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

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