Vladimir Kepe*, Mateen C. Moghbel*, Bengt Långström, Habib Zaidi, Harry V. Vinters, Sung-Cheng Huang, Nagichettiar Satyamurthy, Doris Doudet, Eyal Mishani, Robert M. Cohen, Poul F. Høilund-Carlsen, Abass Alavi, Jorge R. Barrio *These authors contributed equally to this work.
Amyloid-β Positron Emission Tomography Imaging Probes: A Critical Review
Abstract: The rapidly rising prevalence and cost of Alzheimer’s disease in recent decades has made the imaging of amyloid-β deposits the focus of intense research. Several amyloid imaging probes with purported specificity for amyloid-β plaques are currently at various stages of FDA approval. However, a number of factors appear to preclude these probes from clinical utilization. As the available ‘amyloid specific’ positron emission tomography imaging probes have failed to demonstrate diagnostic value and have shown limited utility to monitor therapeutic interventions in humans, a debate on their significance has emerged. The aim of this review is to identify and discuss critically the scientific issues contributing to the extensive inconsistencies reported in the literature on their purported in vivo amyloid specificity and potential utilization in patients.
Svetlana A. Khmeleva, Yuri V. Mezentsev, Sergey A. Kozin, Philipp O. Tsvetkov, Alexis S. Ivanov, Nikolay V. Bodoev, Alexander A. Makarov, Sergey P. Radko (Handling Associate Editor: Vladimir Buchman)
Zinc-Induced Interaction of the Metal-Binding Domain of Amyloid-β Peptide with DNA
Abstract: The interaction of the 16-mer synthetic peptide (Aβ16), which represents the metal-binding domain of the amyloid-β with DNA, was studied employing the surface plasmon resonance technique. It has been shown that Aβ16 binds to the duplex DNA in the presence of zinc ions and thus the metal-binding domain can serve as a zinc-dependent DNA-binding site of the amyloid-β. The interaction of Aβ16 with DNA most probably depends on oligomerization of the peptide and is dominated by interaction with phosphates of the DNA backbone.
Joel A. Saydoff, Ana Olariu, Jin Sheng, Zhongyi Hu, Qin Li, Rolando Garcia, Jiong Pei, Grace Y. Sun, Reid von Borstel (Handling Associate Editor: Russell Swerdlow)
Uridine Prodrug Improves Memory in Tg2576 and TAPP Mice and Reduces Pathological Factors associated with Alzheimer’s Disease in Related Models
Abstract: Uridine prodrug PN401 has been shown to have neuroprotective effects in models of Parkinson’s disease and Huntington’s disease. These age-related neurodegenerative diseases including Alzheimer’s disease (AD) are associated with mitochondrial dysfunction, oxidative stress, and inflammation. Attenuation of these pathological factors in AD, in addition to amyloid fibrils and neurofibrillary tangles, is critical to prevent cognitive impairment. The effects of PN401 treatment were tested in the Tg2576 and Tg2576 X P301L (TAPP) mouse models of AD. Treatment with PN401 reduced impairments in the Tg2576 mice in contextual fear conditioning and novel object recognition. In the TAPP mice, PN401 reduced the impairments in novel object recognition and social transmission of food preference. PN401 also improved motor behavior and reduced anxiety-like behavior in the TAPP mice. TAPP mouse hippocampal tau phosphorylation and lipid peroxidation were reduced by PN401 treatment. Increased tau phosphorylation was significantly correlated with worsening novel object recognition memory. PN401 did not affect amyloid plaque area in the AD mice. In other AD-related animal studies, PN401 treatment reduced blood-brain barrier damage due to intracortical LPS, elevation of serum TNFα due to systemic LPS, and hippocampal CA1 neuronal loss in the gerbil stroke model. Uridine dose-dependently protected cells from chemical hypoxia and ceramide, and decreased formation of reactive oxygen species and mitochondrial DNA damage due to hydrogen peroxide. These protective effects were achieved by raising uridine levels to at least 25-50 μM and serum uridine levels in this range in humans were obtained with oral PN401.
