Neuropsychological and psychiatric differences between Alzheimer's disease and Parkinson's disease with dementia

OBJECTIVE: To examine neuropsychological and neuropsychiatric differences between patients with probable Alzheimer's disease and patients with Parkinson's disease and dementia. METHODS: Thirty three patients with probable Alzheimer's disease and 33 patients with Parkinson's disease and dementia were matched for age, sex, and mini mental state examination scores and given a battery of neuropsychological and neuropsychiatric tests. RESULTS: Patients with Parkinson's disease with dementia had a significantly higher prevalence of major depression than patients with Alzheimer's disease; patients with Alzheimer's disease showed more severe anosognosia and disinhibition than patients with Parkinson's disease. Whereas no significant between group differences were found on tests of memory and language, demented patients with Parkinson's disease had a significantly greater impairment on a test of visual reasoning than patients with Alzheimer's disease. CONCLUSION: There were significant psychiatric differences between patients with Alzheimer's disease and demented patients with Parkinson's disease, but neuropsychological differences were restricted to a single cognitive domain.     

Circulating plasma levels of nucleosomes in patients with systemic lupus erythematosus: correlation with serum antinucleosome antibody titers and absence of clear association with disease activity

OBJECTIVE: To assess nucleosome plasma levels in patients with systemic lupus erythematosus (SLE) and to study the correlations with serum antinucleosome, anti-double-stranded DNA (anti-dsDNA), and antihistone antibody activities, as well as with disease activity (by the SLE Disease Activity Index [SLEDAI]). METHODS: In a cross-sectional study, we assessed 58 SLE patients for their plasma nucleosome levels. Plasma nucleosome levels as well as serum antinucleosome, anti-double-stranded DNA, and antihistone antibody activities were assessed by enzyme-linked immunosorbent assay. SLE activity was evaluated using the SLEDAI: RESULTS: The mean (+/-SD) plasma nucleosome concentration in SLE patients was 52 +/- 159 ng/ml (range 5-1,180), and was significantly higher than that of the controls (16 +/- 8.8 ng/ml, range 8-52; P = 0.03). Thirteen of the 58 lupus patients had levels over the range of normal (defined as the control mean + 3 SD, or 42 ng/ml). An inverse correlation was found between nucleosome plasma levels and serum antinucleosome antibody activity in the entire group of SLE patients, those with active disease, and those with inactive disease, respectively. No correlation was found between the SLEDAI and nucleosome plasma concentrations. CONCLUSION: Nucleosome plasma levels may be normal or increased in SLE, and found in patients with active or inactive SLE. Longitudinal studies are needed to further establish whether high levels of circulating nucleosomes may predict the occurrence of an SLE flare.     

Concordant but different: Cognitive function, cerebral anatomy, and metabolism in monozygotic twins with Alzheimer's disease.

To illustrate the utility of the twin method in Alzheimer's disease (AD) research, a pair of monozygotic twins, concordant for the disease but markedly different in their clinical presentations, was studied in detail. Neuropsychological evaluation, magnetic resonance imaging (MRI), and cerebral glucose metabolic studies revealed a typical behavioral presentation for AD in Twin A. In contrast, Twin B showed prominent visuospatial impairments. Although there was no identified cause for the disparate presentations, a close correspondence was observed between the neuropsychological findings and the regional brain measures. The results suggest that the trajectory of AD may vary widely even in genetically identical individuals. Factors accounting for the variability include potential intrauterine, early developmental, and environmental differences. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Interindividual differences in circadian patterns of catecholamine excretion, body temperature, performance, and subjective arousal

Interindividual differences in circadian rhythms of urinary catecholamine excretion, performance, self-ratings of arousal and oral temperature were studied in 80 subjects divided into three groups--morning-active, evening-active, and intermediate. Catecholamine excretion, body temperature, and self-ratings of arousal exhibited pronounced circadian variations. Morning-active subjects exceeded other groups in the 24 h level of adrenaline excretion but crest phases did not differ, occurring close to 13.00 h. No differences between groups were found for noradrenaline excretion. Crest phases occurred close to noon. Self-rated alertness exhibited a significantly earlier (14.12 h) crest phase for morning-active than for evening-active subjects (16.09 h). The performance did not differ between groups.     

