aged dog or polar bear. Neuritic plaques in AD brain typically immunostained with antibodies against AbetaN1(D) and AbetaN3(pE), but not AbetaN17(L) or AbetaN1(rD). Neuritic deposits in nondemented individuals with atherosclerotic and vascular hypertensive changes could be identified with AbetaN1(D), AbetaN3(pE), and AbetaN1(rD). The presence of AbetaN1(rD) in neuritic plaques in nondemented individuals with atherosclerosis or hypertension, but not in AD, suggests a different evolution of the plaques in the two conditions. AbetaN1(rD) was usually absent in human CVA, except in AD cases with atherosclerotic and vascular hypertensive changes. Together, the results demonstrate that diffuse plaques, neuritic plaques, and CVA deposits are each associated with distinct profiles of Abeta N-terminal isoforms.

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.

Providing dental care for patients diagnosed with Alzheimer's disease.

Alzheimer's disease is the most common dementing illness affecting over 4 million Americans. As the population ages, dentists and other health care providers will be faced with the daunting task of managing an increasing number of people with this disease. Currently, there are no definitive medications to treat this disease, although there are a number of recent drugs which may help to alleviate some symptoms. This article reviews the current medical treatment and the dental concerns which face the dentist, patient, and family. Suggestions for dental management are given along with practical recommendations for caregivers.

Carboxy terminal of beta-amyloid deposits in aged human, canine, and polar bear brains.

Immunocytochemistry, using antibodies specific for different carboxy termini of beta-amyloid. A beta 40 and A beta 42(43), was used to compare beta-amyloid deposits in aged animal models to nondemented and demented Alzheimer's disease human cases. Aged beagle dogs exhibit diffuse plaques in the absence of neurofibrillary pathology and the aged polar bear brains contain diffuse plaques and PHF-1-positive neurofibrillary tangles. The brains of nondemented human subjects displayed abundant diffuse plaques, whereas the AD cases had both diffuse and mature (cored) neuritic plaques. Diffuse plaques were positively immunostained with an antibody against A beta 42(43) in all examined species, whereas A beta 40 immunopositive mature plaques were observed only in the human brain. Anti-A beta 40 strongly immunolabeled cerebrovascular beta-amyloid deposits in each of the species examined, although some deposits in the polar bear brain were preferentially labeled with anti-A beta 42(43). beta-amyloid deposition was evident in the outer molecular layer of the dentate gyrus in the aged dog, polar bear, and human. Within this layer, A beta 42 was present as diffuse deposits, although these deposits were morphologically distinct in each of the examined animal models. In dogs, A beta 42 was cloud-like in nature; the polar bear demonstrated a more aggregated type of deposition, and the nondemented human displayed well-defined deposits. Alzheimer's disease cases were most frequently marked by neuritic plaques in this region. Taken together, the data indicate that beta-amyloid deposition in aged mammals is similar to the earliest stages observed in human brain. In each species, A beta 42(43) is the initially deposited isoform in diffuse plaques.

Linguistic ability in early life and cognitive function and Alzheimer's disease in late life. Findings from the Nun Study.

OBJECTIVE: To determine if linguistic ability in early life is associated with cognitive function and Alzheimer's disease in late life. DESIGN: Two measures of linguistic ability in early life, idea density and grammatical complexity, were derived from autobiographies written at a mean age of 22 years. Approximately 58 years later, the women who wrote these autobiographies participated in an assessment of cognitive function, and those who subsequently died were evaluated neuropathologically. SETTING: Convents in the United States participating in the Nun Study; primarily convents in the Milwaukee, Wis, area. PARTICIPANTS: Cognitive function was investigated in 93 participants who were aged 75 to 95 years at the time of their assessments, and Alzheimer's disease was investigated in the 14 participants who died at 79 to 96 years of age. MAIN OUTCOME MEASURES: Seven neuropsychological tests and neuropathologically confirmed Alzheimer's disease. RESULTS: Low idea density and low grammatical complexity in autobiographies written in early life were associated with low cognitive test scores in late life. Low idea density in early life had stronger and more consistent associations with poor cognitive function than did low grammatical complexity. Among the 14 sisters who died, neuropathologically confirmed Alzheimer's disease was present in all of those with low idea density in early life and in none of those with high idea density. CONCLUSIONS: Low linguistic ability in early life was a strong predictor of poor cognitive function and Alzheimer's disease in late life.

Self report on sleep symptoms in older adults: correlates of daytime sleepiness and health.

Sleep problems in the healthy elderly were studied in 628 community-dwelling older adults. Self-report of daytime sleepiness in this group was evaluated. Self-reported snoring was significantly associated with reports of daytime sleepiness (p < 0.001), and reported health showed significant associations with age group (p < 0.001), reports of breathing problems (p < 0.001), and reports of excessive daytime sleepiness (p < 0.01). The data strongly support the impact of sleep-related factors on self-perceptions of health in community dwelling older adults. Even as a subjective self-report measure, snoring readily predicts self-reported problems with daytime sleepiness.

Dental amalgam and cognitive function in older women: findings from the Nun Study.

The authors determined the number and surface area of occlusal dental amalgams in a group of 129 Roman Catholic sisters who were 75 to 102 years of age. Findings from this study of women with relatively homogeneous adult lifestyles and environments suggest that existing amalgams are not associated with lower performance on eight different tests of cognitive function.

