The contribution of luteinizing hormone to Alzheimer disease pathogenesis.

Clin Med Res. 2007 Sep;5(3):177-83

Authors: Webber KM, Perry G, Smith MA, Casadesus G

Several hypotheses have been proposed that attempt to explain the pathogenesis of Alzheimer Disease (AD) including theories involving senile plaque and neurofibrillary tangle formation, increased oxidative stress, and cell cycle abnormalities, since evidence for each of these pathological phenomena have been well documented in AD. Recent epidemiological and experimental data also support a role for the gonadotropin luteinizing hormone in AD. Paralleling the female predominance for developing AD, luteinizing hormone levels are significantly higher in females as compared to males, and furthermore, luteinizing hormone levels are higher still in individuals who succumb to AD. Luteinizing hormone, which is capable of modulating cognitive behavior, is not only present in the brain, but also has the highest receptor levels in the hippocampus, a key processor of cognition that is severely deteriorated in AD. Furthermore, we recently examined cognitive performance in a well-characterized transgenic mouse that over-expresses luteinizing hormone and found that these animals show decreased cognitive performance when compared to controls. We have also found that abolishing luteinizing hormone in amyloid-beta protein precursor transgenic mice (Tg2576) using a potent gonadotropin-lowering gonadotropin-releasing hormone agonist, leuprolide acetate, resulted in improved hippocampally-related cognitive performance and decreased amyloid-beta deposition. These findings, together with data indicating that luteinizing hormone modulates amyloid-beta protein precursor processing in vivo and in vitro, suggest that luteinizing hormone may contribute to AD pathology through an amyloid-dependent mechanism. These promising findings support the importance of luteinizing hormone in AD and bring to the forefront an alternative, and much needed, therapeutic avenue for the treatment of this insidious disease.

PMID: 18056027 [PubMed - in process]

Cholinesterase inhibitors in mild cognitive impairment: a systematic review of randomised trials.

PLoS Med. 2007 Nov 27;4(11):e338

Authors: Raschetti R, Albanese E, Vanacore N, Maggini M

BACKGROUND: Mild cognitive impairment (MCI) refers to a transitional zone between normal ageing and dementia. Despite the uncertainty regarding the definition of MCI as a clinical entity, clinical trials have been conducted in the attempt to study the role of cholinesterase inhibitors (ChEIs) currently approved for symptomatic treatment of mild to moderate Alzheimer disease (AD), in preventing progression from MCI to AD. The objective of this review is to assess the effects of ChEIs (donepezil, rivastigmine, and galantamine) in delaying the conversion from MCI to Alzheimer disease or dementia. METHODS AND FINDINGS: The terms "donepezil", "rivastigmine", "galantamine", and "mild cognitive impairment" and their variants, synonyms, and acronyms were used as search terms in four electronic databases (MEDLINE, EMBASE, Cochrane, PsycINFO) and three registers: the Cochrane Collaboration Trial Register, Current Controlled Trials, and ClinicalTrials.gov. Published and unpublished studies were included if they were randomized clinical trials published (or described) in English and conducted among persons who had received a diagnosis of MCI and/or abnormal memory function documented by a neuropsychological assessment. A standardized data extraction form was used. The reporting quality was assessed using the Jadad scale. Three published and five unpublished trials met the inclusion criteria (three on donepezil, two on rivastigmine, and three on galantamine). Enrolment criteria differed among the trials, so the study populations were not homogeneous. The duration of the trials ranged from 24 wk to 3 y. No significant differences emerged in the probability of conversion from MCI to AD or dementia between the treated groups and the placebo groups. The rate of conversion ranged from 13% (over 2 y) to 25% (over 3 y) among treated patients, and from 18% (over 2 y) to 28% (over 3 y) among those in the placebo groups. Only for two studies was it possible to derive point estimates of the relative risk of conversion: 0.85 (95% confidence interval 0.64-1.12), and 0.84 (0.57-1.25). Statistically significant differences emerged for three secondary end points. However, when adjusting for multiple comparisons, only one difference remained significant (i.e., the rate of atrophy in the whole brain). CONCLUSIONS: The use of ChEIs in MCI was not associated with any delay in the onset of AD or dementia. Moreover, the safety profile showed that the risks associated with ChEIs are not negligible. The uncertainty regarding MCI as a clinical entity raises the question as to the scientific validity of these trials.

PMID: 18044984 [PubMed - in process]

[ABCA-transporters: regulators of cellular lipid transport]

Tidsskr Nor Laegeforen. 2007 Nov 15;127(22):2930-3

Authors: Piehler AP, Haug KB, Wenzel JJ, Kierulf PB, Kaminski WE

BACKGROUND: The transport of lipids, which is orchestrated by a multitude of molecular factors, is a key feature of the physiology of living cells. A new group of transporter protein, the A-subclass of ATP-binding cassette (ABC) transporters, was recently discovered. ABCA-transporters play pivotal roles in cellular lipid transport and their discovery has brought important new insights into the molecular basis of this process. This review article presents the biology of ABCA-transport proteins and their implication for clinical medicine. MATERIAL AND METHODS: Literature retrieved from Pubmed, including own research results, formed the basis for the article. RESULTS AND INTERPRETATION: Mutations in ABCA-transporter genes have been shown to result in hereditary diseases involving major physiologicical processes in the cardiovascular, respiratory, visual and integumentary systems. Accumulated evidence suggests that ABCA-transporters play critical roles in the pathogenesis of complex multifactorial disorders with a high incidence; such as atherosclerosis, age-related macula degeneration and Alzheimer's disease.

PMID: 18026239 [PubMed - indexed for MEDLINE]

Systematic in vivo analysis of the intrinsic determinants of amyloid Beta pathogenicity.

PLoS Biol. 2007 Oct 30;5(11):e290

Authors: Luheshi LM, Tartaglia GG, Brorsson AC, Pawar AP, Watson IE, Chiti F, Vendruscolo M, Lomas DA, Dobson CM, Crowther DC

Protein aggregation into amyloid fibrils and protofibrillar aggregates is associated with a number of the most common neurodegenerative diseases. We have established, using a computational approach, that knowledge of the primary sequences of proteins is sufficient to predict their in vitro aggregation propensities. Here we demonstrate, using rational mutagenesis of the Abeta42 peptide based on such computational predictions of aggregation propensity, the existence of a strong correlation between the propensity of Abeta42 to form protofibrils and its effect on neuronal dysfunction and degeneration in a Drosophila model of Alzheimer disease. Our findings provide a quantitative description of the molecular basis for the pathogenicity of Abeta and link directly and systematically the intrinsic properties of biomolecules, predicted in silico and confirmed in vitro, to pathogenic events taking place in a living organism.

PMID: 17973577 [PubMed - in process]

ACTIVITY AND SUBCELLULAR TRAFFICKING OF THE SODIUM-COUPLED CHOLINE TRANSPORTER CHT IS REGULATED ACUTELY BY PEROXYNITRITE.

Mol Pharmacol. 2007 Oct 30;

Authors: Pinthong M, Black S, Ribeiro F, Pholpramool C, Ferguson SS, Rylett RJ

Excess formation of nitric oxide and superoxide by-products (peroxynitrite, reactive oxygen and reactive nitrogen species) attenuates cholinergic transmission potentially having a role in Alzheimer disease pathogenesis. In this study, we investigated mechanisms by which acute exposure to peroxynitrite impairs function of the sodium-dependent, hemicholinium-3 (HC-3)-sensitive choline transporter (CHT) that provides substrate for acetylcholine synthesis. The peroxynitrite generator SIN-1 acutely inhibited choline uptake in cells stably-expressing FLAG-tagged rat CHT in a dose- and time-dependent manner with an IC50 = 0.9 +/- 0.14 mM and t1/2 = 4 min. SIN-1 significantly reduced Vmax of choline uptake without altering the Km. This correlated with a SIN-1-induced decrease in cell surface CHT protein, observed as lowered levels of HC-binding and biotinylated-CHT at the plasma membrane. Importantly, acute exposure of cells to SIN-1 accelerated the rate of internalization of CHT from the plasma membrane, but did not alter return of CHT back to the cell surface. SIN-1 did not disrupt cell membrane integrity or cause cell death. Thus, the inhibitory effect of SIN-1 on choline uptake activity and HC-3 binding was related to enhanced internalization of CHT proteins from the plasma membrane to subcellular organelles.

PMID: 17971421 [PubMed - as supplied by publisher]

Valsartan lowers brain beta-amyloid protein levels and improves spatial learning in a mouse model of Alzheimer disease.

J Clin Invest. 2007 Nov;117(11):3393-402

Authors: Wang J, Ho L, Chen L, Zhao Z, Zhao W, Qian X, Humala N, Seror I, Bartholomew S, Rosendorff C, Pasinetti GM

Recent epidemiological evidence suggests that some antihypertensive medications may reduce the risk for Alzheimer disease (AD). We screened 55 clinically prescribed antihypertensive medications for AD-modifying activity using primary cortico-hippocampal neuron cultures generated from the Tg2576 AD mouse model. These agents represent all drug classes used for hypertension pharmacotherapy. We identified 7 candidate antihypertensive agents that significantly reduced AD-type beta-amyloid protein (Abeta) accumulation. Through in vitro studies, we found that only 1 of the candidate drugs, valsartan, was capable of attenuating oligomerization of Abeta peptides into high-molecular-weight (HMW) oligomeric peptides, known to be involved in cognitive deterioration. We found that preventive treatment of Tg2576 mice with valsartan significantly reduced AD-type neuropathology and the content of soluble HMW extracellular oligomeric Abeta peptides in the brain. Most importantly, valsartan administration also attenuated the development of Abeta-mediated cognitive deterioration, even when delivered at a dose about 2-fold lower than that used for hypertension treatment in humans. These preclinical studies suggest that certain antihypertensive drugs may have AD-modifying activity and may protect against progressive Abeta-related memory deficits in subjects with AD or in those at high risk of developing AD.

