Alzheimer Disease: Dickson D

McKhann GM, Albert MS, Grossman M, Miller B, Dickson D, Trojanowski JQ, Anonymous00019. · Department of Neurology, Zanvyl Krieger Mind/Brain Institute, Johns Hopkins University School of Medicine, 338 Krieger Hall, 3400 N Charles St, Baltimore, MD 21218-2685, USA. · Arch Neurol. · Pubmed #11708987 links to  free full text

Abstract: An international group of clinical and basic scientists participated in the Frontotemporal Dementia and Pick's Disease Criteria Conference at the National Institutes of Health in Bethesda, Md, on July 7, 2000, to reassess clinical and neuropathological criteria for the diagnosis of frontotemporal dementia (FTD). Previous criteria for FTD have primarily been designed for research purposes. The goal of this meeting was to propose guidelines that would enable clinicians (particularly neurologists, psychiatrists, and neuropsychologists) to recognize patients with FTD and, if appropriate, to expedite their referral to a diagnostic center. In addition, recommendations for the neuropathological criteria of FTD were reviewed, relative to classical neuropathology and modern molecular biology.

Golde TE, Dickson D, Hutton M. · Mayo Clinic College of Medicine, Department of Neuroscience, Mayo Clinic Jacksonville 4500 San Pablo Rd., Jacksonville, Florida 32224, USA. · Curr Alzheimer Res. · Pubmed #17168641 No free full text.

Abstract: Advances in the understanding of Alzheimer's disease (AD) pathogenesis provide strong support for a modified version of the amyloid cascade hypothesis, which is now often referred to as the amyloid beta protein (Abeta) cascade hypothesis. The basic tenant of this modified hypothesis is that Abeta aggregates trigger a complex pathological cascade leading to neurodegeneration. Thus, as opposed to the original amyloid hypothesis, whose basic tenant was that amyloid deposits cause AD, the Abeta hypothesis is more inclusive in that it takes into account the possibility that several different Abeta assemblies might contribute to AD pathogenesis and not merely the detectable amyloid deposits within the brain. Significantly, the Abeta hypothesis has provided the rationale for a plethora of therapeutic interventions that target Abeta production, aggregation or clearance. Indeed, AD research is entering an exciting phase in which strategies derived from basic research will be tested in humans. Despite this progress, many aspects of AD pathogenesis, particularly those downstream of Abeta accumulation are not well understood. Herein, we explore several observations that serve to illustrate the more enigmatic aspects of the Abeta hypothesis, and discuss why further basic research may be critical in order to develop therapies designed to halt neurodegeneration and reverse cognitive decline in patients already suffering from AD dementia.

McKeith I, Mintzer J, Aarsland D, Burn D, Chiu H, Cohen-Mansfield J, Dickson D, Dubois B, Duda JE, Feldman H, Gauthier S, Halliday G, Lawlor B, Lippa C, Lopez OL, Carlos Machado J, O'Brien J, Playfer J, Reid W, Anonymous00116. · Institute for Ageing and Health, University of Newcastle, Newcastle upon Tyne, UK. · Lancet Neurol. · Pubmed #14693108 No free full text.

Abstract: Dementia with Lewy bodies (DLB) is the second commonest cause of neurodegenerative dementia in older people. It is part of the range of clinical presentations that share a neuritic pathology based on abnormal aggregation of the synaptic protein alpha-synuclein. DLB has many of the clinical and pathological characteristics of the dementia that occurs during the course of Parkinson's disease. Here we review the current state of scientific knowledge on DLB. Accurate identification of patients is important because they have specific symptoms, impairments, and functional disabilities that differ from those of other common types of dementia. Severe neuroleptic sensitivity reactions are associated with significantly increased morbidity and mortality. Treatment with cholinesterase inhibitors is well tolerated by most patients and substantially improves cognitive and neuropsychiatric symptoms. Clear guidance on the management of DLB is urgently needed. Virtually unrecognised 20 years ago, DLB could within this decade be one of the most treatable neurodegenerative disorders of late life.

