Journal of Alzheimer's Disease - Volume 35, issue 1

Authors: Bondareff, William

Article Type: Review Article

Abstract: Alzheimer's disease is a neurodegenerative disease in which aging is not only a major risk factor but a major determinant of onset, course, and pathogenesis. The synthesis of amyloid-β (Aβ) peptides by neurons and their excretion into the extracellular space (ECS) is a core feature of AD that begins more than two decades before the onset of clinical symptoms. The ECS resembles a syncytium with the appearance in electron micrographs of continuous channels and lakes separating the outer membranes of the neurons, neuroglia, and vascular elements embedded in it. It consists primarily of a proteoglycan matrix through which circulates an …interstitial fluid, derived in part from cerebrospinal fluid (CSF). The process by which Aβ accumulates in the ECS includes decreased production of CSF, matrix proteoglycans, and ECS volume, all of which become more severe with advancing age and lead to an age-related increase in the Aβ pool. Although the relationship between Aβ and the appearance of cognitive symptoms is uncertain, available data support a strong relationship between the toxicity of Aβ for neurons and the total Aβ burden, including the soluble and fibrillar Aβ, the Aβ42 /Aβ40 ratio, and Aβ-proteoglycan reactivity. Proteoglycans have been shown to foster the formation of neurotoxic fibrillar Aβ42 and neuritic plaques that enhance neuronal and synaptic damage and eventual loss culminating in the onset and progression of dementia. As this process depends upon age-related events, it suggests that the successful control of AD lies in finding effective means of prevention. Show more

Keywords: Aging, Alzheimer's disease, brain, extracellular matrix, extracellular space

DOI: 10.3233/JAD-122305

Citation: Journal of Alzheimer's Disease, vol. 35, no. 1, pp. 1-6, 2013

Authors: Walton, J.R.

Article Type: Review Article

Abstract: The neuroanatomic specificity with which Alzheimer's disease (AD) progresses could provide clues to AD etiopathology. Magnetic resonance imaging studies of AD clinical progression have confirmed general conclusions from earlier studies of AD neuropathological progression wherein neurofibrillary tangle pathology was observed to spread along a well-defined sequence of corticocortical and corticosubcortical connections, preferentially affecting certain cell types, while sparing others. Identical and non-identical twin studies have consistently shown AD has mixed (environmental and genetic) etiopathogenesis. The decades-long prodromal phase over which AD develops suggests slow but progressive accumulation of a toxic or infective agent over time. Major environmental candidates are reviewed …to assess which best fits the profile of an agent that slowly accrues in susceptible cell types of AD-vulnerable brain regions to toxic levels by old age, giving rise to AD neuropathology without rapid neuronal lysis. Chronic aluminum neurotoxicity best matches this profile. Many humans routinely ingest aluminum salts as additives contained in processed foods and alum-treated drinking water. The physical properties of aluminum and ferric iron ions are similar, allowing aluminum to use mechanisms evolved for iron to enter vulnerable neurons involved in AD progression, accumulate in those neurons, and cause neurofibrillary damage. The genetic component of AD etiopathogenesis apparently involves a susceptibility gene, yet to be identified, that increases aluminum absorption because AD and Down syndrome patients have higher than normal plasma, and brain, aluminum levels. This review describes evidence for aluminum involvement in AD neuropathology and the clinical progression of sporadic AD. Show more

Keywords: Aluminum compounds, Alzheimer's disease, amyloid-β protein precursor, animal, causality, disease models, intestinal absorption, neurofibrillary tangles, neurotoxicity syndromes, translational medical research

DOI: 10.3233/JAD-121909

Citation: Journal of Alzheimer's Disease, vol. 35, no. 1, pp. 7-43, 2013

Authors: Pottier, Cyril | Wallon, David | Rousseau, Stephane | Rovelet-Lecrux, Anne | Richard, Anne-Claire | Rollin-Sillaire, Adeline | Frebourg, Thierry | Campion, Dominique | Hannequin, Didier | GMAJ/COMAJ collaborators

