Current Alzheimer Research (v.7, #6)

Alzheimer's Disease: SPECT and PET Tracers for Beta-Amyloid Imaging by V. Valotassiou, S. Archimandritis, N. Sifakis, J. Papatriantafyllou, P. Georgoulias (477-486).
The definite diagnosis of Alzheimer's disease (AD) is based on the detection of beta amyloid (Aand#946;) plaques and neurofibrillary tangles (NFTs) - which are the pathological hallmarks of the disease- in the postmortem brains. Although regional Cerebral Blood Flow (rCBF) and Cerebral Glucose Metabolism (CGM) abnormalities have already been studied in AD patients with Single Photon Emission Computed Tomography (SPECT) and Positron Emission Tomography (PET), the development of specific imaging agents for direct mapping of Aand#946; plaques in the living brain, is a great challenge. Aand#946; probes could significantly contribute to the early diagnosis of AD, the elucidation of the underlying neuropathological processes and the evaluation of anti-amyloid therapies which are currently under investigation. The development of SPECT and PET tracers for Aand#946; imaging represents an active area in radiopharmaceutical design. A substantial number of potential Aand#946; imaging radioligands have been designed and used in-vitro. They are either monoclonal antibodies to Aand#946; and radiolabeled Aand#946; peptides, or derivatives of histopathological stains such as Congo red (CR), chrysamine-G (CG) and Thioflavin T (TT). Though, only few of them, that display high binding affinity to Aand#946; as well as sufficient brain penetration, have been used primarily in in-vivo studies and to a smaller degree on human subjects. Since Aand#946; plaques are not homogenous and contain multiple binding sites that can accommodate structurally diverse compounds, they offer flexibility in designing various different probes, as potential amyloid imaging agents.

Diagnosis of Alzheimer's Disease from EEG Signals: Where Are We Standing? by J. Dauwels, F. Vialatte, A. Cichocki (487-505).
This paper reviews recent progress in the diagnosis of Alzheimer's disease (AD) from electroencephalograms (EEG). Three major effects of AD on EEG have been observed: slowing of the EEG, reduced complexity of the EEG signals, and perturbations in EEG synchrony. In recent years, a variety of sophisticated computational approaches has been proposed to detect those subtle perturbations in the EEG of AD patients. The paper first describes methods that try to detect slowing of the EEG. Next the paper deals with several measures for EEG complexity, and explains how those measures have been used to study fluctuations in EEG complexity in AD patients. Then various measures of EEG synchrony are considered in the context of AD diagnosis. Also the issue of EEG preprocessing is briefly addressed. Before one can analyze EEG, it is necessary to remove artifacts due to for example head and eye movement or interference from electronic equipment. Pre-processing of EEG has in recent years received much attention. In this paper, several state-of-the-art pre-processing techniques are outlined, for example, based on blind source separation and other non-linear filtering paradigms. In addition, the paper outlines opportunities and limitations of computational approaches for diagnosing AD based on EEG. At last, future challenges and open problems are discussed.

Loss of norepinephrine (NE) releasing neurons, in the locus coeruleus of the brainstem, is well documented to occur in Alzheimer's disease (AD). However, this process does not necessarily result in decreased release of NE, since compensatory mechanisms may produce increased release of this neurotransmitter. Independent of potential loss of locus coeruleus cells, brain NE levels may be elevated in some persons with AD, both before and during disease progression. Here I examine evidence that elevated, endogenous brain NE is an etiological factor in some cases of AD, and not merely an epiphenomenon of the disease. To explore this etiological hypothesis in AD, I examine the following eight lines of evidence: 1) direct evidence of elevated NE or its metabolites in AD; 2) studies of tricyclic antidepressants, which may principally boost NE; 3) studies of clonidine and other alpha2 adrenergic agonist drugs, which may principally lower the concentration of NE; 4) studies of beta adrenoceptor blocking drugs, including propranolol; 5) comorbidity of AD and bipolar disorder, where both disorders may involve elevated NE; 6) comorbidity of AD and hypertension; 7) comorbidity of AD and obesity; and 8) potential interaction between AD and psychological stress, where stressors are known to release NE. These lines of evidence tend to support the elevated NE etiological hypothesis.

