Journal of Alzheimer's Disease - Volume 30, issue 1

Authors: Smits, Lieke L. | Pijnenburg, Yolande A.L. | Koedam, Esther L.G.E. | van der Vlies, Annelies E. | Reuling, Ilona E.W. | Koene, Teddy | Teunissen, Charlotte E. | Scheltens, Philip | van der Flier, Wiesje M.

Article Type: Research Article

Abstract: Alzheimer's disease (AD) in younger patients is associated with a higher prevalence of atypical symptoms. We examined neuropsychological performance according to age-at-onset. We assessed cognition in 172 patients with AD (81 early and 91 late onset) in five cognitive domains (memory, language, visuo-spatial functioning, executive functioning, attention). Dementia severity was assessed using the Mini-Mental State Examination (MMSE) and global cognitive decline using Cambridge Cognitive Examination (CAMCOG). Analyses of variance were performed with age-at-onset as between-subjects factor, and gender and education as covariates. Analysis was repeated after stratification for dementia severity (based on median MMSE). In early onset AD, age (mean …± SD) was 60 ± 4 years; 44 (54%) were female. In late onset AD, age was 72 ± 5 years; 47 (52%) were female. Dementia severity and global cognitive decline did not differ between groups (early onset: MMSE: 20 ± 5, CAMCOG: 69 ± 15, late onset: MMSE: 21 ± 5, CAMCOG: 70 ± 15; p > 0.05). Early onset patients performed worse than late onset patients on visuo-spatial functioning (p < 0.01), executive functioning (p < 0.001), and attention (p < 0.01). Late onset patients performed worse on memory, although not significantly (p = 0.11). Stratification for dementia severity showed that in mildly demented early onset patients, memory function was remarkably preserved compared to late onset patients (p < 0.01). In moderate AD, differences in memory function disappeared, but early onset patients performed worse on visuo-spatial functioning (p < 0.01), executive functioning (p < 0.001), and attention (p < 0.01) than late onset patients. Adjustment for APOE left results unchanged. In conclusion, early onset AD presents with a different cognitive profile and the disease course seems different. Relative sparing of memory function in early stages stresses the need to adequately test other cognitive domains. Show more

Keywords: Alzheimer's disease, cognition, dementia, early onset, neuropsychology

DOI: 10.3233/JAD-2012-111934

Citation: Journal of Alzheimer's Disease, vol. 30, no. 1, pp. 101-108, 2012

Authors: Alegret, Montserrat | Cuberas-Borrós, Gemma | Vinyes-Junqué, Georgina | Espinosa, Ana | Valero, Sergi | Hernández, Isabel | Roca, Isabel | Ruíz, Agustín | Rosende-Roca, Maitée | Mauleón, Ana | Becker, James T. | Castell-Conesa, Joan | Tárraga, Lluís | Boada, Mercè

Article Type: Research Article

Abstract: The 15-Objects Test (15-OT) provides useful gradation of visuoperceptual impairment from normal aging through Alzheimer's disease (AD) and correlates with temporo-parietal perfusion. The objectives of this study were to analyze progression of 15-OT performance in mild cognitive impairment (MCI) and AD, and its correlates with cognition and single photon emission computerized tomography (SPECT), as well as to examine neuropsychological and SPECT differences between the MCI patients who developed AD and those who did not. From the initial 126 participants (42/group), 38 AD, 39 MCI, and 38 elderly controls (EC) were reassessed (SPECT: 35 AD, 33 MCI, 35 EC) after two …years. The progression of cognitive and SPECT scores during this period was compared between groups, and baseline data between converters and non-converters. The 15-OT was the only measure of progression that differed between the three groups; worsening scores on 15-OT were associated with worsening in verbal and visual retention, and decreased perfusion on left postsubicular area. In the MCI patients, cerebral perfusion fell over the two years in medial-posterior cingulate and fronto-temporo-parietal regions; AD showed extensive changes involving almost all cerebral regions. No SPECT changes were detected in controls. At baseline, the MCI patients who developed AD differed from non-converters in verbal recognition memory, but not in SPECT perfusion. In conclusion, SPECT and 15-OT appear to provide a potential measure to differentiate between normal aging, MCI, and AD. Worsening on 15-OT was related to decreased perfusion in postsubicular area; but further longitudinal studies are needed to determine the contribution of 15-OT as a predictor of AD from MCI. Show more

Keywords: 15-objects test, Alzheimer's disease, brain SPECT, cerebral perfusion, longitudinal, mild cognitive impairment, prospective, two-year follow-up, visuoperception