Article Type: Short Communication

Abstract: The rs75932628-T variant of the gene encoding the triggering receptor expressed on myeloid cells 2 (TREM2) has recently been identified as a rare risk factor for late-onset Alzheimer's disease (AD). In this study we examined the association between TREM2 exon 2 variants and early-onset AD in a sample of Caucasian subjects of French origin including 726 patients with age of onset ≤65 years and 783 controls. Only the rs75932628-T variant (predicted to cause an R47H substitution) conferred a significant risk for early-onset AD (OR, 4.07; 95% CI, 1.3 to 16.9; p = 0.009). These results confirm the association between this …variant and AD and underline its involvement in early-onset cases. Show more

Keywords: Early onset Alzheimer's disease, rare variant, risk factor, TREM2

DOI: 10.3233/JAD-122311

Citation: Journal of Alzheimer's Disease, vol. 35, no. 1, pp. 45-49, 2013

Authors: Daborg, Jonny | Holmgren, Sandra | Abramsson, Alexandra | Andreasson, Ulf | Zetterberg, Madeleine | Nilsson, Staffan | Minthon, Lennart | Skoog, Ingmar | Blennow, Kaj | Pekna, Marcela | Hanse, Eric | Zetterberg, Henrik

Article Type: Research Article

Abstract: The complement system has been implicated in both physiological synapse elimination and Alzheimer's disease (AD). Here, we investigated associations between four single nucleotide polymorphisms (SNPs) in complement genes and cerebrospinal fluid (CSF) biomarkers for AD in 452 neurochemically or neuropathologically verified AD cases and 678 cognitively normal controls. None of the SNPs associated with risk of AD but there were potential associations of rs9332739 in the C2 gene and rs4151667 in the complement factor B gene with CSF tau levels (p = 0.023) and Mini-Mental State Examination scores (p = 0.012), both of which may be considered markers of disease …intensity/severity. Show more

Keywords: Alzheimer's disease, complement, microglia, single nucleotide polymorphisms

DOI: 10.3233/JAD-121930

Citation: Journal of Alzheimer's Disease, vol. 35, no. 1, pp. 51-57, 2013

Authors: Rhodehouse, Bryce C. | Erickson, Michelle A. | Banks, William A. | Bearden, Shawn E.

Article Type: Research Article

Abstract: Hyperhomocysteinemia (HHcy) is associated with cognitive impairment and Alzheimer's disease. Whether this association is mechanistic remains unclear. Here, we used a mouse model to test the hypothesis that HHcy increases levels of amyloid-β (Aβ) transporters in microvessels that form the blood-brain barrier, elevates Aβ content (Aβ40 and Aβ42 ) in the brain, and impairs cognitive performance. Mice with HHcy and age-matched, non-HHcy controls (Ctrl) were studied in two age groups: adult (6.2 ± 0.4 months of age) and old (19 ± 2.0 months of age). Levels of Aβ transporters, RAGE, LRP1, and Pgp, were not different between HHcy and …Ctrl mice. Though there was an increase in overall brain Aβ levels with age, there were no differences between HHcy and Ctrl groups in cortex, hippocampus, or midbrain/diencephalon. Despite the lack of difference in Aβ, old mice with HHcy showed significant cognitive impairment on Morris water maze tests compared with Ctrl mice. We conclude that HHcy leads to cognitive impairment without many of the changes currently thought to be relevant to promoting the AD phenotype. Show more

Keywords: Homocysteine, dementia, cognitive impairment, Alzheimer's disease, blood-brain barrier, microvessels, microvascular permeability

DOI: 10.3233/JAD-122347

Citation: Journal of Alzheimer's Disease, vol. 35, no. 1, pp. 59-66, 2013

Authors: Engelborghs, Sebastiaan | Sleegers, Kristel | Van der Mussele, Stefan | Le Bastard, Nathalie | Brouwers, Nathalie | Van Broeckhoven, Christine | De Deyn, Peter Paul