Fen Sun, XiaoOu Mao, Lin Xie, David A. Greenberg, Kunlin Jin
Neuroglobin Protein is Upregulated in Alzheimer’s Disease
Abstract: Neuroglobin is a neuronal protein with protective effects in animal models of stroke and Alzheimer’s disease, but the relevance of these effects to Alzheimer’s disease in humans is unknown. We measured neuroglobin levels by western blot and immunostained hippocampal sections for neuroglobin, cell-type protein markers, and amyloid-β, in brain tissue obtained at autopsy from patients with Alzheimer’s disease. Neuroglobin levels were increased in early and moderately advanced Alzheimer’s disease compared to controls, but declined to control levels in severe disease. In patients with Alzheimer’s disease, neuroglobin was detected within neurons, as well as at extracellular sites associated with amyloid-β deposits. We conclude that, as in transgenic mouse models, neuroglobin may influence the course of clinical Alzheimer’s disease.
Sophie Poole, Sim K. Singhrao, Lakshmyya Kesavalu, Michael A. Curtis, StJohn Crean
Determining the Presence of Periodontopathic Virulence Factors in Short-Term Postmortem Alzheimer’s Disease Brain Tissue
Abstract: The aim of this study was to establish a link between periodontal disease and Alzheimer’s disease (AD) with a view to identifying the major periodontal disease bacteria (Treponema denticola, Tannerella forsythia, and Porphyromonas gingivalis) and/or bacterial components in brain tissue from 12 h postmortem delay. Our request matched 10 AD cases for tissue from Brains for Dementia Research alongside 10 non-AD age-related controls with similar or greater postmortem interval. We exposed SVGp12, an astrocyte cell line, to culture supernatant containing lipopolysaccharide (LPS) from the putative periodontal bacteria P. gingivalis. The challenged SVGp12 cells and cryosections from AD and control brains were immunolabeled and immunoblotted using a battery of antibodies including the anti-P. gingivalis-specific monoclonal antibody. Immunofluorescence labeling demonstrated the SVGp12 cell line was able to adsorb LPS from culture supernatant on its surface membrane; similar labeling was observed in four out of 10 AD cases. Immunoblotting demonstrated bands corresponding to LPS from P. gingivalis in the SVGp12 cell lysate and in the same four AD brain specimens which were positive when screened by immunofluorescence. All controls remained negative throughout while the same four cases were consistently positive for P. gingivalis LPS (p = 0.029). This study confirms that LPS from periodontal bacteria can access the AD brain during life as labeling in the corresponding controls, with equivalent/longer postmortem interval, was absent. Demonstration of a known chronic oral-pathogen-related virulence factor reaching the human brains suggests an inflammatory role in the existing AD pathology.
Ane Korff, Changqin Liu, Carmen Ginghina, Min Shi, Jing Zhang, for the Alzheimer’s Disease Neuroimaging Initiative
α-Synuclein in Cerebrospinal Fluid of Alzheimer’s Disease and Mild Cognitive Impairment
Abstract: Background: In addition to amyloid-β (Aβ) and tau, α-synuclein, best known for its role in Parkinson’s disease (PD), has been suggested to be involved in cognition and pathogenesis of Alzheimer’s disease (AD). Objective: Here we investigate the potential of α-synuclein in cerebrospinal fluid (CSF) as a biomarker of cognitive decline in AD, and its prodromal phase, mild cognitive impairment (MCI). Methods: Using an established, sensitive Luminex assay, we measured α-synuclein levels in the CSF of a cohort of close to 400 healthy control, MCI, and AD subjects obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and factored in APOE genotype in data analysis. Results: CSF α-synuclein levels were significantly higher in the MCI (p = 0.005) and AD (p < 0.001) groups, compared to controls. However, receiver operating characteristic (ROC) curve analysis suggests that CSF α-synuclein level on its own only offered modest sensitivity (65%) and specificity (74%) as a diagnostic marker of AD, with an area under the curve (AUC) value of 0.719 for AD versus controls. The effect of APOE genotype, if any, was quite subtle. However, there was a significant correlation between α-synuclein and cognition (p = 0.001), with increased α-synuclein levels associated with decreased Mini-Mental State Exam scores. Conclusion: Our results support a role for α-synuclein even in MCI, the early phase of AD, in addition to be a potential contributor in MCI and AD diagnosis or monitoring of disease progression.
