Altered glucose metabolism in microvessels from patients with Alzheimer's disease

Microvessels isolated from temporal cortex of patients with Alzheimer's disease showed decreased uptake of glucose when compared with vessels from age-matched or young control subjects. This was due to decreased hexokinase activity in the Alzheimer samples, as determined by ion exchange chromatography. This finding was confirmed independently by determination of the phosphorylation constant for hexokinase, K3, using positron emission tomography. The results suggest that Alzheimer's disease may result from a global defect in brain energy metabolism.     

Altered brain response for semantic knowledge in Alzheimer's disease

Word retrieval deficits are common in Alzheimer's disease (AD) and are thought to reflect a degradation of semantic memory. Yet, the nature of semantic deterioration in AD and the underlying neural correlates of these semantic memory changes remain largely unknown. We examined the semantic memory impairment in AD by investigating the neural correlates of category knowledge (e.g., living vs. nonliving) and featural processing (global vs. local visual information). During event-related fMRI, 10 adults diagnosed with mild AD and 22 cognitively normal (CN) older adults named aloud items from three categories for which processing of specific visual features has previously been dissociated from categorical features. Results showed widespread group differences in the categorical representation of semantic knowledge in several language-related brain areas. For example, the right inferior frontal gyrus showed selective brain response for nonliving items in the CN group but living items in the AD group. Additionally, the AD group showed increased brain response for word retrieval irrespective of category in Broca's homologue in the right hemisphere and rostral cingulate cortex bilaterally, which suggests greater recruitment of frontally mediated neural compensatory mechanisms in the face of semantic alteration.     

Altered chromatin conformation in Alzheimer's disease.

Chromatin samples were prepared from forty human brains. Chromatin was separated into a heavy heterochromatin fraction and two euchromatin fractions: intermediate euchromatin and light euchromatin. Employing a bacterial RNA polymerase as probe, only the euchromatin fractions were capable of RNA synthesis. In Control human brains, in brains of patients with dialysis dementia and in brains of elderly individuals without or with dementia of a type other than Alzheimer's disease, the euchromatin fractions accounted for about 75 per cent of the total DNA. In contrast, in brains of patients with advanced senile dementia or presenile dementia of the Alzheimer type, a wide range of euchromatin content was encountered with an average value of 55 per cent. Heterochromatization occurred in both neuron and glia enriched fractions suggesting that a major alteration in protein metabolism occurs in Alzheimer's disease.     

Altered neurogenesis in Alzheimer's disease

BACKGROUND: Exciting preliminary work indicates an increase in progenitor activity in the subgranular zone of the dentate gyrus of people with Alzheimer's disease (AD) compared to that of controls. We examine progenitor activity in the other main progenitor niche, the subventricular zone (SVZ), as well as potential associations with key pathological and neurochemical substrates. METHOD: Immunocytochemistry techniques utilizing nestin and Musashi1 antibodies were used to examine progenitor activity in the SVZ and to enable comparisons between seven patients with AD and seven controls, based upon the quantification of the percentage area covered, using the Image Pro Plus v.4.1 image analysis system. AD pathology was staged using the Consortium to Establish a Registry for Alzheimer's Disease and Braak criteria. Choline acetyl transferase (ChAT) was measured in the temporal cortex as an indication of the severity of cortical cholinergic deficits. Glial fibrillary acidic protein (GFAP) was used to label astrocytes. RESULTS: There was a significant ninefold decrease (Z = 2.2, P = .046) of Musashi1 immunoreactivity in the SVZ of patients with AD in comparison with that of controls, but there was a significant increase in nestin immunoreactivity in the same region (Z = 2.2, P = .028) without any significant change in GFAP immunoreactivity. Reduced ChAT enzymatic activity was the main association of Musashi immunoreactivity (R = -.90, P = .03). DISCUSSION: The current results indicate a significant reduction of progenitor cells (as labeled by Musashi1) in the SVZ of patients with AD, but an increase in GFAP-negative astrocyte-like cells with progenitor characteristics. Cortical cholinergic loss was strongly associated with the reduction of progenitors, with potential implications of important treatment targets.     

