Conversion from mild cognitive impairment to Alzheimer's disease is predicted by sources and coherence of brain electroencephalography rhythms.

Objective. Can quantitative electroencephalography (EEG) predict the conversion from mild cognitive impairment (MCI) to Alzheimer's disease (AD)? Methods. Sixty-nine subjects fulfilling criteria for MCI were enrolled; cortical connectivity (spectral coherence) and (low resolution brain electromagnetic tomography) sources of EEG rhythms (delta=2-4 Hz; theta=4-8 Hz; alpha 1=8-10.5 Hz; alpha 2=10.5-13 Hz: beta 1=13-20 Hz; beta 2=20-30 Hz; and gamma=30-40) were evaluated at baseline (time of MCI diagnosis) and follow up (about 14 months later). At follow-up, 45 subjects were still MCI (MCI Stable) and 24 subjects were converted to AD (MCI Converted). Results. At baseline, fronto-parietal midline coherence as well as delta (temporal), theta (parietal, occipital and temporal), and alpha 1 (central, parietal, occipital, temporal, limbic) sources were stronger in MCI Converted than stable subjects (P<0.05). Cox regression modeling showed low midline coherence and weak temporal source associated with 10% annual rate AD conversion, while this rate increased up to 40% and 60% when strong temporal delta source and high midline gamma coherence were observed respectively. Interpretation. Low-cost and diffuse computerized EEG techniques are able to statistically predict MCI to AD conversion.

Neuropathology in controls and demented subjects from the Baltimore Longitudinal Study of Aging.

To establish correlations among cognitive states and neuropathology, we have examined 22 subjects (69-97 years of age) from the Baltimore Longitudinal Study of Aging (BLSA), of whom 15 had normal and stable cognitive performances and seven had dementia of variable severity. In the majority of normal subjects, few or no beta-amyloid (A beta) deposits or senile plaques (SP) were present in the neocortex, but neurofibrillary tangles (NFT) were consistently found in CA1 of hippocampus and layer II of entorhinal cortex. In two (15%) normal individuals, the densities of SP were consistent with the diagnosis of possible Alzheimer's disease (AD). We speculate that these cases with normal cognitive states and abundant neocortical SP may represent preclinical AD. We conclude that the neocortex of a majority of cognitively intact individuals can remain free of A beta deposits or SP, even into the tenth decade of life.

Cognitive decline strongly correlates with cortical atrophy in Alzheimer's dementia.

Alzheimer's disease (AD) is characterized by progressive dementia and distinct neuropathology at autopsy. In order to test the relationship between dementia severity and loss of brain volumes, we prospectively documented the neurological/medical health of 26 male and 26 female controls and AD cases, and evaluated a subset of controls and AD cases using the Mini Mental State Examination (MMSE). At autopsy, Consortium to Establish a Registry for Alzheimer's Disease (CERAD) criteria confirmed diagnoses in 33 AD cases and 19 controls, and using unbiased stereology we quantified total volumes of cortical gray matter, subcortical grey matter including white matter, and forebrain. For ages of death between 50 to 100 years, controls showed minor cortical atrophy in the absence of cognitive decline. Cortical atrophy in AD cases was 20 to 25% greater than that in controls; AD patients dying at older ages showed less severe cortical atrophy than those dying at younger ages. Across all AD cases there was a strong correlation between cognitive performance on the Mini Mental State Examination and cortical volume loss. These findings confirm fundamental differences in the temporal patterns of cortical volume loss in aging and AD, and support cortical degeneration as the primary basis for cognitive decline in AD.

Apolipoprotein E genotype and rate of decline in probable Alzheimer's disease.