Article Type: Research Article

Abstract: A prospective, longitudinal study was set up to investigate possible genetic associations of behavioral and psychological signs and symptoms of dementia (BPSD) in Alzheimer's disease (AD) with two candidate genes in the serotonergic neurotransmitter pathway: serotonin transporter (SLC6A4) and brain-specific tryptophan hydroxylase (TPH2). Patients with probable AD (n = 249) were diagnosed according to NINCDS/ADRDA criteria. During follow-up, autopsy-confirmation of clinical diagnosis was obtained in 32 AD patients. Taking into account follow-up behavioral assessments by means of validated behavioral assessment scales (Middelheim Frontality Score and Behave-AD), behavioral ratings reflecting the highest scores on any behavioral item ever observed since dementia …onset were calculated and applied for statistical analyses. A functional insertion/deletion polymorphism in the promoter region of SLC6A4 (5-HTTLPR) and 10 selected SNPs within TPH2 were genotyped. Single-marker allelic association analyses (TPH2, 5-HTTLPR) were performed. TPH2 allelic analyses revealed significant associations with frontal lobe symptoms, as well as with diurnal rhythm disturbances. 5-HTTLPR S allele carriers had an increased risk to display loss of insight and judgment, another frontal lobe symptom. The present prospective, longitudinal study showed that mainly frontal lobe symptoms were significantly associated with TPH2 and 5-HTTLPR polymorphisms, pointing toward a role of the serotonergic neurotransmitter system in the pathophysiology of frontal lobe symptoms in AD. Show more

Keywords: Alzheimer's disease, behavior, behavioral and psychological signs and symptoms of dementia (BPSD), dementia, serotonin, TPH2

DOI: 10.3233/JAD-101305

Citation: Journal of Alzheimer's Disease, vol. 35, no. 1, pp. 67-73, 2013

Authors: Mitolo, Micaela | Gardini, Simona | Fasano, Fabrizio | Crisi, Girolamo | Pelosi, Annalisa | Pazzaglia, Francesca | Caffarra, Paolo

Article Type: Research Article

Abstract: Spatial abilities decline in normal aging and decrease faster and earlier in Alzheimer's disease (AD), but these deficits are under investigated. The main goals of this study were to assess visuospatial memory abilities in mild cognitive impairment (MCI), in order to verify whether these tasks might be valid as the standard cognitive test to differentiate MCI individuals from normal controls and to investigate the brain structural correlates of visuospatial deficits. Twenty MCI patients and fourteen healthy elderly controls underwent an experimental visuospatial battery, which also included self-rating spatial questionnaires, and structural MRI brain imaging. Compared to healthy elderly controls, MCI …patients scored significantly worse in almost all visuospatial tasks. ROC analysis showed that visuospatial tasks had an elevated discriminant power between groups (AUC >0.90). Voxel-based morphometry analysis, compared to controls, disclosed a higher level of atrophy in frontal and medio-temporal regions and a different pattern of correlation between grey matter values and visuospatial performance, with wider distributed areas of the occipital and middle temporal cortex in the map and route learning. This study indicates that visuospatial memory tests are valid tools in completing the diagnostic evaluation of MCI. Show more

Keywords: Alzheimer's disease, magnetic resonance imaging, mild cognitive impairment, spatial navigation, visuospatial memory

DOI: 10.3233/JAD-121288

Citation: Journal of Alzheimer's Disease, vol. 35, no. 1, pp. 75-90, 2013

Authors: Jiang, Xia | Jia, Lin-Wei | Li, Xiao-Hong | Cheng, Xiang-Shu | Xie, Jia-Zhao | Ma, Zhi-Wei | Xu, Wei-Jie | Liu, Yue | Yao, Yun | Du, Lai-Ling | Zhou, Xin-Wen

