Journal of Alzheimer's Disease - Volume 18, issue 3

Authors: Mrak, Robert E.

Article Type: Review Article

Abstract: A role for innate immunity in neurodegenerative diseases is now widely accepted, although debate continues over the relative contributions of these processes to disease progression and/or to disease amelioration. The idea that microglia and cytokines are important in neurodegeneration arose from neuropathological observations, especially in Alzheimer's disease. Microglia are invariant components of the Aβ plaques of Alzheimer's disease, where they show a waxing and waning of numbers, activation state, and cytokine expression during plaque progression. This is in contrast to diffuse Aβ deposits sometimes found in abundance in the brain of non-demented elderly individuals, which do not contain activated microglia. …In Alzheimer's disease, plaque-associated astrocytes, which also produce paracrine mediators, show a pattern similar to that of microglia; and the associated plaque progression is accompanied by progressive damage to and loss of adjacent neurons. Further, activated microglia and astrocytes show a progressive pattern of association with neurofibrillary tangles. These observations, together with known functions of the involved cytokines, originally suggested a central role for immunological phenomena in driving disease progression in Alzheimer's disease. Further observations have extended these ideas to α-synuclein-based diseases (Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy) as well as other neurodegenerative diseases and conditions. Show more

Keywords: Alzheimer's disease, amyloid-β plaques, astrocytes, cytokines, interleukin-1, Lewy bodies, microglia, neurofibrillary tangles, neuroinflammation, S100B

DOI: 10.3233/JAD-2009-1158

Citation: Journal of Alzheimer's Disease, vol. 18, no. 3, pp. 473-481, 2009

Authors: Cardoso, Susana | Correia, Sónia | Santos, Renato X. | Carvalho, Cristina | Santos, Maria S. | Oliveira, Catarina R. | Perry, George | Smith, Mark A. | Zhu, Xiongwei | Moreira, Paula I.

Article Type: Review Article

Abstract: Insulin, long known as an important regulator of blood glucose levels, plays important and multifaceted roles in the brain. It has been reported that insulin is an important neuromodulator, contributing to several neurobiological processes in particular energy homeostasis and cognition. Dysregulation of insulin signaling has been linked to aging and metabolic and neurodegenerative disorders. The first part of this review is devoted to discussion of the critical role of insulin signaling in normal brain function. Then the involvement of impaired insulin signaling in the pathophysiology of diabetes, Alzheimer's, Parkinson's and Huntington's diseases and amyotrophic lateral sclerosis will be discussed. Finally, …the potential therapeutic effect of insulin and insulin sensitizers will be examined. Show more

Keywords: Brain, insulin, insulin sensitizers, insulin signaling, neurodegenerative disorders

DOI: 10.3233/JAD-2009-1155

Citation: Journal of Alzheimer's Disease, vol. 18, no. 3, pp. 483-507, 2009

Authors: Glodzik, Lidia | De Santi, Susan | Rich, Kenneth E. | Brys, Miroslaw | Pirraglia, Elizabeth | Mistur, Rachel | Switalski, Remigiusz | Mosconi, Lisa | Sadowski, Martin | Zetterberg, Henrik | Blennow, Kaj | de Leon, Mony J.

Article Type: Short Communication

Abstract: Previous studies showed that memantine inhibits tau hyperphosphorylation in vitro. In this study, phosphorylated tau (P-tau) and total tau (T-tau) were measured before and after 6 month treatment with memantine in 12 subjects ranging from normal cognition with subjective memory complaints, through mild cognitive impairment to mild Alzheimer's disease. Thirteen non-treated individuals served as controls. Treatment was associated with a reduction of P-tau in subjects with normal cognition. No treatment effects were seen among impaired individuals, suggesting that longer treatment time may be necessary to achieve biomarker effect in this group.

