Cerebrospinal fluid microglial antibodies: potential diagnostic markers for immune mechanisms in Alzheimer's disease

Hallmark lesions of Alzheimer's disease (AD) are filled with reactive immunocompetent microglia, suggesting that immunological aberrations may participate in the pathophysiology of this disorder. Microglia may participate in the initial stages of neurodegeneration before the onset of dementia. If immune mediated processes are closely linked to neuronal breakdown it would be of importance to have a reliable means to detect these processes. Serum and cerebrospinal fluid (CSF) antibodies are discussed as such potential sources. The serendipitous use of the developing rat central nervous system (CNS) to screen CSF antibrain antibodies produced some unexpected findings. Firstly, CSF antibodies of AD and other dementia patients recognized distinctly different neuronal structures in the developing rat brain. Secondly, some AD CSF recognized fiber networks whereas others recognized amoeboid microglial cells. The same AD CSF which recognized amoeboid microglia cells also specifically marked activated microglia and neural macrophages in experimentally induced lesions. AD CSF microglial antibodies appear to be significant in view of the increasing association between microglia and neurogenerative processes in AD. In addition, CSF microglial antibodies are present in numerous at-risk descendants of familial AD patients. Some have subsequently developed the disorder. These findings together with the fact that microglial antibodies are usually found in the early stages of AD suggest that AD CSF microglial antibodies could be of value in detecting neurodegenerative processes before the onset of dementia. These findings add further support to the concept that inflammation and similar immune mechanisms may contribute to AD pathogenesis.     

Quantitative MR volumetry in Alzheimer's disease. Topographic markers and the effects of sex and education

We determined topographic selectivity and diagnostic utility of brain atrophy in probable Alzheimer's disease (AD) and correlations with demographic factors such as age, sex, and education. Computerized imaging analysis techniques were applied to MR images in 32 patients with probable AD and 20 age- and sex-matched normal control subjects using tissue segmentation and three-dimensional surface rendering to obtain individualized lobar volumes, corrected for head size by a residualization technique. Group differences emerged in gray and white matter compartments particularly in parietal and temporal lobes. Logistic regression demonstrated that larger parietal and temporal ventricular CSF compartments and smaller temporal gray matter predicted AD group membership with an area under the receiver operating characteristic curve of 0.92. On multiple regression analysis using age, sex, education, duration, and severity of cognitive decline to predict regional atrophy in the AD subjects, sex consistently entered the model for the frontal, temporal, and parietal ventricular compartments. In the parietal region, for example, sex accounted for 27% of the variance in the parietal CSF compartment and years of education accounted for an additional 15%, with women showing less ventricular enlargement and individuals with more years of education showing more ventricular enlargement in this region. Topographic selectivity of atrophic changes can be detected using quantitative volumetry and can differentiate AD from normal aging. Differential effects of sex and years of education can also be detected by these methods. Quantification of tissue volumes in vulnerable regions offers the potential for monitoring longitudinal change in response to treatment.     

Coping with specific stressors in Alzheimer's disease caregiving

Strategies used to cope with specific caregiving stressors were examined in a sample of 170 Alzheimer's disease (AD) caregivers. The most commonly identified stressors were memory deficits, loss of ability to communicate, and gradual decline of a loved one. Wishfulness was related to more depressed affect, regardless of stressor type. Other strategies related to more depressed affect included taking direct action when coping with patient memory deficits and stoicism in response to decline of a loved one. Strategies related to less depressed affect included relaxation in response to memory deficits, acceptance in dealing with communication impairments and decline of a loved one, and seeking social support in coping with decline of a loved one.     