PMID: 17965777 [PubMed - in process]

BAG-1 Associates with Hsc70{middle dot}Tau Complex and Regulates the Proteasomal Degradation of Tau Protein.

J Biol Chem. 2007 Dec 21;282(51):37276-84

Authors: Elliott E, Tsvetkov P, Ginzburg I

Intraneuronal accumulation of phosphorylated Tau protein is a molecular pathology found in many forms of dementia, including Alzheimer disease. Research into possible mechanisms leading to the accumulation of modified Tau protein and the possibility of removing Tau protein from the system have revealed that the chaperone protein system can interact with Tau and mediate its degradation. Hsp70/Hsc70, a member of the chaperone protein family, interacts with Tau protein and mediates proper folding of Tau and can promote degradation of Tau protein under certain circumstances. However, because Hsp70/Hsc70 has many binding partners that can mediate its activity, there is still much to discover about how Hsp70 acts in vivo to regulate Tau protein. BAG-1, an Hsp70/Hsc70 binding partner, has been implicated as a mediator of neuronal function. In this work we show that BAG-1 associates with Tau protein in an Hsc70-dependent manner. Overexpression of BAG-1 induced an increase in Tau levels, which is shown to be due to an inhibition of protein degradation. We further show that BAG-1 can inhibit the degradation of Tau protein by the 20 S proteasome but does not affect the ubiquitination of Tau protein. RNA-mediated interference depletion of BAG-1 leads to a decrease in total Tau protein levels as well as promoting hyperphosphorylation of the remaining protein. Induction of Hsp70 by heat shock enhanced the increase of Tau levels in cells overexpressing BAG-1 but induced a decrease of Tau levels in cells that were depleted of BAG-1. Finally, BAG-1 is highly expressed in neurons bearing Tau tangles in a mouse model of Alzheimer disease. This data suggests a molecular mechanism through which Tau protein levels are regulated in the cell and possible consequences for the pathology and treatment of Alzheimer disease.

PMID: 17954934 [PubMed - in process]

Signal Peptide Peptidase and {gamma}-Secretase Share Equivalent Inhibitor Binding Pharmacology.

J Biol Chem. 2007 Dec 21;282(51):36829-36

Authors: Iben LG, Olson RE, Balanda LA, Jayachandra S, Robertson BJ, Hay V, Corradi J, Prasad CV, Zaczek R, Albright CF, Toyn JH

The enzyme gamma-secretase has long been considered a potential pharmaceutical target for Alzheimer disease. Presenilin (the catalytic subunit of gamma-secretase) and signal peptide peptidase (SPP) are related transmembrane aspartyl proteases that cleave transmembrane substrates. SPP and gamma-secretase are pharmacologically similar in that they are targeted by many of the same small molecules, including transition state analogs, non-transition state inhibitors, and amyloid beta-peptide modulators. One difference between presenilin and SPP is that the proteolytic activity of presenilin functions only within a multisubunit complex, whereas SPP requires no additional protein cofactors for activity. In this study, gamma-secretase inhibitor radioligands were used to evaluate SPP and gamma-secretase inhibitor binding pharmacology. We found that the SPP enzyme exhibited distinct binding sites for transition state analogs, non-transition state inhibitors, and the nonsteroidal anti-inflammatory drug sulindac sulfide, analogous to those reported previously for gamma-secretase. In the course of this study, cultured cells were found to contain an abundance of SPP binding activity, most likely contributed by several of the SPP family proteins. The number of SPP binding sites was in excess of gamma-secretase binding sites, making it essential to use selective radioligands for evaluation of gamma-secretase binding under these conditions. This study provides further support for the idea that SPP is a useful model of inhibitory mechanisms and structure in the SPP/presenilin protein family.

PMID: 17932033 [PubMed - in process]

Beta-amyloid imaging and memory in non-demented individuals: evidence for preclinical Alzheimer's disease.

Brain. 2007 Nov;130(Pt 11):2837-44

Authors: Pike KE, Savage G, Villemagne VL, Ng S, Moss SA, Maruff P, Mathis CA, Klunk WE, Masters CL, Rowe CC

Beta-amyloid (Abeta) deposition is pathognomic for Alzheimer's disease (AD), but may occur in normal elderly people without apparent cognitive effect. Episodic memory impairment is an early and prominent sign of AD, but its relationship with Abeta burden in non-demented persons and in AD patients is unclear. We examined this relationship using 11C-PIB-PET as a quantitative marker of Abeta burden in vivo in healthy ageing (HA), mild cognitive impairment (MCI) and AD. Thirty-one AD, 33 MCI and 32 HA participants completed neuropsychological assessment and a 11C-PIB-PET brain scan. Multiple linear regression analyses were conducted relating episodic memory performance and other cognitive functions to Abeta burden. Ninety-seven percent of AD, 61% of MCI and 22% of HA cases had increased cortical PIB binding, indicating the presence of Abeta plaques. There was a strong relationship between impaired episodic memory performance and PIB binding, both in MCI and HA. This relationship was weaker in AD and less robust for non-memory cognitive domains. Abeta deposition in the asymptomatic elderly is associated with episodic memory impairment. This finding, together with the strong relationship between PIB binding and the severity of memory impairment in MCI, suggests that individuals with increased cortical PIB binding are on the path to Alzheimer's disease. The data also suggests that early intervention trials for AD targeted to non-demented individuals with cerebral Abeta deposition are warranted.

PMID: 17928318 [PubMed - indexed for MEDLINE]

Neurofurans: Novel indices of oxidant stress derived from docosahexaenoic acid.

J Biol Chem. 2007 Oct 6;

Authors: Song WL, Lawson JA, Reilly D, Rokach J, Chang CT, Giasson B, Fitzgerald GA

Isoeicosanoids are free radical catalyzed isomers of the enzymatic products of arachidonic acid (AA). They are formed in situ in cell membranes, are cleaved, circulate and are excreted in urine. Isomers of prostaglandin F(2a) - the F(2)-isoprostanes (iPs) have emerged as sensitive indices of lipid peroxidation in vivo. Analogous compounds formed from docosahexaenoic acid (DHA) are termed neuroprostanes (nPs) and are more abundant than iPs in brain. Isofurans (iFs) are another class of isoeicosanoids characterized by a substituted tetrahydrofuran ring. They are preferentially formed, relative to iPs, under conditions of elevated oxygen tension. Here, we report the discovery of neurofurans (nFs), the analogous family of compounds formed from DHA. Formation of nFs is characterized by mass spectrometry and confirmed by oxidation of DHA in vitro and following CCl(4) administration in liver in vivo. It is demonstrated that the levels of nFs are elevated in the brain cortex of a mouse model of Alzheimer disease and are depressed in the brain cortex by deletion of p47phox, an essential component of the phagocyte NADPH oxidase. Measurement of the nFs may ultimately prove useful in diagnosis, timing and selection of dose in the treatment and chemoprevention of neurodegenerative disease.

PMID: 17921521 [PubMed - as supplied by publisher]

Fibril specific, conformation dependent antibodies recognize a generic epitope common to amyloid fibrils and fibrillar oligomers that is absent in prefibrillar oligomers.

Mol Neurodegener. 2007;2:18

Authors: Kayed R, Head E, Sarsoza F, Saing T, Cotman CW, Necula M, Margol L, Wu J, Breydo L, Thompson JL, Rasool S, Gurlo T, Butler P, Glabe CG

ABSTRACT: BACKGROUND: Amyloid-related degenerative diseases are associated with the accumulation of misfolded proteins as amyloid fibrils in tissue. In Alzheimer disease (AD), amyloid accumulates in several distinct types of insoluble plaque deposits, intracellular Abeta and as soluble oligomers and the relationships between these deposits and their pathological significance remains unclear. Conformation dependent antibodies have been reported that specifically recognize distinct assembly states of amyloids, including prefibrillar oligomers and fibrils. RESULTS: We immunized rabbits with a morphologically homogeneous population of Abeta42 fibrils. The resulting immune serum (OC) specifically recognizes fibrils, but not random coil monomer or prefibrillar oligomers, indicating fibrils display a distinct conformation dependent epitope that is absent in prefibrillar oligomers. The fibril epitope is also displayed by fibrils of other types of amyloids, indicating that the epitope is a generic feature of the polypeptide backbone. The fibril specific antibody also recognizes 100,000 x G soluble fibrillar oligomers ranging in size from dimer to greater than 250 kDa on western blots. The fibrillar oligomers recognized by OC are immunologically distinct from prefibrillar oligomers recognized by A11, even though their sizes overlap broadly, indicating that size is not a reliable indicator of oligomer conformation. The immune response to prefibrillar oligomers and fibrils is not sequence specific and antisera of the same specificity are produced in response to immunization with islet amyloid polypeptide prefibrillar oligomer mimics and fibrils. The fibril specific antibodies stain all types of amyloid deposits in human AD brain. Diffuse amyloid deposits stain intensely with anti-fibril antibody although they are thioflavin S negative, suggesting that they are indeed fibrillar in conformation. OC also stains islet amyloid deposits in transgenic mouse models of type II diabetes, demonstrating its generic specificity for amyloid fibrils. CONCLUSION: Since the fibril specific antibodies are conformation dependent, sequence-independent, and recognize epitopes that are distinct from those present in prefibrillar oligomers, they may have broad utility for detecting and characterizing the accumulation of amyloid fibrils and fibrillar type oligomers in degenerative diseases.

PMID: 17897471 [PubMed - in process]

Molecular basis for passive immunotherapy of Alzheimer's disease.