Dickey C, Kraft C, Jinwal U, Koren J, Johnson A, Anderson L, Lebson L, Lee D, Dickson D, de Silva R, Binder LI, Morgan D, Lewis J. · Department of Molecular Pharmacology and Physiology, Johnnie B. Byrd Sr. Alzheimer's Institute, University of South Florida, Tampa, Florida 33612, USA. · Am J Pathol. · Pubmed #19074615 links to  free full text

Abstract: We have extensively analyzed the biochemical and histochemical profiles of the tau protein from the rTg4510 transgenic mouse model in which the animals uniquely develop forebrain tau pathologies similar to those found in human tauopathies. Levels of several soluble phosphorylated tau species were highest at 1 month relative to later time points, suggesting that certain tau hyperphosphorylation events were insufficient to drive tangle formation in young mice. Despite a robust, pre-tangle-like accumulation of phospho-tau in 1-month-old mice, this material was cleared by 3 months, indicating that the young mouse brain either fails to facilitate tau insolubility or possesses an enhanced ability to clear tau relative to the adult. We also found that while heat shock protein expression increased with normal aging, this process was accelerated in rTg4510 mice. Moreover, by exploiting an exon 10 (-) specific antibody, we demonstrated that endogenous mouse tau turnover was slowed in response to human tau over-expression, and that this endogenous tau adopted disease-related properties. These data suggest that a younger brain fails to develop lasting tau pathology despite elevated levels of phosphorylated tau, perhaps because of reduced expression of stress-related proteins. Moreover, we show that the active production of small amounts of abnormal tau protein facilitates dysfunction and accumulation of otherwise normal tau, a significant implication for the pathogenesis of patients with Alzheimer's disease.

Vega IE, Traverso EE, Ferrer-Acosta Y, Matos E, Colon M, Gonzalez J, Dickson D, Hutton M, Lewis J, Yen SH. · Department of Biology, University of Puerto Rico-Rio Piedras Campus, San Juan, Puerto Rico. · J Neurochem. · Pubmed #18346207 No free full text.

Abstract: Tauopathies are a group of neurological disorders characterized by the presence of intraneuronal hyperphosphorylated and filamentous tau. Mutations in the tau gene have been found in kindred with tauopathy. The expression of the human tau mutant in transgenic mice induced neurodegeneration, indicating that tau plays a central pathological role. However, the molecular mechanism leading to tau-mediated neurodegeneration is poorly understood. To gain insights into the role that tau plays in neurodegeneration, human tau proteins were immunoprecipitated from brain lysates of the tauopathy mouse model JNPL3, which develops neurodegeneration in age-dependent manner. In the present work, a novel EF-hand domain-containing protein was found associated with tau proteins in brain lysate of 12-month-old JNPL3 mice. The association between tau proteins and the novel identified protein appears to be induced by the neurodegeneration process as these two proteins were not found associated in young JNPL3 mice. Consistently, the novel protein co-purified with the pathological sarkosyl insoluble tau in terminally ill JNPL3 mice. Calcium-binding assays demonstrated that this protein binds calcium effectively. Finally, the association between tau and the novel calcium-binding protein is conserved in human and enriched in Alzheimer's disease brain. Taken together, the identification of a novel calcium-binding protein associated with tau protein in terminally ill tauopathy mouse model and its confirmation in human brain lysate suggests that this association may play an important physiological and/or pathological role.

Zhang YJ, Xu YF, Dickey CA, Buratti E, Baralle F, Bailey R, Pickering-Brown S, Dickson D, Petrucelli L. · Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida 32224, USA. · J Neurosci. · Pubmed #17898224 links to  free full text

Abstract: TAR DNA binding protein-43 (TDP-43) is the pathologic substrate of neuronal and glial inclusions in frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTDL-U) and in amyotrophic lateral sclerosis (ALS). Mutations in the progranulin gene (PGRN) have been shown to cause familial FTLD-U. The relationship between progranulin and TDP-43 and their respective roles in neurodegeneration is unknown. We report that progranulin mediates proteolytic cleavage of TDP-43 to generate approximately 35 and approximately 25 kDa species. Suppression of PGRN expression with small interfering RNA leads to caspase-dependent accumulation of TDP-43 fragments that can be inhibited with caspase inhibitor treatment. Cells treated with staurosporine also induced caspase-dependent cleavage and redistribution of TDP-43 from its nuclear localization to cytoplasm. Altered cleavage and redistribution of TDP-43 in cell culture models are similar to findings in FTLD-U and ALS. The results suggest that abnormal metabolism of TDP-43 mediated by progranulin may play a pivotal role in neurodegeneration.

Rademakers R, Baker M, Gass J, Adamson J, Huey ED, Momeni P, Spina S, Coppola G, Karydas AM, Stewart H, Johnson N, Hsiung GY, Kelley B, Kuntz K, Steinbart E, Wood EM, Yu CE, Josephs K, Sorenson E, Womack KB, Weintraub S, Pickering-Brown SM, Schofield PR, Brooks WS, Van Deerlin VM, Snowden J, Clark CM, Kertesz A, Boylan K, Ghetti B, Neary D, Schellenberg GD, Beach TG, Mesulam M, Mann D, Grafman J, Mackenzie IR, Feldman H, Bird T, Petersen R, Knopman D, Boeve B, Geschwind DH, Miller B, Wszolek Z, Lippa C, Bigio EH, Dickson D, Graff-Radford N, Hutton M. · Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA. · Lancet Neurol. · Pubmed #17826340 No free full text.