Article Type: Research Article

Abstract: Hyperphosphorylated tau aggregated into neurofibrillary tangles is a hallmark lesion of Alzheimer's disease (AD) and is linked to synaptic and cognitive impairments. In animal models, cold water stress (CWS) can cause cognitive disorder and tau hyperphosphorylation. Capsaicin (CAP), a specific TRPV1 agonist, is neuroprotective against stress-induced impairment, but the detailed mechanisms are still elusive. Here, we investigated whether CAP mitigates CWS-induced cognitive and AD-like pathological alterations in rats. The animals were administered CAP (10 mg/kg in 0.2 ml, 0.1% ethanol) or a control (0.2 ml normal saline, 0.1% ethanol) by intragastric infusion 1 h before CWS treatment. Our results showed …that CAP significantly attenuated CWS-induced spatial memory impairment and suppression of PP-DG long-term potentiation; CAP abolished CWS-induced dendritic regression and enhanced several memory-associated proteins decreased by CWS, such as synapsin I and PSD93; CAP also prevented CWS-induced tau hyperphosphorylation by abolishing inhibition of protein phosphatase 2A. Taken together, this study demonstrated that activation of TRPV1 can mitigate CWS-induced AD-like neuropathological alterations and cognitive impairment and may be a promising target for therapeutic intervention in AD. Show more

Keywords: Alzheimer's disease, capsaicin, dendritic arborization, spatial memory, tau hyperphosphorylation

DOI: 10.3233/JAD-121837

Citation: Journal of Alzheimer's Disease, vol. 35, no. 1, pp. 91-105, 2013

Authors: Hochard, Arnaud | Oumata, Nassima | Bettayeb, Karima | Gloulou, Olfa | Fant, Xavier | Durieu, Emilie | Buron, Nelly | Porceddu, Mathieu | Borgne-Sanchez, Annie | Galons, Hervé | Flajolet, Marc | Meijer, Laurent

Article Type: Research Article

Abstract: Increased production of amyloid-β (Aβ)42 peptide, derived from the amyloid-β protein precursor, and its subsequent aggregation into oligomers and plaques constitutes a hallmark of Alzheimer's disease (AD). We here report on a family of low molecular weight molecules, the Aftins (Amyloid-β Forty-Two Inducers), which, in cultured cells, dramatically affect the production of extracellular/secreted amyloid peptides. Aftins trigger β-secretase inhibitor and γ-secretase inhibitors (GSIs) sensitive, robust upregulation of Aβ42 , and parallel down-regulation of Aβ38 , while Aβ40 levels remain stable. In contrast, intracellular levels of these amyloids appear to remain stable. In terms of their effects on Aβ38 …/Aβ40 /Aβ42 relative abundance, Aftins act opposite to γ-secretase modulators (GSMs). Aβ42 upregulation induced by Aftin-5 is unlikely to originate from reduced proteolytic degradation or diminished autophagy. Aftin-5 has little effects on mitochondrial functional parameters (swelling, transmembrane potential loss, cytochrome c release, oxygen consumption) but reversibly alters the ultrastructure of mitochondria. Aftins thus alter the Aβ levels in a fashion similar to that described in the brain of AD patients. Aftins therefore constitute new pharmacological tools to investigate this essential aspect of AD, in cell cultures, allowing (1) the detection of inhibitors of Aftin induced action (potential ‘anti-AD compounds’, including GSIs and GSMs) but also (2) the identification, in the human chemical exposome, of compounds that, like Aftins, might trigger sustained Aβ42 production and Aβ38 down-regulation (potential ‘pro-AD compounds’). Show more

Keywords: Aftins, Alzheimer's disease, amyloid-β, Aβ38, Aβ40, Aβ42, γ-secretase, γ-secretase modulators, mitochondria

DOI: 10.3233/JAD-121777

Citation: Journal of Alzheimer's Disease, vol. 35, no. 1, pp. 107-120, 2013

Authors: Sjölander, Annica | Minthon, Lennart | Nuytinck, Lieve | Vanmechelen, Eugeen | Blennow, Kaj | Nilsson, Staffan

