Journal of Alzheimer's Disease - Volume 55, issue 4

Authors: Kazui, Hiroaki | Takahashi, Ryuichi | Yamamoto, Yuki | Yoshiyama, Kenji | Kanemoto, Hideki | Suzuki, Yukiko | Sato, Shunsuke | Azuma, Shingo | Suehiro, Takashi | Shimosegawa, Eku | Ishii, Kazunari | Tanaka, Toshihisa

Article Type: Research Article

Abstract: Background: Although apathy is associated with damage to the frontal and temporal lobes in Alzheimer’s disease (AD), the crucial regions for apathy in patients with amnestic mild cognitive impairment (aMCI) are unknown. Objective: To identify brain regions associated with apathy in aMCI patients. Methods: The subjects of this study were 98 aMCI patients who were entered in our dementia registry between March 1, 2009 and April 30, 2015 and who satisfied our criteria for aMCI. The association between the apathy score of the Neuropsychiatric Inventory and regional gray matter volume was analyzed using voxel-based morphometry. …The association between apathy score and regional cerebral blood flow (rCBF) measured with single photon emission computed tomography (SPECT) was analyzed using Statistical Parametric Mapping. Results: The aMCI patients were classified into aMCI with and without “SPECT images suggestive of AD” (aMCI-AD+ and aMCI-AD–, respectively) based on the Z-score summation analysis method. In aMCI-AD+ (n  = 31), apathy was significantly and negatively correlated with gray matter volume in the right caudate nucleus and with rCBF in five regions (left posterior-medial frontal lobe, right superior frontal lobe, bilateral culmen-fusiform gyri, and left occipital lobe). In aMCI-AD–(n  = 67), apathy was significantly and negatively correlated with gray matter volumes in five regions but it was not correlated with rCBF in any regions. Conclusion: In patients with a high probability of being in the aMCI stage of AD, apathy was associated with atrophy of the right caudate nucleus and hypoperfusion in the frontal, temporal and occipital lobes. Show more

Keywords: Alzheimer’s disease, amnestic mild cognitive impairment, apathy, caudate nucleus, cerebral blood flow, gray matter volume, statistical parametric mapping, voxel-based morphometry

DOI: 10.3233/JAD-160223

Citation: Journal of Alzheimer's Disease, vol. 55, no. 4, pp. 1403-1416, 2017

Authors: Voyle, Nicola | Patel, Hamel | Folarin, Amos | Newhouse, Stephen | Johnston, Caroline | Visser, Pieter Jelle | Dobson, Richard J.B. | Kiddle, Steven J. | the EDAR and DESCRIPA study groups and the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: The search for a biomarker of Alzheimer’s disease (AD) pathology (amyloid-β (Aβ) and tau) is ongoing, with the best markers currently being measurements of Aβ and tau in cerebrospinal fluid (CSF) and via positron emission tomography (PET) scanning. These methods are relatively invasive, costly, and often have high screening failure rates. Consequently, research is aiming to elucidate blood biomarkers of Aβ and tau. Objective: This study aims to investigate a case/control polygenic risk score (PGRS) as a marker of tau and investigate blood markers of a combined Aβ and tau outcome for the first time. A …sub-study also considers plasma tau as markers of Aβ and tau pathology in CSF. Methods: We used data from the EDAR*, DESCRIPA**, and Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohorts in a logistic regression analysis to investigate blood markers of Aβ and tau in CSF. In particular, we investigated the extent to which a case/control PGRS is predictive of CSF tau, CSF amyloid, and a combined amyloid and tau outcome. The predictive ability of models was compared to that of age, gender, and APOE genotype (‘basic model’). Results: In EDAR and DESCRIPA test data, inclusion of a case/control PGRS was no more predictive of Aβ, and a combined Aβ and tau endpoint than the basic models (accuracies of 66.0%, and 73.3% respectively). The tau model saw a small increase in accuracy compared to basic models (59.6%). ADNI 2 test data also showed a slight increase in accuracy for the Aβ model when compared to the basic models (61.4%). Conclusion: We see some evidence that a case/control PGRS is marginally more predictive of Aβ and tau pathology than the basic models. The search for predictive factors of Aβ and tau pathologies, above and beyond demographic information, is still ongoing. Better understanding of AD risk alleles, development of more sensitive assays, and studies of larger sample size are three avenues that may provide such factors. However, the clinical utility of possible predictors of brain Aβ and tau pathologies must also be investigated. *‘Beta amyloid oligomers in the early diagnosis of AD and as marker for treatment response’ **‘Development of screening guidelines and criteria for pre-dementia Alzheimer’s disease’ Show more