Daniel A. Nation, Christina E. Wierenga, Lindsay R. Clark, Sheena I. Dev, Nikki H. Stricker, Amy J. Jak, David P. Salmon, Lisa Delano-Wood, Katherine J. Bangen, Robert A. Rissman, Thomas T. Liu, Mark W. Bondi (Handling Associate Editor: David Knopman)
Cortical and Subcortical Cerebrovascular Resistance Index in Mild Cognitive Impairment and Alzheimer’s Disease
Abstract: Background. Reduced regional cerebral blood flow (rCBF) is a well-established finding in Alzheimer’s disease (AD), although fewer studies have examined the role of increased regional cerebrovascular resistance. By calculating the ratio of mean arterial pressure to rCBF, it is possible to estimate an index of regional cerebrovascular resistance (CVRi) that may be a sensitive measure of occult cerebrovascular disease. Objective. To compare probable AD patients to mild cognitive impairment (MCI) and normal control (NC) participants on CVRi, the ratio of mean arterial pressure to rCBF. Methods. Eighty-one participants (12 AD, 23 MCI, 46 NC) were compared on CVRi using voxel-wise analyses. Region-of-interest analyses examined correlations between subcortical CVRi and both cognition and white matter lesion (WML) volume. Results. Voxel-wise analyses revealed CVRi elevation in AD relative to NCs (subcortical, medial temporal, posterior cingulate, precuneus, inferior parietal, superior temporal) and MCI (subcortical, posterior cingulate). MCI participants exhibited intermediate CVRi values within cortical and medial temporal areas. Significant CVRi clusters were larger and more widespread than those of parallel CBF analyses. Among MCI and AD participants, subcortical CVRi elevation was associated with lower Dementia Rating Scale score (r = -0.52, p = 0.001, for both thalamus and caudate), and caudate CVRi correlated with WML volume (r = 0.45, p = 0.001). Conclusions. Cortical and subcortical CVRi is elevated in AD, particularly within the caudate and thalamus, where it is associated with decreased cognitive performance and increased WMLs. Findings suggest CVRi may play a role in cognitive decline and cerebrovascular disease in MCI and AD.
Brenna Cholerton, Eric. B. Larson, Laura D. Baker, Suzanne Craft, Paul K. Crane, Steven P. Millard, Joshua A. Sonnen, Thomas J. Montine (Handling Associate Editor: Thomas Beach)
Neuropathologic Correlates of Cognition in a Population-Based Sample
Abstract: Many cognitively normal older adults have underlying neuropathologic changes of Alzheimer’s disease (AD), vascular brain injury (VBI), or Lewy body disease (LBD), which confer an increased risk of dementia. The current study focused on the association between multiple neuropathologic indices and performance on specific cognitive domains in a community sample of older adults. Of 438 participants in the Adult Changes in Thought population-based study of brain aging who were autopsied, 363 subjects had cognitive testing at their final study visit and were included. Associations were measured between performance on the Cognitive Abilities Screening Instrument prior to death and neuropathologic endpoints, including AD neuropathologic changes, LBD, cerebral amyloid angiopathy, and measures of VBI. Braak stage for neurofibrillary tangles, lower brain weight, and VBI as measured by cerebral cortical microvascular lesions (µVBI) explained a significant proportion of the variance associated with global cognitive test performance (R2=0.31, p<0.0001) both in the entire sample and when analysis was restricted to non-demented subjects (R2=0.23, p<0.0001). Specific cognitive domains were differentially related to neuropathologic lesion type: memory and executive function with AD pathologic changes and cortical µVBI, executive function with subcortical µVBI, and visuospatial construction with LBD. Thus, neuropathologic lesions of LBD and µVBI are associated with poorer cognitive performance over and above AD neuropathologic changes in subjects without dementia in this cohort. These findings underscore that cognitive impairment is a complex convergent trait that has important implications for clinical investigation and medical management of older adults.
