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

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