Objective The study aimed to describe the prevalence of Neuropsychiatric symptoms (NPS) in Alzheimer's disease (AD), amnestic mild cognitive impairment (MCI) and controls using the 12-item Neuropsychiatric Inventory (NPI) and to analyze the relationships between neuropsychiatric symptoms with specific neuropsychological tests.Patients and methods; We prospectively studied 485 patients from the Memory Unit in Cruces Hospital (Spain), 344 met the criteria of NINCDS-ADRDA for probable AD (99 were classified as mild and 245 as moderate-severe), 91 for MCI and 50 were controls. Mini-mental State Examination (MMSE) and CDR (Clinical Dementia Rating) were used to evaluate global cognitive function and to classify the severity of cognitive impairment. The neuropsychological test battery included memory test, verbal fluency, visuoespatial skills and daily living scales. The 12-items Neuropsychiatric Inventory (NPI) version was used to assess neuropsychiatric symptoms. All patients underwent a neuroimaging study (CT scan and/or MRI). Patients were not treated with antidementia or psychotropic drugs. Results;Apathy and depression were more prevalent NPS in moderate-severe AD (78.4and#x25; and 44.1and#x25;, respectively), mild AD (64.6and#x25; and 41.4and#x25;, respectively) and MCI (50.5and#x25; and 33and#x25;, respectively) patients than in controls (6and#x25; and 8and#x25;, respectively). The prevalence and the mean scores of all symptoms increased along the severity of the disease, except for sleep and appetite disorders. In patients with mild AD a relationship was found between the presence of NPS and RDRS-2 scale (p = 0.003); and between NPS and RDRS-2 (p = 0.029) and SS-IQCODE scales (p = 0.039) in moderate-severe patients.Conclusions; NPS were more prevalent in AD and MCI patients than in controls. In AD and MCI patients apathy and depression were the most prevalent NPS. The prevalence and the mean scores of all symptoms gradually increased along the severity of the disease, except for sleep and appetite disorders. We have no found a relationship between neuropsycological test and the presence of NPS, but in patients with mild and moderate-severe AD there is a relationship with daily living scales.

Impacts of Hyper-Homocysteinemia and White Matter Hyper-Intensity in Alzheimer's Disease Patients with Normal Creatinine: An MRI-Based Study with Longitudinal Follow-up by C. W. Huang, W. N. Chang, C. C. Lui, C. F. Chen, C. H. Lu, Y. L. Wang, C. Chen, Y. Y. Juang, Y. T. Lin, M. C. Tu, C. C. Chang (527-533).
Background: White matter hyper-intensities (WMHs) on magnetic resonance imaging (MRI) are commonly found in Alzheimer's disease (AD). Cerebro-vascular risk factors including plasma total homocysteine (tHcy) may result in WMHs. This study examined the association between tHcy and WMHs, and their effects on cognitive functions in AD patients over a two-year follow-up period. Methods: One hundred and fifty-seven AD patients with a clinical dementia rating of 1 or 2 were enrolled and follow-up for two years. tHcy, biochemistry tests, and mini-mental state examination (MMSE) scores were collected. WMHs were visually rated on brain MRI and classified as deep white matter hyper-intensities (DWMHs) or peri-ventricular white matter hyper-intensities (PWMHs). MMSEs were performed every six months to survey cognitive decline. Results: In the cross sectional study, tHcy was significantly associated with total WMHs especially in DWMHs even after adjusting for age and other cerebrovascular risk factors. Initial MMSE was inversely correlated with WMH severity but not with tHcy level. In the longitudinal analysis, no differences were found either in tHcy or WMHs score in the two AD groups defined by the cognitive decline rate. Conclusions: tHcy is an independent risk factor for developing moderate to severe DWMHs in AD but shows nonsignificant effect on cognitive performance. The close association between high WMH score and poor initial MMSE suggests an additive impact in AD. The long-term effect of elevated tHcy on cognitive decline was not conclusive in the twoyear follow-up period.

Background and Purpuse: Cerebral White matter changes (WMC) are a frequent finding on CT and MRI scans of elderly individuals, particularly in those with vascular risk factors, cerberovascular disease, and cognitive impairment. Methods: 56 subjects were included in the study after the review of reports of more than 200 consecutive brain Computerized Tomography (CT) and magnetic resonance imaging (MRI) examinations from the out-patient and in-patient units of the Department of Geriatric Medicine at Karolinska University Hospital, Huddinge during 2001-2002. MRI was performed using a 1.5 T system and WMC lesions were graded 1-3 using a visual scale. Total-cholesterol (TC), high density lipoprotein (HDL), low density lipoprotein (LDL) and triglyceride (TG) levels were determined using enzymatic techniques after 12 hours overnight fasting. Apo E genotyping was performed as described. Results: Low HDL levels were associated with higher severity of WMC on MRI (p=0.002). Subjects with the Apo E4 allele had higher LDL (p=0.002) and apoB levels (p=0.005). The presence of the Apo E4 allele was higher in the group of subjects with severe WMC (grade 3). However, there was no statistically significant group difference in severity of WMC lesions between carriers and noncarriers of Apo E4 allele. Conclusions: Low HDL is strongly associated with adverse coronary and cerebrovascular outcomes. Our results indicate that low HDL levels are also associated with more severe WMC lesions on MRI. Dietary or medical adjustment of HDL levels could have important implications for treatment and prevention of cerebral WMC, cerebrovascular and neurodegenerative diseases such as stroke and dementia.

