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

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