Keywords: Alzheimer's disease, biomarkers, cerebrospinal fluid, memantine, phosphorylated tau, total tau

DOI: 10.3233/JAD-2009-1183

Citation: Journal of Alzheimer's Disease, vol. 18, no. 3, pp. 509-513, 2009

Authors: Jiang, Xu | Zhang, Dongli | Shi, Jianting | Chen, Yiqun | Zhang, Ping | Mei, Bing

Article Type: Research Article

Abstract: It has been reported that conditional double knockout of presenilin-1 and presenilin-2 in forebrain of mice (dKO mice) induce symptoms most analogous to that of neurodegenerative diseases, especially Alzheimer's disease, however, there is no deposition of extra amyloid-β (Aβ40 or Aβ42 ) in dKO brain. In the present study, we thoroughly measured the inflammatory response in dKO mice, which is another global symptom in neurodegenerative diseases. We demonstrated that glial cells were dramatically activated from early age (3 months) in dKO brain when compared with control mice. In addition, complement C1qα and C4, the key components in the classical …complement pathway, were also stimulated in dKO mice brain. Antibody array and ELISA analysis indicated that cytokine and chemokine levels were also significantly increased in dKO brain. Moreover, we found that leukocytes were elevated beginning at 6 months of age, and multiple inflammatory mediators changed in dKO mice serum at 9 months, showing that the inflammatory responses gradually expanded to systemic tissue. These findings confirm that presenilins double knockout results in robust inflammatory response both in brain and in periphery and suggest that dKO mice may be useful to further understand the effects of inflammation on the pathological processes of neurodegenerative diseases. Show more

Keywords: Antibody array, inflammatory response, neurodegenerative disease, presenilins

DOI: 10.3233/JAD-2009-1164

Citation: Journal of Alzheimer's Disease, vol. 18, no. 3, pp. 515-523, 2009

Authors: Seidl, Ulrich | Thomann, Philipp A. | Schröder, Johannes

Article Type: Research Article

Abstract: Neurological soft signs (NSS), i.e., minor motor and sensory changes, are a common feature in psychiatric disorders related to brain changes. Nevertheless, they have rarely been investigated in patients with Alzheimer's disease (AD). NSS were examined in 104 nursing home residents with AD with respect to dementia severity, neuropsychiatric symptoms, and Parkinsonian signs as well as potential medication effects. 16 cognitively unimpaired residents served as a control group. NSS scores were significantly higher in residents with AD and were associated with both severity of cognitive deficits and non-cognitive symptoms, in particular apathy, but neither with Parkinsonian signs nor with antipsychotic …medication. Our results demonstrate that NSS increase with progression of AD and one may hypothesize that they are linked to degenerative cerebellar changes. NSS in AD are clinically significant and thus, besides other neurological symptoms, are to be considered in diagnostics and therapy. Show more

Keywords: Alzheimer's disease, antipsychotic medication, neurological soft signs, neuropsychiatric symptoms, Parkinsonian signs

DOI: 10.3233/JAD-2009-1159

Citation: Journal of Alzheimer's Disease, vol. 18, no. 3, pp. 525-532, 2009

Authors: Carrión-Baralt, José R. | Meléndez-Cabrero, Josefina | Rodríguez-Ubiñas, Heide | Schmeidler, James | Beeri, Michal Schnaider | Angelo, Gary | Sano, Mary | Silverman, Jeremy M.

Article Type: Research Article

Abstract: APOE ε4 is a major risk factor for Alzheimer's disease. It has also been associated with cognitive impairment and cognitive decline in young-olds, but the impact of the ε4 allele on cognitive function in very late life is still unclear. The object of this study was to evaluate the association of the ε4 allele of APOE with the cognitive performance of a sample of non-demented oldest-olds. Eighty-seven Spanish-speaking Puerto Rican non-demented nonagenarians were administered a complete neuropsychological assessment and provided a blood sample used for APOE genotyping. A factor analysis generated two factors: 1) verbal memory; and 2) visuo-spatial, naming …and attention tasks, accounting for 43.6% of the overall variance in the 13 original neuropsychological variables. The multivariate analysis reflected, after controlling for gender, education, and age, the APOE ε4 carriers performed better in overall cognition (both factors analyzed together) than non-carriers (T2 = 0.082, F(2,80) = 3.289, p = 0.042). Neither gender nor the gender by APOE ε4 status interaction was associated with differences in cognition. In conclusion, the results of this study suggest that, among these Puerto Rican non-demented nonagenarians, being an APOE ε4 allele carrier is associated with better cognition. Show more