Abstract: BACKGROUND: The progranulin gene (GRN) is mutated in 5-10% of patients with frontotemporal lobar degeneration (FTLD) and in about 20% of patients with familial FTLD. The most common mutation in GRN is Arg493X. We aimed to establish the contribution of this mutation to FTLD and related disorders. METHODS: We measured the frequency of Arg493X in 3405 unrelated patients with various neurodegenerative diseases using Taqman single-nucleotide polymorphism (SNP) genotyping. Clinicopathological characterisation and shared haplotype analysis were done for 30 families with FTLD who carry Arg493X. To investigate the effect of potential modifying loci, we did linear regression analyses with onset age as the covariate for GRN variants, for genotypes of the apolipoprotein E gene (APOE), and for haplotypes of the microtubule-associated protein tau gene (MAPT). FINDINGS: Of 731 patients with FTLD, 16 (2%) carried Arg493X. This mutation was not detected in 2674 patients who did not have FTLD. In 37 patients with Arg493X from 30 families with FTLD, clinical diagnoses included frontotemporal dementia, primary progressive aphasia, corticobasal syndrome, and Alzheimer's disease. Range of onset age was 44-69 years. In all patients who came to autopsy (n=13), the pathological diagnosis was FTLD with neuronal inclusions that contained TAR DNA-binding protein or ubiquitin, but not tau. Neurofibrillary tangle pathology in the form of Braak staging correlated with overall neuropathology in the Arg493X carriers. Haplotype analyses suggested that Arg493X arose twice, with a single founder for 27 families. Linear regression analyses suggested that patients with SNP rs9897528 on their wild-type GRN allele have delayed symptom onset. Onset ages were not associated with the MAPT H1 or H2 haplotypes or APOE genotypes, but early memory deficits were associated with the presence of an APOE epsilon4 allele. INTERPRETATION: Clinical heterogeneity is associated with GRN haploinsufficiency, and genetic variability on the wild-type GRN allele might have a role in the age-related disease penetrance of GRN mutations.

Rogaeva E, Meng Y, Lee JH, Gu Y, Kawarai T, Zou F, Katayama T, Baldwin CT, Cheng R, Hasegawa H, Chen F, Shibata N, Lunetta KL, Pardossi-Piquard R, Bohm C, Wakutani Y, Cupples LA, Cuenco KT, Green RC, Pinessi L, Rainero I, Sorbi S, Bruni A, Duara R, Friedland RP, Inzelberg R, Hampe W, Bujo H, Song YQ, Andersen OM, Willnow TE, Graff-Radford N, Petersen RC, Dickson D, Der SD, Fraser PE, Schmitt-Ulms G, Younkin S, Mayeux R, Farrer LA, St George-Hyslop P. · Centre for Research in Neurodegenerative Diseases, Department of Medicine, Department, University of Toronto, Toronto, Ontario, Canada. · Nat Genet. · Pubmed #17220890 links to  free full text

Abstract: The recycling of the amyloid precursor protein (APP) from the cell surface via the endocytic pathways plays a key role in the generation of amyloid beta peptide (Abeta) in Alzheimer disease. We report here that inherited variants in the SORL1 neuronal sorting receptor are associated with late-onset Alzheimer disease. These variants, which occur in at least two different clusters of intronic sequences within the SORL1 gene (also known as LR11 or SORLA) may regulate tissue-specific expression of SORL1. We also show that SORL1 directs trafficking of APP into recycling pathways and that when SORL1 is underexpressed, APP is sorted into Abeta-generating compartments. These data suggest that inherited or acquired changes in SORL1 expression or function are mechanistically involved in causing Alzheimer disease.

Chand P, Grafman J, Dickson D, Ishizawa K, Litvan I. · Department of Neurology, University of Louisville School of Medicine, Louisville, Kentucky 40202, USA. · Mov Disord. · Pubmed #16977625 No free full text.

Abstract: A 60-year-old man presented with slowly progressive left hemi-Parkinsonism, left hand apraxia, myoclonus, dystonia, visuospatial disturbances, and alien limb phenomenon, resembling corticobasal syndrome. Eight years later, neuropathology revealed features of Alzheimer's disease, with asymmetrical (right more than left) cortical tau burden with image analysis. The videotaped clinical features, neuropsychological aspects, and neuropathological correlates are presented and discussed.