DOI: 10.3233/JAD-2012-111850

Citation: Journal of Alzheimer's Disease, vol. 30, no. 1, pp. 109-120, 2012

Authors: Arroyo-Anlló, Eva Ma | Ingrand, Pierre | Gil, Roger

Article Type: Research Article

Abstract: This paper studies the procedural learning of semantic categorization in 20 patients with mild Alzheimer's disease (AD). We investigated if the AD group was able to develop semantic skill using a cognitive procedural task, developed in our laboratory, by applying a manual and serial reaction time paradigm to semantic categorization. The AD group had markedly lower scores than the normal group on semantic categorization and had longer reaction times than the control subjects. Nevertheless, we observed an improvement of semantic categorization reaction times over time with practice, even with new verbal material to categorize, in both the AD and control …groups. These results support the notion that AD patients are able to acquire semantic skill without awareness simply by repeated exposure, although their semantic accuracy will not reach normal levels. Show more

Keywords: Aging, Alzheimer's disease, implicit memory, procedural learning, reaction time

DOI: 10.3233/JAD-2012-111856

Citation: Journal of Alzheimer's Disease, vol. 30, no. 1, pp. 121-129, 2012

Authors: Verheij, Simone | Muilwijk, Danya | Pel, Johan J.M. | van der Cammen, Tischa J.M. | Mattace-Raso, Francesco U.S. | van der Steen, Johannes

Article Type: Research Article

Abstract: Although memory complaints are one of the first clinical symptoms in patients with Alzheimer's disease (AD), damage to the parietal lobe, a key structure in the visuomotor coordination network, was recently identified in early-stage AD. The aim of this study was to quantify visuomotor coordination in patients with probable AD and to compare their visuomotor performance with controls using five eye-hand coordination tasks of variable complexity. Eye and hand movements were measured in 16 AD patients and 18 controls. The measurement setup consisted of a touch screen, an eye-tracking device, and a motion capturing system. We investigated eye-hand coordination by …quantifying absolute and relative latencies of eye and hand movements and by analyzing eye and hand kinematics. We found that AD patients need significantly more time to initiate and execute goal-directed hand movements. AD patients are also unable to suppress reflexive eye and, to a lesser extent, hand movements. Furthermore, AD patients use a stepwise approach of eye and hand movements to touch a sequence of stimuli, whereas controls more often show an anticipatory approach. The impairments in reflex suppression of eye and hand movements, and changes in relative timing of eye-hand coordination, in AD patients support the notion that cortical networks involving the posterior parietal cortex are affected at an early disease-stage. It also suggests that the problems of AD patients to perform daily activities that require eye-hand coordination are not only caused by cognitive decline, but also by degeneration of neural networks involved in visuomotor coordination. Show more

Keywords: Alzheimer's disease, dementia, eye-hand coordination, motor activity, visuomotor integration

DOI: 10.3233/JAD-2012-111883

Citation: Journal of Alzheimer's Disease, vol. 30, no. 1, pp. 131-143, 2012

Authors: Flammang, Brice | Pardossi-Piquard, Raphaëlle | Sevalle, Jean | Debayle, Delphine | Dabert-Gay, Anne-Sophie | Thévenet, Aurélie | Lauritzen, Inger | Checler, Frédéric

Article Type: Research Article

Abstract: One of the major pathological hallmarks of brains affected with Alzheimer's disease (AD) is the senile plaque, an extracellular deposit mainly composed of a set of highly insoluble peptides of various lengths (39–43 amino acids) referred to as amyloid-β (Aβ) peptides. Aβ peptides are derived from combined proteolytic cleavages undergone on the amyloid-β protein precursor (AβPP) by a set of enzymes called secretases. Several lines of anatomical and biological evidence suggest that Aβ peptides would not account for all pathological stigmata and molecular dysfunctions taking place in AD. In amyloidogenic and non-amyloidogenic pathways, AβPP first undergoes β- or α-secretases-mediated cleavages …yielding C99 and C83, respectively. These two membrane-embedded C-terminal fragments are both potential targets of subsequent γ-secretase-mediated proteolysis. The latter cleavage not only generates either p3 or Aβ peptides but similarly gives rise to an AβPP IntraCellular Domain (AICD fragment) that could modulate the transcription of several genes linked to AD pathology. It is therefore striking that AICD theoretically derives from both amyloidogenic and non-amyloidogenic AβPP processing pathways. Here we show that AICD predominantly derives from C99 by means of recombinant substrates and transiently transfected cells expressing C99. Our data suggest a preferred pathogenic pathway for AICD production and suggests that this fragment, in addition to C99 and Aβ peptides, could contribute to AD pathology. Show more