Altered lymphocyte distribution in Alzheimer's disease

The contribution of immunological factors in the etiopathogenesis of Alzheimer's disease (AD) is increasingly noted. Apart from cerebral immunological findings, peripheral changes of the immune systems have been reported including lymphocyte function and subset distribution. As data still remain inconsistent, we investigated a sample of 43 patients with AD and of 34 healthy age-matched controls. Distribution of the T-, B- and NK cell subsets was determined by flow cytometry (FACS). We found a significant decrease of CD3(+) lymphocytes as well as of CD19(+) lymphocytes. A slight increase of the CD4(+) and a decrease of the CD8(+) subpopulation could be observed, without significant change of the CD4(+)/CD8(+) ratio. CD16(+)56(+) cells were not altered. Our findings of decreased T- and B-Cell numbers in AD sustain the hypothesis of a general decline of immune activity in AD. A putative association with premature immunosenescence in AD and possible pathogenetic implications are discussed.     

Altered glycosylation of acetylcholinesterase in lumbar cerebrospinal fluid of patients with Alzheimer's disease

As clinical diagnosis of Alzheimer's disease is only 80%-90% accurate, there is a need to identify biochemical markers of Alzheimer's disease. Previous studies have shown an abnormality in the glycosylation of acetylcholinesterase (AChE) in the CSF collected postmortem from patients with Alzheimer's disease. This abnormality was very specific for Alzheimer's disease, as it was not detected in other illnesses causing dementia. We report here that the glycosylation of AChE is also altered in lumbar CSF collected antemortem. The altered glycosylation was due to increased concentrations of a minor AChE isoform that does not bind to concanavalin A (Con A). Glycosylation of AChE may eventually be of diagnostic value, especially when used in combination with other CSF markers.     

Prediction of psychiatric response to donepezil in patients with mild to moderate Alzheimer's disease

Donepezil is a selective acetylcholinesterase inhibitor approved for the symptomatic treatment of mild to moderate Alzheimer's disease (AD). Since behavioral symptoms severely affect quality of life for AD patients and their caregivers, predicting behavioral responses to donepezil will be useful in managing patients with AD. In this study, we analyzed 70 consecutive cases with mild to moderate AD. Caregivers were interviewed with the Neuropsychiatric Inventory for behavioral assessment and 4-point improvement at week 12 was accepted as a treatment response. Twenty-one (30.0%) patients showed a behavioral response, while 42 (60.0%) showed no behavioral change and 7 (10.0%) worsened. Dysphoria, anxiety and apathy significantly improved after treatment among the responder group. The baseline profile including age, sex, Mini-Mental State Examination (MMSE), the Alzheimer's Disease Assessment Scale (ADAS-cog) and the Geriatric Depression Scale did not differ significantly among the three groups. Statistical Parametric Mapping analysis of single photon emission computed tomography (SPECT) images at baseline showed that cerebral blood flow in the premotor and parietotemporal cortices was significantly higher in the responder group than in the worse group. The present study suggested usefulness of SPECT imaging in the prediction of behavioral response to donepezil among AD patients even with similar psychiatric symptoms and cognitive functions.     

Altered levels of microtubule proteins in brains of Alzheimer's disease patients

Summary The amount of microtubule protein present in the total soluble protein from brains of Alzheimer's disease patients and from brains of non-Alzheimer age-matched controls, were determined by radioimmunoassay. No differences were found in the amount of tubulin or microtubule-associated protein MAP2 present in either group. However, the amount of tau protein or MAP1 from the brains of Alzheimer's disease patients was about half of that present in their control counterparts.Supported by Grants from the Comisión Asesora para el Desarrollo Tecnológico y Científico and Fondo de Investigaciones Sanitarias     

Altered verbal working memory process in patients with Alzheimer's disease: an fMRI investigation