Shiarli AM, Jennings R, Shi J, Bailey K, Davidson Y, Tian J, Bigio EH, Ghetti B, Murrell JR, Delisle MB, Mirra S, Crain B, Zolo P, Arima K, Iseki E, Murayama S, Kretzschmar H, Neumann M, Lippa C, Halliday G, Mackenzie J, Khan N, Ravid R, Dickson D, Wszolek Z, Iwatsubo T, Pickering-Brown SM, Mann DM. · Clinical Neuroscience Research Group, University of Manchester, Greater Manchester Neurosciences Centre, Hope Hospital, Salford, UK. · Neuropathol Appl Neurobiol. · Pubmed #16866983 No free full text.

Abstract: In order to gain insight into the pathogenesis of frontotemporal lobar degeneration (FTLD), the mean tau load in frontal cortex was compared in 34 patients with frontotemporal dementia linked to chromosome 17 (FTDP-17) with 12 different mutations in the tau gene (MAPT), 11 patients with sporadic FTLD with Pick bodies and 25 patients with early onset Alzheimer's disease (EOAD). Tau load was determined, as percentage of tissue occupied by stained product, by image analysis of immunohistochemically stained sections using the phospho-dependent antibodies AT8, AT100 and AT180. With AT8 and AT180 antibodies, the amount of tau was significantly (P < 0.001 in each instance) less than that in EOAD for both FTDP-17 (8.5% and 10.0% respectively) and sporadic FTLD with Pick bodies (16.1% and 10.0% respectively). With AT100, the amount of tau detected in FTDP-17 was 54% (P < 0.001) of that detected in EOAD, but no tau was detected in sporadic FTLD with Pick bodies using this particular antibody. The amount of insoluble tau deposited within the brain in FTDP-17 did not depend in any systematic way upon where the MAPT mutation was topographically located within the gene, or on the physiological or structural change generated by the mutation, regardless of which anti-tau antibody was used. Not only does the amount of tau deposited in the brain differ between the three disorders, but the pattern of phosphorylation of tau also varies according to disease. These findings raise important questions relating to the role of aggregated tau in neurodegeneration - whether this represents an adaptive response which promotes the survival of neurones, or whether it is a detrimental change that directly, or indirectly, brings about the demize of the affected cell.

Kumar-Singh S, Pirici D, McGowan E, Serneels S, Ceuterick C, Hardy J, Duff K, Dickson D, Van Broeckhoven C. · Department of Molecular Genetics VIB8, Neurodegenerative Brain Diseases Research Group, Molecular Neuropathology Project, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium. · Am J Pathol. · Pubmed #16049337 links to  free full text

Abstract: Occurrence of amyloid beta (Abeta) dense-core plaques in the brain is one of the chief hallmarks of Alzheimer's disease (AD). It is not yet clear what factors are responsible for the aggregation of Abeta in the formation of these plaques. Using Tg2576 and PSAPP mouse models that exhibit age-related development of amyloid plaques similar to that observed in AD, we showed that approximately 95% of dense plaques in Tg2576 and approximately 85% in PSAPP mice are centered on vessel walls or in the immediate perivascular regions. Stereoscopy and simulation studies focusing on smaller plaques suggested that vascular associations for both Tg2576 and PSAPP mice were dramatically higher than those encountered by chance alone. We further identified ultrastructural microvascular abnormalities occurring in association with dense plaques. Although occurrence of gross cerebral hemorrhage was infrequent, we identified considerable infiltration of the serum proteins immunoglobulin and albumin in association with dense plaques. Together with earlier evidence of vascular clearance of Abeta, our data suggest that perturbed vascular transport and/or perivascular enrichment of Abeta leads to the formation of vasocentric dense plaques in Tg2576 and PSAPP mouse models of AD.

Mazur-Kolecka B, Dickson D, Frackowiak J. · New York State Institute for Basic Research in Developmental Disabilities, Department of Developmental Neurobiology, 1050 Forest Hill Road, Staten Island, NY 10314, USA. · Neurobiol Aging. · Pubmed #15993987 No free full text.