Proc Natl Acad Sci U S A. 2007 Oct 2;104(40):15659-64

Authors: Gardberg AS, Dice LT, Ou S, Rich RL, Helmbrecht E, Ko J, Wetzel R, Myszka DG, Patterson PH, Dealwis C

Amyloid aggregates of the amyloid-beta (Abeta) peptide are implicated in the pathology of Alzheimer's disease. Anti-Abeta monoclonal antibodies (mAbs) have been shown to reduce amyloid plaques in vitro and in animal studies. Consequently, passive immunization is being considered for treating Alzheimer's, and anti-Abeta mAbs are now in phase II trials. We report the isolation of two mAbs (PFA1 and PFA2) that recognize Abeta monomers, protofibrils, and fibrils and the structures of their antigen binding fragments (Fabs) in complex with the Abeta(1-8) peptide DAEFRHDS. The immunodominant EFRHD sequence forms salt bridges, hydrogen bonds, and hydrophobic contacts, including interactions with a striking WWDDD motif of the antigen binding fragments. We also show that a similar sequence (AKFRHD) derived from the human protein GRIP1 is able to cross-react with both PFA1 and PFA2 and, when cocrystallized with PFA1, binds in an identical conformation to Abeta(1-8). Because such cross-reactivity has implications for potential side effects of immunotherapy, our structures provide a template for designing derivative mAbs that target Abeta with improved specificity and higher affinity.

PMID: 17895381 [PubMed - indexed for MEDLINE]

The evaluation of disability and its related factors among the elderly population in Kashan, Iran.

BMC Public Health. 2007;7:261

Authors: Adib-Hajbaghery M, Aghahoseini S

BACKGROUND: Recent literature indicates that developing countries in Asia are aging faster than other countries in the world and disability has become one of the greater public health concern in these countries. Pausity of published data on the elderly disability in Iran signifies the importance of this study designed to evaluate the disability and its related factors among the elderly population in Kashan, Iran during 2006-2007. METHODS/DESIGN: A cross-sectional study is conducting on a multi-stage random sample of elderly people in Kashan ages 65 years and older. Volunteer participants were included by age 65 and older and excluded if they had the medical diagnosis of Alzheimer disease. The WHO DAS II was used as the generic disability measure in this survey. The original version of WHO DAS II was translated into Farsi according to the standardized guidelines for cross-cultural adaptation of health-related measures. Upon completion of data collection the descriptive statistics will compute all the variables. Chi-square, t-test analysis and ANOVA will be used to examine significant differences between the subgroups. DISCUSSION: This is the first research protocol to study disability among the Iranian elderly population. Presently, 80% of eligible subjects have been selected. The results of this study will help to develop more effective protocols to assist Iranian elderly population with disabilities.

PMID: 17888171 [PubMed - indexed for MEDLINE]

Calcium-sensitive regulation of monoamine oxidase-A contributes to the production of peroxyradicals in hippocampal cultures: implications for Alzheimer disease-related pathology.

BMC Neurosci. 2007;8:73

Authors: Cao X, Wei Z, Gabriel GG, Li X, Mousseau DD

BACKGROUND: Calcium (Ca2+) has recently been shown to selectively increase the activity of monoamine oxidase-A (MAO-A), a mitochondria-bound enzyme that generates peroxyradicals as a natural by-product of the deamination of neurotransmitters such as serotonin. It has also been suggested that increased intracellular free Ca2+ levels as well as MAO-A may be contributing to the oxidative stress associated with Alzheimer disease (AD). RESULTS: Incubation with Ca2+ selectively increases MAO-A enzymatic activity in protein extracts from mouse hippocampal HT-22 cell cultures. Treatment of HT-22 cultures with the Ca2+ ionophore A23187 also increases MAO-A activity, whereas overexpression of calbindin-D28K (CB-28K), a Ca2+-binding protein in brain that is greatly reduced in AD, decreases MAO-A activity. The effects of A23187 and CB-28K are both independent of any change in MAO-A protein or gene expression. The toxicity (via production of peroxyradicals and/or chromatin condensation) associated with either A23187 or the AD-related beta-amyloid peptide, which also increases free intracellular Ca2+, is attenuated by MAO-A inhibition in HT-22 cells as well as in primary hippocampal cultures. CONCLUSION: These data suggest that increases in intracellular Ca2+ availability could contribute to a MAO-A-mediated mechanism with a role in AD-related oxidative stress.

PMID: 17868476 [PubMed - in process]

[Protection of Tianshen Yizhi Recipe against low expression of nicotinic receptor and neurotoxicity induced by beta-amyloid peptide]

Zhong Xi Yi Jie He Xue Bao. 2007 Sep;5(5):564-9

Authors: Gu R, Liu RY, Zhang LJ, Hao XY, Xiao Y, Qi XL, Shan KR, Ren XL, Luo J, Guan ZZ

OBJECTIVE: To investigate the inhibition effects of Tianshen Yizhi Recipe (TSYZR), a compound traditional Chinese herbal medicine, on decreased expression of nicotinic acetylcholine receptor (nAChR) and the neurotoxicity as well as lipid peroxidation induced by beta-amyloid peptide (Abeta) in human SH-SY5Y neuroblastoma cells. METHODS: The SH-SY5Y cells were treated by a certain concentration of TSYZR, and then exposed to Abeta(25-35). Methyl thiazolyl tetrazolium reduction assay was carried out to understand the influences of the drugs on cellular viability. Expressions of nAChR subunits (alpha3 and alpha7) at protein and mRNA levels were detected by Western-blotting and reverse transcription polymerase chain reaction, respectively. Lipid peroxidation was measured by thiobarbituric acid to observe the capacity of antioxidant of the drugs. RESULTS: TSYZR at a safe concentration could increase alpha7 protein in the cells, inhibit decreased expressions of alpha3 and alpha7 nAChR subunit proteins, prevent lower expression of alpha7 mRNA in SH-SY5Y cells induced by Abeta, reduce the neurotoxicity and lipid peroxidation resulting from Abeta, but had no significant effect on the lower expression of alpha3 mRNA. CONCLUSIONS: TSYZR can up-regulate the expression of alpha7 nAChR subunit protein and prevent decreased expressions of nAChRs and neurotoxicity as well as lipid peroxidation induced by Abeta. This drug may play an important therapeutic role in treatment of Alzheimer disease.

PMID: 17854561 [PubMed - in process]

[Prefrontal cortex: implications for memory functions and dementia]

Turk Psikiyatri Derg. 2007;18(3):262-9

Authors: Erberk Ozen N, Rezaki M

OBJECTIVE: The prefrontal cortex (PFC), which is one of the most complex areas of the human brain, is a frontal lobe segment that is consistently implicated in motor behaviors. In recent years it has been suggested that it is involved in memory functions via its diffuse anatomical networks. In this review, it was aimed to summarize the recent literature about PFC neuroanatomy, and its role in memory, normal aging, and dementias. METHOD: We retrospectively reviewed the literature, including recent relevant studies. In addition, textbooks were included for essential themes. PubMed and the Google search engine were used, and the keywords chosen for searches were: prefrontal cortex, dementia/types, and memory. RESULTS: Although the PFC has considerable cognitive and social functions, only minor cognitive dysfunction is observed when the frontal lobes are severely damaged. It is possible to say that the memory deficits could be masked by rigorous behavioral symptoms. The PFC has a critical role in memory retrieval. There is growing evidence that the PFC is involved not only in frontal lobe-type dementias, but also Alzheimer disease, mild cognitive impairment, and normal aging. The psychiatric and behavioral symptoms in such cases may be related to PFC dysfunction. CONCLUSION: Memory-related disorders are commonly associated with the frontal lobes and PFC. It may be considered that different parts of the PFC are related to different memory types and memory dysfunctions. Further studies with advanced neuroimaging techniques and valid animal models for all types and stages of dementias will help us to understand the role of the PFC in memory, physiology, and pathologies.

PMID: 17853981 [PubMed - indexed for MEDLINE]

[The delayed word recall task using ADAS-Jcog word booklet effectively divides patients with mild cognitive impairment from normal elderly people]

Nippon Ronen Igakkai Zasshi. 2007 Jul;44(4):490-6

Authors: Kawano N, Umegaki H, Suzuki Y, Yamamoto S, Mogi N, Iguchi A

AIM: A new screening test for detecting mild cognitive impairment (MCI) with higher sensitivity that can easily be administered at the bedside is necessary. In this study, we proposed the delayed recall task using the word booklet of Alzheimer's Disease Assessment Scale-cognitive component-Japanese version (ADAS-Jcog) and compared the score of the task in patients with MCI with that of cognitive normal elderly (NE) and patients with AD. METHODS: Thirty six patients with MCI, 13 very mild AD, 104 mild AD, 13 moderate AD, and age- and education-matched 19 NE, recruited from the memory clinic of Nagoya University Hospital, were evaluated by the ADAS-Jcog word recall task which consisted of immediate recall (IR), a classical method on ADAS-Jcog, and delayed recall (DR) that has been newly introduced. RESULTS: Compared with controls, patients with MCI were significantly impaired on both IR and DR. On the other hand, DR is more sensitive than IR for distinguishing MCI from NE. The highest sensitivity (94.4%) and specificity (68.4%) were achieved when the results of IR were combined with those of DR. CONCLUSION: The result suggests that the delayed word recall task using the word booklet of ADAS-Jcog may be a useful tool as a screening method for the detection of MCI.