Formation of the nicotinic acetylcholine receptor binding sites

Nicotinic acetylcholine receptors (AChRs) are activated by ACh binding to two sites located on different alpha subunits. The two alpha subunits, alpha gamma and alpha delta, are distinguished by their interface with gamma and delta subunits. We have characterized the formation of the ACh binding sites and found, contrary to the current model, that the sites form at different times and in a set order. The first site forms on alpha gamma subunits during the process of subunit assembly. Our data are consistent with the appearance of this site on alpha beta gamma delta subunit tetramers soon after the site for the competitive antagonist alpha-bungarotoxin has formed and delta subunits have assembled with alpha beta gamma trimers. The second site is located on alpha delta subunits and forms after AChR subunits have assembled into alpha2 beta gamma delta pentamers. By determining the order in which the ACh binding sites form, we have also identified the sites in which the delta and second alpha subunits associate during subunit assembly.     

Alterations in glucose metabolism in patients with Alzheimer's disease

OBJECTIVE: To determine the alterations in glucose metabolism that occur in patients with Alzheimer's Disease (AD). DESIGN: Cross-sectional comparison of AD and healthy controls. SETTING: A University teaching hospital. PATIENTS: Healthy controls (n = 14, BMI: 24.9 +/- 0.5 kg/M2, age 73 +/- 1 years) and patients with AD (n = 12, BMI: 23.9 +/- 1.0 kg/M2, age 72 +/- 1 years). All controls and patients with AD had a normal history and physical examination, a negative family history of diabetes, and took no medications. MEASUREMENTS: All patients and controls underwent an assessment of their dietary intake and physical activity, a 3-hour oral glucose tolerance test (OGTT), and a 2-hour hyperglycemic glucose clamp study. RESULTS: Total caloric intake (AD: 27.1 +/- 1.3 kcal/kg/day; Control: 23.6 +/- 1.6 kcal/kg/day; P = ns) and intake of complex carbohydrates (AD: 5.9 +/- 0.4 kcal/kg/day; Control: 6.5 +/- 0.3 kcal/kg/day; P = ns) were not different between groups. Leisure time physical activity was greater in controls (AD: 2970 +/- 411 kcal/week; Control: 5229 +/- 864 kcal/week; P < 0.05). Patients with AD had higher fasting glucose (AD: 5.9 +/- 0.2 mmol/L; Control: 5.1 +/- 0.1 mmol/L; P < 0.01) and insulin (AD: 144 +/- 20 pmol/L; Control: 100 +/- 6 pmol/L; P < 0.05) values. In response to the OGTT, the area under the curve for glucose and insulin was similar in both groups. During the hyperglycemic clamp, steady-state glucose values were higher in the Alzheimer's patients (AD: 11.5 +/- 0.2 mmol/L; Control: 10.9 +/- 0.1 mmol/L, P < 0.01). First- and second-phase insulin responses were similar in each group. The insulin sensitivity index (units: mL/kg.min per pmol/L x 100), a measure of tissue sensitivity to insulin, was reduced in the patients with AD (AD: 0.59 +/- 0.06; Control: 0.79 +/- 0.07; P < 0.05). CONCLUSIONS: We conclude that early AD is characterized by alterations in peripheral glucose metabolism, which may relate, in part, to alterations in physical activity.     

(3H)hemicholinium-3 binding sites in postmortem brains of human patients with Alzheimer's disease and multi-infarct dementia

(3H)Hemicholinium-3 ((3H)HCh-3), a potent, selective, and competitive inhibitor of the high-affinity choline uptake process was used for the detection of high-affinity choline carriers in the hippocampus (gyrus parahippocampalis), neocortex (gyrus frontalis medius), and cerebellum (lobulus semilunaris inferior) in autopsy samples of people with Alzheimer's disease, multi-infarct dementia and from other psychiatric and nonpsychiatric patients. The effect of postmortem delay was eliminated by means of the cerebellum used as an individual standard. The density of (3H)HCh-3 binding sites was decreased in the hippocampus and neocortex from individuals with multi-infarct dementia and unchanged in the brain tissue from people with Alzheimer's disease in comparison with control patients. No changes in dissociation constants were found. In Alzheimer's disease, high-affinity choline transport appears to be reduced by a dysfunction of cholinergic neuronal membrane rather than by a significant decrease in the number of presynaptic cholinergic nerve terminals. Results provide evidence of a decrease in the number of nerve endings in people with multi-infarct dementia and suggest different vulnerability of particular brain areas to vascular disorders.     