Keywords: APOE, cognition, Hispanic, nonagenarian

DOI: 10.3233/JAD-2009-1160

Citation: Journal of Alzheimer's Disease, vol. 18, no. 3, pp. 533-540, 2009

Authors: García-Rodríguez, Beatriz | Fusari, Anna | Rodríguez, Beatriz | Hernández, José Martín Zurdo | Ellgring, Heiner

Article Type: Research Article

Abstract: Implicit memory for emotional facial expressions (EFEs) was investigated in young adults, healthy old adults, and mild Alzheimer's disease (AD) patients. Implicit memory is revealed by the effect of experience on performance by studying previously encoded versus novel stimuli, a phenomenon referred to as perceptual priming. The aim was to assess the changes in the patterns of priming as a function of aging and dementia. Participants identified EFEs taken from the Facial Action Coding System and the stimuli used represented the emotions of happiness, sadness, surprise, fear, anger, and disgust. In the study phase, participants rated the pleasantness of 36 …faces using a Likert-type scale. Subsequently, the response to the 36 previously studied and 36 novel EFEs was tested when they were randomly presented in a cued naming task. The results showed that implicit memory for EFEs is preserved in AD and aging, and no specific age-related effects on implicit memory for EFEs were observed. However, different priming patterns were evident in AD patients that may reflect pathological brain damage and the effect of stimulus complexity. These findings provide evidence of how progressive neuropathological changes in the temporal and frontal areas may affect emotional processing in more advanced stages of the disease. Show more

Keywords: Aging, Alzheimer's disease, emotional facial expression identification, implicit memory, priming

DOI: 10.3233/JAD-2009-1161

Citation: Journal of Alzheimer's Disease, vol. 18, no. 3, pp. 541-551, 2009

Authors: Honea, Robyn A. | Vidoni, Eric | Harsha, Amith | Burns, Jeffrey M.

Article Type: Research Article

Abstract: Neuroimaging studies of apolipoprotein E (ApoE4) have implicated its association with brain atrophy in Alzheimer's disease. To date, few studies have used automated morphological analysis techniques to assess ApoE4-related brain structure change in both gray and white matter in nondemented older adults. Nondemented (CDR = 0, n = 53) subjects over 60 had MRI, diffusion tensor imaging, and neurocognitive assessments. We assessed differences in cognition and brain structure associated with ApoE4 genetic variation using voxel-based morphometry techniques, and tract-based spatial statistics of fractional anisotropy change. In nondemented older adults with the E4 allele, cognitive performance was reduced, and atrophy was …present in the hippocampus and amygdala compared to ApoE4 negative participants. We also report that E4 carriers have decreased fractional anisotropy in the left parahippocampal gyrus white matter. In conclusion, the presence of an ApoE4 allele in nondemented older adults is associated with decreases in cognition and gray and white matter changes in the medial temporal cortex. Overall we provide further evidence of the effects of genetic variance related to imaging and cognitive measures of risk for Alzheimer's disease. Show more

Keywords: Aging, Alzheimer's disease, apolipoprotein (APOE), cognition, dementia, diffusion tensor imaging (DTI), fractional anisotropy (FA), genetics, hippocampus, voxel-based morphometry (VBM)

DOI: 10.3233/JAD-2009-1163

Citation: Journal of Alzheimer's Disease, vol. 18, no. 3, pp. 553-564, 2009

Authors: Linkous, David H. | Adlard, Paul A. | Wanschura, Patricia B. | Conko, Kathryn M. | Flinn, Jane M.

Article Type: Research Article

Abstract: There is considerable evidence suggesting that metals play a central role in the pathogenesis of Alzheimer's disease. Reports suggest that elevated dietary metals may both precipitate and potentiate an Alzheimer's disease phenotype. Despite this, there remain few studies that have examined the behavioral consequences of elevated dietary metals in wild type and Alzheimer's disease animals. To further investigate this in the current study, two separate transgenic models of AD (Tg2576 and TgCRND8), together with wild type littermates were administered 10 ppm (0.153 mM) Zn. Tg2576 animals were maintained on a zinc-enriched diet both pre- and postnatally until 11 months of …age, while TgCRND8 animals were treated for five months following weaning. Behavioral testing, consisting of “Atlantis” and “moving” platform versions of the Morris water maze, were conducted at the end of the study, and tissues were collected for immunohistochemical analysis of amyloid-β burden. Our data demonstrate that the provision of a zinc-enriched diet potentiated Alzheimer-like spatial memory impairments in the transgenic animals and was associated with reduced hippocampal amyloid-β plaque deposits. Zinc-related behavioral deficits were also demonstrated in wild type mice, which were sometimes as great as those present in the transgenic animals. However, zinc-related cognitive impairments in transgenic mice were greater than the summation of zinc effects in the wild type mice and the transgene effects. Show more