PMID: 17827808 [PubMed - indexed for MEDLINE]

[The benefit of angiotensin converting enzyme inhibitor for geriatric syndrome in the elderly]

Nippon Ronen Igakkai Zasshi. 2007 Jul;44(4):448-51

Authors: Ebihara T, Ohrui T, Ebihara S, Tsuji I, Sasaki H, Arai H

Angiotensin converting enzyme (ACE) inhibitor plays an important role not only as an antihypertensive drug but also for prevention of various complications related to geriatric syndrome. Pneumonia in the disabled elderly is mostly due to silent aspiration of oropharyngeal bacterial pathogens to the lower respiratory tract. Aspiration is related to the dysfunction of dopaminergic neurons by cerebrovascular disease, resulting in impairments in both the swallowing and cough reflexes. ACE inhibitor can increase in the sensitivity of the cough reflex particularly in older post-menopausal women, and improvement of the swallowing reflex. In a 2-year follow-up study in stroke patients, patients who did not receive ACE inhibitors had a higher risk of mortality due to pneumonia than in stroke patients who were treated with ACE inhibitor. Moreover, the mortality of pneumonia was significantly lower in older hypertensive patients given ACE inhibitors than in those treated with other antihypertensive drugs. On the other hand, we found a new benefit of ACE inhibitor on the central nervous system. The mortality in Alzheimer's disease patients who received brain-penetrating ACE inhibitor was lower than in those who received other antihypertensive drugs. In a 1-year follow-up study, cognitive decline was lower in patients receiving brain-penetrating ACE inhibitors than in patients receiving a non-brain-penetrating ACE inhibitor or a calcium channel blocker. Brain-penetrating ACE inhibitors may slow cognitive decline in patients with mild to moderate Alzheimer's disease. ACE inhibitor might be effective for the disabled elderly, resulting in the prevention of aspiration pneumonia and Alzheimer's disease for the elderly.

PMID: 17827800 [PubMed - indexed for MEDLINE]

A novel p38 alpha MAPK inhibitor suppresses brain proinflammatory cytokine up-regulation and attenuates synaptic dysfunction and behavioral deficits in an Alzheimer's disease mouse model.

J Neuroinflammation. 2007;4:21

Authors: Munoz L, Ranaivo HR, Roy SM, Hu W, Craft JM, McNamara LK, Chico LW, Van Eldik LJ, Watterson DM

BACKGROUND: An accumulating body of evidence is consistent with the hypothesis that excessive or prolonged increases in proinflammatory cytokine production by activated glia is a contributor to the progression of pathophysiology that is causally linked to synaptic dysfunction and hippocampal behavior deficits in neurodegenerative diseases such as Alzheimer's disease (AD). This raises the opportunity for the development of new classes of potentially disease-modifying therapeutics. A logical candidate CNS target is p38 alpha MAPK, a well-established drug discovery molecular target for altering proinflammatory cytokine cascades in peripheral tissue disorders. Activated p38 MAPK is seen in human AD brain tissue and in AD-relevant animal models, and cell culture studies strongly implicate p38 MAPK in the increased production of proinflammatory cytokines by glia activated with human amyloid-beta (A beta) and other disease-relevant stressors. However, the vast majority of small molecule drugs do not have sufficient penetrance of the blood-brain barrier to allow their use as in vivo research tools or as therapeutics for neurodegenerative disorders. The goal of this study was to test the hypothesis that brain p38 alpha MAPK is a potential in vivo target for orally bioavailable, small molecules capable of suppressing excessive cytokine production by activated glia back towards homeostasis, allowing an improvement in neurologic outcomes. METHODS: A novel synthetic small molecule based on a molecular scaffold used previously was designed, synthesized, and subjected to analyses to demonstrate its potential in vivo bioavailability, metabolic stability, safety and brain uptake. Testing for in vivo efficacy used an AD-relevant mouse model. RESULTS: A novel, CNS-penetrant, non-toxic, orally bioavailable, small molecule inhibitor of p38 alpha MAPK (MW01-2-069A-SRM) was developed. Oral administration of the compound at a low dose (2.5 mg/kg) resulted in attenuation of excessive proinflammatory cytokine production in the hippocampus back towards normal in the animal model. Animals with attenuated cytokine production had reductions in synaptic dysfunction and hippocampus-dependent behavioral deficits. CONCLUSION: The p38 alpha MAPK pathway is quantitatively important in the A beta-induced production of proinflammatory cytokines in hippocampus, and brain p38 alpha MAPK is a viable molecular target for future development of potential disease-modifying therapeutics in AD and related neurodegenerative disorders.

PMID: 17784957 [PubMed - indexed for MEDLINE]

In vitro and in vivo neurotoxicity of prion protein oligomers.

PLoS Pathog. 2007 Aug 31;3(8):e125

Authors: Simoneau S, Rezaei H, Salès N, Kaiser-Schulz G, Lefebvre-Roque M, Vidal C, Fournier JG, Comte J, Wopfner F, Grosclaude J, Schätzl H, Lasmézas CI

The mechanisms underlying prion-linked neurodegeneration remain to be elucidated, despite several recent advances in this field. Herein, we show that soluble, low molecular weight oligomers of the full-length prion protein (PrP), which possess characteristics of PrP to PrPsc conversion intermediates such as partial protease resistance, are neurotoxic in vitro on primary cultures of neurons and in vivo after subcortical stereotaxic injection. Monomeric PrP was not toxic. Insoluble, fibrillar forms of PrP exhibited no toxicity in vitro and were less toxic than their oligomeric counterparts in vivo. The toxicity was independent of PrP expression in the neurons both in vitro and in vivo for the PrP oligomers and in vivo for the PrP fibrils. Rescue experiments with antibodies showed that the exposure of the hydrophobic stretch of PrP at the oligomeric surface was necessary for toxicity. This study identifies toxic PrP species in vivo. It shows that PrP-induced neurodegeneration shares common mechanisms with other brain amyloidoses like Alzheimer disease and opens new avenues for neuroprotective intervention strategies of prion diseases targeting PrP oligomers.

PMID: 17784787 [PubMed - indexed for MEDLINE]

The clinical meaningfulness of ADAS-Cog changes in Alzheimer's disease patients treated with donepezil in an open-label trial.

BMC Neurol. 2007;7:26

Authors: Rockwood K, Fay S, Gorman M, Carver D, Graham JE

BACKGROUND: In 6-month anti-dementia drug trials, a 4-point change in the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) is held to be clinically important. We examined how this change compared with measures of clinical meaningfulness. METHODS: This is a secondary analysis of a 12 month open-label study of 100 patients (71 women) diagnosed with mild to moderate AD treated with 5-10 mg of donepezil daily. We studied the observed case, 6-month change from baseline on the ADAS-Cog, the Clinician's Interview Based Impression of Change-Plus Caregiver Input (CIBIC-Plus), patient-Goal Attainment Scaling (PGAS) and clinician-GAS (CGAS). RESULTS: At 6 months, donepezil-treated patients (n = 95) were more likely to show no change (+/- 3 points) on the ADAS-Cog (56%) than to improve (20%) or decline (24%) by 4-points. ADAS-Cog change scores were little correlated with other measures: from -0.09 for PGAS to 0.27 for the CIBIC-Plus. While patients who improved on the ADAS-Cog were less likely to decline on the clinical measures (26%), 43% of patients who declined on the ADAS-Cog improved on at least two of the clinical measures. CONCLUSION: The ADAS-Cog did not capture all clinically important effects. In general, ADAS-Cog improvement indicates clinical improvement, whereas many people with ADAS-Cog decline do not show clinical decline. The open-label design of this study does not allow us to know whether this is a treatment effect, which requires further investigation.

PMID: 17760991 [PubMed - indexed for MEDLINE]

Reducing amyloid plaque burden via ex vivo gene delivery of an Abeta-degrading protease: a novel therapeutic approach to Alzheimer disease.

PLoS Med. 2007 Aug 28;4(8):e262

Authors: Hemming ML, Patterson M, Reske-Nielsen C, Lin L, Isacson O, Selkoe DJ

BACKGROUND: Understanding the mechanisms of amyloid-beta protein (Abeta) production and clearance in the brain has been essential to elucidating the etiology of Alzheimer disease (AD). Chronically decreasing brain Abeta levels is an emerging therapeutic approach for AD, but no such disease-modifying agents have achieved clinical validation. Certain proteases are responsible for the catabolism of brain Abeta in vivo, and some experimental evidence suggests they could be used as therapeutic tools to reduce Abeta levels in AD. The objective of this study was to determine if enhancing the clearance of Abeta in the brain by ex vivo gene delivery of an Abeta-degrading protease can reduce amyloid plaque burden. METHODS AND FINDINGS: We generated a secreted form of the Abeta-degrading protease neprilysin, which significantly lowers the levels of naturally secreted Abeta in cell culture. We then used an ex vivo gene delivery approach utilizing primary fibroblasts to introduce this soluble protease into the brains of beta-amyloid precursor protein (APP) transgenic mice with advanced plaque deposition. Brain examination after cell implantation revealed robust clearance of plaques at the site of engraftment (72% reduction, p = 0.0269), as well as significant reductions in plaque burden in both the medial and lateral hippocampus distal to the implantation site (34% reduction, p = 0.0020; and 55% reduction, p = 0.0081, respectively). CONCLUSIONS: Ex vivo gene delivery of an Abeta-degrading protease reduces amyloid plaque burden in transgenic mice expressing human APP. These results support the use of Abeta-degrading proteases as a means to therapeutically lower Abeta levels and encourage further exploration of ex vivo gene delivery for the treatment of Alzheimer disease.

PMID: 17760499 [PubMed - indexed for MEDLINE]

Role of apolipoprotein E in anxiety.

Neural Plast. 2007;:91236

Authors: Raber J

Anxiety is most common among Alzheimer's disease (AD) patients with an age at onset under age 65. Apolipoprotein E4 (apoE4) is a risk factor for developing AD at an earlier age and might contribute to this effect. In mice, apoE plays a role in the regulation of anxiety, which might involve histamine receptor-mediated signaling and steroidogenesis in the adrenal gland. In addition, human apoE isoforms have differential effects on anxiety in adult mice lacking apoE and probable AD patients. Compared to wild-type mice, mice lacking apoE and apoE4 mice showed pathological alterations in the central nucleus of the amygdala, which is involved in regulation of anxiety. ApoE4, but not mice lacking apoE, or apoE3 mice showed impaired dexamethasone suppression of plasma corticosterone. Understanding how apoE modulates measures of anxiety might help the developments of therapeutic targets to reduce or even prevent measures of anxiety in health and in dementing illnesses.

