Journal of Alzheimer's Disease - Volume 22, issue 3

Authors: Ebenezer, Philip J. | Weidner, Adam M. | LeVine III, Harry | Markesbery, William R. | Murphy, M. Paul | Zhang, Le | Dasuri, Kalavathi | Fernandez-Kim, Sun Ok | Bruce-Keller, Annadora J. | Gavilán, Elena | Keller, Jeffrey N.

Article Type: Research Article

Abstract: Recent studies have demonstrated a potential role for oligomeric forms of amyloid-β (Aβ) in the pathogenesis of Alzheimer's disease (AD), although it remains unclear which aspects of AD may be mediated by oligomeric Aβ. In the present study, we found that primary cultures of rat cortical neurons exhibit a dose-dependent increase in cell death following Aβ oligomer administration, while primary cultures of astrocytes exhibited no overt toxicity with even the highest concentrations of oligomer treatment. Neither cell type exhibited toxicity when treated by equal concentrations of monomeric Aβ. The neuron death induced by oligomer treatment was associated with an increase …in reactive oxygen species (ROS), altered expression of mitochondrial fission and fusion proteins, and JUN kinase activation. Pharmacological inhibition of JUN kinase ameliorated oligomeric Aβ toxicity in neurons. These data indicate that oligomeric Aβ is sufficient to selectively induce toxicity in neurons, but not astrocytes, with neuron death occurring in a JUN kinase-dependent manner. Additionally, these observations implicate a role for oligomeric Aβ as a contributor to neuronal oxidative stress and mitochondrial disturbances in AD. Show more

Keywords: Alzheimer's disease, amyloid-β, neurotoxicity, protein oxidation

DOI: 10.3233/JAD-2010-101161

Citation: Journal of Alzheimer's Disease, vol. 22, no. 3, pp. 839-848, 2010

Authors: Candela, Pietra | Gosselet, Fabien | Saint-Pol, Julien | Sevin, Emmanuel | Boucau, Marie-Christine | Boulanger, Eric | Cecchelli, Roméo | Fenart, Laurence

Article Type: Research Article

Abstract: Several studies have highlighted the close relationship between Alzheimer's disease (AD) and alterations in the bidirectional transport of amyloid-β (Aβ) peptides across the blood-brain barrier (BBB). The brain capillary endothelial cells (BCECs) that compose the BBB express the receptors and transporters that enable this transport process. There is significant in vivo evidence to suggest that P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) restrict Aβ peptides entry into the brain, whereas the receptor for advanced glycation end-products (RAGE) seems to mediate apical-to-basolateral passage across the BBB. However, deciphering the molecular mechanisms underlying these in vivo processes requires further in vitro …characterization. Using an in vitro BBB model and specific competition experiments against RAGE, we have observed a significant decrease in apical-to-basolateral (but not basolateral-to-apical) transport of Aβ1–40 and Aβ1–42 peptides through BCECs. This transport is a caveolae-dependent process and fits with the apical location of RAGE observed in confocal microscopy experiments. Inhibition of P-gp and BCRP using different inhibitors increases transport of Aβ peptides suggesting that these efflux pumps are involved in Aβ peptide transport at the BCECs level. Taken as a whole, these results demonstrate the involvement of the caveolae-dependent transcytosis of Aβ peptides through the BBB in a RAGE-mediated transport process, reinforcing the hypothesis whereby this receptor is a potential drug target in AD. Show more

Keywords: Alzheimer's disease, amyloid-β peptide, BCRP, blood-brain barrier, brain capillary endothelial cells, caveolae, P-gp, RAGE

DOI: 10.3233/JAD-2010-100462

Citation: Journal of Alzheimer's Disease, vol. 22, no. 3, pp. 849-859, 2010

Authors: Motawaj, Mouhammad | Peoc'h, Katell | Callebert, Jacques | Arrang, Jean-Michel

Article Type: Research Article

Abstract: Neuropathological studies have reported a strong neurofibrillary degeneration of the tuberomamillary nucleus, the region of origin of histamine neurons, in Alzheimer's disease (AD). Histaminergic neurons enhance cognition and memory, suggesting that their degeneration may contribute to the cognitive decline of AD. Besides neurons, the brain histaminergic system comprises mast cells and microglia that can also produce histamine. The level of activity of this histaminergic system in AD remained unknown. In the present study, we have measured the levels of the main histamine metabolite in brain, tele-methylhistamine (t-MeHA), an index of histaminergic system activity, in the cerebrospinal fluid (CSF) of 97 …non-AD (controls) and 91 AD patients, males or females. t-MeHA levels in CSF of controls tended to be higher, although non-significantly, in females than in males. t-MeHA levels of controls and AD significantly increased with age (1.66 ± 0.13, 2.04 ± 0.12, and 2.76 ± 0.12 pmol/ml at 40, 60 and 80 years, respectively). In spite of the strong degeneration of histamine neurons in the disease, t-MeHA levels in CSF were only slightly decreased in AD compared to controls (2.14 ± 0.10 vs 2.76 ± 0.13 pmol/ml, –22%, p < 0.01). This decrease was similar whatever the age, and was slightly higher in females than in males. The increase observed with age, and the limited magnitude of the decrease in AD even at late stages may result from the compensatory activation of spared neurons, as well as the neuroinflammation-induced activation of microglia occurring in senescence and AD. Show more

