Biomedical subjects

Milos D Ikonomovic

Publications and source records attributed to Milos D Ikonomovic.

26 records · Page 2Linked to original sources

PubMed2003

Plasma and cerebrospinal fluid alpha1-antichymotrypsin levels in Alzheimer's disease: correlation with cognitive impairment.

alpha-1-Antichymotrypsin (ACT) is present in neuritic plaques in which it participates in the inflammatory cascade of Alzheimer's disease (AD). Reports of blood ACT levels in AD, and its usefulness as a disease biomarker, have been conflicting. In an effort to clarify this, we measured plasma ACT levels in 516 white subjects including 359 subjects with probable or possible AD, 44 subjects with other late-life dementias, and 113 nondemented people. Subjects with systemic inflammatory diseases or who were taking antiinflammatory medications were excluded. All patients underwent extensive medical and detailed neuropsychological examinations at the time their blood was drawn. We found that plasma ACT levels were elevated in AD patients compared with the control group (p = 0.01) and were associated with severity of AD dementia; there was a negative association with the Mattis Dementia Rating Scale (a global measure of cognition) and a positive association with the Clinical Dementia Rating Scale (a global functional assessment). These relationships remained significant after controlling for demographic and genetic variables. When AD subjects were stratified into subgroups by dementia severity, matched by age, education, and gender, increased serum ACT correlated with Clinical Dementia Rating Scale (p = 0.0041) or Mattis Dementia Rating Scale (p = 0.0031) scores. ACT measurements in cerebrospinal fluid from an additional 34 AD cases and 16 controls showed elevated levels (p = 0.02) in AD. There was a negative correlation (p = 0.037) between cerebrospinal fluid ACT levels and clinical severity as measured by the Mini-Mental State Examination. Our results demonstrate that peripheral ACT levels are elevated in AD, but not in dementias other than AD, and they increase with progression of AD dementia. Although not useful as a diagnostic biomarker, ACT may reflect disease severity and may be helpful as a within subject biomarker in interventions (particularly with antiinflammatory agents) directed at slowing or halting progression of disease.

Aged↗

PubMed2003

Alterations in hippocampal voltage-gated calcium channel alpha 1 subunit expression patterns after kainate-induced status epilepticus in aging rats.

Young adult and aged male Fisher 344 rats underwent kainate-induced convulsive status epilepticus (SE) for 4 h prior to sacrifice to determine potential aging-related differences in the effect of prolonged SE on the expression of hippocampal voltage-gated calcium channels (VGCCs). Immunohistochemistry was performed on hippocampal sections using antibodies directed against the alpha1 subunit of class A-D VGCCs. Compared to age-matched controls, SE animals showed a marked loss of alpha1A immunoreactivity (IR) in CA3 and the hilus, which was more prominent in aged animals. Alpha1B-IR was decreased selectively in the stratum lucidum of CA3. Alpha1C-IR was increased on neuronal somata in the pyramidal and granule cell layers of both age groups. In contrast, there was a marked decrease of alpha1C-IR in the neuropil of CA3 stratum pyramidale and portions of CA1, which was more pronounced in aged animals. Alpha1D-IR was decreased in CA3 and the hilus, which was more prominent in aged animals. Nissl staining demonstrated mild somal dysmorphia in the pyramidal cell layer of CA3, which was more apparent in aged animals. Fluoro-Jade B staining was prominent in the stratum pyramidale of CA3 and in the hilus of aged SE animals. These results demonstrated that expression patterns of hippocampal high-threshold VGCC alpha1 subunits were altered variably during prolonged convulsive SE and were associated with prominent early degenerative changes in aged neurons in CA3 and the hilus.

Aging↗

PubMed2003

Human cholinergic basal forebrain: chemoanatomy and neurologic dysfunction.

The human cholinergic basal forebrain (CBF) is comprised of magnocellular hyperchromic neurons within the septal/diagonal band complex and nucleus basalis (NB) of Meynert. CBF neurons provide the major cholinergic innervation to the hippocampus, amygdala and neocortex. They play a role in cognition and attentional behaviors, and are dysfunctional in Alzheimer's disease (AD). The human CBF displays a continuum of large cells that contain various cholinergic markers, nerve growth factor (NGF) and its cognate receptors, calbindin, glutamate receptors, and the estrogen receptors, ERalpha and ERbeta. Admixed with these cholinergic neuronal phenotypes are smaller interneurons containing the m2 muscarinic acetylcholine receptor (mAChRs), NADPH-diaphorase, GABA, calcium binding proteins and several inhibitory neuropeptides including galanin (GAL), which is over expressed in AD. Studies using human autopsy material indicate an age-related dissociation of calbindin and the glutamate receptor GluR2 within CBF neurons, suggesting that these molecules act synergistically to induce excitotoxic cell death during aging, and possibly during AD. Choline acetyltrasnferease (ChAT) activity and CBF neuron number is preserved in the cholinergic basocortical system and up regulated in the septohippocampal system during prodromal as compared with end stage AD. In contrast, the number of CBF neurons containing NGF receptors is reduced early in the disease process suggesting a phenotypic silence and not a frank loss of neurons. In end stage AD, there is a selective reduction in trkA mRNA but not p75(NTR) in single CBF cells suggesting a neurotrophic defect throughout the progression of AD. These observations indicate the complexity of the chemoanatomy of the human CBF and suggest that multiple factors play different roles in its dysfunction in aging and AD.