Article Type: Research Article

Abstract: Mannan-Binding lectin (MBL) is a serum lectin and an important constituent of the innate immune system. Processes linked to the innate immune response have previously been implicated in Alzheimer's disease (AD). MBL is associated with blood vessels in the brain and AD patients demonstrate lower MBL levels in the cerebrospinal fluid compared to controls. We investigated six single nucleotide polymorphisms, linked to MBL deficiency, in the corresponding MBL2 gene in AD patients and controls. Two MBL2 haplotypes, LXP and LYQ, were significantly associated with AD risk (OR = 1.6, p = 0.01 and OR = 1.5, p = 0.02, respectively). …The present study is the first investigating MBL2 genotypes and haplotypes in relation to AD. Our findings support that the MBL2 gene impact the disease risk. Show more

Keywords: Alzheimer's disease, cerebrospinal fluid, gene, immune response, Mannan-Binding lectin, single nucleotide polymorphism

DOI: 10.3233/JAD-122044

Citation: Journal of Alzheimer's Disease, vol. 35, no. 1, pp. 121-127, 2013

Authors: Kim, Hee-Jin | Moon, Won-Jin | Han, Seol-Heui

Article Type: Research Article

Abstract: Background: This study aimed to evaluate the relationship between loss of white matter cholinergic pathways, atrophy of the nucleus basalis of Meynert (NBM), and cognitive function in patients with subcortical ischemic vascular dementia (SIVD) or Alzheimer’s disease (AD). Methods: The participants included 26 SIVD, 17 probable AD with or without white-matter changes, and 20 age-matched healthy controls. Thin-section coronal T2-weighted images were acquired using 3.0 T MR. The extent of white matter hyperintensities within cholinergic pathways were assessed using the cholinergic pathways hyperintensities scale (CHIPS). NBM atrophy was assessed from the thickness of the substantia innominata (SI) at …the level of the crossing of the anterior commissure. Cognitive impairment was measured using the Mini-Mental State Examination (MMSE) and Clinical Dementia Rating (CDR). Correlations between CHIPSs, SI thickness, and cognitive impairment were evaluated using the Spearman ranked correlation test. Results: In AD, MMSE scores and CDR were correlated with SI thickness (ρ = 0.450, p = 0.006 and ρ = −0.520, p = 0.030, respectively) but not with CHIPS scores (ρ = −0.160, p = 0.530 and ρ = 0.270, p = 0.292, respectively). By contrast, aggravated MMSE score and CDR in SIVD had a tendency to correlate with elevated CHIPS scores (ρ = −0.344, p = 0.127 and ρ = 0.521, p = 0.021, respectively) but not with SI thickness (ρ = −0.210, p = 0.480 and ρ = 0.080, p = 0.736, respectively). Conclusions: Loss of cholinergic pathways correlates with cognitive dysfunction in both AD and SIVD. The mechanisms appear to differ: NBM atrophy is likely to be the predominant contributor to cognitive impairments in AD, whereas, the cognitive dysfunction of SIVD was associated with compromised subcortical cholinergic fibers not with nucleus itself. Show more

Keywords: Alzheimer's disease, cholinergic pathway, nucleus basalis of Meynert, subcortical ischemic vascular dementia

DOI: 10.3233/JAD-122320

Citation: Journal of Alzheimer's Disease, vol. 35, no. 1, pp. 129-136, 2013

Authors: Slaets, Sylvie | Le Bastard, Nathalie | Theuns, Jessie | Sleegers, Kristel | Verstraeten, Aline | De Leenheir, Evelyn | Luyckx, Jill | Martin, Jean-Jacques | Van Broeckhoven, Christine | Engelborghs, Sebastiaan