BACKGROUND: The risk of Alzheimer's disease (AD) appears to increase, and the age at onset to decrease, with the number of epsilon 4 alleles. If this relationship is due to increased rate of pathophysiological change, the presence of epsilon 4 would be expected to influence progression of disease, predicting a more rapid decline with increasing number of epsilon 4 alleles. OBJECTIVE: To determine if the frequency of the epsilon 4 allele of the apolipoprotein E (ApoE) gene affects the rate of clinical progression in AD. SETTING: Alzheimer's Disease Research Center. SUBJECTS: One hundred one subjects meeting criteria of the National Institute of Neurological Disorders and Stroke for probable AD or of the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) for definite AD; 78 of these subjects met the additional criterion of having a Mini-Mental State Examination score of at least 10 for analysis of rate of decline. MEASUREMENTS: The subjects' characteristics and neuropsychological battery, including the Mini-Mental state Examination, Spatial Delayed Recognition Span, Boston Naming Test, Category Fluency Test, and the Physical Capacity Subscale of the Psychogeriatric Dependency Rating Scale. DESIGN: The subjects were followed up longitudinally for approximately one decade. Medical histories were taken and physical and neurologic examinations and neuropsychological testing were performed every 6 months. Three and a half years of data were available for most tests and 5.5 for the Psychogeriatric Dependency Rating Scale; thereafter, patients were no longer testable. A general linear model analysis of variance was used to assess the influence of ApoE on demographic characteristics and baseline performances on neuropsychological measures. A random-effects regression model was used to predict change over time associated with presence of epsilon 4 on clinical and cognitive measures. RESULTS: The age at onset was greatest for the epsilon 4-heterozygous subjects and least for the epsilon 4-negative subjects. The heterozygous subjects declined more rapidly on the Mini-Mental State Examination and the Category Fluency Test than the subjects without the epsilon 4 allele or with epsilon homozygosity. The homozygous subjects declined faster on only one subscale: the Physical Capacity subscale of the Psychogeriatric Dependency Rating Scale. Covarying for age at onset did not affect the results. CONCLUSIONS: The ApoE genotype does not strongly influence the rate of decline in AD, implying that epsilon 4 might predispose to the development of the disease without accelerating its pathogenesis or progression. The effects of epsilon 4 on both age at onset and rate of decline need to be further investigated.

APOE genotype and survival in men and women with Alzheimer's disease.

BACKGROUND: The epsilon 4 allele of the APOE gene (APOE) is more frequent in patients with AD than in the general population, but studies are inconclusive as to whether it affects rate of progression or survival. Because survival in AD is generally longer in women than in men, the authors investigated whether APOE affects 10-year survival equally in men and women. METHODS: APOE testing was performed on 125 patients with probable AD enrolled in the Johns Hopkins AD Research Center between November 1984 and March 1987. The 39 men and 86 women were followed at 6-month intervals until censoring (by death or withdrawal from the study) or March 1997. Patients were dichotomized into those with and those without at least one epsilon 4 allele. For each sex, a Cox proportional hazards regression, allowing for delayed entry and covarying for age at onset, was used to examine the effect of epsilon 4 on survival. RESULTS: All patients who died during the study period and had autopsy (n = 92) were found to have definite AD. Average survival from disease onset did not differ by sex (12.1 years in men; 12.3 years in women). In neither sex were differences found between epsilon 4-positive and epsilon 4-negative subgroups in education, duration of AD at entry, or severity of dementia. However, in both sexes the epsilon 4-positive subgroup was approximately 3 years older at onset of AD and at entry to the study than the epsilon 4-negative subgroup. Adjusting for age at onset, the presence of an epsilon 4 allele significantly increased the relative risk of death only for men (RR = 2.69; 95% CI = 1.23 to 5.87). CONCLUSIONS: In this sample of mostly white, well-educated research participants with AD, the APOE epsilon 4 allele was associated with shorter survival in men but not in women.

Elevation of serum copper levels in Alzheimer's disease.