Keywords: Alzheimer's disease, cerebrospinal fluid, cognitive deficits, histaminergic system activity, mast cells, microglia, neuroinflammation, neurons, tele-methylhistamine

DOI: 10.3233/JAD-2010-100381

Citation: Journal of Alzheimer's Disease, vol. 22, no. 3, pp. 861-871, 2010

Authors: Jyoti, Amar | Plano, Andrea | Riedel, Gernot | Platt, Bettina

Article Type: Research Article

Abstract: Since sleep and electroencephalogram (EEG) disturbances are endophenotypes of Alzheimer's disease (AD) patients alongside cognitive dysfunction, we here characterized these parameters in transgenic mice carrying transgenes for amyloid-β protein precursor (AβPPswe ) and presenilin 1 (PSEN1A246E ) at 5 (pre-plaque) and 20 months, relative to PSEN1 and wild-type (WT) mice, using a novel wireless microchip device. While circadian rhythms were not affected, we obtained significantly higher overall activity at 5 months in the AβPP/PSEN1 strain (p < 0.001) compared to both PSEN1 and WT animals. Vigilance staging revealed that AβPP/PSEN1 animals present with an age-independent increase in wakefulness (p < …0.001) and a decrease in non rapid-eye movement (NREM) sleep (p < 0.01). These changes were age- and genotype-dependent only during the light phase, while dark phase activity pattern were equally affected at both ages. In all genotypes, the amount of REM sleep was lower at 20 months indicating a general age-related profile. Spectral power of qEEG changed in AβPP/PSEN1 mice at 5 months during wakefulness and REM sleep; during wakefulness hippocampal delta (0.5–5 Hz) was reduced and theta (5–9 Hz) power enhanced. By contrast, NREM EEG spectra were affected by age and genotype. Interestingly, PSEN1 animals also showed spectral EEG changes, these differed from both WT and AβPP/PSEN1 animals. Our results indicate that AβPP/PSEN1 mice exhibit abnormalities in activity and sleep architecture preceding amyloid plaque deposition as well as age-related changes in cortical EEG power. Though not fully recapitulating the profile of AD patients, this suggests activity and EEG recordings as sensitive and translational biomarkers in murine models. Show more

Keywords: Alzheimer's disease, amyloid, circadian activity, EEG, FFT, power spectrum, presenilin, sleep

DOI: 10.3233/JAD-2010-100879

Citation: Journal of Alzheimer's Disease, vol. 22, no. 3, pp. 873-887, 2010

Authors: Cacho, Jesús | Benito-León, Julián | García-García, Ricardo | Fernández-Calvo, Bernardino | Vicente-Villardón, José Luis | Mitchell, Alex J.

Article Type: Research Article

Abstract: There is currently a need to develop tools to identify patients with mild AD and mild cognitive impairment (MCI). We determined the validity and reliability of a brief, easily administered cognitive screening battery consisting of fusion of two well-known brief tests (Mini-Mental Status Examination [MMSE] and Clock Drawing Test [CDT]) (Mini-clock) to differentiate between patients with mild AD, MCI, and healthy control subjects. 66 consecutive patients with mild AD, 21 with MCI, and 66 healthy controls seen in a memory clinic setting were compared. Receiver operating characteristic (ROC) curve analysis was used to calculate the cut-off value permitting discrimination between …mild AD, MCI, and healthy control subjects. Interrater and test-retest reliability were also assessed. Mean cognitive scores for patients with AD, MCI, and control subjects on all two individual tests were significantly different (for each, p < 0.001). The mean area under the ROC curve for Mini-clock was higher than that obtained with MMSE or CDT in differentiating mild AD from controls (0.973 vs. 0.952 and 0.881, respectively) and MCI from controls (0.855 vs. 0.821 and 0.779, respectively). Test-retest reliability for the Mini-clock was 0.99, meanwhile interrater reliability was 0.87. The mean time to complete the test for all subjects was 8 min and 50 s. The Mini-clock is highly sensitive and specific in the detection of mild AD and reasonably accurate when attempting to separate MCI from health controls. It has a high interrater and test-retest reliability, can be quickly administered, and does not require major training. Show more