Article Type: Research Article

Abstract: A significant proportion of patients with dementia with Lewy bodies (DLB) show Alzheimer's disease (AD) pathology like senile plaques and neurofibrillary tangles. Biomarkers in cerebrospinal fluid (CSF), such as amyloid-β1-42 (Aβ1-42 ), total tau (T-tau), and hyperphosphorylated tau (P-tau181P ), are linked to the different pathological hallmarks of AD. We set up a study to investigate the influence of AD co-pathology on CSF biomarker concentrations and profiles in autopsy-confirmed DLB. DLB patients with senile plaques showed significantly lower CSF Aβ1-42 concentrations than DLB patients without senile plaques, but not compared to the AD patients. There were no significant …differences in CSF T-tau or P-tau181P concentrations between DLB patients with and without neurofibrillary tangles. A correlation was found between the number of APOE ε4 alleles and Aβ1-42 CSF levels in DLB patients with senile plaques. Although the CSF biomarkers Aβ1-42 , T-tau, and P-tau181P have an added diagnostic value for the differential dementia diagnosis, concomitant amyloid pathology in DLB limits the use of CSF Aβ1-42 for the differential diagnosis of AD versus DLB. Show more

Keywords: Alzheimer's disease, autopsy-confirmed, biological markers, dementia, dementia with Lewy bodies

DOI: 10.3233/JAD-122176

Citation: Journal of Alzheimer's Disease, vol. 35, no. 1, pp. 137-146, 2013

Authors: Merrill, David A. | Siddarth, Prabha | Kepe, Vladimir | Raja, Pushpa V. | Saito, Nathan | Ercoli, Linda M. | Miller, Karen J. | Lavretsky, Helen | Bookheimer, Susan Y. | Barrio, Jorge R. | Small, Gary W.

Article Type: Research Article

Abstract: The relationship of cerebrovascular risk and Alzheimer's disease (AD) pathology to cognition in pre-dementia has been extensively investigated and is well-established. Cerebrovascular risk can be measured using a Framingham Stroke Risk Profile (FSRP) score, while positron emission tomography (PET) scans with 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile (FDDNP) measure AD neuropathology (i.e., amyloid-β plaques and tau tangles). Here we report results of 75 healthy non-demented subjects (mean age, 63 years) who underwent neuropsychological testing, physical assessments, and FDDNP-PET scans. Controlling for AD family history, education, and APOE4 status in a general linear model, higher FSRP risk and global FDDNP-PET binding were each associated with poorer …cognitive functioning. The interaction of FSRP and global FDDNP-PET binding was not significant in the model, indicating that stroke risk and plaque and tangle burden each contributed to worse cognitive performance. Within our healthy volunteers, age, blood pressure, and antihypertensive medication use were vascular risks that contributed significantly to the above findings. These findings suggest that even mild cerebrovascular risk may influence the extent of cognitive dysfunction in pre-dementia, along with amyloid-β and tau burden. Show more

Keywords: Aging, Alzheimer's disease, amyloid-β plaques, FDDNP, Framingham stroke risk profile, mild cognitive impairment, older adults, positron emission tomography, tau tangles

DOI: 10.3233/JAD-121903

Citation: Journal of Alzheimer's Disease, vol. 35, no. 1, pp. 147-157, 2013

Authors: Dong, YanHong | Pang, Wan Shin | Lim, Leon Ben Swie | Yang, Yuan-Han | Morris, John C. | Hilal, Saima | Venketasubramanian, Narayanaswamy | Chen, Christopher Li-Hsian