Regional specificity of alterations in NGF, BDNF and NT-3 levels in Alzheimer's disease

Using two-site enzyme immunoassays (EIAs), we measured the levels of neurotrophins, nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) simultaneously in three brain regions (motor cortex, dentate gyrus and entorhinal cortex) of patients with Alzheimer's disease (AD) and control individuals. Significant differences between the neurotrophin levels of these two groups were found in the different brain regions depending on the neurotrophin. The NGF level in the dentate gyrus of AD patients was higher, whereas the BDNF level in the entorhinal cortex and the NT-3 level in the motor cortex were lower than the corresponding control levels. These results indicate that protein levels of individual neurotrophins in different brain regions are affected differently by AD, and such differential changes may contribute to the complex pathology of AD.     

Cerebrospinal fluid C3a increases with age, but does not increase further in Alzheimer's disease

Complement activation is present in the brain in Alzheimer's disease (AD), and C1q concentrations are decreased in AD cerebrospinal fluid (CSF). To determine whether concentrations of other complement proteins are also altered in AD CSF, we measured concentrations of C3a and SC5b-9 in CSF from patients with probable AD (n = 19), normal aged controls (n = 11), and normal younger controls (n = 15). C3a concentrations were similar between AD and aged controls, but threefold higher than in younger controls (p < 0.05 vs. both groups). A similar pattern was found with SC5b-9, though the increase was only twofold and statistically significant only for AD vs. younger controls. These results suggest that an increased generation of complement proteins in localized areas of the AD brain does not result in elevated concentrations of these proteins in CSF, compared with age-matched controls. Increased C3a (and, to a lesser extent, SC5b-9) in aged controls may be due to increased complement activation, increased central nervous system production, and/or blood-brain barrier leakage of these proteins.     

Differential vasopressin and oxytocin innervation of the human parabrachial nucleus: no changes in Alzheimer's disease

The distribution of vasopressin and oxytocin immunoreactive fibers was examined in the pontine parabrachial nucleus of the human brain using purified polyclonal antibodies. The results revealed a striking predominance of vasopressin in this brain region. No obvious density difference, either in vasopressin or in oxytocin innervation, was found between Alzheimer's disease patients and matched controls. The present study corroborates other reports that suggest that in Alzheimer's disease the vasopressin innervation in the caudal part of the human brain is not affected.     

Training to criterion in eyeblink classical conditioning in Alzheimer's disease, Down's syndrome with Alzheimer's disease, and healthy elderly.

The cholinergic antagonist scopolamine delays acquisition of eyeblink classical conditioning (EBCC) in rabbits and humans, but scopolamine-treated organisms eventually acquire conditioned responses (CRs). Patients with probable Alzheimer's disease (AD) and older adults with Down's syndrome (DS/AD) have disrupted cholinergic systems and perform EBCC very poorly. It was hypothesized that patients with probable AD and DS/AD, like scopolamine-injected organisms, would acquire CRs if given sufficient training. Twelve probable AD patients, 12 DS/AD patients, and 6 healthy elderly control individuals participated in 5 daily 90-trial sessions of EBCC. Fifty-eight percent of the probable AD, 92% of the DS-AD, and 100% of the control participants achieved learning criterion. Probable AD, DS/AD, and control participants had statistically significant increases in the percentage of CRs produced over 5 EBCC sessions. The neural substrate for EBCC was not eliminated in probable AD or DS/AD patients, although the learning mechanism was disrupted. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Expression of high-affinity neuronal and glial glutamate transporters in the rat optic nerve