Abstract: The reduced antioxidant defense in apolipoprotein E epsilon4/epsilon4 carriers may contribute to beta-amyloidosis. Previously we found that Fe(2+)-induced oxidative stress caused greater protein oxidation in epsilon4/epsilon4 than in epsilon3/epsilon3 human brain vascular smooth muscle cells. Moreover, Fe(2+) induced lysosomal accumulation of endogenous Abeta and APOE in cultured cells, and Abeta deposition in vascular tunica media in organotypic cultures of brain vessels. Here we demonstrated that Fe(2+) enhanced an uptake of exogenous Abeta 1-40 and its deposition together with APOE in lysosomes in myocytes. Abeta deposits were associated with lipid-peroxidation and protein ubiquitination, and were more abundant and stable in epsilon4/epsilon4 than in epsilon3/epsilon3 cells. In organotypic cultures of brain vessels Fe(2+) induced deposition of non-fibrillar and fibrillar Abeta 1-40 in vascular tunica media. We hypothesize that locally increased concentrations of iron induce accumulation of exogenous and endogenous Abeta in SMCs, triggering beta-amyloid angiopathy. The greater susceptibility of epsilon4 carriers to Fe(2+) ions may result in an increased risk of beta-amyloidosis.

Frackowiak J, Potempska A, LeVine H, Haske T, Dickson D, Mazur-Kolecka B. · NYS Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, NY 10314, USA. · J Neuropathol Exp Neurol. · Pubmed #15715088 No free full text.

Abstract: Alzheimer disease (AD) and Down syndrome (DS) brains contain deposits of amyloid-beta peptide that are located extracellularly in the neuropil and in blood vessels walls. A small fraction of brain Abeta is detected intracellularly in neurons, smooth muscle cells, and microglia. The roles of these extracellular and intracellular pools of Abeta in pathogenesis of AD-type dementia are controversial. Cell culture models of vascular amyloidosis-beta revealed intracellular, but not extracellular deposition of Abeta. Here we demonstrate for the first time, formation of extracellular deposits of Abeta in primary cultures of vascular smooth muscle cells isolated from AD cases with cerebrovascular amyloid angiopathy. Extracellular Abeta deposition required the use of cultures that produced high quantities of Abeta, which contained at least 50% of cells forming intracellular Abeta deposits, and providing extracellular matrix proteins. During 12 days of culture in this system, we observed accumulation of nonfibrillar, granular deposits in extracellular matrix, similar to early stages of vascular amyloidogenesis in vivo. This is a valuable system to study the effects of various potential amyloidogenic factors on formation of extracellular Abeta deposits.

Sahara N, Vega IE, Ishizawa T, Lewis J, McGowan E, Hutton M, Dickson D, Yen SH. · Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA. · J Neurochem. · Pubmed #15287888 No free full text.

Abstract: Neurofibrillary tangles (NFT) accumulated in Alzheimer's diseases and related disorders contain hyperphosphorylated tau and display immunoreactivity for active forms of various kinases. To understand the role of p38MAPK (mitogen-activated protein kinase) in NFT formation, we have studied a transgenic (Tg) mouse model of tauopathy, JNPL3, that expresses P301L mutant tau, and bigenic mice, TAPP, generated by cross-breeding of JNPL3 with Tg2576 mice. Age-matched non-Tg mice (NTg), wild-type human tau Tg mice (JN25), and Tg2576 mice were used as controls. Phosphorylated p38MAPK (active form) immunoreactivity was consistently located in NFT and granulovaculolar degeneration in JNPL3 and TAPP mice older than 5 months of age. Unphosphorylated/total-p38MAPK was not detectable in spinal cord and brain sections from 2- to 11-month-old mice, even though JNPL3 mice, but not controls had an age-dependent increase of total-p38MAPK by western blotting. Spinal cord/brain extracts from mice and human with tauopathy were demonstrated to have insignificant amount of active-p38MAPK. However, they contained antiactive-p38MAPK cross-reactive proteins insoluble in sarkosyl and similar to phosphorylated tau in size. Consistently, antiactive-p38MAPK immunoprecipitates displayed tau immunoreactivity, but not total-p38MAPK, and antitau immunoprecipitates displayed active-p38MAPK immunoreactivity. Together, the results indicate that the cross-reactivity of antiactive-p38MAPK antibody with phosphorylated tau is responsible for the immunolabeling of tau-positive inclusion.