Keywords: Alzheimer’s disease, biomarker, blood, multi-modal, polygenic risk score, tau

DOI: 10.3233/JAD-160707

Citation: Journal of Alzheimer's Disease, vol. 55, no. 4, pp. 1417-1427, 2017

Authors: Abrevaya, Sofía | Sedeño, Lucas | Fitipaldi, Sol | Pineda, David | Lopera, Francisco | Buritica, Omar | Villegas, Andrés | Bustamante, Catalina | Gomez, Diana | Trujillo, Natalia | Pautassi, Ricardo | Ibáñez, Agustín | García, Adolfo M.

Article Type: Research Article

Abstract: Action verbs are critically embodied in motor brain networks. In Parkinson’s disease (PD), damage to the latter compromises access to such words. However, patients are not fully incapable of processing them, as their performance is far from floor level. Here we tested the hypothesis that action-verb processing in PD may rely on alternative disembodied semantic circuits. Seventeen PD patients and 15 healthy controls listened to action verbs and nouns during functional MRI scanning. Using cluster-mass analysis with a permutation test, we assessed task-related functional connectivity considering seeds differentially engaged by action and non-action words (namely, putamen and M1 versus posterior …superior temporal lobe, respectively). The putamen seed showed reduced connectivity within the basal ganglia in patients for both lexical categories. However, only action verbs recruited different cortical networks in each group. Specifically, the M1 seed exhibited more anterior connectivity for controls and more posterior connectivity for patients, with no differences in the temporal seed. Moreover, the patients’ level of basal ganglia atrophy positively correlated with their reliance on M1-posterior connectivity during action-verb processing. PD patients seem to have processed action verbs via non-motor cortical networks subserving amodal semantics. Such circuits may afford alternative pathways to process words when default embodied mechanisms are disturbed. Moreover, the greater the level of basal ganglia atrophy, the greater the patients’ reliance on this alternative route. Our findings offer new insights into differential neurofunctional mechanisms recruited to process action semantics in PD. Show more

Keywords: Functional magnetic resonance imaging, language, motor cortex, Parkinson’s disease, semantics

DOI: 10.3233/JAD-160737

Citation: Journal of Alzheimer's Disease, vol. 55, no. 4, pp. 1429-1435, 2017

Authors: Arroyo-Anlló, Eva Ma | Bouston, Adèle Turpin | Fargeau, Marie-Noëlle | Orgaz Baz, Begoña | Gil, Roger

Article Type: Research Article

Abstract: Self-consciousness (SC) is multifaceted and considered to be the consciousness of one’s own mental states. The main aim of this paper is to compare SC in patients with Alzheimer’s disease (AD) and behavioral variant frontotemporal dementia (bvFTD). Three groups (control and patient groups) of 23 subjects each were assessed using an SC questionnaire. Both types of dementia clearly induce an alteration of SC. The bvFTD group showed a greater impairment in SC than the AD and control groups. The SC score was strongly associated with frontal functions. The most significantly impaired SC aspects in the bvFTD group were Anosognosia, Introspection, …and Moral Judgments. For the AD group, the significantly impaired aspects of SC were Anosognosia and Prospective Memory. The differences in SC between the AD and bvFTD groups were essentially centered on the Anosognosia, Moral Judgments, and Introspection aspects, which were highly impaired in the bvFTD patients. This suggests that SC is related to orbito-frontal functioning and thus, to the default mode network. Show more