Impaired working memory processing is one of the broad range of cognitive deficits in patients with Alzheimer's disease (AD). We aimed to elucidate the differences in brain activities involved in the process of working memory between AD patients and healthy comparison subjects. Twelve patients with AD were recruited along with 12 healthy volunteers as a comparison group. Functional magnetic resonance imaging was employed to assess cortical activities during the performance of a 1-back working memory paradigm using the Korean alphabet as mnemonic content. Subsequently, the difference in neural activities between the 2 groups was analyzed. The AD group performed the tasks with reduced accuracy. Group comparison analysis revealed that the AD group showed decreased brain activity in the left frontal pole (Brodmann area, BA, 10), the left ventrolateral prefrontal cortex (BA47), the left insula (BA13) and the right premotor cortex (BA6) compared to the control group. The AD group showed increased activation in the left precuneus (BA7) compared to the control group. A decreased level of activation in the prefrontal cortex and an increased level of activation in the parietal neural networks from the patient group may document an altered verbal working memory process in the patients with AD.     

Aging and Alzheimer's disease. Altered cortical serotonergic binding

The binding of tritiated serotonin and tritiated spiperone to crude membrane preparations from human frontal poles was determined in both controls and subjects with Alzheimer's disease (AD). Using the dopamine-specific receptor antagonist sulpiride, spiperone binding in the cortex was shown to be essentially serotonergic. A decline in both serotonin and spiperone binding was found in normal aging, and an AD-related decrease was found for spiperone binding only. The AD-related decrement of spiperone binding occurred irrespective of patient age and duration of disease. Scatchard analysis indicates that both age- and disease-related decrements represent a decrease in receptor number.     

Altered blood-brain-barrier function in Alzheimer's disease?

Alzheimer's disease (AD) and vascular dementia (VD) are the two most common causes of dementia. As yet, no definitive biological antemortem marker has been established for differential diagnosis of AD or VD. In this study, proteins of cerebrospinal fluid (CSF) from AD, VD and control patients were analyzed by two-dimensional (2-D) electrophoresis with immobilized pH gradients in the first dimension. No specific changes for AD or VD could be detected in the 2-D CSF patterns. However, a spot of haptoglobin alpha-1 chains (13.5 kDa; approximate pI 4.6) was found to be present in the majority of 2-D CSF maps from the dementia cases, suggesting a high-molecular-weight transudate type of alteration in the blood-brain barrier with considerable frequency in AD.     

Altered angioarchitecture in selected areas of brains with Alzheimer's disease

Summary It was the aim of this study to determine, qualitatively and quantitatively, alterations in the blood vessels of brains removed postmortem from patients with Alzheimer's disease (AD), and to compare these findings with the appearance of cerebral blood vessels in a group of individuals without brain disorders. Celloidin sections of brain tissue from four cerebral areas, pre-frontal (Brodmann's area 9), basal forebrain, sensorimotor, and hippocampus, were subjected to an alkaline phosphatase reaction to facilitate the evaluation of the vascular distribution. The vascular density in five sections was determined by counting the number of vascular intersections with a microscopic test grid of 100 squares; ten fields per section were examined in this manner. Analysis of 16 AD and 6 control brains, showed that there was a striking and statistically significant reduction in the vascular net density specifically in the basal forebrain region and the hippocampus of AD brains. In addition, vessels in the AD brains exhibited extensive topographical changes, such as kinking and looping. These results indicate that modifications in vascular density are present in AD brains with a marked regional specificity.Supported in part by the St. Louis Alzheimer's Disease and Related Disorders Association and the Department of Community Medicine. St. Louis University Medical Center     

EEG dynamics in patients with Alzheimer's disease.