Das P, Howard V, Loosbrock N, Dickson D, Murphy MP, Golde TE. · Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224, USA. · J Neurosci. · Pubmed #13679422 links to  free full text

Abstract: Direct immunization with amyloid beta protein (Abeta) and passive transfer of anti-Abeta antibodies reduce Abeta accumulation and attenuate cognitive deficits in transgenic models of Alzheimer's disease (AD). The reduction in Abeta deposition has been proposed to involve microglial phagocytosis of Abeta immune complexes via Fc receptors (FcRs). We have examined the efficacy of Abeta immunization in amyloid precursor protein (APP) transgenic mice crossed into FcR-gamma chain knock-out mice (FcRgamma-/-). As might be expected from previous studies on macrophages, phagocytosis of Abeta immune complexes via FcR was completely impaired in microglia cells isolated from FcRgamma-/- mice. Thus, we immunized APP Tg2576 transgenic mice that were crossed in the FcRgamma-/- background with Abeta1-42 and then analyzed the effect on Abeta accumulation. In APP Tg2576 transgenic mice crossed to FcRgamma-/-, Abeta1-42 immunization significantly attenuated Abeta deposition, as assessed by both biochemical and immunohistological methods. The reduction in Abeta accumulation was equivalent to the reduction in deposition seen in Abeta1-42 immunized, age-matched, FcR-sufficient Tg2576 mice. We conclude that after Abeta immunization, the effects of anti-Abeta antibodies on Abeta deposition in APP Tg2576 transgenic mice are not dependent on FcR-mediated phagocytic events.

Barker WW, Luis CA, Kashuba A, Luis M, Harwood DG, Loewenstein D, Waters C, Jimison P, Shepherd E, Sevush S, Graff-Radford N, Newland D, Todd M, Miller B, Gold M, Heilman K, Doty L, Goodman I, Robinson B, Pearl G, Dickson D, Duara R. · Wien Center for Alzheimer's Disease and Memory Disorders, Mount Sinai Medical Center, Miami Beach, FL 33140, USA. · Alzheimer Dis Assoc Disord. · Pubmed #12468894 No free full text.

Abstract: Alzheimer disease (AD) is the most common dementing illness in the elderly, but there is equivocal evidence regarding the frequency of other disorders such as Lewy body disease (LBD), vascular dementia (VaD), frontotemporal dementia (FTD), and hippocampal sclerosis (HS). This ambiguity may be related to factors such as the age and gender of subjects with dementia. Therefore, the objective of this study was to calculate the relative frequencies of AD, LBD, VaD, FTD, and HS among 382 subjects with dementia from the State of Florida Brain Bank and to study the effect of age and gender on these frequencies. AD was the most frequent pathologic finding (77%), followed by LBD (26%), VaD (18%), HS (13%), and FTD (5%). Mixed pathology was common: Concomitant AD was present in 66% of LBD patients, 77% of VaD patients, and 66% of HS patients. The relative frequency of VaD increased with age, whereas the relative frequencies of FTD and LBD declined with age. Males were overrepresented among those with LBD, whereas females were overrepresented among AD subjects with onset age over 70 years. These estimates of the a priori probabilities of dementing disorders have implications for clinicians and researchers.

Mazur-Kolecka B, Frackowiak J, Kowal D, Krzeslowska J, Dickson D. · New York State Institute for Basic Research in Developmental Disabilities, Department of Pathological Neurobiology, 1050 Forest Hill Rd, Staten Island, NY 10314, USA. · Neuroreport. · Pubmed #11930162 No free full text.

Abstract: The epsilon4 allele of apolipoprotein E (apoE) is a risk factor for Alzheimer's disease. The reduced antioxidant defense in epsilon4 carriers is suggested to contribute to beta-amyloidosis. We found that oxidative stress induced by treatment with Fe2+ ions raised more protein carbonyls in vascular smooth muscle cells isolated from human brains with apoE genotype epsilon4/epsilon4 than with 3epsilon/epsilon3 and epsilon3/epsilon4. Antioxidant vitamin E prevented formation of carbonyls but not in cells with genotype epsilon4/epsilon4. Treatment with Fe2+ ions induced cellular accumulation of amyloid-beta protein (Abeta)-immunoreactive material that co-localized with heme oxygenase, a marker of oxidative stress, and apoE. We hypothesize that the damage caused by oxidation in epsilon4/epsilon4 carriers facilitates development of beta-amyloidosis.

Frackowiak J, Mazur-Kolecka B, Kaczmarski W, Dickson D. · Department of Pathological Neurobiology, NYS Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, NY 10314, USA. · Brain Res. · Pubmed #11430884 No free full text.