Keywords: Alzheimer's disease, amyloid plaques, metals, Morris water maze, nutrition, spatial memory, Tg2576, transgenic mice, Westaway, zinc

DOI: 10.3233/JAD-2009-1162

Citation: Journal of Alzheimer's Disease, vol. 18, no. 3, pp. 565-579, 2009

Authors: Zhu, Ying-Ying | Ni, Dao-Feng | Xu, Cai-Min

Article Type: Research Article

Abstract: Abnormalities and impaired functions of the olfactory system have been reported in Alzheimer's disease (AD), and these changes may appear much earlier than other clinical symptoms of AD. However, little is known about these abnormalities at the level of gene expression. In this study, we investigated alterations of expression of 22,012 genes in the olfactory bulbs of a rat model of AD by using a microarray approach. The rat model was produced by intracerebroventricular injection of amyloid-β25-35 , which demonstrated pathological changes in olfactory bulbs and memory impairment in the Morris water maze test. We found that expression of 811 …genes among the 22,012 genes was altered by more than 1.5-fold in the amyloid-β-injected rats as compared with control injected rats. We analyzed the distribution of the 811 altered genes according to the Affymetrix criteria and found that the majority of these genes were related to cellular processes, binding, and enzyme activities. The alterations of three of these genes, i.e., calcineurin, olfactory receptor, and protein kinase C, were also confirmed by RT-PCR and Western blots. These studies provide new insight into the abnormalities of the olfactory system in AD and might help to further the understanding of the molecular mechanisms of AD. Show more

Keywords: Alzheimer's disease, gene expression profile, microarray, olfactory bulb, rat

DOI: 10.3233/JAD-2009-1201

Citation: Journal of Alzheimer's Disease, vol. 18, no. 3, pp. 581-593, 2009

Authors: Watson, G. Stennis | Baker, Laura D. | Cholerton, Brenna A. | Rhoads, Kristoffer W. | Merriam, George R. | Schellenberg, Gerard D. | Asthana, Sanjay | Cherrier, Monique | Craft, Suzanne

Article Type: Research Article

Abstract: Both insulin alone and the somatostatin analogue octreotide alone facilitate memory in patients with Alzheimer's disease (AD). Since octreotide inhibits endogenous insulin secretion, the cognitive effects of insulin and octreotide may not be independent. This study tested the individual and interactive effects of insulin and octreotide on memory and plasma growth hormone (GH) levels in older adults. Participants were 16 memory-impaired (AD = 7, amnestic mild cognitive impairment = 9; apolipoprotein E [APOE] ε4- [no ε4 alleles] = 9, ε4+ [1–2 ε4 alleles] = 7), and 19 cognitively-intact older adults (APOE ε4- = 17, ε4+ = 1). On separate days, …fasting participants received counterbalanced infusions of: 1) insulin (1 mU·kg-1 ·min-1 ) and dextrose to maintain euglycemia; 2) octreotide (150 μg/h); 3) insulin, dextrose, and octreotide; or 4) saline. Story recall was the principal endpoint. Insulin alone facilitated delayed recall for ε4- patients, relative to ε4+ patients (P = 0.0012). Furthermore, ε4- patients with higher Mattis Dementia Rating Scale (DRS) scores had greater octreotide-induced memory facilitation (P = 0.0298). For healthy adults, octreotide facilitated memory (P = 0.0122). Unexpectedly, hyperinsulinemia with euglycemia increased GH levels in healthy controls (P = 0.0299). Thus, insulin and octreotide appear to regulate memory in older adults. APOE ε4 genotype modulates responses to insulin and octreotide. Finally, insulin may regulate GH levels during euglycemia. Show more

Keywords: Acetylcholine, Alzheimer's disease (AD), apolipoprotein E (APOE), growth hormone (GH), insulin, memory, mild cognitive impairment (MCI), octreotide, somatostatin