Recent studies have revealed that a dynamic axon-glial signaling occurs in the rat optic nerve, which is devoid of synapses. This interaction is postulated to be mediated by non-vesicular release of glutamate via a reversal of high-affinity glutamate transporters. Here we examined the expression of glial glutamate transporters (GLAST and GLT-1) and a neuronal transporter (EAAC1) in the rat optic nerve. RT-PCR analysis revealed the presence of mRNAs for GLT-1 and GLAST, but not EAAC1. RNase protection assays showed that of the two glial transporters, mRNA for GLAST was expressed at much higher level than was GLT-1. A similar expression pattern was found in primary astrocyte culture cells. GLAST mRNA level in the optic nerve was comparable to that in the cerebellum. Developmentally, GLAST mRNA level was highest at P2 and dropped slightly by adulthood. Nerve transection resulted in little or no change in mRNA levels for GLAST and GLT-1 assayed at 4 to 14 days post-transection, but GLAST mRNA level was decreased at 64 days. Western blot analysis revealed that the rat optic nerve showed immunoreactivity to antibodies against GLT-1, GLAST, and EAAC1. In conclusion, we suggest that glial and neuronal transporters are present in the rat optic nerve, where dynamic axon-glial interaction has been known to occur. In particular, the unusually high level of expression of GLAST in the optic nerve suggests a possible role for this glial transporter in protecting optic nerves from neurotoxicity during postnatal development.     

Localization and function of five glutamate transporters cloned from the salamander retina

Glutamate is the major excitatory neurotransmitter in the vertebrate retina. Native glutamate transporters have been well characterized in several retinal neurons, particularly from the salamander retina. We have cloned five distinct glutamate transporters from the salamander retina and examined their localization and functional properties: sEAAT1, sEEAAT2A, sEAAT2B, sEAAT5A and sEAAT5B. sEAAT1 is a homologue of the glutamate transporter EAAT1 (GLAST), sEAAT2A and sEAAT2B are homologues of EAAT2 (GLT-1) and sEAAT5A and sEAAT5B are homologues of the recently cloned human retinal glutamate transporter EAAT5. Localization was determined by immunocytochemical techniques using antibodies directed at portions of the highly divergent carboxy terminal. Glutamate transporters were found in glial, photoreceptor, bipolar, amacrine and ganglion cells. The pharmacology and ionic dependence were determined by two-electrode voltage clamp recordings from Xenopus laevis oocytes which had previously been injected with one of the glutamate transporter mRNAs. Each of the transporters behaved in a manner consistent with a glutamate transporter and there were some distinguishing characteristics which make it possible to link the function in native cells with the behavior of the cloned transporters in this study.     

Gender differences in the phenotypic expression of Alzheimer's disease in Down's syndrome (trisomy 21)

Twenty-eight individuals with typical Down's syndrome (DS) phenotype (17 males and 11 females; age range: 10-74 years) were investigated for gender differences in the phenotypic expression of Alzheimer-type pathology (ATP). Quantitative neuropathology was performed in the 4 neocortical lobes of the right hemisphere, by counting senile plaques (SP), and neurofibrillary tangles (NFT). ATP was present in 25 middle-aged (> 40 years) individuals (16 males and 9 females). Females had significantly higher (p = 0.03) mean neocortical NFT densities (36.6 per mm2; s.e.m. +/- 6.6) than males (17.9 per mm2; s.e.m. +/- 4.7). None of the females had NFT densities below 10 per mm2, compared with 6 males in whom NFT were either absent or seen in very low densities (< 4 per mm2). Assessment of SP densities in the same cortical regions showed non-significant differences in females (42.4 per mm2; s.e.m. +/- 5.1) compared with males (33.6 per mm2; s.e.m. +/- 2.1). There was clinical evidence of dementia in all the female (8/8) individuals who were prospectively assessed, compared with only 54% (7/13) of males. The male individuals without clinical dementia had absent or low neocortical NFT densities regardless of high SP densities. Female DS cases (mean age: 48.8 years; s.e.m. +/- 1.9) had an earlier onset of dementia than males (mean age: 53.6 years; s.e.m. +/- 1.3; p = 0.05). Female middle-aged DS individuals have an earlier onset, and a more severe form of AD which correlates with higher neocortical NFT rather than SP density.     