Keywords: AICD, Alzheimer's disease, amyloid-β, amyloidogenic pathway, C83, C99, secretases

DOI: 10.3233/JAD-2012-112186

Citation: Journal of Alzheimer's Disease, vol. 30, no. 1, pp. 145-153, 2012

Authors: Do, Tuan Minh | Noel-Hudson, Marie-Sophie | Ribes, Sandy | Besengez, Capucine | Smirnova, Maria | Cisternino, Salvatore | Buyse, Marion | Calon, Frédéric | Chimini, Giovanna | Chacun, Hélène | Scherrmann, Jean-Michel | Farinotti, Robert | Bourasset, Fanchon

Article Type: Research Article

Abstract: The accumulation of amyloid-β peptide (Aβ) in the brain is a critical hallmark of Alzheimer's disease. This high cerebral Aβ concentration may be partly caused by impaired clearance of Aβ across the blood-brain barrier (BBB). The low-density lipoprotein receptor-related protein-1 (LRP-1) and the ATP-binding cassette (ABC) protein ABCB1 (P-glycoprotein) are involved in the efflux of Aβ across the BBB. We hypothesized that other ABC proteins, such as members of the G subfamily, are also involved in the BBB clearance of Aβ. We therefore investigated the roles of ABCG2 (BCRP) and ABCG4 in the efflux of [3 H] Aβ1-40 from …HEK293 cells stably transfected with human ABCG2 or mouse abcg4. We showed that ABCG2 and Abcg4 mediate the cellular efflux of [3 H] Aβ1-40 . In addition, probucol fully inhibited the efflux of [3 H] Aβ1-40 from HEK293-abcg4 cells. Using the in situ brain perfusion technique, we showed that GF120918 (dual inhibitor of Abcb1 and Abcg2) strongly enhanced the uptake (Clup , μl/g/s) of [3 H] Aβ1-40 by the brains of Abcb1-deficient mice, but not by the brains of Abcb1/Abcg2-deficient mice, suggesting that Abcg2 is involved in the transport of Aβ at the mouse BBB. Perfusing the brains of Abcb1/Abcg2- and Abca1-deficient mice with [3 H] Aβ1-40 plus probucol significantly increased the Clup of Aβ. This suggests that a probucol-sensitive transporter that is different from Abca1, Abcb1, and Abcg2 is involved in the brain efflux of Aβ. We suggest that this probucol-sensitive transporter is Abcg4. We conclude that Abcg4 acts in concert with Abcg2 to efflux Aβ from the brain across the BBB. Show more

Keywords: Abca1, Abcb1, Abcg4, Abcg2, Alzheimer's disease, amyloid-β, blood-brain barrier, in situ brain perfusion, mouse

DOI: 10.3233/JAD-2012-112189

Citation: Journal of Alzheimer's Disease, vol. 30, no. 1, pp. 155-166, 2012

Authors: Prasanthi, Jaya R.P. | Schrag, Matthew | Dasari, Bhanu | Marwarha, Gurdeep | Dickson, April | Kirsch, Wolff M. | Ghribi, Othman

Article Type: Research Article

Abstract: Accumulation of amyloid-β (Aβ) peptide and the hyperphosphorylation of tau protein are major hallmarks of Alzheimer's disease (AD). The causes of AD are not well known but a number of environmental and dietary factors are suggested to increase the risk of developing AD. Additionally, altered metabolism of iron may have a role in the pathogenesis of AD. We have previously demonstrated that cholesterol-enriched diet causes AD-like pathology with iron deposition in rabbit brain. However, the extent to which chelation of iron protects against this pathology has not been determined. In this study, we administered the iron chelator deferiprone in drinking …water to rabbits fed with a 2% cholesterol diet for 12 weeks. We found that deferiprone (both at 10 and 50 mg/kg/day) significantly decreased levels of Aβ40 and Aβ42 as well as BACE1, the enzyme that initiates cleavage of amyloid-β protein precursor to yield Aβ. Deferiprone also reduced the cholesterol diet-induced increase in phosphorylation of tau but failed to reduce reactive oxygen species generation. While deferiprone treatment was not associated with any change in brain iron levels, it was associated with a significant reduction in plasma iron and cholesterol levels. These results demonstrate that deferiprone confers important protection against hypercholesterolemia-induced AD pathology but the mechanism(s) may involve reduction in plasma iron and cholesterol levels rather than chelation of brain iron. We propose that adding an antioxidant therapy to deferiprone may be necessary to fully protect against cholesterol-enriched diet-induced AD-like pathology. Show more