Keywords: Alzheimer’s disease, awareness, consciousness, dementia, executive, frontotemporal

DOI: 10.3233/JAD-160770

Citation: Journal of Alzheimer's Disease, vol. 55, no. 4, pp. 1437-1443, 2017

Authors: Sarno, Tamires Alves | Talib, Leda Leme | Joaquim, Helena Passarelli Giroud | Bram, Jessyka Maria de França | Gattaz, Wagner Farid | Forlenza, Orestes Vicente

Article Type: Research Article

Abstract: Background: Abnormal amyloid-β protein precursor (AβPP) metabolism is a key feature of Alzheimer’s disease (AD). Platelets contain most of the enzymatic machinery required for AβPP processing, and correlates of intracerebral abnormalities have been demonstrated in platelets of patients with AD. Thus, AβPP-related molecules in platelets may be regarded as peripheral markers of AD. Objective: We sought to determine the protein expression of the AβPP secretases (ADAM10, BACE1, and PSEN1) and AβPP ratio in platelets of patients with mild or moderate AD compared to healthy controls. We further determined whether the protein expression of these markers might be …modified by chronic treatment with donepezil. Methods: Platelet samples were obtained from patients and controls at baseline and after 3 and 6 months of continuous treatment with therapeutic doses of donepezil. The protein expression of platelet markers was determined by western blotting. Results: AD patients had a significant decrease in AβPP ratio, ADAM10, and PSEN1 compared to controls at baseline, but these differences were not modified by the treatment. Nonetheless, a significant reduction in the protein expression of BACE1 was observed in patients treated with donepezil for 6 months. Conclusion: Our results corroborate previous findings from our group and others of decreased AβPP ratio and protein expression of ADAM10 in AD. We further show that PSEN1 is decreased in AD platelets, and that the protein expression of BACE1 is downregulated by chronic treatment with donepezil. This effect may be interpreted as evidence of disease modification. Show more

Keywords: ADAM10, Alzheimer’s disease, amyloid-β protein precursor, BACE1, donepezil, platelet, PSEN1, secretases

DOI: 10.3233/JAD-160813

Citation: Journal of Alzheimer's Disease, vol. 55, no. 4, pp. 1445-1451, 2017

Authors: Paraskevas, George P. | Kasselimis, Dimitrios | Kourtidou, Evie | Constantinides, Vasilios | Bougea, Anastasia | Potagas, Costas | Evdokimidis, Ioannis | Kapaki, Elisabeth

Article Type: Research Article

Abstract: Background: Primary progressive aphasia (PPA) may present with three main clinical variants, namely nonfluent agrammatic (nfaPPA), semantic (sPPA), and logopenic (lPPA) subtypes. Frontotemporal lobar degenerations (FTLD) or Alzheimer’s disease (AD) are the most common etiologies. Objective: To study the potential of cerebrospinal fluid (CSF) biomarkers for identifying the underlying pathology in patients with PPA. Methods: CSF levels of total tau protein (τ T ), amyloid-β peptide (Aβ42 ), and tau phosphorylated at threonine-181 (τ P - 181 ) were measured by double sandwich, enzyme-linked immunosorbent assay (ELISA) in 43 patients with PPA, 26 patients with AD, and …17 healthy controls. Results: All patients could be classified as compatible with the AD or non-AD biomarker profile, either with the three biomarkers (90.7%) or their ratios, especially the τ P - 181 /Aβ42 ratio (9.3%). An AD-compatible biomarker profile was present in 39.5% of all PPA patients, specifically 22.2%, 35.7%, and 75% of nfaPPA, sPPA, and lPPA, respectively. In PPA patients with a non-AD profile (presumably FTLD), two different clusters could be identified according to the τ P - 181 /τ T ratio, possibly corresponding to the two major FTLD pathologies (tau and TDP-43). Conclusion: CSF biomarkers may be a valuable tool for the discrimination between PPA patients with AD and non-AD pathophysiology and possibly between FTLD patients with tau and TDP-43 pathology. Show more