OBJECTIVE: To determine whether serum trace metals and oxidative species are related to abnormal cognition in AD. METHODS: The authors studied serum peroxides, copper, iron, transferrin, and antioxidant capacity in 79 patients with AD (mean age 74.3 years; 25 men, 54 women) and in 76 cognitively normal individuals (mean age 70.1 years; 33 men, 43 women). The relation of these oxidative and trace metals to APOE epsilon4 allele frequency, neuropsychological performance, and cerebrovascular or atrophic burden, as estimated by brain MRI and ultrasonography of cerebral vessels, was evaluated. RESULTS: Copper level was higher (p < 0.001) in subjects with AD than control subjects (specificity = 95%, sensitivity = 60%) with a cutoff serum level of 16 micro mol/L (1.02 mg/L). An increase of 1 micro mol/L in serum copper accounted for 80% of the risk of having AD and correlated with poor neuropsychological performance and medial temporal lobe atrophy (p < 0.03). Antioxidant capacity decreased and correlated with medial temporal lobe atrophy (p < 0.009) and with APOE epsilon4 allele (p = 0.004). CONCLUSIONS: Copper may play a role in neurodegenerative processes in AD, and serum copper measurement may prove to be a peripheral diagnostic marker for AD.

Analysis of the CCKB receptor antagonism of virginiamycin in guinea-pig ileum longitudinal myenteric plexus.

1. Virginiamycin, a macrolide reported to bind selectively to CCKB/gastrin receptors has been studied in a functional test, namely cholecystokinin-induced contraction of guinea-pig ileum myenteric plexus (LMMP). 2. Virginiamycin (1-10 microM) antagonized the selective CCKB agonist cholecystokinin tetrapeptide (CCK-4). The antagonism appeared not to be competitive as the highest concentration (10 microM) caused a reduction of its maximal effect. An apparent pA2 of 6.64 +/- 0.06 (s.e.) could be estimated if this depression was ignored. The selective CCKB antagonist, L-365,260 (0.01-0.3 microM) antagonized competitively the CCK-4 induced contraction and a pKB of 8.60 +/- 0.16 (s.e.) was estimated. 3. The combined dose-ratio analysis for virginiamycin, tested at 3 and 10 microM in association with 0.03 and 0.1 microM L-365,260, respectively, resulted in observed log dose-ratios of 1.39 and 1.53. That was consistent with both antagonists acting on the same receptor in LMMP. 4. These data, represent the first evidence of the antagonism of virginiamycin in a functional assay and they support the hypothesis of homogeneity between CCKB receptors in the CNS and in peripheral tissues.

Receptor binding characteristics of the novel NMDA receptor glycine site antagonist [3H]GV150526A in rat cerebral cortical membranes.

Binding of the glycine site antagonist 3-[2-(Phenylamino-carbonyl)ethenyl]-4,6-dichloro-indole-2-carboxylic acid sodium salt ([3H]GV150526A) was characterised in rat cerebral cortical membranes. Saturation experiments indicated the existence of a high affinity binding site, with a pK(d) value of 9.08 (K(d)=0. 8 nM) and a B(max) of 3.4 pmol/mg of protein. A strong linear correlation was observed between the displacement potencies for [3H]GV150526A and [3H]glycine of 13 glycine site ligands (r=0.991). The association kinetics of [3H]GV150526A binding was monophasic, with a k(on) value of 0.047 (nM)(-1) min(-1). Dissociation was induced by the addition of an excess of glycine, GV150526A, or 5,7-dichlorokynurenic acid (DCKA), another glycine antagonist. With GV150526A and DCKA, the dissociation curves presented similar k(off) values (0.068 and 0.069 min(-1), respectively), as expected from ligands binding to the same site. Conversely, a significantly lower k(off) value (0.027 min(-1)) was found with glycine. Although these data may suggest that glycine agonists and antagonists bind to discrete sites with an allosteric linkage (rather than interacting competitively), the reason for this difference remains to be elucidated. It is concluded that [3H]GV150526A can be considered a new valuable tool to further investigate the properties of the glycine site of the NMDA receptor.

On the predictability of violent behavior: considerations and guidelines.

Following a semantic discussion of dangerousness, and having established its dynamic concept, the authors define the prediction of dangerous behavior as the anticipation of an antisocial act towards others. The present-day dilemma of predicting dangerous behavior is discussed. An extensive review of sociological and psychiatric studies is presented. Further, the authors stress the vital importance of predicting violent behavior in view of statistical data concerning rampant violent crime in the United States. They encourage more cooperation between psychiatric experts and the judicial system in view of the common social problem all are faced with. Better diagnostic procedures and more logically deductive factual expert reports are hoped for. The authors postulate that prediction is strictly connected with the possible prevention of dangerous behavior and the continuation of a civilized, secure society.