Abstract: L-3-hydroxyacyl-coenzyme A dehydrogenase type II (HADH) was described as an endoplasmic reticulum amyloid beta-peptide-binding protein (ERAB), which enhances Abeta toxicity, and accumulates in neurons in Alzheimer's disease (AD). Hence, HADH/ERAB was suggested to mediate the amyloid-induced neurodegeneration. We estimated the in vivo interactions of HADH and Abeta in an immunocytochemical study of ten Alzheimer's disease and seven normal brains using five monoclonal HADH-specific antibodies. We found no HADH in amyloid plaques or vascular amyloid. The neuronal expression of HADH was not correlated with the severity of amyloid load in neuropil. HADH was expressed in vascular smooth muscle cells in young and old controls and in amyloid-free blood vessels in AD cases, but little or no HADH was in smooth muscle cells in arteries with amyloid deposits. The putative intracellular interaction between HADH and Abeta in amyloid-producing cells was further studied in vascular smooth muscle cells isolated from brain blood vessels with amyloid-beta angiopathy - the cells that were shown previously to accumulate Abeta intracellularly ['Research advances in Alzheimer's disease and related disorders' (1995) 747; Brain Res. 676 (1995) 225; Neurosci. Lett. 183 (1995) 120]. HADH had a mitochondrial localization and did not co-localize with an endoplasmic reticulum marker. Cells that accumulated Abeta were those with low expression of HADH and the proteins did not co-localize. Explanation of the association between low levels of HADH and deposition of Abeta by brain smooth muscle cells requires further studies.

Haugabook SJ, Le T, Yager D, Zenk B, Healy BM, Eckman EA, Prada C, Younkin L, Murphy P, Pinnix I, Onstead L, Sambamurti K, Golde TE, Dickson D, Younkin SG, Eckman CB. · Mayo Clinic Jacksonville, Jacksonville, Florida 32224, USA. · FASEB J. · Pubmed #11099491 links to  free full text

Abstract: The abnormal accumulation of the amyloid beta protein (Abeta) has been implicated as an early and critical event in the etiology and pathogenesis of Alzheimer's disease (AD). Compounds that reduce Abeta accumulation may therefore be useful therapeutically. In cell-based screens we detected a significant reduction in Abeta concentration after treatment with the phosphatidylinositol kinase inhibitors wortmannin and LY294002. To determine the effect of this class of compounds on in vivo Abeta accumulation, we administered wortmannin to the Tg2576 mouse model of AD. Oral administration of wortmannin over four months resulted in a significant, non-overlapping 40%-50% reduction in the number of senile plaques, one of the pathological hallmarks of AD. Sandwich ELISA analysis of formic acid extractable Abeta in the brain of treated animals indicates that both Abeta40 and the longer, more amyloidogenic form of the peptide, Abeta42, were significantly reduced. These data provide the first direct evidence that compounds identified by their ability to reduce Abeta concentration in vitro can reduce Abeta accumulation and deposition in the brain, thus establishing a basic paradigm for the identification and evaluation of additional compounds that lower Abeta accumulation.

Crystal HA, Dickson D, Davies P, Masur D, Grober E, Lipton RB. · Einstein Aging Study, Department of Neurology, Albert Einstein College of Medicine, Bronx, NY 10461, USA. · Arch Neurol. · Pubmed #10815138 links to  free full text

Abstract: CONTEXT: With the recent change in pathological criteria for Alzheimer disease (AD), a group of patients has emerged who do not meet pathological criteria for any well-characterized degenerative dementias. Whether these unclassified patients have vascular dementia or some other form of dementia is not known. OBJECTIVE: To determine the clinical characteristics, pathological substrate, and relative frequency of dementia not caused by well-characterized degenerative dementias. DESIGN/SETTING: Clinicopathological study of a prospectively observed sample of elderly nondemented and demented subjects recruited from our urban community. METHODS: In our series of 128 subjects with prospective neuropsychological evaluations as well as neuropathology, we identified 35 clinically nondemented subjects and 20 demented patients who did not meet pathological criteria for well-characterized degenerative dementias such as AD or dementia with Lewy bodies. The 20 demented patients were grouped together under the term dementia of unknown etiology (DUE). We compared clinical, genetic, neuropsychological, pathological, and neurochemical characteristics of the nondemented group, patients with DUE, and 28 patients with AD and no other pathological abnormality. RESULTS: Mean age at death for patients with DUE was 89.1 +/- 5.8 years compared with 79.9 +/- 11.4 years for AD (P<.001). Patients with AD and DUE did not differ in sex, risk factors, apolipoprotein E genotype, neuropsychological features, or neurological features. Hippocampal sclerosis (in 11 patients with dementia and no controls) and leukoencephalopathy (in 7 patients with dementia and 1 control) were associated with cognitive impairment; other vascular markers were not. Dementia of unknown etiology accounted for 5% of all cases of dementia among patients dying in their 70s, 21% for patients dying in their 80s, and 48% for patients dying in their 90s. CONCLUSIONS: A significant percentage of demented patients older than 80 years do not meet pathological criteria for AD or dementia with Lewy bodies. Hippocampal sclerosis and leukoencephalopathy are common in these patients but rare in clinically nondemented subjects.