DOI: 10.3233/JAD-2009-1165

Citation: Journal of Alzheimer's Disease, vol. 18, no. 3, pp. 595-602, 2009

Authors: Fenoglio, Chiara | Galimberti, Daniela | Cortini, Francesca | Kauwe, John S.K. | Cruchaga, Carlos | Venturelli, Eliana | Villa, Chiara | Serpente, Maria | Scalabrini, Diego | Mayo, Kevin | Piccio, Laura M. | Clerici, Francesca | Albani, Diego | Mariani, Claudio | Forloni, Gianluigi | Bresolin, Nereo | Goate, Alison M. | Scarpini, Elio

Article Type: Research Article

Abstract: Mutations in the progranulin gene (GRN), causative for Frontotemporal Lobar Degeneration with ubiquitin-immunoreactive neuronal inclusions (FTLD-U), could also be associated with Alzheimer's disease (AD). The influence of GRN genetic variability on susceptibility to AD and on expression levels in a series of neuropathologically-confirmed AD patients as well as in peripheral mononuclear cells (PBMC) and in cells isolated from cerebrospinal fluid (CSF) was investigated. An association study of rs9897526 and rs5848 was carried out in an Italian population and in a replication population of European American patients and controls. None of the variants tested act as unequivocal susceptibility factor in both …populations although rs9897526 anticipated the onset of the disease in the Italian population. GRN expression in the parietal lobe of AD cases showed a 0.76-fold decrease compared with controls (1.31 ± 0.07 versus 1.73 ± 0.12, P = 0.0025). Patients carrying the rs5848 TT genotype had the lowest GRN expression levels (0.96 ± 0.12, P = 0.014). Despite no significant differences were found in the relative PBMC and CSF GRN expression in patients compared to controls, stratifying patients according to the presence of rs5848 T allele, a 0.57-fold decrease in GRN mRNA levels over C carriers was found in PBMC (1.22 ± 0.23 versus 0.70 ± 0.12, P = 0.04). Similarly to data obtained in brain samples, patients carrying the TT genotype showed the lowest GRN mRNA levels (TT = 0.46 ± 0.14, CC = 1.22 ± 0.23; P = 0.013). These data argue against a direct role of GRN as a susceptibility factor for sporadic AD but support a role of GRN as a disease-modifying gene, possibly contributing to the failure of neuronal survival. Show more

Keywords: Alzheimer's disease (AD), cerebrospinal fluid (CSF), peripheral mononuclear cells (PBMC), progranulin (GRN), single nucleotide polymorphism (SNP)

DOI: 10.3233/JAD-2009-1170

Citation: Journal of Alzheimer's Disease, vol. 18, no. 3, pp. 603-612, 2009

Authors: Klafki, Hans-Wolfgang | Lewczuk, Piotr | Kamrowski-Kruck, Heike | Maler, Juan Manuel | Müller, Katharina | Peters, Oliver | Heuser, Isabella | Jessen, Frank | Popp, Julius | Frölich, Lutz | Wolf, Stefanie | Prinz, Berit | Luckhaus, Christian | Schröder, Johannes | Pantel, Johannes | Gertz, Hermann-Josef | Kölsch, Heike | Müller, Bernhard W. | Esselmann, Hermann | Bibl, Mirko | Kornhuber, Johannes | Wiltfang, Jens

Article Type: Research Article

Abstract: The clinical diagnosis of neurodegenerative disorders can be supported by soluble biomarkers in cerebrospinal fluid (CSF), such as tau protein, phospho-tau, and amyloid-β peptides. In particular, increased CSF levels of phospho-tau in Alzheimer's disease appear to reflect disease specific pathological processes. We report here evidence for the presence of soluble MAP-kinase ERK1/2 in a small set of human CSF samples from patients with Alzheimer's disease, frontotemporal degeneration, and mild cognitive impairment. The level of total ERK1/2 in CSF as measured by electrochemiluminescent assay was correlated with that of total tau and phospho-tau. A small fraction of ERK1/2 in a pooled …CSF sample was found to be in the doubly phosphorylated (activated) state. Our findings suggest that i) MAP kinase ERK1/2 is apparently released under neurodegenerative conditions in parallel with tau and phospho-tau and ii) in the future, it might be possible to find in CSF samples evidence for disease related alterations in brain kinase signaling pathways by use of highly sensitive and activation-state specific anti-kinase antibodies. Show more

Keywords: Alzheimer's disease, cerebrospinal fluid, ERK1/2, frontotemporal degeneration, MAP kinase, mild cognitive impairment, tau

DOI: 10.3233/JAD-2009-1167

Citation: Journal of Alzheimer's Disease, vol. 18, no. 3, pp. 613-622, 2009

Authors: Kowall, Neil W.