Keywords: Alzheimer's disease, diagnosis, screening

DOI: 10.3233/JAD-2010-101182

Citation: Journal of Alzheimer's Disease, vol. 22, no. 3, pp. 889-896, 2010

Authors: Collette, Fabienne | Van der Linden, Martial | Salmon, Eric

Article Type: Research Article

Abstract: A decline of cognitive functioning affecting several cognitive domains was frequently reported in patients with frontotemporal dementia. We were interested in determining if these deficits can be interpreted as reflecting an impairment of controlled cognitive processes by using an assessment tool specifically developed to explore the distinction between automatic and controlled processes, namely the process dissociation procedure (PDP) developed by Jacoby [1]. The PDP was applied to a word stem completion task to determine the contribution of automatic and controlled processes to episodic memory performance and was administered to a group of 12 patients with the behavioral variant of frontotemporal …dementia (bv-FTD) and 20 control subjects (CS). Bv-FTD patients obtained a lower performance than CS for the estimates of controlled processes, but no group differences was observed for estimates of automatic processes. The between-groups comparison of the estimates of controlled and automatic processes showed a larger contribution of automatic processes to performance in bv-FTD, while a slightly more important contribution of controlled processes was observed in control subjects. These results are clearly indicative of an alteration of controlled memory processes in bv-FTD. Show more

Keywords: Behavior, controlled processes, dementia, executive functions, frontotemporal

DOI: 10.3233/JAD-2010-100042

Citation: Journal of Alzheimer's Disease, vol. 22, no. 3, pp. 897-907, 2010

Authors: Fortea, Juan | Sala-Llonch, Roser | Bartrés-Faz, David | Bosch, Beatriz | Lladó, Albert | Bargalló, Nuria | Molinuevo, José Luis | Sánchez-Valle, Raquel

Article Type: Research Article

Abstract: Neuroimaging studies of familial Alzheimer's disease allow investigation of the disease process before clinical onset. We performed semi-automated MRI analysis to evaluate cortical thickness (CTh), grey matter (GM) volumes, and GM diffusivity indexes in PSEN1 mutation carriers (MC). We recruited 11 MC from 4 families with PSEN1 mutations (L286P, M139T, K239N) and 6 familial and 12 non-familial healthy controls. MC were classified as either asymptomatic (n = 6) or symptomatic (n = 5). Subjects underwent structural and diffusion-weighted 3-Tesla MRI scanning. CTh and GM volumes of subcortical structures and diffusivity indexes were calculated and group comparisons were performed. Structural images …were reanalyzed with voxel-based morphometry methodology. Cerebrospinal fluid amyloid-β1–42 levels (Aβ) were measured. We found that symptomatic MC presented widespread cortical thinning, especially in precuneus and parietotemporal areas (p < 0.01) and increased mean diffusivity (MD) in these areas compared to controls. Unexpectedly, asymptomatic MC, 9.9 years prior to the predicted age of disease onset, presented increased CTh in the precuneus and parietotemporal areas (p < 0.01), increased caudate volumes (p < 0.01), and decreased MD (p < 0.05) in these areas compared to HC. In MC, CTh correlated with adjusted age. Aβ values were within normal limits in AMC. In conclusion, at early preclinical stages, CTh in the precuneus and parietotemporal regions and caudate volume increase in PSEN1 MC and decrease thereafter with disease progression. The different trends in MD in asymptomatic and symptomatic MC suggest that different microstructural changes underlie the contrasting morphometric findings. Reactive neuronal hypertrophy or/and inflammation may account for increased CTh and decreased MD in asymptomatic MC. Show more

Keywords: Alzheimer disease, amyloid, cerebrospinal fluid, magnetic resonance imaging, presenilin 1

DOI: 10.3233/JAD-2010-100678

Citation: Journal of Alzheimer's Disease, vol. 22, no. 3, pp. 909-922, 2010

Authors: Padovani, Alessandro | Cosseddu, Maura | Premi, Enrico | Archetti, Silvana | Papetti, Alice | Agosti, Chiara | Bigni, Barbara | Cerini, Carlo | Paghera, Barbara | Bellelli, Giuseppe | Borroni, Barbara