PMID: 17710250 [PubMed - indexed for MEDLINE]

Defective DNA base excision repair in brain from individuals with Alzheimer's disease and amnestic mild cognitive impairment.

Nucleic Acids Res. 2007;35(16):5545-55

Authors: Weissman L, Jo DG, Sørensen MM, de Souza-Pinto NC, Markesbery WR, Mattson MP, Bohr VA

Oxidative stress is thought to play a role in the pathogenesis of Alzheimer's disease (AD) and increased oxidative DNA damage has been observed in brain tissue from AD patients. Base excision repair (BER) is the primary DNA repair pathway for small base modifications such as alkylation, deamination and oxidation. In this study, we have investigated alterations in the BER capacity in brains of AD patients. We employed a set of functional assays to measure BER activities in brain tissue from short post-mortem interval autopsies of 10 sporadic AD patients and 10 age-matched controls. BER activities were also measured in brain samples from 9 amnestic mild cognitive impairment (MCI) subjects. We found significant BER deficiencies in brains of AD patients due to limited DNA base damage processing by DNA glycosylases and reduced DNA synthesis capacity by DNA polymerase beta. The BER impairment was not restricted to damaged brain regions and was also detected in the brains of amnestic MCI patients, where it correlated with the abundance of neurofibrillary tangles. These findings suggest that BER dysfunction is a general feature of AD brains which could occur at the earliest stages of the disease. The results support the hypothesis that defective BER may play an important role in the progression of AD.

PMID: 17704129 [PubMed - indexed for MEDLINE]

PIB is a non-specific imaging marker of amyloid-beta (Abeta) peptide-related cerebral amyloidosis.

Brain. 2007 Oct;130(Pt 10):2607-15

Authors: Lockhart A, Lamb JR, Osredkar T, Sue LI, Joyce JN, Ye L, Libri V, Leppert D, Beach TG

The in vivo imaging probe [11C]-PIB (Pittsburgh Compound B, N-methyl[11C]2-(4'-methylaminophenyl-6-hydroxybenzathiazole) is under evaluation as a key imaging tool in Alzheimer's disease (AD) and to date has been assumed to bind with high affinity and specificity to the amyloid structures associated with classical plaques (CPs), one of the pathological hallmarks of the disease. However, no studies have systematically investigated PIB binding to human neuropathological brain specimens at the tracer concentrations achieved during in vivo imaging scans. Using a combination of autoradiography and histochemical techniques, we demonstrate that PIB, in addition to binding CPs clearly delineates diffuse plaques and cerebrovascular amyloid angiopathy (CAA). The interaction of PIB with CAA was not fully displaceable and this may be linked to the apolipoprotein E-epsilon4 allele. PIB was also found to label neurofibrillary tangles, although the overall intensity of this binding was markedly lower than that associated with the amyloid-beta (Abeta) pathology. The data provide a molecular explanation for PIB's limited specificity in diagnosing and monitoring disease progression in AD and instead indicate that the ligand is primarily a non-specific marker of Abeta-peptide related cerebral amyloidosis.

PMID: 17698496 [PubMed - indexed for MEDLINE]

Comparing treatment effects in a clinical sample of patients with probable Alzheimer's disease treated with two different cholinesterase inhibitors.

Acta Biomed. 2007;78(1):16-21

Authors: Caffarra P, Vezzadini G, Copelli S, Dieci F, Messa G, Nonis E, Venneri A

BACKGROUND: The aim of this study was to compare the effect of treatment with different cholinesterase inhibitors (ChEIs) on mental status and every day function in a natural outpatient clinic setting, so that this evaluation could more realistically reveal the effects which are likely to be observed in patients attending ordinary dementia clinics rather than in the context of a randomised controlled drug trial. METHODS: Long term outcome of treatment with the ChEIs donepezil and rivastigmine was retrospectively evaluated in 147 patients with a clinical diagnosis of probable Alzheimer's disease of mild to moderate level of severity who had been monitored for a period of nine months. Measures included Mini Mental State Examination, Activity of Daily Living and Instrumental Activity of Daily Living scales. RESULTS: Response rate was similar to that of other published clinical trials on ChEIs. Patients who responded well to treatment with ChEIs better maintained their improved performance. CONCLUSIONS: Treatment with both ChEIs resulted in improved performance in those patients responding to therapy. Greater response was observed in previously untreated patients who had a shorter disease history but overall the findings in this unselected clinical sample confirmed that patients gain some benefit from intervention with ChEI treatment.

PMID: 17687812 [PubMed - indexed for MEDLINE]

Molecular basis of human CD36 gene mutations.

Mol Med. 2007 May-Jun;13(5-6):288-96

Authors: Rać ME, Safranow K, Poncyljusz W

CD36 is a transmembrane glycoprotein of the class B scavenger receptor family. The CD36 gene is located on chromosome 7 q11.2 and is encoded by 15 exons. Defective CD36 is a likely candidate gene for impaired fatty acid metabolism, glucose intolerance, atherosclerosis, arterial hypertension, diabetes, cardiomyopathy, Alzheimer disease, and modification of the clinical course of malaria. Contradictory data concerning the effects of antiatherosclerotic drugs on CD36 expression indicate that further investigation of the role of CD36 in the development of atherosclerosis may be important for the prevention and treatment of this disease. This review summarizes current knowledge of CD36 gene structure, splicing, and mutations and the molecular, metabolic, and clinical consequences of these phenomena.

PMID: 17673938 [PubMed - indexed for MEDLINE]

Differences in extracellular matrix production and basic fibroblast growth factor response in skin fibroblasts from sporadic and familial Alzheimer's disease.

Mol Med. 2007 Sep-Oct;13(9-10):542-50

Authors: Bellucci C, Lilli C, Baroni T, Parnetti L, Sorbi S, Emiliani C, Lumare E, Calabresi P, Balloni S, Bodo M

Extracellular matrix (ECM) molecules and growth factors, such as fibroblast growth factor (FGF), play a crucial role in Alzheimer's disease (AD). The purpose of this investigation was to determine whether phenotypic alterations in ECM production are present in non-neuronal AD cells associated with different FGF expression and response. Synthesis of glycosaminoglycans (GAG) and collagen were measured in skin fibroblasts from patients with familial, sporadic AD (FAD and SAD respectively), and from age-matched controls by radiolabeled precursors. Proteoglycans (PG), metalloprotease (MMP)-1, and FGF gene expressions were measured by reverse transcription-polymerase chain reaction. The results showed different ECM neosynthesis and mRNA levels in the two AD fibroblast populations. FAD accumulated more collagen and secreted less GAG than SAD. Biglycan PG was upregulated in FAD while betaglycan, syndecan, and decorin were markedly downregulated in SAD fibroblasts. We found a significant decrease of MMP1, more marked in FAD than in SAD fibroblasts. Constitutive FGF expression was greatly reduced in both pathological conditions (SAD>FAD). Moreover, an inverse high affinity/low affinity FGF receptor ratio between SAD and FAD fibroblasts was observed. FGF treatment differently modulated ECM molecule production and gene expression in the two cell populations. These observations in association with the changes in FGF gene expression and in the FGF receptor number, suggest that cellular mechanisms downstream from FGF receptor binding are involved in the two different forms of AD.

PMID: 17660861 [PubMed - indexed for MEDLINE]

Stable insertion of Alzheimer Abeta peptide into the ER membrane strongly correlates with its length.

FEBS Lett. 2007 Aug 7;581(20):3809-13

Authors: Lundin C, Johansson S, Johnson AE, Näslund J, von Heijne G, Nilsson I

Alzheimer's disease is characterized by the deposition of amyloid beta-peptide (Abeta) plaques in the brain. Full-length amyloid-beta precursor protein (APP) is processed by alpha- and beta-secretases to yield soluble APP derivatives and membrane-bound C-terminal fragments, which are further processed by gamma-secretase to a non-amyloidogenic 3 kDa product or to Abeta fragments. As different Abeta fragments contain different parts of the APP transmembrane helix, one may speculate that they are retained more or less efficiently in the membrane. Here, we use the translocon-mediated insertion of different APP-derived polypeptide segments into the endoplasmic reticulum membrane to assess the propensities for membrane retention of Abeta fragments. Our results show a strong correlation between the length of an Abeta-derived segment and its ability to integrate into the microsomal membrane.

PMID: 17659280 [PubMed - indexed for MEDLINE]

Variability in the kinesin light chain 1 gene may influence risk of age-related cataract.

Mol Vis. 2007;13:993-6

Authors: Andersson ME, Zetterberg M, Tasa G, Seibt-Palmér M, Juronen E, Teesalu P, Blennow K, Zetterberg H

PURPOSE: Kinesin-mediated cargo vesicle transport is fundamental to the maintenance of a proper lens fiber structure, which is essential for the transparency of the lens. Here, we test the hypothesis that the rs8702 polymorphism in the kinesin light chain 1 gene (KLC1), previously linked to Alzheimer disease (AD), may play a role in cataractogenesis. METHODS: Patients with nuclear (n=76), cortical (n=154), posterior subcapsular (n=117), and mixed (n=148) cataract as well as 183 controls were analyzed for the KLC1 rs8702 polymorphism using the dynamic allele-specific hybridization (DASH) technique. RESULTS: The GG genotype of rs8702 was significantly over-represented among cataract patients as compared to controls (63% versus 52%, respectively, p=0.008) and associated with an age-adjusted odds ratio for cataract development of 1.61 (95% confidence interval 1.12-2.31). This association was not confined to any particular cataract type. CONCLUSIONS: The KLC1 gene may be a novel susceptibility gene for age-related cataract.

PMID: 17653041 [PubMed - indexed for MEDLINE]

Chronic administration of R-flurbiprofen attenuates learning impairments in transgenic amyloid precursor protein mice.