Affective disorders in Alzheimer's disease

The links between depressive syndrome and Alzheimer's disease are problematic concerning the diagnosis and the therapeutic choice. The concepts of pseudo-dementia and late onset depression are shortly discussed. The hypothesis concerning the relationship between depression and Alzheimer's disease are summarized. The clinical data relevant for the diagnosis and the therapeutic guidelines are discussed.     

Mental-behavioral disorders in Alzheimer's disease

Behavioural and psychological disorders are often observed in Alzheimer's disease. Some are common, such as symptoms of depression, apathy, aggressivity, agitation, psychotic disturbances, disorders of sleep rhythm, etc. Many factors contribute to the aetiology of these disorders, mainly cerebral lesions, environmental changes, somatic illnesses, iatrogenic factors and psychological reaction mechanisms. Management must take each into account. Treatment comprises medication (symptomatic treatment of the various disorders, cholinergic treatment) and other means (adaptation of the inhabitation, informing family and friends, psychotherapy, etc.).     

Oxidative alterations in Alzheimer's disease

The expression of heparin-binding epidermal growth factor-like growth factor (HB-EGF), an EGF receptor ligand, was investigated in rat forebrain under basal conditions and after kainate-induced excitotoxic seizures. In addition, a potential neuroprotective role for HB-EGF was assessed in hippocampal cultures. In situ hybridization analysis of HB-EGF mRNA in developing rat hippocampus revealed its expression in all principle cell layers of hippocampus from birth to postnatal day (P) 7, whereas from P14 through adulthood, expression decreased in the pyramidal cell layer versus the dentate gyrus granule cells. After kainate-induced excitotoxic seizures, levels of HB-EGF mRNA increased markedly in the hippocampus, as well as in several other cortical and limbic forebrain regions. In the hippocampus, HB-EGF mRNA expression increased within 3 hr after kainate treatment, continued to increase until 24 hr, and then decreased; increases occurred in the dentate gyrus granule cells, in the molecular layer of the dentate gyrus, and in and around hippocampal pyramidal CA3 and CA1 neurons. At 48 hr after kainate treatment, HB-EGF mRNA remained elevated in vulnerable brain regions of the hippocampus and amygdaloid complex. Western blot analysis revealed increased levels of HB-EGF protein in the hippocampus after kainate administration, with a peak at 24 hr. Pretreatment of embryonic hippocampal cell cultures with HB-EGF protected neurons against kainate toxicity. The kainate-induced elevation of [Ca2+]i in hippocampal neurons was not altered in cultures pretreated with HB-EGF, suggesting an excitoprotective mechanism different from that of previously characterized excitoprotective growth factors. Taken together, these results suggest that HB-EGF may function as an endogenous neuroprotective agent after seizure-induced neural activity/injury.     

Propionibacterium acnes in the cortex of patients with Alzheimer's disease

Propionibacterium acnes was found in the cortex of three patients with Alzheimer's disease and in one frontal cortex of an elderly patient with cardiovascular risk factors and hypoxia due to a large glioblastoma of the right frontal lobe with severely increased intracranial pressure. Propionibacterium acnes is an atypical anaerobic bacterium which is sensitive to cephalosporins, but insensitive to metronidazole. It is concluded that a capillary microangiopathy (in consequence of old age and cardiovascular risk factors such as high blood pressure) leads to cortical hypoxia and reduced resistance of the cortical immune system. Prevention by dietary regimes counteracting microangiopathy and treatment with cephalosporins are recommended.     