Article Type: Research Article

Abstract: The FOXP2 gene is mutated in a severe monogenic form of speech and language deficits, but no study on the influence of genetic variations within FOXP2 in neurological disorders characterized by language impairment is available yet. In the present study, we investigated the impact of common FOXP2 polymorphisms with regard to frontotemporal lobar degeneration (FTLD). Two-hundred ten FTLD patients underwent clinical and a wide standardized neuropsychological examination as well as brain imaging. In all patients, and in 200 age-matched healthy controls, four FOXP2 polymorphisms were evaluated, namely rs2396753, rs1456031, rs17137124 and rs1852469. SPECT images were analyzed by Statistical Parametric Mapping …(SPM5). No significant differences of the four FOXP2 polymorphisms in genotype distribution and allele frequency between FTLD and controls were observed. A significant and specific association between rs1456031 TT and rs17137124 TT genotypes and verbal fluency scores was reported. The two polymorphisms showed an addictive effect. When the analysis was computed on the number of observations over time, and 391 assessments considered, comparable results were obtained. FTLD patients carrying at-risk polymorphisms showed greater hypoperfusion in the frontal areas, namely the left inferior frontal gyrus, and putamen, compared to the non-carriers (p < 0.005). Genetic variations within FOXP2 do not represent a genetic risk to FTLD per se, but modulate FTLD presentation when disease is overt, affecting language performances and leading to hypoperfusion in language-associated brain areas. Show more

Keywords: FOXP2, frontotemporal dementia, frontotemporal lobar degeneration, genetics, SPECT

DOI: 10.3233/JAD-2010-101206

Citation: Journal of Alzheimer's Disease, vol. 22, no. 3, pp. 923-931, 2010

Authors: Maetzler, Walter | Stoycheva, Velichka | Schmid, Benjamin | Schulte, Claudia | Hauser, Ann-Kathrin | Brockmann, Kathrin | Melms, Arthur | Gasser, Thomas | Berg, Daniela

Article Type: Research Article

Abstract: Lewy body disease, defined by the occurrence of α-synuclein aggregates as fibrils in Lewy bodies and Lewy neurites, is associated with increased probabilities for both co-occurrence of dementia, and co-occurrence of Alzheimer's disease (AD)-like pathology, in particular amyloid-β (Aβ) plaques and lowered cerebrospinal fluid (CSF) Aβ42 levels. Not surprisingly, in patients with Lewy body disease patients, there is a strong association between dementia and Aβ42 pathology. Neprilysin (NEP) is an Aβ-degrading protein found at presynaptic terminals and in body fluids. Reduced CSF NEP activity levels have been shown to occur in early AD, suggesting that altered CSF NEP …activity levels may also be associated with dementia and lowered CSF Aβ42 levels in Lewy body disease. Hypothesizing a relation between CSF NEP activity and dementia in Lewy body disease, we determined CSF and serum NEP activity, and Aβ42 levels of 41 demented Lewy body disease patients, 38 non-demented Lewy body disease patients, and of 23 elderly controls. Demented Lewy body disease patients had lowered CSF NEP activity levels (0.3 pmol/min*ml, 0.2–81.5), compared to both non-demented Lewy body disease subjects (8.5 pmol/min*ml, 0.2–87.2; p = 0.004) and controls (21.5 pmol/ml*min, 0.15–413.4; p = 0.02). In addition, CSF NEP activity levels correlated positively with CSF Aβ42 levels (Rho = 0.28, p = 0.008) which was not explained by the presence or absence of ApoE4. Serum NEP activity levels were not significantly different between the groups. We conclude that, in Lewy body disease, CSF NEP activity levels are associated with dementia, probably via the Aβ pathway. Show more

Keywords: Alzheimer's disease, enzyme, Lewy body disease, metalloendopeptidase, Parkinson's disease, spinal puncture

DOI: 10.3233/JAD-2010-101197

Citation: Journal of Alzheimer's Disease, vol. 22, no. 3, pp. 933-938, 2010

Authors: Virta, Jyri J. | Järvenpää, Tarja | Heikkilä, Kauko | Perola, Markus | Koskenvuo, Markku | Räihä, Ismo | Rinne, Juha O. | Kaprio, Jaakko

Article Type: Research Article

Abstract: In this prospective follow-up study, we monitored the effects of midlife alcohol consumption and drinking patterns on cognitive impairment risks in late life. 1,486 subjects recruited from the Finnish Twin Cohort were included in the analyses. Alcohol consumption data was obtained with structured questionnaires in 1975 and 1981, and subjects were contacted between 1999 and 2007 to conduct a telephone interview evaluating cognitive function. The mean follow-up period was 22.8 years (standard deviation 2.1 years). Both abstainers and heavy drinkers were found to have an increased risk of cognitive impairment in comparison to light drinkers (relative risk ratios 1.44; 95% …confidence interval: 1.02–2.10 and 1.94, 1.10–3.44, respectively. Also, binge drinking at least monthly in 1975 and 1981, as well as more than two pass-outs due to excess drinking in 1981 were associated with an increased risk of cognitive impairment (1.98, 1.08–3.64 and 3.85, 1.51–9.83, respectively), even when excluding abstainers and controlling for total alcohol consumption. Subgroup analyses based on apolipoprotein E ε4 status suggest that the increased risk of cognitive impairment associated with being an abstainer is limited to subjects without an ε4 allele. Our results add to the evidence that light to moderate alcohol use is associated with a lower risk of cognitive impairment compared with higher levels of consumption. In addition, binge drinking was found to be an independent risk factor for cognitive impairment. Show more