Genital Paget's disease with clear cells in the epidermis of the axilla

We report an 84-year-old man with extramammary Paget's disease (EMPD) involving the genital region. Microscopic examination revealed very few clear cells appearing pagetoid in the lower portion of prickle cell layer of the right axilla epidermis, with no clinically detectable eruption. Their histochemical, immunohistochemical and lectin-binding reactions were almost identical to those in the genital lesion. However, although the axillary lesion was diagnosed as subclinical Paget's condition, the clinical course showed no aggressive or destructive nature. Our case suggests that not all subclinical Paget's conditions become malignant, and that in some cases the clear cells may be precursors of Paget's cells developing multifocally.     

Interindividual differences and intraindividual variability in the cortisol awakening response: An examination of age and gender.

This article shows age and gender differences in the magnitude and day-to-day variability of the cortisol awakening response (CAR) using a national sample of 1,143 adults who completed the second wave of the National Study of Daily Experiences, a part of the Midlife Development in the United States survey. Participants between the ages of 33 and 84 years completed 8 consecutive nightly interviews and provided 4 saliva samples (upon waking, 30 min after waking, before lunch, and before bed) on 4 consecutive interview days. Results revealed substantial day-to-day variability in the CAR as well as significant Age × Gender interactions, indicating that although no systematic age-related differences emerged for women, the magnitude and day-to-day variability of the CAR increased with age among men. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Increased DNA oxidation and decreased levels of repair products in Alzheimer's disease ventricular CSF

One of the leading etiologic hypotheses regarding Alzheimer's disease (AD) is the involvement of free radical-mediated oxidative stress in neuronal degeneration. Although several recent studies show an increase in levels of brain DNA oxidation in both aging and AD, there have been no studies of levels of markers of DNA oxidation in ventricular CSF. This is a study of levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG), the predominant marker of oxidative DNA damage, in intact DNA and as the "free" repair product that results from repair mechanisms. Free 8-OHdG was isolated from CSF from nine AD and five age-matched control subjects using solid-phase extraction columns and measured using gas chromatography/mass spectrometry with selective ion monitoring. Intact DNA was isolated from the same samples and the levels of 8-OHdG determined in the intact structures. Quantification of results was carried out using stable isotope-labeled 8-OHdG. By using this sensitive methodology, statistically significant elevations (p < 0.05) of 8-OHdG were observed in intact DNA in AD subjects compared with age-matched control subjects. In contrast, levels of free 8-OHdG, removed via repair mechanisms, were depleted significantly in AD samples (p < 0.05). Our results demonstrate an increase in unrepaired oxygen radical-mediated damage in AD DNA as evidenced by the increased presence of 8-OHdG in intact DNA and decreased concentrations of the free repair product. These data suggest that the brain in AD may be subject to the double insult of increased oxidative stress, as well as deficiencies in repair mechanisms responsible for removal of oxidized bases.     