'Free' copper in serum of Alzheimer's disease patients correlates with markers of liver function.

Non-ceruloplasmin bound copper ('free') seems slightly elevated in Alzheimer's disease (AD) patients. To test the hypothesis of a correlation between 'free' copper and liver function in AD. We evaluated 51 AD patients and 53 controls through typical tests for chronic liver disease (AST, ALT, gamma-GT, Albumin, prothrombin time - PT-, bilirubins), along with copper, ceruloplasmin, iron, cholesterol in the serum and apolipoprotein E epsilon4 (APOE4) genotype. Absolute serum copper and 'free' copper were higher, albumin was lower and PT longer in AD patients than in controls. 'Free' copper correlated negatively with markers of liver function, in that albumin and albumin/PT ratio (r = -0.43, p = 0.004), and positively with direct bilirubin. Copper and 'free' copper were higher in the APOE4 carriers. These results suggest that abnormalities in copper metabolism might have an effect on liver function in AD.

Excess of nonceruloplasmin serum copper in AD correlates with MMSE, CSF [beta]-amyloid, and h-tau.

OBJECTIVE: To assess whether serum copper in Alzheimer disease (AD) correlates with cognitive scores, beta-amyloid, and other CSF markers of neurodegeneration. METHODS: The authors studied copper, ceruloplasmin, total peroxide, and antioxidants levels (TRAP) in serum; beta-amyloid in plasma; and copper, beta-amyloid, h-tau, and P-tau in the CSF of 28 patients with AD and 25 healthy controls, in relation to clinical status. RESULTS: Serum copper (p < 0.0001), peroxides (p = 0.002), a copper fraction unexplained by ceruloplasmin (p < 0.0001), and CSF h-tau (p = 0.001) were increased in AD, whereas serum TRAP (p = 0.03) and CSF beta-amyloid were decreased (p < 0.0001). Plasma beta-amyloid increased with age in healthy controls (r = 0.6; p = 0.05). CSF markers of AD correlated with serum copper variables. CSF copper was partially dependent on the serum copper fraction unexplained by ceruloplasmin (t = 2.2, p = 0.04). CSF beta-amyloid seemed to be related to serum copper (r = -0.46; p = 0.002). Mini-Mental Status Examination scores correlated positively with beta-amyloid (r = 0.46, p = 0.002) and inversely with copper unexplained by ceruloplasmin (r = -0.45, p = 0.003). CONCLUSIONS: The authors' results confirm the existence of changes in copper component distribution, particularly the copper fraction unexplained by ceruloplasmin and support the hypothesis of a beta-amyloid and copper connection in Alzheimer disease.

Excess of serum copper not related to ceruloplasmin in Alzheimer disease.

OBJECTIVE: To assess the role of serum copper in relation to ceruloplasmin and other peripheral markers of inflammation in Alzheimer disease (AD). METHODS: The authors studied serum levels of copper, ceruloplasmin, and transferrin, as well as total peroxides, antioxidants, and other peripheral markers of inflammation in 47 patients with AD, 24 patients with vascular dementia (VaD), and 44 healthy controls. Biochemical variables were related to the patients' and controls' clinical status. RESULTS: The authors found that copper (p < 0.001), peroxides (p = 0.026), and ceruloplasmin (p = 0.052) were increased and TRAP was decreased (p = 0.006) in patients with AD, while no other markers of inflammation were altered. The calculation of the ratio between copper and ceruloplasmin suggested the presence in the serum of AD patients, but not of VaD or normal controls, of a large pool of non-ceruloplasmin-bound copper. CONCLUSIONS: Changes in the distribution of the serum copper components, consisting of an increase of a copper fraction not explained by ceruloplasmin, seem to be characteristic of Alzheimer disease and may be implicated in the pathogenesis of the disease.

Cognitive problems in the elderly.