Keywords: Alcohol drinking, Alzheimer's disease, cohort studies, dementia, risk factors

DOI: 10.3233/JAD-2010-100870

Citation: Journal of Alzheimer's Disease, vol. 22, no. 3, pp. 939-948, 2010

Authors: Bermejo-Pareja, Félix | Benito-León, Julián | Louis, Elan D. | Trincado, Rocío | Carro, Eva | Villarejo, Alberto | de la Cámara, Agustín Gómez

Article Type: Research Article

Abstract: Arterial hypertension in midlife may increase the risk of late-life dementia. Notably, there is conflicting data as to whether hypertension in the elderly (age 65 years and older) is a risk factor for dementia and Alzheimer's disease (AD). We determined whether drug-untreated hypertension was associated with a higher risk of incident dementia and AD. In a population-based study of older people in central Spain (NEDICES), non-demented participants were followed prospectively. Dementia at follow-up was diagnosed using DSM-IV criteria. Using Cox proportional hazards models, the risk of dementia was estimated in participants with drug-untreated hypertension and in participants with drug-treated hypertension …versus controls. The 3,824 participants had a mean duration of follow-up of 3.2 years. Sixty-two (3.3%) of 1,870 participants without baseline hypertension developed incident dementia versus 78 (4.7%) of 1,657 with drug-treated, baseline hypertension and 19 (12.0%) with drug-untreated, baseline hypertension. In an unadjusted Cox model, risk of dementia was increased in participants with drug-untreated hypertension (relative risk [RR] = 1.93, 95% confidence interval [CI] = 1.15–3.23, p = 0.01) and in participants with drug-treated hypertension (RR = 1.43, 95% CI = 1.02–2.0, p = 0.035) versus participants without hypertension (reference group). In a fully adjusted Cox model, the risk of dementia remained increased in participants with drug-untreated hypertension (RR = 2.38, 95% CI = 1.32–4.29, p = 0.004). Results were similar for risk of AD. Our results suggest that drug-untreated hypertension may be an independent risk factor for dementia and AD in the elderly. Show more

Keywords: Dementia, elderly, epidemiology, hypertension

DOI: 10.3233/JAD-2010-101110

Citation: Journal of Alzheimer's Disease, vol. 22, no. 3, pp. 949-958, 2010

Authors: Belinson, Haim | Kariv-Inbal, Zehavit | Kayed, Rakez | Masliah, Eliezer | Michaelson, Daniel M.

Article Type: Research Article

Abstract: According to the amyloid hypothesis, the accumulation of oligomerized amyloid-β (Aβ) is a primary event in the pathogenesis of Alzheimer's disease (AD). The trigger of the amyloid cascade and of Aβ oligomerization in sporadic AD, the most prevalent form of the disease, remains elusive. Here, we examined the hypothesis that apolipoprotein E4 (ApoE4), the most prevalent genetic risk factor for AD, triggers the accumulation of intraneuronal oligomerized Aβ following activation of the amyloid cascade. We investigated the intracellular organelles that are targeted by these processes and govern their pathological consequences. This revealed that activation of the amyloid cascade in vivo …by inhibition of the Aβ degrading enzyme neprilysin specifically results in accumulation of Aβ and oligomerized Aβ and of ApoE4 in the CA1 neurons of ApoE4 mice. This was accompanied by lysosomal and mitochondrial pathology and the co-localization of Aβ, oligomerized Aβ, and ApoE4 with enlarged lysosomes and of Aβ and oligomerized Aβ with mitochondria. The time course of the lysosomal effects paralleled that of the loss of CA1 neurons, whereas the mitochondrial effects reached an earlier plateau. These findings suggest that ApoE4 potentiates the pathological effects of Aβ and the amyloid cascade by triggering the oligomerization of Aβ, which in turn, impairs intraneuronal mitochondria and lysosomes and drives neurodegeneration. Show more

Keywords: Amyloid-β, apolipoprotein E4, CA1 neurons, lysosomes, mitochondria, neurodegeneration