BMC Neurosci. 2007;8:54

Authors: Kukar T, Prescott S, Eriksen JL, Holloway V, Murphy MP, Koo EH, Golde TE, Nicolle MM

BACKGROUND: Long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) is associated with a reduced incidence of Alzheimer's disease (AD). We and others have shown that certain NSAIDs reduce secretion of Abeta42 in cell culture and animal models, and that the effect of NSAIDs on Abeta42 is independent of the inhibition of cyclooxygenase by these compounds. Since Abeta42 is hypothesized to be the initiating pathologic molecule in AD, the ability of these compounds to lower Abeta42 selectively may be associated with their protective effect. We have previously identified R-flurbiprofen (tarenflurbil) as a selective Abeta42 lowering agent with greatly reduced cyclooxygenase activity that shows promise for testing this hypothesis. In this study we report the effect of chronic R-flurbiprofen treatment on cognition and Abeta loads in Tg2576 APP mice. RESULTS: A four-month preventative treatment regimen with R-flurbiprofen (10 mg/kg/day) was administered to young Tg2576 mice prior to robust plaque or Abeta pathology. This treatment regimen improved spatial learning as assessed by the Morris water maze, indicated by an increased spatial bias during the third probe trial and an increased utilization of a place strategy to solve the water maze. These results are consistent with an improvement in hippocampal- and medial temporal lobe-dependent memory function. A modest, though not statistically significant, reduction in formic acid-soluble levels of Abeta was also observed. To determine if R-flurbiprofen could reverse cognitive deficits in Tg2576 mice where plaque pathology was already robust, a two-week therapeutic treatment was given to older Tg2576 mice with the same dose of R-flurbiprofen. This approach resulted in a significant decrease in Abeta plaque burden but no significant improvement in spatial learning. CONCLUSION: We have found that chronic administration of R-flurbiprofen is able to attenuate spatial learning deficits if given prior to plaque deposition in Tg2576 mice. Given its ability to selectively target Abeta42 production and improve cognitive impairments in transgenic APP mice, as well as promising data from a phase 2 human clinical trial, future studies are needed to investigate the utility of R-flurbiprofen as an AD therapeutic and its possible mechanisms of action.

PMID: 17650315 [PubMed - indexed for MEDLINE]

[Clinical heterogeneity of Alzheimer's disease according to the age of onset]

Rev Neurol. 2007 Jul 16-31;45(2):67-72

Authors: Vilalta-Franch J, Lopez-Pousa S, Garre-Olmo J, Turon-Estrada A, Pericot-Nierga I

INTRODUCTION: The age of onset of Alzheimer's disease (AD) has been linked to the degree of clinical heterogeneity. Some studies have suggested that the presenile and senile forms may be different conditions. AIM: To describe the clinical and developmental characteristics of patients with AD according to the age of onset. PATIENTS AND METHODS: A clinical sample of AD patients was evaluated by means of the Cambridge Examination for Mental Disorders of the Elderly protocol together with other tests and clinical scales (Trail Making Test, Neuropsychiatric Inventory, Rapid-Disability Rating Scale-2 and Zarit Burden Interview). Patients were reassessed at 12 months. RESULTS: Of the 492 participants, 419 (85.2%) were cases of late-onset AD and 73 cases (14.8%) had early-onset AD. For this latter group, the time between onset of the first symptoms and diagnosis of the disease was higher (3.85 versus 2.5 years) and there was a higher frequency of family histories of dementia (35.6%) and personal histories of psychiatric disorders (13.7%). This group also presented better scores on the functional evaluation scales and on the neuropsychological tests, as well as more frequent and severe symptoms of depression. At 12 months no clinical differences were recorded between the two groups, except for an increase in the frequency and severity of apathy. CONCLUSIONS: From the differences found between early-onset and late-onset AD we cannot consider them to be two different conditions from the clinical and/or neuropsychological point of view.

PMID: 17642044 [PubMed - indexed for MEDLINE]

Domperidone is effective in the prevention of rivastigmine-related gastrointestinal disturbances.

Funct Neurol. 2007 Apr-Jun;22(2):101-4

Authors: Scarzella L, Costanza A, Vastola K

Nausea and/or vomiting are frequent dose-limiting class effects of cholinesterase inhibitors, occurring mostly during the dose-escalation phase. These untoward effects make it difficult to increase rivastigmine dosage above 6 mg daily in most patients. The antiemetic domperidone was given to 22 patients with Alzheimer's disease (9 men, 13 women; mean age 74.5+/-4.6 years; mean age at diagnosis: 73.1+/-5.0 years) in 15-day prophylactic cycles, starting 15 days before each dose escalation of rivastigmine above 6 mg daily. Only four patients (18.2%) experienced nausea, which was so mild that all patients reached >or=9 mg rivastigmine daily and 16 (72.7%) reached and maintained the top dosage (12 mg daily). An improvement or stabilization of Mini Mental State Examination scores was achieved in 54.5% of the patients. The treatment regimen was well tolerated; no patients stopped treatment because of adverse events. Further investigations assessing the role of domperidone in the prevention of rivastigmine-related gastrointestinal disturbances are warranted.

PMID: 17637213 [PubMed - indexed for MEDLINE]

Occludin is overexpressed in Alzheimer's disease and vascular dementia.

J Cell Mol Med. 2007 May-Jun;11(3):569-79

Authors: Romanitan MO, Popescu BO, Winblad B, Bajenaru OA, Bogdanovic N

The tight junctions (TJs) are key players in the control of blood-brain barrier (BBB) properties, the most complex TJs in the vascular system being found in the endothelial cells of brain capillaries. One of the main TJs proteins is occludin, which anchors plasma membranes of neighbour cells and is present in large amounts in the brain endothelia. Previous studies demonstrated that disruption of BBB in various pathological situations associates with changes in occludin expression, and this change could be responsible for malfunction of BBB. Therefore in this study, applying an immunohistochemical approach, we decided to explore the occludin expression in frontal cortex (FC) and basal ganglia in ageing control, Alzheimer's disease (AD), and vascular dementia (VD) brains, as far as all these pathologies associate microangiopathy and disruption of BBB. Strikingly, we found selected neurons, astrocytes and oligodendrocytes expressing occludin, in all cases studied. To estimate the number of occludin-expressing neurons, we applied a stereological approach with random systematic sampling and the unbiased optical fractionator method. We report here a significant increase in ratio of occludin-expressing neurons in FC and basal ganglia regions in both AD and VD as compared to ageing controls. Within the cerebral cortex, occludin was selectively expressed by pyramidal neurons, which are the ones responsible for cognitive processes and affected by AD pathology. Our findings could be important in unravelling new pathogenic pathways in dementia disorders and new functions of occludin and TJs.

PMID: 17635647 [PubMed - indexed for MEDLINE]

Alzheimer's disease: cholesterol, membrane rafts, isoprenoids and statins.

J Cell Mol Med. 2007 May-Jun;11(3):383-92

Authors: Reid PC, Urano Y, Kodama T, Hamakubo T

Alzheimer's disease (AD) is a heterogeneous neurodegenerative disorder and the most prevalent form of dementia worldwide. AD is characterized pathologically by amyloid-? plaques, neurofibrillary tangles and neuronal loss, and clinically by a progressive loss of cognitive abilities. At present, the fundamental molecular mechanisms underlying the disease are unclear and no treatment for AD is known. Epidemiological evidence continues to mount linking vascular diseases, such as hypertension and diabetes, and hypercholesterolaemia with an increased risk for developing AD. A growing amount of evidence suggests a mechanistic link between cholesterol metabolism in the brain and the formation of amyloid plaques in AD development. Cholesterol and statins clearly modulate ?-amyloid precursor protein (?APP) processing in cell culture and animal models. Statins not only reduce endogenous cholesterol synthesis but also exert other various pleiotrophic effects, such as the reduction in protein isoprenylation. Through these effects statins modulate a variety of cellular functions involving both cholesterol (and membrane rafts) and isoprenylation. Although clearly other factors, such as vascular inflammation, oxidative stress and genetic factors, are intimately linked with the progression of AD, this review focuses on the present research findings describing the effect of cholesterol, membrane rafts and isoprenylation in regulating ?APP processing and in particular ?-secretase complex assembly and function and AD progression, along with consideration for the potential role statins may play in modulating these events.

PMID: 17635634 [PubMed - indexed for MEDLINE]

B vitamins and berries and age-related neurodegenerative disorders.

Evid Rep Technol Assess (Full Rep). 2006 Apr;(134):1-161

Authors: Balk E, Chung M, Raman G, Tatsioni A, Chew P, Ip S, DeVine D, Lau J

OBJECTIVES: To assess the effects, associations, mechanisms of action, and safety of B vitamins and, separately, berries and their constituents on age-related neurocognitive disorders-primarily Alzheimer's (AD) and Parkinson's disease (PD). DATA SOURCES: MEDLINE and CAB Abstracts. Additional studies were identified from reference lists and technical experts. REVIEW METHODS: Vitamins B1, B2, B6, B12, and folate, and a dozen types of berries and their constituents were evaluated. Human, animal, and in vitro studies were evaluated. Outcomes of interest from human studies were neurocognitive function or diagnosis with AD, cognitive decline, PD, or related conditions. Intervention studies, associations between dietary intake and outcomes, and associations between B vitamin levels and outcomes were evaluated. Specific mechanisms of action were evaluated in animal and in vitro studies. Studies were extracted for study design, demographics, intervention or predictor, and neurocognitive outcomes. Studies were graded for quality and applicability. RESULTS: In animal studies, deficiencies in vitamins B1 or folate generally cause neurological dysfunction; supplementation with B6, B12, or folate may improve neurocognitive function. In animal experiments folate and B12 protect against genetic deficiencies used to model AD; thiamine and folate also affect neurovascular function and health. Human studies were generally of poor quality. Weak evidence suggests possible benefits of B1 supplementation and injected B12 in AD. The effects of B6 and folate are unclear. Overall, dietary intake studies do not support an association between B vitamin intake and AD. Studies evaluating B vitamin status were mostly inadequate due to poor study design. Overall, studies do not support an association between B vitamin status and age-related neurocognitive disorders. Only one study evaluated human berry consumption, finding no association with PD. Animal studies of berries have almost all been conducted by the same research group. Several berry constituents have been shown to affect brain and nerve tissue function. Blueberry and strawberry extract were protective of markers of disease, although effects on neurocognitive tests were less consistent. Berry extracts may protect against the deleterious effects of compounds associated with AD. Reporting of adverse events was uncommon. When reported, actual adverse events from B vitamins were rare and minor. CONCLUSIONS: The current research on B vitamins is largely inadequate to confidently assess their mechanisms of action on age-related neurocognitive disorders, their associations with disease, or their effectiveness as supplements. B vitamin supplementation may be of value for neurocognitive function, but the evidence is inconclusive.