Grober E, Dickson D, Sliwinski MJ, Buschke H, Katz M, Crystal H, Lipton RB. · Department of Neurology, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY, USA. · Neurobiol Aging. · Pubmed #10674422 No free full text.

Abstract: We assessed the relationships of performance on memory and mental status tests and neuropathologic stage of Alzheimer's disease as defined by Braak and Braak in 29 patients from a prospective clinicopathologic series. We predicted that memory changes would occur at an earlier Braak stage than mental status changes. Staging was accomplished by matching the topographic distribution of neurofibrillary lesions detected with tau immunocytochemistry to the best fitting diagram published by Braak and Braak. Higher Braak stages were associated with decrements in performance on both memory and mental status tests. As predicted, memory performance declined from stages II to III and mental status did not decline until stages III to IV. The association between memory and Braak stage was unchanged after adjusting for neocortical senile plaques, whereas adjustments for Braak stage eliminated the association between cognitive functioning and amyloid burden. We conclude that Braak staging provides a useful summary of Alzheimer's disease neuropathology, which is associated with both memory and mental status performance.

McGowan E, Sanders S, Iwatsubo T, Takeuchi A, Saido T, Zehr C, Yu X, Uljon S, Wang R, Mann D, Dickson D, Duff K. · Mayo Clinic, Jacksonville, Florida, 32224, USA. · Neurobiol Dis. · Pubmed #10448051 No free full text.

Abstract: Doubly transgenic mice (PSAPP) overexpressing mutant APP and PS1 transgenes were examined using antibodies to Abeta subtypes and glial fibrillary acidic protein (GFAP). Visible Abeta deposition began primarily in the cingulate cortex of PSAPP mice at approximately 10 weeks of age. By 6 months, the mice had extensive amyloid deposition throughout the hippocampus and cortex as well as other regions of the brain. Highly congophilic deposits consisting of N-terminal normal and modified forms of Abeta were identified, reminiscent of those found in human AD brain. Both immunohistochemistry and mass spectrometry showed that Abeta42 forms were underrepresented relative to Abeta40, and Abeta43 was undetectable. Deposits were associated with prominent gliosis which increased with age, but in 14-month-old PSAPP mice, GFAP immunoreactivity in the vicinity of amyloid deposits was substantially reduced compared to APP littermates. These mice have considerable utility in the study of the amyloid phenotype of AD.

Luis CA, Barker WW, Gajaraj K, Harwood D, Petersen R, Kashuba A, Waters C, Jimison P, Pearl G, Petito C, Dickson D, Duara R. · Wien Center for Alzheimer's Disease and Memory Disorders, Mount Sinai Medical Center, Miami Beach, FL 33141, USA. · Int J Geriatr Psychiatry. · Pubmed #10440972 No free full text.

Abstract: OBJECTIVE: To evaluate the sensitivity and specificity of the clinical features of three published diagnostic criteria for diffuse Lewy body disease (DLBD) using autopsy-confirmed Alzheimer's (AD), DLBD and AD+DLBD (mixed) dementia cases. DESIGN: Retrospective chart review of an autopsy series of 56 patients selected from the State of Florida Brain Bank on the basis of a pathological diagnosis of either pure AD, DLBD (pure and common forms) or AD+DLBD (mixed) dementia. Clinical features were assessed by three raters blind to the pathological diagnosis. RESULTS: The existing criteria for a clinical diagnosis of DLBD were highly specific (90-100%) but not very sensitive (49-63%) in the differential diagnosis of DLBD versus AD; sensitivity did improve (61-74%) when mixed AD+DLBD cases were eliminated. Clinical features that occur more frequently in DLBD than in AD were unspecified hallucinations, unspecified EPS, fluctuating course and rapid progression. Post-hoc analysis also indicated that hallucinations and EPS were more common early in the disease course of DLBD than in AD. Empirically derived criteria, formulated using the most prevalent clinical features, demonstrated sensitivity values of 57-96% for pure forms and 43-91% for mixed forms. CONCLUSIONS: This study demonstrated that additional improvements in the established criteria for DLBD are needed. Our empirically derived criteria enhanced the distinction of DLBD from AD while allowing the clinician the choice of maximizing sensitivity with acceptable specificity, and vice versa.