DOI: 10.3233/JAD-2010-101008

Citation: Journal of Alzheimer's Disease, vol. 22, no. 3, pp. 959-970, 2010

Authors: Haldenwanger, Andreas | Eling, Paul | Kastrup, Andreas | Hildebrandt, Helmut

Article Type: Research Article

Abstract: Decreased delayed recall, decreased amyloid-β peptides (Aβ1–42 ), and increased tau protein concentration in cerebrospinal fluid (CSF) are generally regarded to be valid neuropsychological and biological markers for Alzheimer's disease (AD). Previous studies failed to demonstrate clear-cut correlations between neuropsychological impairment and CSF markers. In this study we test recent models of disease progression, that propose that changes in CSF biomarkers already reach a plateau in a preclinical phase, before cognitive decline begins, that is, even before MCI can be diagnosed. We recruited 73 patients with probable AD (n = 36) and mild cognitive impairment (MCI) (amnesic MCI = 25; …non-amnesic MCI = 12). We used the CERAD-NP, a widely used neuropsychological battery with norms for different age and education groups, and additional neuropsychological tests for assessing the cognitive profile of these patient groups. We found a significant correlation between Aβ1–42 in the CSF and memory performance for amnesic MCI patients, but not for non-amnesic MCI and AD patients. All other correlations between cognitive tasks and Aβ1–42 were not significant. Tau protein concentration in the CSF was not correlated with any neuropsychological marker in any of the patients groups. We conclude that the decrease of Aβ1–42 in the CSF mirrors disease progression during the early stages up into AD and therefore is not restricted to the preclinical phase. The decrease of Aβ1–42 reaches a plateau only in the full blown demented syndrome and further functional disease progression is then related to neurodegeneration without further reduction of Aβ1–42 in the CSF. Show more

Keywords: Aβ1–42, Alzheimer's disease, cognitive speed, MCI, memory, total tau

DOI: 10.3233/JAD-2010-101203

Citation: Journal of Alzheimer's Disease, vol. 22, no. 3, pp. 971-980, 2010

Authors: Schofield, Emma C. | Halliday, Glenda M. | Kwok, John | Loy, Clement | Double, Kay L. | Hodges, John R.

Article Type: Research Article

Abstract: Serum progranulin is decreased in frontotemporal dementia (FTD) patients with progranulin gene (PGRN) mutations. We investigate the utility of prospective serum screening as a surrogate diagnostic marker for progranulin mutations. A commercial ELISA was used to measure progranulin protein concentration in serum from 63 FTD patients and 32 normal controls, and DNA screening then performed. Four patients (2/17 behavioral variant, 2/8 corticobasal syndrome) had abnormally low progranulin levels with PGRN mutations confirmed on DNA testing. Surprisingly, elevated levels were found in 6/16 patients with progressive non-fluent aphasia, the significance of which is unclear. Serum testing is an accurate and cost …effective means of predicting PGRN mutations. Show more

Keywords: Enzyme-linked immunosorbent assay, frontotemporal dementia, GRN protein, hematologic tests, human, mutation

DOI: 10.3233/JAD-2010-101032

Citation: Journal of Alzheimer's Disease, vol. 22, no. 3, pp. 981-984, 2010

Authors: Ghidoni, Roberta | Benussi, Luisa | Glionna, Michela | Desenzani, Silvia | Albertini, Valentina | Levy, Efrat | Emanuele, Enzo | Binetti, Giuliano

Article Type: Research Article

Abstract: Recent years have witnessed an increasing interest in mild cognitive impairment (MCI), particularly as a possible prodromal stage of Alzheimer's disease (AD). Experimental and clinical data have suggested that cystatin C (CysC) is protective against the development of AD. In this study, we sought to cross-sectionally and longitudinally investigate the changes in plasma CysC levels in patients with MCI and whether the levels of this molecule might serve as a biochemical predictor of cognitive decline in this patient group. Cross-sectional analysis of baseline data showed a borderline significant difference in plasma CysC levels among the three study groups (Controls, n …= 63; AD, n = 63; MCI, n = 59) (p = 0.032) that disappeared after post hoc analysis. Plasma CysC levels did not differ at baseline (t1) and at follow-up (t2) both in MCI patients that converted to AD (n = 32) and those that did not convert (n = 27). However, a significant independent association between CysC at t1 and CysC at t2 was found in non-converters but not in converters MCI subjects. Moreover, when disease onset was evaluated in patients groups stratified on the basis of their CysC plasma levels, a significant anticipation of the conversion to dementia in MCI subjects with CysC levels below the median (CysC < 1067 ng/ml) (p = 0.0011) was observed. Altogether, this work adds to the growing body of literature suggesting that CysC modulates the clinical expression of cognitive decline, and opens a new area of investigation of CysC as a therapeutic target for neurodegenerative disorders. Show more