PMID: 17628125 [PubMed - indexed for MEDLINE]

Inhibition of Pin1 reduces glutamate-induced perikaryal accumulation of phosphorylated neurofilament-H in neurons.

Mol Biol Cell. 2007 Sep;18(9):3645-55

Authors: Kesavapany S, Patel V, Zheng YL, Pareek TK, Bjelogrlic M, Albers W, Amin N, Jaffe H, Gutkind JS, Strong MJ, Grant P, Pant HC

Under normal conditions, the proline-directed serine/threonine residues of neurofilament tail-domain repeats are exclusively phosphorylated in axons. In pathological conditions such as amyotrophic lateral sclerosis (ALS), motor neurons contain abnormal perikaryal accumulations of phosphorylated neurofilament proteins. The precise mechanisms for this compartment-specific phosphorylation of neurofilaments are not completely understood. Although localization of kinases and phosphatases is certainly implicated, another possibility involves Pin1 modulation of phosphorylation of the proline-directed serine/threonine residues. Pin1, a prolyl isomerase, selectively binds to phosphorylated proline-directed serine/threonine residues in target proteins and isomerizes cis isomers to more stable trans configurations. In this study we show that Pin1 associates with phosphorylated neurofilament-H (p-NF-H) in neurons and is colocalized in ALS-affected spinal cord neuronal inclusions. To mimic the pathology of neurodegeneration, we studied glutamate-stressed neurons that displayed increased p-NF-H in perikaryal accumulations that colocalized with Pin1 and led to cell death. Both effects were reduced upon inhibition of Pin1 activity by the use of an inhibitor juglone and down-regulating Pin1 levels through the use of Pin1 small interfering RNA. Thus, isomerization of lys-ser-pro repeat residues that are abundant in NF-H tail domains by Pin1 can regulate NF-H phosphorylation, which suggests that Pin1 inhibition may be an attractive therapeutic target to reduce pathological accumulations of p-NF-H.

PMID: 17626162 [PubMed - indexed for MEDLINE]

[Apolipoprotein E polymorphism in first-degree relatives of patients with familial or sporadic Alzheimer's disease]

Arq Neuropsiquiatr. 2007 Jun;65(2A):295-8

Authors: de Castilho Cação J, Souza DR, Tognola WA, de Godoy MR, de Souza Pinhel MA

INTRODUCTION: Apolipoprotein E (apo E) has been recognized as a risk factor for Alzheimer disease (AD). OBJECTIVE: To analyze apo E polymorphism in first-degree relatives of patients with familial or sporadic late-onset AD comparing with families without AD. METHOD: Forty patients with familial or sporadic late-onset of AD, being both groups classified as probable, according of NINCS-ADRDAs criteria. RESULTS: Allele epsilon3 was the most frequent in all of these groups. Higher frequency of epsilon4 when comparing the relatives of the probands with the relatives of the control group (p<0,0001) was observed. Allele epsilon2 showed significant difference only between relatives of familial AD and relatives of control group (p=0,026). CONCLUSION: Apo E polymorphism has not differentiated familial from sporadic AD. The study of families allows to amplify the alelles epsilon2 and epsilon4 representative, revealing, their value as protecting factor and of risk for AD, respectively.

PMID: 17607431 [PubMed - in process]

Treatment guidelines for Alzheimer's disease: redefining perceptions in primary care.

Prim Care Companion J Clin Psychiatry. 2007;9(2):113-21

Authors: Geldmacher DS

Background: Current treatment guidelines for Alzheimer's disease (AD) do not reflect more recently collected data on therapeutic outcomes other than cognitive function and memory, and this has led to a limited understanding of the value of drug therapy in AD.Objectives: To evaluate the need to revise treatment guidelines for AD, to review data that have become available since the publication of current guidelines, and to communicate how existing guidelines and relevant new data can be valuable to the primary care provider who assesses and treats patients with AD.Data Sources: A MEDLINE search was conducted to identify existing treatment guidelines using the MeSH headings Alzheimer disease-drug therapy AND practice guidelines. The alternative terms treatment guidelines, practice parameter, and practice recommendation were also searched in conjunction with the MeSH term Alzheimer disease-drug therapy. Additionally, MEDLINE was searched using the term dementia and publication type "practice guideline." All searches were limited to articles published within the last 10 years, in English. A total of 116 articles were identified by these searches. Additional publications were identified by manually searching the reference lists of these articles and of published clinical trials of AD therapies.Study Selection and Data Extraction: Current AD treatment guidelines and clinical trial results for AD treatment options were extracted, reviewed, and summarized to meet the objectives of this article.Data Synthesis: Current guidelines support the use of cholinesterase inhibitors in patients with mild to moderate AD. More recent clinical research indicates that cholinesterase inhibitor treatment provides effectiveness across a wide range of dementia severity and multiple symptom domains. These medications also significantly decrease caregiver burden and may lower the risk for nursing home placement.Conclusions: The expanding literature on AD medications suggests that treatment guidelines need to be reexamined. Recent data emphasize preservation of abilities and delay of adverse outcomes in AD patients rather than short-term improvements in cognitive test scores. Treatment appears to provide the greatest benefit when it is initiated early in the course of the disease and maintained over the long term. Revised treatment guidelines should address newer medications and more recent outcomes considerations, as well as provide guidance on how long to continue and when to discontinue pharmacotherapy for AD.

PMID: 17607333 [PubMed - in process]

Nox enzymes, ROS, and chronic disease: an example of antagonistic pleiotropy.

Free Radic Biol Med. 2007 Aug 1;43(3):332-47

Authors: Lambeth JD

Reactive oxygen species (ROS) are considered to be chemically reactive with and damaging to biomolecules including DNA, protein, and lipid, and excessive exposure to ROS induces oxidative stress and causes genetic mutations. However, the recently described family of Nox and Duox enzymes generates ROS in a variety of tissues as part of normal physiological functions, which include innate immunity, signal transduction, and biochemical reactions, e.g., to produce thyroid hormone. Nature's "choice" of ROS to carry out these biological functions seems odd indeed, given its predisposition to cause molecular damage. This review describes normal biological roles of Nox enzymes as well as pathological conditions that are associated with ROS production by Nox enzymes. By far the most common conditions associated with Nox-derived ROS are chronic diseases that tend to appear late in life, including atherosclerosis, hypertension, diabetic nephropathy, lung fibrosis, cancer, Alzheimer's disease, and others. In almost all cases, with the exception of a few rare inherited conditions (e.g., related to innate immunity, gravity perception, and hypothyroidism), diseases are associated with overproduction of ROS by Nox enzymes; this results in oxidative stress that damages tissues over time. I propose that these pathological roles of Nox enzymes can be understood in terms of antagonistic pleiotropy: genes that confer a reproductive advantage early in life can have harmful effects late in life. Such genes are retained during evolution despite their harmful effects, because the force of natural selection declines with advanced age. This review discusses some of the proposed physiologic roles of Nox enzymes, and emphasizes the role of Nox enzymes in disease and the likely beneficial effects of drugs that target Nox enzymes, particularly in chronic diseases associated with an aging population.

PMID: 17602948 [PubMed - indexed for MEDLINE]

A genetic association analysis of cognitive ability and cognitive ageing using 325 markers for 109 genes associated with oxidative stress or cognition.

BMC Genet. 2007;8:43

Authors: Harris SE, Fox H, Wright AF, Hayward C, Starr JM, Whalley LJ, Deary IJ

BACKGROUND: Non-pathological cognitive ageing is a distressing condition affecting an increasing number of people in our 'ageing society'. Oxidative stress is hypothesised to have a major role in cellular ageing, including brain ageing. RESULTS: Associations between cognitive ageing and 325 single nucleotide polymorphisms (SNPs), located in 109 genes implicated in oxidative stress and/or cognition, were examined in a unique cohort of relatively healthy older people, on whom we have cognitive ability scores at ages 11 and 79 years (LBC1921). SNPs showing a significant positive association were then genotyped in a second cohort for whom we have cognitive ability scores at the ages of 11 and 64 years (ABC1936). An intronic SNP in the APP gene (rs2830102) was significantly associated with cognitive ageing in both LBC1921 and a combined LBC1921/ABC1936 analysis (p < 0.01), but not in ABC1936 alone. CONCLUSION: This study suggests a possible role for APP in normal cognitive ageing, in addition to its role in Alzheimer's disease.

PMID: 17601350 [PubMed - indexed for MEDLINE]

Calpain-calcineurin signaling in the pathogenesis of calcium-dependent disorder.