Acetylcholine↗

PubMed2003

Plasticity of glutamate and GABAA receptors in the hippocampus of patients with Alzheimer's disease.

AIM: In Alzheimer's disease (AD) it is well known that specific regions of the brain are particularly vulnerable to the pathologic insults of the disease. In particular, the hippocampus is affected very early in the disease and by end stage AD is ravaged by neurofibrillary tangles and senile plaques (i.e., the pathologic hallmarks of AD). Throughout the past several years our laboratory has sought to determine the molecular mechanisms underlying the selective vulnerability of neurons in AD. METHODS: To this end, we employed immunohistochemical, biochemical, and in situ hybrization methods to examine glutamate and gamma-aminobutyric acid (GABAA) receptor subtypes in the hippocampus of patients displaying the full spectrum of AD pathology. RESULTS: Despite the fact that the hippocampus is characterized by a marked loss of neurons in the late stages of the disease, our data demonstrate a rather remarkable preservation among some glutamate and GABAA receptor subtypes. CONCLUSIONS: Collectively, our data support the view that the relatively constant levels of selected receptor subtypes represent a compensatory up-regulation of these receptors subunits in surviving neurons. The demonstration that glutamate and GABA receptor subunits are comparably unaffected implies that even in the terminal stages of the discase the brain is "attempting" to maintain a balance in excitatory and inhibitory tone. Our data also support the concept that receptor subunits are differentially affected in AD with some subunits displaying no change while others display alterations in protein and mRNA levels within selected regions of the hippocampus. Although many of these changes are modest, they do suggest that the subunit composition of these receptors may be altered and hence affect the pharmacokinetic and physiological properties of the receptor. The latter findings stress the importance of understanding the subunit composition of individual glutamate/GABA receptors in the diseased brain prior to the development of drugs targeted towards those receptors.

Adaptation, Physiological↗

PubMed2003

Cholinergic plasticity in hippocampus of individuals with mild cognitive impairment: correlation with Alzheimer's neuropathology.

Several recent studies indicate that activity of cholinergic enzymes in the cortex of people with mild cognitive impairment (MCI) and early Alzheimer's disease (AD) are preserved. We correlated levels of hippocampal choline acetyltransferase (ChAT) activity with the extent of AD lesions in subjects from the Religious Order Study, including cases with no cognitive impairment (NCI), MCI, and with mild to moderate AD. Hippocampal ChAT activity levels were also determined in a group of end-stage AD patients who were enrolled in the University of Pittsburgh Alzheimer's Disease Research Center. MCI subjects were characterized with increased hippocampal ChAT activity. This elevation was no longer present in mild AD cases, which were not different from NCI subjects. Severe AD cases showed markedly depleted hippocampal ChAT levels. In NCI, MCI, and mild-moderate AD, there was a positive correlation between hippocampal ChAT activity levels and progression of neuritic plaque pathology in entorhinal cortex and hippocampus. A significant elevation of hippocampal ChAT in the MCI group was found selectively in the limbic (i.e., entorhinal-hippocampal, III/IV) Braak stages. We hypothesize that cholinergic changes in the hippocampus of MCI subjects reflect a compensatory response to the progressive denervation of the hippocampus by lost entorhinal cortex input. Moreover, the present findings suggest that the short-term memory loss observed in MCI is not caused by cholinergic deficits; it more likely relates to disrupted entorhinal-hippocampal connectivity.

Aged↗

PubMed2002

Upregulation of choline acetyltransferase activity in hippocampus and frontal cortex of elderly subjects with mild cognitive impairment.