Keywords: Amyloid, APOE, biomarkers, cystatins, dementia, humans, longitudinal studies, plasma

DOI: 10.3233/JAD-2010-101095

Citation: Journal of Alzheimer's Disease, vol. 22, no. 3, pp. 985-991, 2010

Authors: Nobili, Flavio | Mazzei, Debora | Dessi, Barbara | Morbelli, Silvia | Brugnolo, Andrea | Barbieri, Paola | Girtler, Nicola | Sambuceti, Gianmario | Rodriguez, Guido | Pagani, Marco

Article Type: Research Article

Abstract: To unveil the brain metabolic correlates of (un)awareness of memory deficit in subjects with amnestic mild cognitive impairment (aMCI), forty-two outpatients underwent brain 18 F-FDG-PET. Awareness of memory deficit was assessed with the Memory Complaint Questionnaire (MAC-Q), identifying two groups: low (MCI/unaware; 17 patients) and good (MCI/aware; 25 patients) aMCI awareness. Twenty-nine age-matched healthy subjects represented the control group. SPM2 was used to assess the correlation between brain metabolism and MAC-Q score, for comparisons between each patient group and controls, and between aMCI/unaware and aMCI/aware groups. The two aMCI groups were comparable in terms of age, gender, education, depression, and …neuropsychological tests scores. In the whole 42-patient group, a positive correlation was found between MAC-Q score and metabolism in posterior cingulate cortex in both hemispheres and in inferior parietal lobule, middle cingulate cortex, precuneus and angular gyrus in the left hemisphere. Compared to controls, hypometabolism was found in aMCI/unaware in three large clusters, including precuneus, inferior parietal lobule and superior occipital gyrus, in the left hemisphere, and in inferior parietal lobule, angular gyrus and middle temporal gyrus in the right hemisphere. Smaller clusters of hypometabolism were found in bilateral temporal lobe in aMCI/aware. Hypometabolism in inferior parietal lobule, angular gyrus and superior temporal gyrus in the left hemisphere was highlighted in aMCI/unaware versus aMCI/aware. The significant correlation in all 42 aMCI patients points to posteromedial cortex as a key node of the network being involved in awareness of memory deficit. Patients with low awareness show a more severe hypometabolic pattern, typical of Alzheimer's disease and therefore could be more at risk of developing dementia. Show more

Keywords: Alzheimer's disease, amnestic mild cognitive impairment, awareness, FDG-PET, memory deficit

DOI: 10.3233/JAD-2010-100423

Citation: Journal of Alzheimer's Disease, vol. 22, no. 3, pp. 993-1003, 2010

Authors: Israeli-Korn, Simon D. | Massarwa, Magda | Schechtman, Edna | Strugatsky, Rosa | Avni, Shiri | Farrer, Lindsay A. | Friedland, Robert P. | Inzelberg, Rivka

Article Type: Research Article

Abstract: Mild cognitive impairment (MCI) and healthy aging have been shown to be associated with mild parkinsonian signs (MPS). We performed a door-to-door observational and follow-up study amongst consenting residents of Wadi Ara Arab villages in northern Israel aged ⩾ 65 years (n = 687) to examine whether MPS represent a risk factor for MCI and/or conversion from MCI to Alzheimer's disease (AD). In Phase 1, 223 cognitively normal (CN) and 173 MCI subjects were assessed by interview for medical history, neurological examination, motor part of the Unified Parkinson Disease Rating Scale (mUPDRS) (divided into item-clusters: axial, limb bradykinesia, tremor and …rigidity) and cognitive tests. MCI subjects (n = 111) were re-evaluated in Phase 2 for conversion to AD at least one year after initial assessment. MCI subjects had a higher frequency of axial dysfunction (8.7% vs. 1.3%) and limb bradykinesia (10.4% vs. 1.3%) than CN subjects (p < 0.001, both). Stepwise logistic regression analysis estimating the probability of MCI vs. CN revealed higher mUPDRS (OR = 1.19, 95% CI, 1.05 to 1.35, p = 0.006) and higher limb bradykinesia scores (OR = 1.75, 95% CI, 1.2 to 2.56, p = 0.003) and not age as explanatory variables. Presence of MPS did not predict conversion to AD after adjustment for age and time-interval. These results suggest that axial and bradykinetic parkinsonian signs represent risk factors for MCI but MPS may not predict conversion from MCI to AD. Show more

Keywords: Aging, Alzheimer's disease, mild cognitive impairment, mild parkinsonian signs, neuroepidemiology, risk factors