Matthias Grieder, Raffaella M. Crinelli, Kay Jann, Andrea Federspiel, Miranka Wirth, Thomas Koenig, Maria Stein, Lars-Olof Wahlund, Thomas Dierks (Handling Associate Editor: Claudio Babiloni)
Correlation between Topographic N400 Anomalies and Reduced Cerebral Blood Flow in the Anterior Temporal Lobes of Patients with Dementia
Abstract: In Alzheimer’s disease (AD) patients, episodic memory impairments are apparent, yet semantic memory difficulties are also observed. While the episodic pathology has been thoroughly studied, the neurophysiological mechanisms of the semantic impairments remain obscure. Semantic dementia (SD) is characterized by isolated semantic memory deficits. The present study aimed to find an early marker of mild AD and SD by employing a semantic priming paradigm during electroencephalogram recordings. Event-related potentials (ERP) of early (P1, N1) and late (N400) word processing stages were obtained to measure semantic memory functions. Separately, baseline cerebral blood flow (CBF) was acquired with arterial spin labeling. Thus, the analysis focused on linear regressions of CBF with ERP topographical similarity indices in order to find the brain structures that showed altered baseline functionality associated with deviant ERPs. All participant groups showed semantic priming in their reaction times. Furthermore, decreased CBF in the temporal lobes was associated with abnormal N400 topography. No significant CBF clusters were found for the early ERPs. Taken together, the neurophysiological results suggested that the automatic spread of activation during semantic word processing was preserved in mild dementia, while controlled access to the words was impaired. These findings suggested that N400-topography alterations might be a potential marker for the detection of early dementia. Such a marker could be beneficial for differential diagnosis due to its low cost and non-invasive application as well as its relationship with semantic memory dysfunctions that are closely associated to the cortical deterioration in regions crucial for semantic word processing.
Lucas Rasmussen, Roger Delabio, Lie Horiguchi, Igor Mizumoto, Carlos-Renato Terazaki, Diego Mazzotti, Paulo-Henrique Bertolucci, Marcela-Augusta Pinhel, Dorotéia Souza, Henrique Krieger, Carlos Kawamata, Thais Minett, Marilia Cardoso Smith, Spencer-Luiz Payão
Association Between Interleukin 6 Gene Haplotype and Alzheimer’s Disease: A Brazilian Case-Control Study
Abstract: Alzheimer’s disease (AD) is a progressive neurodegenerative disease that takes the form of a local overexpression of cytokines and other inflammatory molecules. We investigated three single-nucleotide polymorphisms (SNP) of the interleukin 6 gene (IL-6) promoter region [-174 G/C (rs 1800795), -572 C/G (rs 1800796), and -597 G/A (rs 1800797)] in 200 patients with late-onset AD and 165 elderly controls in a Brazilian case-control population sample. Genotyping was carried out from blood cells using PCR-RFLP techniques. Statistical analysis was performed to evaluate the Hardy-Weinberg equilibrium and to compare frequencies between groups. No association was found between any IL-6 polymorphism and AD; however the haplotype composed of the -597 A allele and the -174 G allele indicated a crude odds ratio (OR) of 0.15 (p= 0.0021) and a significantly adjusted OR (adjusted for the APOE E4 allele value) of 0.15 (p=0.00294). Linkage disequilibrium was D’= 0.68 among the three SNPs. Our findings revealed a protective effect of AG (-597A, -174G) haplotype, which worked independently of the APOE E4 allele in our Brazilian population sample. Thus, the promoter region of IL-6 gene probably exerts an effect through gene linkage and/or gene interaction.