Amyloid and#946; (Aand#946;) peptide plays a central role in neuronal apoptosis, promoting oxidative stress, lipid peroxidation, caspase pathway activation and neuronal loss. Our previous study has shown that bone marrow-derived mesenchymal stem cells (BM-MSCs) reduce Aand#946; deposition when transplanted into acutely-induced Alzheimer's disease (AD) mice brain. However, the impact of reduced Aand#946; deposition on memory impairment and apoptosis by BM-MSCs has not yet been investigated. Therefore, the aim of the present study was to investigate the neuroprotective mechanism of BM-MSCs in vitro and in vivo. We found that BM-MSCs attenuated Aand#946;-induced apoptotic cell death in primary cultured hippocampal neurons by activation of the cell survival signaling pathway. These anti-apoptotic effects of BM-MSCs were also observed in an acutely-induced AD mice model produced by injecting Aand#946; intrahippocampally. In addition, BM-MSCs diminished Aand#946;-induced oxidative stress and spatial memory impairment in the in vivo model. These findings lead us to hypothesize that BM-MSCs ameliorate Aand#946;-induced neurotoxicity and cognitive decline by inhibiting apoptotic cell death and oxidative stress in the hippocampus. These findings provide support for a potentially beneficial role for BM-MSCs in the treatment of AD.

Ubiquitin Enzymes, Ubiquitin and Proteasome Activity in Blood Mononuclear Cells of MCI, Alzheimer and Parkinson Patients by C. Ullrich, R. Mlekusch, A. Kuschnig, J. Marksteiner, C. Humpel (549-555).
Alzheimer's disease (AD) is a severe chronic neurodegenerative disease. During aging and neurodegeneration, misfolded proteins accumulate and activate the ubiquitin-proteasome system. The aim of the present study is to explore whether ubiquitin-activating enzyme E1, ubiquitin-conjugating enzyme E2, ubiquitin or proteasome activity are affected in peripheral blood mononuclear cells (PBMC) of AD, mild cognitive impairment (MCI) and Parkinson's disease (PD) patients compared to healthy subjects. PBMCs were isolated from EDTA blood samples and extracts were analyzed by Western Blot. Proteasome activity was measured with fluorogenic substrates. When compared to healthy subjects, the concentration of enzyme E1 was increased in PBMCs of AD patients, whereas the concentration of the enzyme E2 was decreased in the same patients. Ubiquitin levels and proteasome activity were unchanged in AD patients. No changes in enzyme expression or proteasome activity was observed in MCI patients compared to healthy and AD subjects. In PD patients E2 levels and proteasomal activity were significantly reduced, while ubiquitin and E1 levels were unchanged. The present investigation demonstrates the differences in enzyme and proteasome activity patterns of AD and PD patients. These results suggest that different mechanisms are involved in regulating the ubiquitin-proteasomal system in different neurodegenerative diseases.

Atheromatosis Extent in Coronary Artery Disease is not Correlated with Apolipoprotein-E Polymorphism and its Plasma Levels, but Associated with Cognitive Decline by L. M. Lima, M.d. G. Carvalho, C. N. Ferreira, A. P. Fernandes, C. P.d.F. Neto, J. C.F. Garcia, H. J. Reis, Z. Janka, A. Palotas, M. d.O. Sousa (556-563).
Background: Apolipoprotein-E (apoE) and#949;4 allele is a known risk factor for Alzheimer's disease (AD). Polymorphism of apoE is also one of the most important genetic markers for coronary artery disease (CAD). The allelic variation in the apoE gene has a significant effect on inter-individual variation of lipids and lipoprotein plasma levels as well. This study investigated whether apoE polymorphism affects the plasma levels of apoE and the possible association to CAD extent and cognitive functions. Methods: Plasma apoE levels and apoE genotypes were evaluated of subjects with normal coronary arteries, and individuals with angiographycally confirmed mild/moderate or severe atheromatosis. The cognitive performance of the volunteers was also measured by mini-mental state examination (MMSE). Results: Out of the 6 expected genotypes, only 5 were detected in participants: E3/3 (56.0and#x25;), E3/4 (23.6and#x25;), E4/4 (8.2and#x25;), E2/4 (3.3and#x25;), E2/3 (8.9and#x25;). The and#949;3 allele (72and#x25;) was the most frequent, followed by and#949;4 (22and#x25;) and and#949;2 (6and#x25;). No difference was found in plasma levels of either apoE or in apoE genotype frequencies among the groups, however MMSE scores of CAD patients irrespective of their atheromatosis extent were significantly lower than that seen in the normal population. Conclusions: Although neither apoE plasma levels, nor apoE polymorphism in patients presenting with mild/moderate or severe atheromatosis showed to be associated with CAD severity, the presence of atheromatosis in the heart vessels positively correlated with cognitive dysfunction.