Article Type: Book Review

DOI: 10.3233/JAD-2009-1213

Citation: Journal of Alzheimer's Disease, vol. 18, no. 3, pp. 623-624, 2009

Authors: Strobel, Gabrielle

Article Type: Meeting Report

DOI: 10.3233/JAD-2009-1234

Citation: Journal of Alzheimer's Disease, vol. 18, no. 3, pp. 625-640, 2009

Authors: Larson, Eric B.

Article Type: Editorial

DOI: 10.3233/JAD-2009-1168

Citation: Journal of Alzheimer's Disease, vol. 18, no. 3, pp. 643-644, 2009

Authors: Brayne, Carol | Richardson, Kathryn | Matthews, Fiona E. | Fleming, Jane | Hunter, Sally | Xuereb, John H. | Paykel, Eugene | Mukaetova-Ladinska, Elizabeta B. | Huppert, Felicia A. | O'Sullivan, Angela | Dening, Tom | the Cambridge City over-75s Cohort (CC75C) study neuropathology collaboration

Article Type: Research Article

Abstract: Key neuropathological changes associated with late-onset dementia are not fully understood. Population-based longitudinal studies offer an opportunity to step back and examine which pathological indices best link to clinical state. CC75C is a longitudinal study of the population aged 75 and over at baseline in Cambridge, UK. We report on the first 213 participants coming to autopsy with sufficient information for an end of life dementia diagnosis. Clinical diagnosis was ascertained by examining retrospective informant interviews, survey responses, and death certificates according to DSM-IV criteria. The neuropathological protocol was based on the Consortium to Establish a Registry of Alzheimer's Disease …(CERAD). Clinical dementia was present in 113 participants (53%): 67% with Alzheimer's disease, 4% vascular dementia, 22% mixed dementia, and 1% dementia with Lewy bodies. As Alzheimer-type pathology was common, the mutually blinded clinical and neuropathological diagnoses were not strongly related. Multivariable analysis identified associations between dementia during life and entorhinal cortex neuritic plaques, hippocampal diffuse plaques, neocortical neurofibrillary tangles, white matter pallor, Lewy bodies, and hippocampal atrophy. These results were consistent in those with clinical Alzheimer's disease. Vascular pathologies, especially microinfarcts, were more common in those with clinical diagnoses including vascular dementia. Alzheimer-type and cerebrovascular pathology are both common in the very old. A greater burden of these pathologies, Lewy bodies, and hippocampal atrophy, are associated with a higher risk of, but do not define, clinical dementia in old age. Show more

Keywords: Alzheimer's disease, cohort study, dementia, neuropathology, old age, vascular dementia

DOI: 10.3233/JAD-2009-1182

Citation: Journal of Alzheimer's Disease, vol. 18, no. 3, pp. 645-658, 2009

Authors: Members EClipSE Collaborative

Article Type: Research Article

Abstract: Epidemiological Clinicopathological Studies in Europe (EClipSE) is the harmonization of neuropathological and longitudinal clinical data from three population-based prospective longitudinal studies of aging. The EClipSE database (Version 1.0) comprises data from the first 970 people who donated their brain at death and this number will increase. EClipSE enables sociodemographic, health, cognitive, and genetic measures collected during life to be related to neuropathology at death, testing hypotheses which require more power than has been previously possible. EClipSE aims to help throw light on relationships between biological, health and psychological factors underlying ageing and the manifestation of clinical dementia.

Keywords: AAging, brain, dementia, epidemiology, health, population

DOI: 10.3233/JAD-2009-1181

Citation: Journal of Alzheimer's Disease, vol. 18, no. 3, pp. 659-663, 2009

Authors: O'Brien, Richard J. | Resnick, Susan M. | Zonderman, Alan B. | Ferrucci, Luigi | Crain, Barbara J. | Pletnikova, Olga | Rudow, Gay | Iacono, Diego | Riudavets, Miguel A. | Driscoll, Ira | Price, Donald L. | Martin, Lee J. | Troncoso, Juan C.