Keywords: Alzheimer's disease, cholesterol, deferiprone, iron, oxidative stress, tau

DOI: 10.3233/JAD-2012-111346

Citation: Journal of Alzheimer's Disease, vol. 30, no. 1, pp. 167-182, 2012

Authors: Clausen, Aaron | Xu, Xiaobo | Bi, Xiaoning | Baudry, Michel

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is characterized by progressive cognitive deficits, accumulation of amyloid-β (Aβ) and intracellular neurofibrillary tangles, and neuronal death. Additionally, mitochondrial dysfunction and free radical damage are hallmarks of AD brain. Here we set out to define the role of oxidative stress in AD pathogenesis and progression by chronically treating 3xTg-AD mice with the superoxide dismutase (SOD)/catalase mimetic, EUK-207. Treatment started at 4 months before onset of pathology and cognitive deficits, and continued until 9 months, when the AD phenotype was established. Cognitive performance was assessed using fear conditioning, and brain oxidative stress, Aβ, and tau pathology were analyzed. …At 9 months, 3xTg-AD mice exhibited a decline in performance in both contextual and cued fear conditioning, as compared to wild-type mice. EUK-207-treated 3xTg-AD mice did not display any deficit in fear conditioning and exhibited reduced Aβ, tau, and phosphorylated tau accumulation in amygdala and hippocampus, as well as brain levels of Aβ42 , oxidized nucleic acids, and lipid peroxidation. The effects of a 3-month treatment after pathology onset at 9 months on cognitive performance, brain oxidative stress, Aβ, and tau pathology were also evaluated. EUK-207-treated 3xTg-AD mice did not display any deficit in fear conditioning and were protected against increases in brain levels of oxidized nucleic acids and lipid peroxidation; they also had reduced Aβ, tau, and hyperphosphorylated tau accumulation in amygdala and hippocampus. Our results confirm a critical role for oxidative stress in AD pathogenesis and progression and suggest the potential usefulness of EUK-207 in AD treatment. Show more

Keywords: Aging, Alzheimer's disease, amyloid-β, antioxidants, fear conditioning, free radicals, learning, oxidative stress, superoxide dismutase/catalase mimetics, tau

DOI: 10.3233/JAD-2012-111298

Citation: Journal of Alzheimer's Disease, vol. 30, no. 1, pp. 183-208, 2012

Authors: Mowszowski, Loren | Hermens, Daniel F. | Diamond, Keri | Norrie, Louisa | Hickie, Ian B. | Lewis, Simon J.G. | Naismith, Sharon L.

Article Type: Research Article

Abstract: Mild cognitive impairment (MCI) refers to a transitory state between healthy aging and dementia. Biomarkers are needed to facilitate early identification of MCI and predict progression to dementia. One potential neurophysiological biomarker, mismatch negativity (MMN), is an event-related potential reflecting fundamental, pre-attentive cognitive processes. MMN is reduced in normal aging and dementia and in neuropsychiatric samples and is associated with verbal memory deficits and poor executive functioning. This study aimed to investigate auditory MMN and its relationship to neuropsychological performance in MCI. Twenty-eight MCI participants and fourteen controls, aged ≥50 years, underwent neurophysiological and neuropsychological assessment, and completed questionnaires pertaining …to disability. Relative to controls, the MCI group demonstrated reduced temporal MMN amplitude (p < 0.01). Reduced right temporal MMN was significantly associated with poorer verbal learning (r = 0.496; p < 0.01) and reduced left temporal MMN was significantly associated with increased self-reported disability (r = −0.419; p < 0.05). These results indicate that patients with MCI exhibit altered pre-attentive information processing, which in turn is associated with memory and psychosocial deficits. These findings overall suggest that MMN may be a viable neurophysiological biomarker of underlying disease in this ‘at risk’ group. Show more

Keywords: Event-related potential, memory, mild cognitive impairment, mismatch negativity, neuropsychological

DOI: 10.3233/JAD-2012-111868

Citation: Journal of Alzheimer's Disease, vol. 30, no. 1, pp. 209-219, 2012

Authors: Whitehouse, Peter

Article Type: Book Review

DOI: 10.3233/JAD-2012-120678

Citation: Journal of Alzheimer's Disease, vol. 30, no. 1, pp. 221-221, 2012