Bone metabolism markers in patients with Basedow-Graves disease

Collagen type I is the main collagen type found in bones. Carboxyterminal propeptide, deriving and cleaved from procollagen type I (PICP) during collagen synthesis, is delivered into the blood, where it might represent an useful marker of bone formation similarly to osteocalcin. PICP, osteocalcin, alkaline phosphatase, serum and urinary calcium excretion were measured in 58 premenopausal females affected by Graves' disease and also 28 of them after attainment of euthyroidism by methimazole treatment to study these biochemical indices of bone remodelling before and after treatment. Before therapy PICP (mean +/- S.D.: 244.2 +/- 112.3 vs. 136.8 +/- 32.4 micrograms/l), osteocalcin (mean +/- S.D.: 17.8 +/- 6.7 vs. 7.5 +/- 2.7 micrograms/l) and other markers were significantly (p < 0.05) higher than sex and age matched controls (n = 24). Treatment induced a significant decrease of PICP, alkaline phosphatase, calcaemia and calciuria compared to pretreatment values, while osteocalcin did not significantly differ (mean +/- S. D.: 17.8 +/- 6.7 vs. 14.7 +/- 8.7 micrograms/l). These data suggest that hyperthyroidism due to Graves' disease causes an increase of serum levels of these markers, but further studies are necessary to asses the differences between PICP and osteocalcin as markers of osteoblast activity in hyperthyroidism.     

Inhibitory processes in covert orienting in patients with Alzheimer's disease

Previous studies of covert orienting in Alzheimer's disease (AD) have investigated exogenous and endogenous processes separately. We aimed to investigate how the 2 modes of orienting interact to control attention in healthy older participants and patients with AD. The covert orienting of visual attention task (COVAT) with abrupt onset cues was used in all experiments. In Experiments 1 and 2, predictive information was added to cues to initiate an endogenous orienting response. Results showed that healthy older participants were able to use endogenous processes to inhibit exogenous orienting. In contrast, patients with AD were unable to inhibit exogenous orienting to cues even when targets rarely appeared there. Experiment 3 investigated inhibition of return (IOR) in patients with AD. Both healthy older controls and patients with AD showed a normal IOR, suggesting that exogenous orienting processes are relatively unaffected by the normal aging process or in patients with AD. A model of covert orienting in which exogenous and endogenous orienting processes interact to control attentional behaviors is discussed.     

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)     

African-American caregiving for a relative with Alzheimer's disease

This study explored the meaning of caregiving to nine African-American caregivers of family members with Alzheimer's disease. Open-ended questions were used. Four major themes emerged from the study: caregiving is a traditional family value, caregiving is an act of love, social support is a mediator of the caregiver burden, and caregiving is a female role.     

Intact text-specific implicit memory in patients with Alzheimer's disease.

The ability of patients with Alzheimer's disease (AD) to acquire and retain text-specific knowledge was investigated in a rereading study. Ten AD patients (aged 59–84 yrs) and 10 normal control Ss read 2 passages 3 times, each as quickly as possible, and answered recognition memory questions after the 3rd reading of each passage. The AD patients had poor explicit memory as evidenced by impaired recognition memory for the passages. In contrast, normal decreases in the times required for successive readings of each passage for AD patients indicated intact implicit memory for the passages. The absence of facilitation across passages indicated that the rereading effect was text specific, suggesting that AD patients may retain the ability to form certain kinds of implicit new associations. Alternative accounts of the mechanism underlying text-specific priming, and of the nature of intact and impaired implicit memory in AD, are considered. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The mere exposure effect in patients with Alzheimer's disease.

The mere exposure effect was examined in patients with mild to moderate Alzheimer's disease (AD). Twenty patients and 20 elderly controls judged the physical characteristics of faces. Implicit memory was tested later by presenting pairs of faces (old and new) and asking participants which faces they liked better. Patients and controls exhibited above chance preference for previously exposed faces. Experiment 2 evaluated whether the preserved implicit memory of patients was mediated by explicit memory. Patients and controls again judged faces but then later chose which faces they had seen before. Patients exhibited impaired recognition memory compared to controls. These findings suggest that a mere exposure affect for unfamiliar faces is present in mild to moderate AD. The results are discussed in terms of perceptual and conceptual priming and relatively spared occipital lobe functioning in early AD. (PsycINFO Database Record (c) 2010 APA, all rights reserved)