Acta Med Okayama. 2007 Jun;61(3):123-37

Authors: Wu HY, Tomizawa K, Matsui H

Intracellular calcium is a powerful secondary messenger that affects a number of calcium sensors, including calpain, a Ca2+-dependent cysteine protease, and calcineurin, a Ca2+/calmodulin-dependent protein phosphatase. Maintenance of low basal levels of intracellular calcium allows for the tightly regulated physiological activation of these proteins, which is crucial to a wide variety of cellular processes, such as fertilization, proliferation, development, learning, and memory. Deregulation of calpain and calcineurin has been implicated in the pathogenesis of several disorders, including hypertension, heart disease, diabetes, cerebral ischemia, and Alzheimer's disease. Recent studies have demonstrated an interplay between calpain and calcineurin, in which calpain can directly regulate calcineurin activity through proteolysis in glutamate-stimulated neurons in culture and in vivo. The calpain-mediated proteolytic cleavage of calcineurin increases phosphatase activity, which promotes caspase-mediated neuronal cell death. Thus, the activation of the calpain-calcineurin pathway could contribute to calcium-dependent disorders, especially those associated with Alzheimer's disease and myocardial hypertrophy. Here, we focus briefly on recent advances in revealing the structural and functional properties of these 2 calcium-activated proteins, as well as on the interplay between the 2, in an effort to understand how calpain-calcineurin signaling may relate to the pathogenesis of calcium- dependent disorders.

PMID: 17593948 [PubMed - indexed for MEDLINE]

Association between vitamin D receptor gene polymorphism and Alzheimer's disease.

Tohoku J Exp Med. 2007 Jul;212(3):275-82

Authors: Gezen-Ak D, Dursun E, Ertan T, Hana&#x11F;asi H, Gürvit H, Emre M, Eker E, Oztürk M, Engin F, Yilmazer S

Vitamin D(3) is known to be involved in neuroprotection and exert its neuroprotective effects by modulating neuronal calcium homeostasis and production of neurotrophins. The single nucleotide polymorphisms (SNP) in vitamin D receptor (VDR) gene which can influence the affinity of vitamin D(3) to its receptor may be related to neurodegenerative diseases and neuronal damage by altering the vitamin D-mediated pathways. In this study, our aim was to determine whether there is an association between VDR gene and late-onset Alzheimer's disease (AD) in order to see if vitamin D contributes to AD or not. One hundred and four cases of dementia of Alzheimer type and 109 age-matched controls were genotyped according to ApaI (a: + restriction site and A: no restriction site) and TaqI (t: + restriction site and T: no restriction site) sites in intron 8 and exon 9 of the ligand-binding site of VDR gene. When the controls and patients were compared for their ApaI genotypes, the frequency of the patients with Aa genotype was significantly higher than the frequency of the healthy individuals with the same genotype (p = 0.008, chi(2) = 9.577, OR = 2.30). Thus, the "Aa" genotype may increase the risk of developing AD 2.3 times when compared with the "AA" genotype. On the other hand, the "AT" haplotype was significantly higher in controls (p = 0.006) indicating a protective role of the "AT" haplotype in AD. Consequently, this study provides evidence for a possible link between AD and vitamin D.

PMID: 17592215 [PubMed - indexed for MEDLINE]

Abeta amyloid deposition in the language system and how the brain responds.

Brain. 2007 Aug;130(Pt 8):2055-69

Authors: Nelissen N, Vandenbulcke M, Fannes K, Verbruggen A, Peeters R, Dupont P, Van Laere K, Bormans G, Vandenberghe R

Post-mortem measures of Abeta amyloid deposition correlate only weakly with cognitive dysfunction antemortem. We tested the hypothesis that functional reorganization forms a critical intermediary step between Abeta amyloid-associated brain injury and clinical disease expression. Fifteen patients with early-stage probable Alzheimer's disease (AD) and 16 cognitively intact controls participated in this combined functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) study. The fMRI design had two factors: task (associative-semantic versus visuoperceptual judgement) and input-modality (written words versus pictures). We measured Abeta amyloid by means of Pittsburgh Compound B (11C-PIB). In the posterior third of the left superior temporal sulcus (STS), the fMRI response during the associative-semantic compared with the visuoperceptual task was lower in AD than in controls, in particular for words. Response amplitude correlated inversely with PIB uptake in this region. Contralaterally, the functional pattern differed substantially: the fMRI response in the right posterior STS during the associative-semantic versus the visuoperceptual task was higher in AD than in controls. Accuracy on the Boston Naming test correlated positively with the degree to which AD patients were able to recruit the right STS (r = 0.84, P(corrected) = 0.014). PIB uptake did not correlate with naming accuracy. Functional reorganization of the language system in response to Abeta amyloid-related brain injury exists in early-stage AD and determines the degree of anomia more than Abeta amyloid load per se does.

PMID: 17586869 [PubMed - indexed for MEDLINE]

Neuropathological findings processed by artificial neural networks (ANNs) can perfectly distinguish Alzheimer's patients from controls in the Nun Study.

BMC Neurol. 2007;7:15

Authors: Grossi E, Buscema MP, Snowdon D, Antuono P

BACKGROUND: Many reports have described that there are fewer differences in AD brain neuropathologic lesions between AD patients and control subjects aged 80 years and older, as compared with the considerable differences between younger persons with AD and controls. In fact some investigators have suggested that since neurofibrillary tangles (NFT) can be identified in the brains of non-demented elderly subjects they should be considered as a consequence of the aging process. At present, there are no universally accepted neuropathological criteria which can mathematically differentiate AD from healthy brain in the oldest old. The aim of this study is to discover the hidden and non-linear associations among AD pathognomonic brain lesions and the clinical diagnosis of AD in participants in the Nun Study through Artificial Neural Networks (ANNs) analysis METHODS: The analyses were based on 26 clinically- and pathologically-confirmed AD cases and 36 controls who had normal cognitive function. The inputs used for the analyses were just NFT and neuritic plaques counts in neocortex and hippocampus, for which, despite substantial differences in mean lesions counts between AD cases and controls, there was a substantial overlap in the range of lesion counts. RESULTS: By taking into account the above four neuropathological features, the overall predictive capability of ANNs in sorting out AD cases from normal controls reached 100%. The corresponding accuracy obtained with Linear Discriminant Analysis was 92.30%. These results were consistently obtained in ten independent experiments. The same experiments were carried out with ANNs on a subgroup of 13 non severe AD patients and on the same 36 controls. The results obtained in terms of prediction accuracy with ANNs were exactly the same. Input relevance analysis confirmed the relative dominance of NFT in neocortex in discriminating between AD patients and controls and indicated the lesser importance played by NP in the hippocampus. CONCLUSION: The results of this study suggest that: a) cortical NFT represent the key variable in AD neuropathology; b) the neuropathologic profile of AD subjects is complex, however, c) ANNs can analyze neuropathologic features and differentiate AD cases from controls.

PMID: 17584929 [PubMed - indexed for MEDLINE]

[A theoretical review of category-specific impairment, its entity and the methodological problems associated with its study]

Rev Neurol. 2007 Jun 16-30;44(12):747-54

Authors: Laws KR, Moreno-Mart&#xED;nez FJ, Goñi-Imízcoz M

INTRODUCTION: Studies on category-specific claim to provide insights on structure and organization of semantic information. This type of phenomenon consists of the selective impairment of the information on a domain, for instance, living things (animals) but the sparing of nonliving things (tools), or vice versa. Despite the large number of studies purportedly documenting double dissociations between both domains, the lack of theoretical debate on how to empirically define such dissociations is unclear, e.g. how they should be evaluated and reported. DEVELOPMENT: In this work, a review of literature on category-specific and the explanatory models is showed. A critical methodological is done, on the basis of three findings: 1) lack of normal control groups in the majority of case studies; 2) the questionable utilization of double dissociations; and 3) the presence of problems due to a 'ceiling effect' in most group studies of Alzheimer disease patients. CONCLUSIONS: It is claimed that while domain specificity may be a legitimate phenomenon, the critical review of literature do not provide a strong empirical foundation for the domain fractionations claimed in this literature.

PMID: 17583869 [PubMed - indexed for MEDLINE]

[Rivastigmine solution prescribing habits in patients with Alzheimer-type dementia in Spain (RIVASOL study)]

Rev Neurol. 2007 Jun 16-30;44(12):705-10

Authors: González-Gutiérrez JL, Gobartt AL,

INTRODUCTION: One of the most notable advances in the treatment of Alzheimer's disease today is the appearance of the drugs rivastigmine, donepezil, galanthamine and memantine. AIMS. We attempt to throw light on the dosage regimens, degree of effectiveness and safety profile of rivastigmine solution by means of a retrospective, descriptive, cross-sectional study known as the RIVASOL study. PATIENTS AND METHODS: The study involved 1516 patients (1386 of whom were evaluable) who had been diagnosed with Alzheimer-type dementia (ATD) according to the criteria in the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV); these patients, who were selected by 157 participating physicians (neurologists, psychiatrists and geriatricians), gave their informed written consent and had been receiving treatment with rivastigmine solution over the past six months. The main variable was the rivastigmine solution treatment regimen and the secondary variables included socio-demographic data, health care data and the researcher's overall clinical impression from the time treatment was begun, among others. RESULTS: Most of the patients who were evaluated were attended by neurologists (57.4%). The mean time elapsed since Alzheimer's disease was diagnosed was 2.14 +/- 1.68 years. After approximately one year's treatment with rivastigmine solution, the mean score on the Folstein minimental test (MMSE) fell by 0.48 points. CONCLUSIONS: Rivastigmine solution represents a convenient means of administration for patients with moderate and moderately advanced phases of ATD; their cognitive performance is significantly improved with a reduction in the side effects due to a slower and more progressive adjustment of the initial dosage.

PMID: 17583861 [PubMed - indexed for MEDLINE]

Loneliness associated with increased risk of Alzheimer's disease.

FDA Consum. 2007 Mar-Apr;41(2):9

Authors:

PMID: 17582858 [PubMed - indexed for MEDLINE]

FPIN's clinical inquiries. Monitoring therapy for patients with Alzheimer's disease.

Am Fam Physician. 2007 Jun 1;75(11):1703-4

Authors: Raetz J, v d Luft E

PMID: 17575663 [PubMed - indexed for MEDLINE]

[Diagnosis disclosure and pharmacotherapy of mild dementia]

Nippon Ronen Igakkai Zasshi. 2007 May;44(3):315-7

Authors: Shigeta M

PMID: 17575431 [PubMed - indexed for MEDLINE]