Article Type: Research Article

Abstract: The Baltimore Longitudinal Study of Aging (BLSA) was established in 1958 and is one the oldest prospective studies of aging in the USA and the world. The BLSA is supported by the National Institute of Aging (NIA) and its mission is to learn what happens to people as they get old and how to sort out changes due to aging from those due to disease or other causes. In 1986, an autopsy program combined with comprehensive neurologic and cognitive evaluations was established in collaboration with the Johns Hopkins University Alzheimer's Disease Research Center (ADRC). Since then, 211 subjects have undergone …autopsy. Here we review the key clinical neuropathological correlations from this autopsy series. The focus is on the morphological and biochemical changes that occur in normal aging, and the early neuropathological changes of neurodegenerative diseases, especially Alzheimer's disease (AD). We highlight the combined clinical, pathologic, morphometric, and biochemical evidence of asymptomatic AD, a state characterized by normal clinical evaluations in subjects with abundant AD pathology. We conclude that in some individuals, successful cognitive aging results from compensatory mechanisms that occur at the neuronal level (i.e., neuronal hypertrophy and synaptic plasticity) whereas a failure of compensation may culminate in disease. Show more

Keywords: α-synuclein, Alzheimer's disease, asymptomatic Alzheimer's disease, amyloid-β, dementia, Parkinson's disease, stereology, successful aging, tau

DOI: 10.3233/JAD-2009-1179

Citation: Journal of Alzheimer's Disease, vol. 18, no. 3, pp. 665-675, 2009

Authors: Oinas, Minna | Polvikoski, Tuomo | Sulkava, Raimo | Myllykangas, Liisa | Juva, Kati | Notkola, Irma-Leena | Rastas, Sari | Niinistö, Leena | Kalimo, Hannu | Paetau, Anders

Article Type: Research Article

Abstract: The consortium on dementia with Lewy bodies has established consensus guidelines for the neuropathologic diagnosis of dementia with Lewy bodies (DLB) including the likelihood that the neuropathologic findings associate with the clinical syndrome. Nevertheless, clinico-pathological correlations remain controversial. We applied the consensus guidelines for determining Lewy-related pathology (LRP) and evaluated the clinical presentation in the prospective, population-based Vantaa 85+ study consisting of individuals at least 85 years of age. LRP was seen in 36% of 304 subjects and categorized as follows: 3% brainstem-predominant, 14% limbic, 15% diffuse neocortical type (4% could not be categorized). The likelihood that the neuropathology predicts …the DLB clinical syndrome was low in 6%, intermediate in 13%, and high in 13% of all 304 subjects. In the latter two groups, 77% were demented, 35% had at least one extrapyramidal symptom, and 15% had visual hallucinations. Surprisingly, DLB clinical features associated better with high neurofibrillary stage than with diffuse neocortical LRP. Moreover, the neurofibrillary stage, substantia nigra neuron loss, and grade of Lewy neurites in hippocampal CA2-3 region, each showed a significant association with the extent of LRP. In conclusion, the neuropathologic DLB in this very elderly population was common, but the clinical symptoms tended to associate better with severe neurofibrillary pathology than with extensive LRP. Show more

Keywords: Aging, α-synuclein, Alzheimer's disease, dementia with Lewy bodies, Lewy-related pathology, neurofibrillary pathology, population-based study

DOI: 10.3233/JAD-2009-1169

Citation: Journal of Alzheimer's Disease, vol. 18, no. 3, pp. 677-689, 2009

Authors: Schneider, Julie A. | Aggarwal, Neelum T. | Barnes, Lisa | Boyle, Patricia | Bennett, David A.