DOI: 10.3233/JAD-2010-101230

Citation: Journal of Alzheimer's Disease, vol. 22, no. 3, pp. 1005-1013, 2010

Authors: Sabbagh, Marwan N. | Malek-Ahmadi, Michael | Kataria, Rahul | Belden, Christine M. | Connor, Donald J. | Pearson, Caleb | Jacobson, Sandra | Davis, Kathryn | Yaari, Roy | Singh, Upinder

Article Type: Research Article

Abstract: The aim of this pilot study is to determine the feasibility and clinical utility of a brief, informant-based screening questionnaire for Alzheimer's disease (AD) that can be administered in a primary care setting. The Alzheimer's Questionnaire (AQ) was administered to the informants of 188 patients in 3 dementia clinics (50 cognitively normal, 69 mild cognitive impairment (MCI), 69 AD). Total score for the AQ is based upon the sum of clinical symptom items in which the informant responds as being present. Clinical symptoms which are known to be highly predictive of the clinical AD diagnosis are given greater weight in …the total AQ score. The mean time of administration of the AQ was 2.6 ± 0.6 minutes. Sensitivity and specificity were found to be high for detecting both AD (98.55, 96.00) and MCI (86.96, 94.00) with ROC curves yielding AUC values of 0.99 and 0.95, respectively. This pilot study indicates that the AQ is a brief, sensitive measure for detecting both MCI and AD and could be easily implemented in a primary care setting. Show more

Keywords: Alzheimer's disease, instrument, questionnaire, primary care

DOI: 10.3233/JAD-2010-101185

Citation: Journal of Alzheimer's Disease, vol. 22, no. 3, pp. 1015-1021, 2010

Authors: Whitehouse, Isobel J. | Jackson, Carolyn | Turner, Anthony J. | Hooper, Nigel M.

Article Type: Research Article

Abstract: The cellular form of the prion protein (PrPC ) has been shown to inhibit the production of amyloid-β which is critically involved in the pathogenesis of Alzheimer's disease (AD). We examined the expression of PrPC by immunoblot analysis in the hippocampus and temporal cortex in sporadic AD, familial AD, and appropriate age-matched controls, and in an aging series (age 20 to 88 years) of brains. PrPC was reduced by 53% (p = 0.032) in the hippocampus in sporadic AD as compared to the age-matched controls. No such reduction in PrPC was seen in familial AD. PrPC …was reduced in the hippocampus with aging (rs = 0.03). The reduction in PrPC in sporadic but not familial AD suggests that reduced PrPC expression reflects a primary mechanism of disease and is not merely a secondary consequence of other AD-associated changes. The reduction of PrPC in the brain with aging suggests that age-related decreases in PrPC may contribute to the increased incidence of AD in older people. Show more

Keywords: Aging, Alzheimer's disease, familial Alzheimer's disease, prion, sporadic Alzheimer's disease

DOI: 10.3233/JAD-2010-101071

Citation: Journal of Alzheimer's Disease, vol. 22, no. 3, pp. 1023-1031, 2010

Authors: Landhuis, Esther | Fagan, Tom

Article Type: Meeting Report

DOI: 10.3233/JAD-2010-1428

Citation: Journal of Alzheimer's Disease, vol. 22, no. 3, pp. 1033-1037, 2010

Article Type: Correction

Abstract: Erratum to Journal of Alzheimer's Disease 16(1), 2009, 93–98, DOI 10.3233/JAD-2009-0923. http://iospress.metapress.com/content/mtkk504n5683x251/

DOI: 10.3233/JAD-2010-1427

Citation: Journal of Alzheimer's Disease, vol. 22, no. 3, pp. 1039-1039, 2010

Article Type: Correction

Abstract: Erratum to Journal of Alzheimer's Disease 21(2), 2010, 389–402, DOI 10.3233/JAD-2010-100174. http://iospress.metapress.com/content/m0405r166l68227w/

DOI: 10.3233/JAD-2010-1429

Citation: Journal of Alzheimer's Disease, vol. 22, no. 3, pp. 1041-1041, 2010

Article Type: Correction

Abstract: Erratum to Journal of Alzheimer's Disease 22(1), 2010, 159–170, DOI 10.3233/JAD-2010-100972. http://iospress.metapress.com/content/3j26rpj93x042107/

DOI: 10.3233/JAD-2010-1431

Citation: Journal of Alzheimer's Disease, vol. 22, no. 3, pp. 1043-1043, 2010

Article Type: Announcement

DOI: 10.3233/JAD-2010-101549

Citation: Journal of Alzheimer's Disease, vol. 22, no. 3, pp. 1045-1046, 2010