In Alzheimer's disease (AD), loss of cortical and hippocampal choline acetyltransferase (ChAT) activity has been correlated with dementia severity and disease duration, and it forms the basis for current therapies. However, the extent to which reductions in ChAT activity are associated with early cognitive decline has not been well established. We quantified ChAT activity in the hippocampus and four cortical regions (superior frontal, inferior parietal, superior temporal, and anterior cingulate) of 58 individuals diagnosed with no cognitive impairment (NCI; n = 26; mean age 81.4 +/- 7.3 years), mild cognitive impairment (MCI; n = 18; mean age 84.5 +/- 5.7), or mild AD (n =14; mean age 86.3 +/- 6.6). Inferior parietal cortex ChAT activity was also assessed in 12 subjects with end-stage AD (mean age 81.4 +/- 4.3 years) and compared to inferior parietal cortex ChAT levels of the other three groups. Only the end-stage AD group had ChAT levels reduced below normal. In individuals with MCI and mild AD, ChAT activity was unchanged in the inferior parietal, superior temporal, and anterior cingulate cortices compared to NCI. In contrast, ChAT activity in the superior frontal cortex was significantly elevated above normal controls in MCI subjects, whereas the mild AD group was not different from NCI or MCI. Hippocampal ChAT activity was significantly higher in MCI subjects than in either NCI or AD. Our results suggest that cognitive deficits in MCI and early AD are not associated with the loss of ChAT and occur despite regionally specific upregulation. Thus, the earliest cognitive deficits in AD involve brain changes other than simply cholinergic system loss. Of importance, the cholinergic system is capable of compensatory responses during the early stage of dementia. The upregulation in frontal cortex and hippocampal ChAT activity could be an important factor in preventing the transition of MCI subjects to AD.

Aged↗

PubMed2002

Changes in expression of amyloid precursor protein and interleukin-1beta after experimental traumatic brain injury in rats.

There is increasing evidence linking neurodegenerative mechanisms in Alzheimer's disease (AD) and traumatic brain injury (TBI), including increased production of amyloid precursor protein (APP), and amyloid-beta (Abeta) peptide. In vitro data indicate that expression of APP may be regulated in part by the inflammatory cytokine IL-1beta. To further investigate the mechanisms involved, we measured APP and IL-1beta protein levels and examined immunohistochemical localization of APP in brain tissue from rats subjected to controlled cortical impact (CCI) injury. Animals were examined at time intervals ranging from 3 h to 4 weeks after TBI. The 24-h time point revealed a dramatic increase in APP immunoreactivity, detected with both N- and C-terminal antibodies, in the hippocampus and cortex ipsilateral to injury. This finding was sustained up to 3 days post-injury. At these early time points, APP increase was particularly robust in the white matter axonal tracts. By 14 days after injury, APP immunoreactivity was not significantly different from sham controls in cortex, but remained slightly elevated in hippocampus. Western blot data corroborated early increases in hippocampal and cortical APP in injured versus control animals. Despite profound APP changes, no Abeta deposits were observed at any time after injury. Hippocampal and cortical IL-1beta increases were even more robust, with IL-1beta levels peaking by 6 h post-injury and returning to baseline by 24-72 h. Our results demonstrate that both APP and IL-1beta are rapidly elevated after injury. Because of the rapidity in the IL-1beta peak increase, it may serve a role in regulation of APP expression after TBI.

Amyloid beta-Protein Precursor↗

PubMedDate not supplied

Distribution of plasma alpha 1-antichymotrypsin levels in Alzheimer disease patients and controls and their genetic controls.

Alzheimer's disease (AD) is a complex multifactorial disease in which many genetic and environmental factors are involved. Recent studies have shown that alpha(1)-antichymotrypsin (ACT) is one of the candidate genes for AD. Elevated levels of ACT have been widely, but not universally reported in the cerebrospinal fluid and plasma of AD patients. The genetic association between the ACT/codon -17*A allele of the signal peptide polymorphism and AD has been shown in some studies. One hypothesis is that the ACT/codon -17*A allele is in linkage disequilibrium with unknown functional mutation(s) in the ACT gene. Alternatively, the more hydrophobic character of the alanine (codon -17*A) may enhance ACT translocation into the endoplasmic reticulum and the Golgi apparatus, thus being secreted at higher levels. Therefore, this study was undertaken to determine the distribution of ACT plasma levels in cases (n = 397) and controls (n = 118) and the impact of ACT polymorphisms, including codon -17, on plasma ACT levels. In our cohort, plasma ACT levels were significantly higher in AD patients than controls (542.13 +/- 7.11 mg/liter vs. 496.62 +/- 12.79 mg/liter; P = 0.002). The ACT/codon -17 polymorphism showed significant association with ACT levels in male AD patients, while the effect of the intron 4 polymorphism was significant in both male and female patients. Codon 227 polymorphism was associated with lower ACT levels in AD patients. In conclusion, ACT may play an important role in the AD pathogenesis and genetic variation in the ACT gene appears to have some effect on plasma ACT concentrations.

Aged↗