Valerio Leoni, Alina Solomon, Anita Lövgren-Sandblom, Lennart Minthon, Kaj Blennow, Oskar Hansson, Lars-Olof Wahlund, Miia Kivipelto, Ingemar Björkhem (Handling Associate Editor: Anders Lonneborg)
Diagnostic Power of 24S-Hydroxycholesterol in Cerebrospinal Fluid: Candidate Marker of Brain Health
Abstract: We evaluated the diagnostic potential of 24S-hydroxycholesterol (24OHC) in cerebrospinal fluid. At a memory clinic, we investigated subjects with subjective cognitive impairment (SCI, n=33), mild cognitive impairment (MCI) patients (n=27), MCI patients with later progression into Alzheimer dementia at follow up (n=10), and patients with AD (n=24). We also had a control group of healthy volunteers who did not later develop cognitive problems (n=13). The fraction of the population with pathological levels of 24OHC was 8% in controls, 34% in SCI, 37% in MCI, 80% in MCI with progression, and 42% in AD. The corresponding fractions for T-tau, P-tau, and Aβ42 were lower in the case of SCI and MCI but higher in the case of controls and AD. In case of MCI with progression, the fraction of pathological levels of 24OHC and Aβ42 were 80% and 63% respectively. We also studied a population of old healthy subjects age 75-99 years (n=25). The fraction of individuals in this population with pathological levels of 24OHC was 0% whereas the fraction of individuals with pathological level of at least one of the other three biomarkers was 40%. The diagnostic power of 24OHC in cerebrospinal fluid seems to be similar to or lower than that of the established biomarkers T-tau, P-tau, and Aβ42 in the diagnosis of established AD. Our data suggest that 24OHC may be more sensitive than the classical biomarkers in an early phase of the neurodegenerative process and a better marker for “brain health” in old age.
Corinne D. Engelman, Rebecca L. Koscik, Erin M. Jonaitis, Ozioma C. Okonkwo, Bruce P. Hermann, Asenath La Rue, Mark A. Sager
Interaction Between Two Cholesterol Metabolism Genes Influences Memory: Findings from the Wisconsin Registry for Alzheimer’s Prevention
Abstract: The strongest genetic factor for late-onset Alzheimer’s disease (AD) is APOE; nine additional susceptibility genes have recently been identified. The effect of these genes is often assumed to be additive and polygenic scores are formed as a summary measure of risk. However, interactions between these genes are likely to be important. We sought to examine the role of interactions between the nine recently identified AD susceptibility genes and APOE in cognitive function and decline in 1,153 participants from the Wisconsin Registry for Alzheimer’s Prevention, a longitudinal study of middle-aged adults enriched for a parental history of AD. Participants underwent extensive cognitive testing at baseline and up to two additional visits approximately 4 and 6 years later. The influence of the interaction between APOE and each of 14 single nucleotide polymorphisms (SNPs) in the nine recently identified genes on three cognitive factor scores (Verbal Learning and Memory, Working Memory, and Immediate Memory) was examined using linear mixed models adjusting for age, gender, and ancestry. Interactions between the APOE ε4 allele and both of the genotyped ABCA7 SNPs, rs3764650 and rs3752246, were associated with all three cognitive factor scores (p-values ≤0.01). Both of these genes are in the cholesterol metabolism pathway leading to AD. This research supports the importance of considering non-additive effects of AD susceptibility genes.
Sylvie Slaets, Nathalie Le Bastard, Jean-Jacques Martin, Kristel Sleegers, Christine Van Broeckhoven, Peter Paul De Deyn, Sebastiaan Engelborghs (Handling Associate Editor: Piotr Lewczuk)
Cerebrospinal Fluid Aβ1-40 Improves Differential Dementia Diagnosis in Patients with Intermediate P-tau181P Levels
Abstract: It is assumed that the concentration of amyloid-β1-40 (Aβ1-40) in cerebrospinal fluid (CSF) reflects the total amount of Aβ protein in the brain and thus allows a better interpretation of inter-individual differences in Aβ quantity than the Aβ1-42 concentration. In this study, Aβ1-40 was added to the existing CSF biomarker panel of Aβ1-42, total tau (T-tau), and phosphorylated tau (P-tau181P) in order to test whether the accuracy of the differential dementia diagnosis improved. The concentration of Aβ1-40 (INNOTEST® β-amyloid(1-40) prototype version, Innogenetics NV, Belgium) and the other biomarkers (INNOTEST®) was determined in CSF samples from 80 Alzheimer’s disease (AD) patients, 75 non-AD dementia patients, and 30 controls. A large proportion of the study population had autopsy-confirmed neurodegeneration (AD: 73/80=91%; non-AD: 38/75=51%). The levels of Aβ1-40 were decreased in AD (10856±4745 pg/mL) and non-AD patients (10519±4491 pg/mL) when compared to controls (14760±7846 pg/mL) (p=0.002 and p=0.001). The Aβ1-42/Aβ1-40 ratio was significantly decreased in AD (0.043±0.021) as compared to non-AD patients (0.064±0.027; p<0.001) and controls (0.053±0.023; p<0.001). In order to differentiate AD from non-AD patients, a decision tree was constructed. The diagnostic accuracy of the decision tree that contained Aβ1-42, Aβ1-40, P-tau181P, and the Aβ1-42/Aβ1-40 ratio was significantly better than the diagnostic accuracy (80% versus 74%) of the decision tree without Aβ1-40 and the Aβ1-42/Aβ1-40 ratio (p<0.001). In conclusion, no difference in Aβ1-40 CSF levels was found between AD and non-AD patients, but adding CSF Aβ1-40 and the CSF Aβ1-42/Aβ1-40 ratio to a biomarker-based decision tree, might have an added value for discriminating AD from non-AD patients in case of intermediate CSF P-tau181P values.