We have summarized the literature on cognitive changes in normal aging. The concepts of normal aging, age-associated memory impairment, and their possible continuum with dementia are discussed. Epidemiologic, genetic, radiological, as well as neuropsychological and endocrine contributions to the understanding of cognition in the elderly, are reviewed.

Evidence for two cholecystokinin receptors mediating the contraction of the guinea pig isolated ileum longitudinal muscle myenteric plexus.

In guinea pig isolated ileum longitudinal muscle myenteric plexus, cholecystokinin octapeptide (CCK-8S) produced a rapid (phasic) contraction followed by a slower tonic phase. The tetrapeptide derivative CCK-4 and pentagastrin elicited only the phasic response up to 10(-6) M, whereas the tonic phase was also apparent at higher concentrations. The rank order of potency for the effect of agonists on the tonic and phasic responses were CCK-8S much greater than gastrin greater than CCK-8US congruent to pentagastrin greater than CCK-4 and CCK-8S greater than gastrin congruent to pentagastrin greater than CCK-4 greater than CCK-8US, respectively. Phasic responses of CCK-8S and CCK-4 were sensitive to atropine, whereas the tonic response could be completely abolished with the neurokinin-1 antagonist GR82334. The CCK-A receptor antagonist L-364,718 up to 10(-7) M had little effect on the phasic contracture of CCK-4. The CCK-B/gastrin receptor antagonist L-365,260 had no effect on the CCK-8S phasic response up to 10(-7) M, but antagonized the phasic response induced by low concentrations of CCK-4 in a competitive manner with an estimated pKB of 8.51. This value is close to that of 8.53 found in a guinea pig cortical binding assay. Both the second phase of the CCK-4 phasic concentration response curve (CRC) and the tonic contraction were insensitive to L-365,260.(ABSTRACT TRUNCATED AT 250 WORDS)

Apo-E genotype and verbal deficits in Alzheimer's disease.

Apo-E genotype was not significantly related to cognitive performance in 157 Alzheimer's disease patients. However, patients homozygous for the epsilon 4 allele appeared most impaired on global cognition but least impaired on language measures. Further study with larger samples may reveal that Apo-E genotype accounts for some of the variability in cognitive deficits observed in Alzheimer's disease.

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.

Potent antihyperalgesic activity without tolerance produced by glycine site antagonist of N-methyl-D-aspartate receptor GV196771A.

Central sensitization is a condition of enhanced excitability of spinal cord neurons that contributes to the exaggerated pain sensation associated with chronic tissue or nerve injury. N-methyl-D-aspartate (NMDA) receptors are thought to play a key role in central sensitization. We have tested this hypothesis by characterizing in vitro and in vivo a novel antagonist of the NMDA receptor acting on its glycine site, GV196771A. GV196771A exhibited an elevated affinity for the NMDA glycine binding site in rat cerebral cortex membranes (pKi = 7.56). Moreover, GV196771A competitively and potently antagonized the activation of NMDA receptors produced by glycine in the presence of NMDA in primary cultures of cortical, spinal, and hippocampal neurons (pKB = 7.46, 8. 04, and 7.86, respectively). In isolated baby rat spinal cords, 10 microM GV196771A depressed wind-up, an electrical correlate of central sensitization. The antihyperalgesic properties of GV196771A were studied in a model of chronic constriction injury (CCI) of the rat sciatic nerve and in the mice formalin test. In the CCI model GV196771A (3 mg/kg twice a day p.o.), administered before and then for 10 days after nerve ligature, blocked the development of thermal hyperalgesia. Moreover, GV196771A (1-10 mg/kg p.o.) reversed the hyperalgesia when tested after the establishment of the CCI-induced hyperalgesia. In the formalin test GV196771A (0.1-10 mg/kg p.o.) dose-dependently reduced the duration of the licking time of the late phase. These antihyperalgesic properties were not accompanied by development of tolerance. These observations strengthen the view that NMDA receptors play a key role in the events underlying plastic phenomena, including hyperalgesia. Moreover, antagonists of the NMDA glycine site receptor could represent a new analgesic class, effective in conditions not sensitive to classical opioids.