Article Type: Research Article

Abstract: Community-based cohorts of older persons may differ neuropathologically from clinic-based cohorts. This study investigated age-related pathologies in persons with and without dementia and included autopsied participants from two community-based cohorts, the Rush Religious Orders Study (n=386) and the Memory and Aging Project (n=195), and one clinic-based cohort, the Clinical Core of the Rush Alzheimer's Disease Center (n=392). Final clinical diagnoses included no cognitive impairment (n=202), mild cognitive impairment (MCI) (n=150), probable Alzheimer's disease (AD) (n=474), possible AD (n=88), and other dementias (n=59). Postmortem diagnoses included pathologic AD, cerebral infarcts, and Lewy body disease. Community-based persons with clinical AD had less …severe AD pathology (p<0.001) and had more cerebral infarcts (p<0.001) compared to clinic-based persons. Additionally, community-based persons with MCI had more infarcts compared to clinic-based persons. Overall, there was a higher proportion of Lewy bodies and atypical pathologies in the clinic-based compared to the community-based cohorts (p<0.001). Community-based persons with probable AD show less severe AD pathology and more often have infarcts and mixed pathologies; those with MCI more often have infarcts and mixed pathologies. Overall, clinic-based persons have more Lewy bodies and atypical pathologies. The spectrum of pathologies underlying cognitive impairment in clinic-based cohorts differs from community-based cohorts. Show more

Keywords: Clinic, community, epidemiology, neuropathology, selection bias

DOI: 10.3233/JAD-2009-1227

Citation: Journal of Alzheimer's Disease, vol. 18, no. 3, pp. 691-701, 2009

Authors: Sonnen, Joshua A. | Larson, Eric B. | Haneuse, Sebastien | Woltjer, Randy | Li, Ge | Crane, Paul K. | Craft, Suzanne | Montine, Thomas J.

Article Type: Research Article

Abstract: The neuropathology underlying dementia syndromes in older populations is complex. The contributions of Alzheimer's and Lewy body pathology are well appreciated. Recent studies with brain autopsies have highlighted the high prevalence of vascular disease as an independent, but often co-morbid contributor to dementia. The Adult Changes in Thought Study is a community-based, longitudinal study of brain aging and cognitive decline which has recently confirmed cerebral microinfarcts as a strong correlate of cognitive impairment and dementia. This study examines correlations between clinical characteristics including extensive, longitudinal medication histories, and longitudinal cognitive testing against structural and biochemical features of disease.

Keywords: Aging, community-based, microinfarct, longitudinal, neuropathology

DOI: 10.3233/JAD-2009-1180

Citation: Journal of Alzheimer's Disease, vol. 18, no. 3, pp. 703-711, 2009

Authors: White, Lon

Article Type: Research Article

Abstract: This report summarizes findings from 443 autopsies on Japanese-American men followed as active participants in the Honolulu-Asia Aging Study from 1991 through 2003. Five distinct neuropathological lesion types were found to have strong, partially, or completely independent associations with cognitive impairment and/or dementia in the final years of life. They were: Alzheimer lesions (neocortical neurofibrillary tangles and neuritic plaques), microvascular infarcts (microinfarcts and lacunar infarcts), neocortical Lewy bodies, hippocampal sclerosis, and generalized brain atrophy. Atrophy was strongly associated with both Alzheimer lesions and microvascular infarcts, but was also observed in decedents with negligible levels of these and the other lesions. …About half of the hippocampal sclerosis cases appeared to be linked to Alzheimer lesions. A weak association of hippocampal sclerosis with microvascular infarcts was also noted. Comparable 3-level indices were defined for each of the five lesion types to facilitate comparisons of associations with cognitive impairment and dementia. Multiple combinations of the five lesion types were observed. The development of dementia in the final years of life was more closely correlated with their combined numbers and severities than with specific lesion types. In this autopsy panel, microvascular infarcts were identified as the sole or dominant lesion in 33.8% of the demented or definitely impaired decedents, compared with Alzheimer lesions in 18.6% and co-dominant lesions (most often Alzheimer and microvascular) in 14.2%. These or one or more of the other lesion types were observed in 87.9% of the demented or definitely impaired decedents. Show more

Keywords: Autopsy, brain, dementia, epidemiology, neuropathology

DOI: 10.3233/JAD-2009-1178

Citation: Journal of Alzheimer's Disease, vol. 18, no. 3, pp. 713-725, 2009

Article Type: Correction

DOI: 10.3233/JAD-2009-18324

Citation: Journal of Alzheimer's Disease, vol. 18, no. 3, pp. 727-727, 2009