Article Type: Research Article

Abstract: The informant AD8 has good discriminatory indices in detecting questionable dementia. However, studies on participant AD8 yielded inconsistent results. This study aims to investigate the discriminatory ability of the AD8 in detecting cognitive impairment at a memory clinic by comparing the informant AD8, participant AD8, Montreal Cognitive Assessment (MoCA), and Mini-Mental State Examination (MMSE). The AD8 was administered to 280 participant-informant dyads. The MoCA and MMSE were administered to all participants, who subsequently received a comprehensive clinical and neuropsychological assessment leading to a consensus diagnosis and a Clinical Dementia Rating (CDR). Area under the receiver operating characteristic curve (ROC) analysis …was used to compare the discriminatory ability of AD8, MoCA, and MMSE. Participants were Chinese (83.6%) females (54.3%) with a mean age and education of 73.4 ± 8.6 years and 6.2 ± 5.6 years, respectively. The discriminant validity of the informant AD8 was significantly superior to the participant AD8 in detecting cognitive impairment (CDR ≥ 0.5) {Area Under Curve (AUC) [95% confidence interval (CI)]: 0.96 (0.93–0.98) versus 0.66 (0.58–0.74), p < 0.01}. Furthermore, the informant AD8 was equivalent to MoCA and MMSE in detecting cognitive impairment {AUC [95% CI]: MoCA [0.98 (0.96–0.99)]; MMSE [0.95 (0.93–0.98)]}. The informant AD8 (≥2) had very good sensitivity and specificity, while the participant AD8 (≥2) had suboptimal sensitivity and specificity in detecting cognitive impairment (sensitivity 0.93 versus 0.59; specificity 0.87 versus 0.65; 91.8% versus 60% correctly classified). The informant AD8 is superior to the participant AD8, and equivalent to the MMSE and MoCA in screening for cognitive impairment in memory clinic patients. Show more

Keywords: AD8, cognitive impairment, dementia, memory clinics, screening instrument

DOI: 10.3233/JAD-122026

Citation: Journal of Alzheimer's Disease, vol. 35, no. 1, pp. 159-168, 2013

Authors: van der Vlies, Annelies E. | Staekenborg, Salka S. | Admiraal-Behloul, Faiza | Prins, Niels D. | Barkhof, Frederik | Vrenken, Hugo | Reiber, Johan H.C. | Scheltens, Philip | van der Flier, Wiesje M.

Article Type: Research Article

Abstract: Aim: To assess the associations of global atrophy and white matter hyperintensities (WMH) with neuropsychological function in early and late onset Alzheimer's disease (AD). Methods: We included 107 patients with sporadic AD (21 early onset and 86 late onset) from our memory clinic. Tests for (working) memory, language, executive function, mental speed, and attention were administered. Global atrophy and global and lobar WMH were measured using 1 Tesla MRI. Linear regression analyses with terms for MRI measures, neuropsychological test results, age, gender, education, and the interaction between separate brain measures and age of onset were performed. Results: Global atrophy was …associated with more severely impaired global cognition, working memory, mental speed, and executive function (p < 0.05). Significant interactions between global atrophy and age at onset showed that these associations were mostly attributable to patients with early onset AD. By contrast, an association between global atrophy and memory was found, which was specifically attributable to late onset AD patients. No associations between global WMH and cognitive function were found. Subsequently we analyzed regional WMH and found that temporal WMH was associated with impaired memory, and frontal WMH was associated with slower mental speed. Conclusion: Cortical atrophy, a key feature of AD, is linked to a wide range of cognitive functions, specifically in early onset AD patients. For WMH, there were no interactions with age at onset, but we found specific associations between temporal WMH and memory and frontal WMH and mental speed. Show more

Keywords: Age of onset, Alzheimer's disease, cognition, magnetic resonance imaging

DOI: 10.3233/JAD-121291

Citation: Journal of Alzheimer's Disease, vol. 35, no. 1, pp. 169-178, 2013

Authors: Acharya, Nimish K. | Levin, Eli C. | Clifford, Peter M. | Han, Min | Tourtellotte, Ryan | Chamberlain, Dean | Pollaro, Michael | Coretti, Nicholas J. | Kosciuk, Mary C. | Nagele, Eric P. | DeMarshall, Cassandra | Freeman, Theresa | Shi, Yi | Guan, Chenbing | Macphee, Colin H. | Wilensky, Robert L. | Nagele, Robert G.