Frontal lobe phosphorus metabolism and neuropsychological function in aging and in Alzheimer's disease.

31P Magnetic resonance spectroscopy of the frontal lobe was performed in 17 patients with Alzheimer's disease (AD), 8 elderly controls (EC), and 17 young controls (YC). The phosphocreatine/inorganic phosphate (PCr/Pi) ratio in AD (2.32 +/- 0.26 SD) was significantly lower than in EC (2.65 +/- 0.41). In AD patients, a correlation was observed between the PCr/Pi ratio and the dementia rating scale (r = -0.50, p = 0.04). A significant positive correlation between PCr/Pi ratio and age was observed in both AD (r = 0.67, p = 0.003) and YC (r = 0.63, p = 0.006) groups, however, suggesting caution in interpretation of this ratio in AD. We did not find differences between AD, EC, or YC in any other spectroscopic measure. A significant sex difference in the phosphomonoester/phosphodiester ratio (PME/PDE) ratio was observed in AD brain. Females had a lower PME/PDE ratio than males.

Laboratory values in fit aging individuals--sexagenarians through centenarians.

We determined approximately 15,000 laboratory values in 236 individuals between the ages of 60 and 90 y, 22 individuals between 90 and 99 y, and 69 individuals greater than or equal to 100 y, and compared these with values in young adults. We tested 47 different analytes in the 60-90-y group and 93 analytes in the greater than or equal to 90-y group. Na, K, Cl, and CO2 values were either identical or showed minimal change with age; pH decreased slightly. Differences in Ca values were only minor, but ionized Ca increased slightly. Phosphate decreased in men, but changed only minimally in women; parathyroid hormone increased with age. Increases with age were also observed for glucose, insulin, and C-peptide. Among the enzymes, alkaline phosphatase increased in women, but in men only greater than 90 y; gamma-glutamyltransferase increased in both sexes. Creatine kinase (CK) decreased slightly in individuals greater than 70 y and markedly in those greater than 90 y of age, whereas CK-MB decreased markedly greater than 70 y, reaching the detection limit in individuals greater than 90 y. Lactate dehydrogenase isoenzyme 5 decreased slightly with age. Urea nitrogen increased gradually with age, but creatinine increased only in individuals greater than or equal to 90 y. The increase in urea is not paralleled by a loss of protein in urine, suggesting that the possible cause of azotemia may not always be renal pathology. Urate increased in women but not in men. Liver function, as measured by total bilirubin and liver enzymes, was exceedingly well maintained. Concentrations of most proteins show little change, except for slight decreases in prealbumin, albumin, and transferrin, proteins used as an index of nutritional status. IgA values increased, IgG ranges were wider, IgM and IgD decreased, and the range for IgE was narrower than in young adults. Cholesterol, high-density lipoprotein cholesterol, and triglyceride values increased with age, but decreased in individuals greater than or equal to 90 y. Among the trace elements, magnesium changed little, zinc and lead decreased, and copper values increased with age. Total triiodothyronine and thyroxine decreased, with concomitant increases in thyroid-stimulating hormone. More individuals had increased microsomal antibodies and thyroglobulin titers in the aging population than in the young. In men, the free, percent free, bioactive, and total testosterone values decreased, but luteinizing hormone (LH) and follicle-stimulating hormone (FSH) values increased. In women, estrone and estradiol values decreased, with concomitant increases in LH and FSH. Androstenedione and progesterone decreased in both sexes.(ABSTRACT TRUNCATED AT 400 WORDS)

Self-perceived information needs and concerns of elderly persons.

The research was intended to identify the dimensions underlying self-perceived information needs and concerns of an elderly population. The spontaneously mentioned needs and concerns expressed in 271 letters from a sample of the population were extracted and a multidimensional scaling procedure was used to represent the 58 most frequently mentioned items in configurations of varying dimensionality. To interpret the multidimensional spaces, another sample of 176 elderly subjects was asked to rate the 58 concerns on eight properties. These ratings were then regressed onto the multidimensional configurations. The results indicate that the most frequently mentioned information needs and concerns of elderly persons can be parsimoniously understood in terms of three underlying dimensions: (1) Improving the Quality of Life vs Securing the Necessities of Life, (2) Health-related vs Not Health-related, and (3) Individual vs Societal Responsibility.

Variation in Initial Procedures and the Stability of Dimensions Extracted from Free Response Data.

The purpose of the research was to examine the stability of dimensions extracted from a body of free response data under conditions of variation in the initial data reduction procedures. Data consisted of over 1500 expressions of concern and questions raised by an elderly population. Complete sequences of analytic steps were conducted on the data by two groups of experimenters working independently. These sequences included determining representative units to be scaled, developing instructions for obtaining proximity measures, recruiting subjects, and administering the sorting tasks necessary to obtain proximity measures. In spite of dramatic differences in procedures at each of these steps, the structures of the resulting multidimensional configurations obtained by the two groups were identical. Selected, independently measured properties were used to interpret the configurations. In both cases, a three dimensional solution defined by the properties Health Related, Quality of Lire, and Individual versus Societal Responsibility appeared optimal.