Ramit Ravona-Springer, Michal Schnaider Beeri, Uri Goldbourt
Satisfaction with Current Status at Work and Lack of Motivation to Improve It During Midlife is Associated with Increased Risk for Dementia in Subjects who Survived Thirty-Seven Years Later
Abstract: The present study aimed to assess the relationship of midlife Motivation to Improve Status at work (MIS) with dementia more than three decades later, In 1963, 9,920 out of 10,059 male participants of the Israel Ischemic Heart disease (IIHD) study, aged 40–65 years, were questioned about their MIS as follows: "Do you want to improve your status at work and do you believe it is possible?". One of four answers was possible: trying to change status and believe it is possible (MIS1) (n=3,060); trying but unsure of success (MIS2) (n=2,618); not trying, unlikely to succeed (MIS3) (n=2,020); not trying, satisfied (MIS4) (n= 2,222). Dementia was assessed over three decades later in 1,714 survivors of the original cohort, including 1,691 who responded in 1963 to the questionnaire regarding MIS. Controlling for age, the estimated odds for dementia relative to MIS1 were 1.45 (95% CI 1.06-2.01) in MIS2, 1.52 (95% CI 1.04-2.23) in MIS3, and 1.96 (95% CI 1.38-2.81) in MIS4. Further adjustment for age and socioeconomic status index resulted in adjusted estimated odds for dementia relative to MIS1 were 1.26 (95% CI 0.90-1.75) in MIS2, 1.10 (95% CI 0.74-1.64) in MIS3, and 1.78 (95% CI 1.23- 2.56) in MIS4. These results were not attenuated when midlife diabetes, blood pressure values, serum-cholesterol levels, and coronary heart disease were controlled for in the analysis. Among tenured working men, lack of MIS together with satisfaction with current status was associated with higher risk for dementia among survivors several decades later. This association was partially attenuated by socioeconomic status.
Narayan R. Bhat, Lakshmi Thirumangalakudi
Increased Tau Phosphorylation and Impaired Brain Insulin/IGF Signaling in Mice Fed a High Fat/High Cholesterol Diet
Abstract: Previous studies demonstrated that a high fat/high cholesterol (HFC) diet results in a loss of working memory in mice correlated with neuroinflammatory changes and increased AβPP processing (Thirumangalakudi et al. (2008) J Neurochem 106, 475-485). To further explore the nature of the molecular correlates of cognitive impairment, in this study, we examined changes in tau phosphorylation, insulin/IGF-1 signaling (IIS) including GSK3, and levels of specific synaptic proteins. Immunoblot analysis of hippocampal tissue from C57BL/6 mice fed HFC for 2 months with anti-phospho-tau (i.e., PHF1 and phospho-Thr-231 tau) antibodies demonstrated the presence of hyperphosphorylated tau. The tau phosphorylation correlated with activated GSK3, a prominent tau kinase normally kept inactive under the control of IIS. That IIS itself was impaired due to the hyperlipidemic diet was confirmed by a down-regulation of insulin receptor substrate-1 and phospho-Akt and levels. Although no significant changes in the levels of the pre-synaptic protein (i.e., synaptophysin) in response to HFC were apparent in immunoblot analysis, there was a clear down-regulation of the post-synaptic protein, PSD95, and drebrin, a dendritic spine-specific protein, indicative of altered synaptic plasticity. The results, in concert with previous findings with the same model, suggest that high dietary fat/cholesterol elicits brain insulin resistance and altered IIS leading to Alzheimer’s disease-like cognitive impairment in ‘normal’ mice.