Metrifonate benefits cognitive, behavioral, and global function in patients with Alzheimer's disease

OBJECTIVE: To evaluate the efficacy and safety of metrifonate, an acetylcholinesterase inhibitor, in patients clinically diagnosed with probable Alzheimer's disease (AD) of mild to moderate severity. METHODS: A prospective, 36-week, multicenter, double-blind, randomized, parallel group study of metrifonate in probable AD patients, including a 2-week screening period, a 26-week double-blind treatment period, and a follow-up visit at 8 weeks post-treatment. A total of 24 ambulatory clinics in the United States in a variety of settings, including contract research organizations, public health facilities, and universities. Patients met diagnostic criteria for probable AD as defined by the work group of the National Institute for Neurological and Communicative Diseases and Stroke and the Alzheimer's Disease and Related Disorders Association. Patients had Mini-Mental State Examination (MMSE) scores of 10 to 26 and Ischemic Scores (Rosen Modification) of <4. A total of 408 patients were enrolled. Percentages of patients completing double-blind treatment were 88% and 79% in the placebo and metrifonate groups, respectively. Rates of discontinuation due to adverse events were 4% in the placebo group and 12% in the metrifonate group. Placebo or metrifonate was administered once daily. Metrifonate-treated patients received a loading dose of 100 to 180 mg based on weight (2.0 mg/kg) for 2 weeks, followed by a maintenance dose of 30 to 60 mg based on weight (0.65 mg/kg) for 24 weeks. Primary efficacy variables were the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) and the Clinician's Interview-Based Impression of Change with Caregiver Input (CIBIC-plus). Secondary efficacy variables included the Neuropsychiatric Inventory (NPI), the Disability Assessment in Dementia, the Global Deterioration Scale (GDS), the ADAS-Noncognitive subscale (ADAS-Noncog), the MMSE, and the Clinician's Interview-Based Impression of Severity with Caregiver Input (CIBIS-plus). Outcome measures reflected changes from baseline at week 26 for all variables. Safety was assessed with incidences of premature termination, treatment-emergent events and mortality, and routine safety evaluations. RESULTS: After 26 weeks of metrifonate therapy, a 2.86-point treatment difference (p = 0.0001) was observed in the ADAS-Cog scores of the intent-to-treat AD patients. The treatment difference in the mean CIBIC-plus score at this time was 0.28 points (p = 0.0071). At week 26, treatment differences also were observed in the mean NPI total score (p = 0.0161). Analysis of the remaining secondary efficacy variables showed treatment differences that favored metrifonate but did not reach statistical significance. Metrifonate adverse events were predominantly mild in intensity. No hepatotoxicity was observed. CONCLUSIONS: Metrifonate was safe and well-tolerated. It enhanced not only the cognitive and global function, but also the behavioral function of patients diagnosed with mild to moderate AD. Therefore, metrifonate appears to be useful in the symptomatic treatment of AD.     

Structural determinants of substrates and inhibitors: probing glutamate transporters with 2,4-methanopyrrolidine-2,4-dicarboxylate

Using an intramolecular [2 + 2] photocyclization, 2,4-methanopyrrolidine-2,4-dicarboxylate was prepared as a conformationally locked analogue of glutamate. This compound, in combination with two other pyrrolidine dicarboxylates, has been used to define the structural elements that differentiate substrate and nonsubstrate inhibitors of a high-affinity, sodium-dependent glutamate transporter.     

Modification of the blood-brain barrier through chronic intoxication by aluminum glutamate. Possible role in the etiology of Alzheimer's disease

The authors have used an experimental rat model of chronic aluminum (Al) intoxication to reproduce pathological signs analogous to those observed in humans for Alzheimer's disease or dialysis encephalopathy. Preliminary chronic intoxication was achieved during 5 wk by daily subcutaneous injection of a suspension of glutamate and Al prior to intravenous (i.v.) administration of sodium L-glutamate and Al chloride. A significant increase in Al content was observed in different areas of the brain, such as the hippocampus, the occipito-parietal cortex, the cerebellum, and the striatum. Moreover, half of the animals subcutaneously treated with Al glutamate had neurological disturbances, such as trembling, equilibrium difficulties, and convulsions leading to death about 1 h after i.v. administration. A significant increase in glutamic acid at the level of the occipito-parietal cortex was found in comparison with controls, which received only sodium L-glutamate or saline solution. These results show that the Al-L-glutamate complex may well induce a modification of the blood-brain barrier.