Article Type: Research Article

Abstract: Diabetes mellitus (DM) and hypercholesterolemia (HC) have emerged as major risk factors for Alzheimer's disease, highlighting the importance of vascular health to normal brain functioning. Our previous study showed that DM and HC favor the development of advanced coronary atherosclerosis in a porcine model, and that treatment with darapladib, an inhibitor of lipoprotein-associated phospholipase A2 , blocks atherosclerosis progression and improves animal alertness and activity levels. In the present study, we examined the effects of DM and HC on the permeability of the blood-brain barrier (BBB) using immunoglobulin G (IgG) as a biomarker. DMHC increased BBB permeability and the leak …of microvascular IgG into the brain interstitium, which was bound preferentially to pyramidal neurons in the cerebral cortex. We also examined the effects of DMHC on the brain deposition of amyloid peptide (Aβ42 ), a well-known pathological feature of Alzheimer's disease. Nearly all detectable Aβ42 was contained within cortical pyramidal neurons and DMHC increased the density of Aβ42 -loaded neurons. Treatment of DMHC animals with darapladib reduced the amount of IgG-immunopositive material that leaked into the brain as well as the density of Aβ42 -containing neurons. Overall, these results suggest that a prolonged state of DMHC may have chronic deleterious effects on the functional integrity of the BBB and that, in this DMHC pig model, darapladib reduces BBB permeability. Also, the preferential binding of IgG and coincident accumulation of Aβ42 in the same neurons suggests a mechanistic link between the leak of IgG through the BBB and intraneuronal deposition of Aβ42 in the brain. Show more

Keywords: Alzheimer's disease, amyloid-β, autoantibodies, blood-brain barrier, cholesterol, darapladib, diabetes mellitus, immunoglobulin, lipoprotein-associated phospholipase-A2 (LpPLA2), microvasculature

DOI: 10.3233/JAD-122254

Citation: Journal of Alzheimer's Disease, vol. 35, no. 1, pp. 179-198, 2013

Authors: Scahill, Rachael I. | Ridgway, Gerard R. | Bartlett, Jonathan W. | Barnes, Josephine | Ryan, Natalie S. | Mead, Simon | Beck, Jonathan | Clarkson, Matthew J. | Crutch, Sebastian J. | Schott, Jonathan M. | Ourselin, Sebastien | Warren, Jason D. | Hardy, John | Rossor, Martin N. | Fox, Nick C.

Article Type: Research Article

Abstract: Mutations in the presenilin1 (PSEN1) and amyloid β-protein precursor (APP) genes account for the majority of cases of autosomal dominantly inherited Alzheimer's disease (AD). We wished to assess and compare the patterns of cerebral loss produced by these two groups of mutations. Volumetric magnetic resonance imaging and neuropsychological assessments were performed in individuals with clinical AD carrying mutations in the APP (n = 10) and PSEN1 (n = 18) genes and in healthy controls (n = 18). Voxel-based morphometry (VBM), cortical thickness, and region of interest analyses were performed. Mini-Mental State Examination scores were similar in the two disease groups …suggesting similar levels of disease severity. There was evidence that APP subjects have smaller hippocampal volume compared with PSEN1 subjects (p = 0.007), and weak evidence that they have larger whole-brain and grey matter volumes (both p = 0.07). Although there was no evidence of statistically significant differences between APP and PSEN1 in VBM or cortical thickness analyses, effect-maps were suggestive of APP subjects having more medial temporal lobe atrophy and conversely PSEN1 subjects showing more neocortical loss. Neuropsychological data were consistent with these regional differences and suggested greater memory deficits in the APP patients and greater impairment in non-memory domains in the PSEN1 group, although these differences were not statistically significant. We conclude that the mechanisms by which APP and PSEN1 mutations cause neuronal loss may differ which furthers our understanding of the neuropathology underlying AD and may inform future therapeutic strategies and trial designs. Show more

Keywords: Alzheimer's disease, APP, atrophy, autosomal dominant, magnetic resonance imaging, PSEN1

DOI: 10.3233/JAD-121255

Citation: Journal of Alzheimer's Disease, vol. 35, no. 1, pp. 199-212, 2013

Article Type: Other

DOI: 10.3233/JAD-122255

Citation: Journal of Alzheimer's Disease, vol. 35, no. 1, pp. 213-215, 2013