Laura C. Lazzeroni, Joshua D. Halbauer, J. Wesson Ashford, Art Noda, Beatriz Hernandez, Virgina Azor, Nikki Hozack, Noelle Hasson, Victor W. Henderson, Jerome A. Yesavage, Jared R. Tinklenberg
Memantine is Associated with Longer Survival than Donepezil in a Veterans Affairs Prescription Database, 1997 to 2008
Abstract: Alzheimer’s disease (AD) shortens life-expectancy, but the effects of pharmacological treatments for this disorder on mortality have not been studied. We compared two commonly prescribed medications, donepezil and memantine, with respect to the length of survival of veterans presumed to have AD. The Computerized Medical Records System at the Veterans Affairs Palo Alto Health Care System (VAPAHCS) was used to identify all patients prescribed these medications between 1997 and 2008. The VAPAHCS approved donepezil in 1997 and memantine in 2004. Kaplan-Meier and Cox regression analyses were used to test for chronological and drug-related associations with survival in 2,083 male veterans aged 55 years and older receiving prescriptions for donepezil, memantine, or both. Overall patient mortality decreased in the 2004 to 2008 era, compared with the 1997 to 2003 era, pre-memantine (HR: 0.75; 95% CI: 0.63, 0.89; p = 0.001). In analyses confined to the 2004 to 2008 era, patients prescribed memantine alone survived significantly longer (median survival 8.9 years) than those prescribed donepezil alone (HR: 2.24; 95% CI: 1.53, 3.28; p < 0.001) or both donepezil and memantine (HR: 1.83; 95% CI: 1.14, 2.94; p = 0.012). While this study has several limitations, these findings suggest that memantine treatment is associated with an increased life-expectancy relative to donepezil treatment. Additional research is needed to replicate these unexpected findings and identify potential mechanisms to explain this apparent association, to establish if the relationship applies to other cholinesterase inhibitors, and to discover whether the findings generalize to women and patient populations with characteristics different from those of the veterans in this study.
Eloi Magnin, Gilles Chopard, Sabrina Ferreira, Geraldine Sylvestre, Elfried Dariel, Ilham Ryff, Catherine Mertz, Charlie Lamidieu, Julie Hidalgo, Gregory Tio, Sophie Haffen, Jean Galmiche, Thierry Moulin, Pierre Vandel, Lucien Rumbach (Handling Associate Editor: Jérémie Pariente)
Initial Neuropsychological Profile of a Series of 20 Patients with Logopenic Variant of Primary Progressive Aphasia
Abstract: Background: Logopenic variant of primary progressive aphasia (LPPA) is classically considered as an isolated language disorder, but verbal short-term memory deficit induces difficulties in neuropsychological tests that are not intended to evaluate language. Objective: The aim of this study is to describe the initial symptoms and neuropsychological profiles of LPPA. Methods: A retrospective study was conducted with a series of 20 consecutive patients diagnosed with LPPA. Clinical, neuroimaging, neuropsychological, and linguistic examinations are reported. The first neuropsychological examinations (mean time between neuropsychological assessment and diagnosis: 11 months) were then compared to 20 patients with mild cognitive impairment (MCI) and 20 patients with Alzheimer’s disease (AD) matched by age, gender, and education level. Results: A recent onset or aggravation of anxiety disorders was frequently reported. An unusual neuropsychological profile, different from that of AD or MCI, was observed: dissociation between verbal and visual memory performances, poor encoding performances on verbal memory tests, and preserved orientation to time, difficulties with mental calculation and fluency tasks. Biparetal abnormality and left hippocampal diaschisis was frequently observed. Asymptomatic dopaminergic depletion was observed in four patients. Conclusion: Our study identifies that de novo or recently worsening anxiety and specific neuropsychological profiles call for screening for LPPA, including a linguistic examination. Sometimes, there may be a continuum between LPPA and corticobasal syndrome.