Alzheimer's disease (AD) is the most common neurodegenerative disorder characterized by cognitive and intellectual deficits and behavior disturbance. The electroencephalogram (EEG) has been used as a tool for diagnosing AD for several decades. The hallmark of EEG abnormalities in AD patients is a shift of the power spectrum to lower frequencies and a decrease in coherence of fast rhythms. These abnormalities are thought to be associated with functional disconnections among cortical areas resulting from death of cortical neurons, axonal pathology, cholinergic deficits, etc. This article reviews main findings of EEG abnormalities in AD patients obtained from conventional spectral analysis and nonlinear dynamical methods. In particular, nonlinear alterations in the EEG of AD patients, i.e. a decreased complexity of EEG patterns and reduced information transmission among cortical areas, and their clinical implications are discussed. For future studies, improvement of the accuracy of differential diagnosis and early detection of AD based on multimodal approaches, longitudinal studies on nonlinear dynamics of the EEG, drug effects on the EEG dynamics, and linear and nonlinear functional connectivity among cortical regions in AD are proposed to be investigated. EEG abnormalities of AD patients are characterized by slowed mean frequency, less complex activity, and reduced coherences among cortical regions. These abnormalities suggest that the EEG has utility as a valuable tool for differential and early diagnosis of AD.     

Growth hormone response to edrophonium in patients with Alzheimer's disease and normal control subjects

The authors found that growth hormone (GH) response to edrophonium was no different in 12 Alzheimer's disease patients than in eight healthy elderly subjects. Previously reported differences could be due to differences in gender or baseline GH concentrations between patients and control subjects.     

Altered deactivation in individuals with genetic risk for Alzheimer's disease

Regions that show task-induced deactivations may be part of a default-mode network related to processes that are more engaged during passive than active task conditions. Alteration of task-induced deactivations with age and dementia is indicated by atypical engagement of default-mode network regions. Genetic studies show a relation between the apolipoprotein E4 (APOE4) allele and the common form of Alzheimer's disease (AD), and altered functional brain activation has been observed in non-demented APOE4 carriers compared to non-carriers. Here we investigate the hypothesis of altered default-mode network brain responses in individuals with genetic risk for AD. Functional MRI was used to assess task-induced deactivation in 60 subjects of which 30 carried at least one copy of the APOE4 allele, and 30 non-carriers. Subjects were scanned while performing a semantic categorization task shown to promote episodic memory encoding. The results show patterns of deactivation consistent with the default-mode network. We also found reduced deactivation in non-demented APOE4 carriers compared to non-carriers, suggesting alterations in the default-mode network in the absence of dementia. These results implicate possibilities for investigating altered properties of task-induced deactivations in individuals with genetic risk for AD, and may prove useful for pre-clinical identification of individuals susceptible to memory problems and AD.     

Altered corticomotor representation in patients with Parkinson's disease.

In 6 patients with Parkinson's disease (PD) and 6 age-matched controls, transcranial magnetic stimulation was applied at 56 regions over the motor cortex and premotor cortex of each hemisphere, with the first dorsal interosseous (FDI) muscle of both hands activated at 15% maximum voluntary contraction during stimulation. For each site, motor evoked potential (MEP) landmarks were recovered, including MEP amplitude, MEP onset latency, and silent period duration. Scaled MEP amplitudes were used to construct individual cortical maps of the FDI muscles. The maps revealed an anterior displacement of the muscle representation in PD patients. This anterior shift over motor cortical areas may reflect increased contributions of corticocortical connections between motor cortex and premotor cortical areas, possibly enhanced by the visual feedback aspect of the task. These alterations may reflect adaptations to the impairments in striatocortical circuits in PD.     

Altered phosphofructokinase mRNA levels but unchanged isoenzyme pattern in brains from patients with Alzheimer's disease

In order to find out whether the increased phosphofructokinase (PFK) activities observed in brains from Alzheimer's disease (AD) patients are associated with alterations in PFK mRNA levels, we determined total PFK mRNA and the three different PFK isoenzyme mRNAs in AD and control patients by ribonuclease protection assay (RPA) and quantitative RT-PCR. PFK mRNA levels were found increased in some brain areas in AD patients. While all three PFK isoenzyme mRNAs were detectable in every studied brain sample, no changes of the PFK isoenzyme pattern were observed in patients with AD.