Keywords: Alzheimer’s disease, Aβ42, biomarkers, cerebrospinal fluid, frontotemporal lobar degeneration, phospho-tau, primary progressive aphasia, tau

DOI: 10.3233/JAD-160494

Citation: Journal of Alzheimer's Disease, vol. 55, no. 4, pp. 1453-1461, 2017

Authors: Müller, Stephan | Preische, Oliver | Heymann, Petra | Elbing, Ulrich | Laske, Christoph

Article Type: Research Article

Abstract: There is a considerable delay in the diagnosis of dementia, which may reduce the effectiveness of available treatments. Thus, it is of great interest to develop fast and easy to perform, non-invasive and non-expensive diagnostic measures for the early detection of cognitive impairment and dementia. Here we investigate movement kinematics between 20 patients with early dementia due to Alzheimer’s disease (eDAT), 30 patients with amnestic mild cognitive impairment (aMCI), and 20 cognitively healthy control (HC) individuals while copying a three-dimensional house using a digitizing tablet. Receiver-operating characteristic (ROC) curves and logistic regression analyzes have been conducted to explore whether alterations …in movement kinematics could be used to discriminate patients with aMCI and eDAT from healthy individuals. Time-in-air (i.e., transitioning from one stroke to the next without touching the surface) differed significantly between patients with aMCI, eDAT, and HCs demonstrating an excellent sensitivity and a moderate specificity to discriminate aMCI subjects from normal elderly and an excellent sensitivity and specificity to discriminate patients affected by mild Alzheimer’s disease from healthy individuals. Time-on-surface (i.e., time while stylus is touching the surface) differed only between HCs and patients with eDAT but not between HCs and patients with aMCI. Furthermore, total-time (i.e., time-in-air plus time-on-surface) did not differ between patients with aMCI and early dementia due to AD. Modern digitizing devices offer the opportunity to measure a broad range of visuoconstructive abilities that may be used as a fast and easy to perform screening instrument for the early detection of cognitive impairment and dementia in primary care. Show more

Keywords: Amnestic mild cognitive impairment, construction, early Alzheimer’s disease, online-drawing, screening, visuospatial

DOI: 10.3233/JAD-160921

Citation: Journal of Alzheimer's Disease, vol. 55, no. 4, pp. 1463-1469, 2017

Authors: Abu Rumeileh, Samir | Lattanzio, Francesca | Stanzani Maserati, Michelangelo | Rizzi, Romana | Capellari, Sabina | Parchi, Piero

Article Type: Research Article

Abstract: According to recent studies, the determination of cerebrospinal fluid (CSF) total tau (t-tau)/phosphorylated tau (p-tau) ratio and total prion protein (t-PrP) levels significantly improves the accuracy of the diagnosis of Alzheimer’s disease (AD) in atypical cases with clinical or laboratory features mimicking Creutzfeldt-Jakob disease (CJD). However, this has neither been validated nor tested in series including atypical CJD variants. Furthermore, the added diagnostic value of amyloid-β (Aβ)42 remains unclear. To address these issues, we measured t-PrP, 14-3-3, t-tau, p-tau, and Aβ42 CSF levels in 45 typical and 44 atypical/rapidly progressive AD patients, 54 typical and 54 atypical CJD …patients, and 33 controls. CJD patients showed significantly lower CSF t-PrP levels than controls and AD patients. Furthermore, atypical CJD was associated with lower t-PrP levels in comparison to typical CJD. T-tau, 14-3-3, or t-PrP alone yielded, respectively, 80.6, 63.0, and 73.0% sensitivity and 75.3, 92.1, and 75% specificity in distinguishing AD from CJD. On receiver operating characteristic (ROC) curve analyses of biomarker combinations, the (t-tau×Aβ42 )/(p-tau×t-PrP) ratio achieved the best accuracy, with 98.1% sensitivity and 97.7% specificity overall, and 96.2% sensitivity and 95.5% specificity for the “atypical” disease groups. Our results show that the combined analysis of CSF t-PrP, t-tau, p-tau, and Aβ42 is clinically useful in the differential diagnosis between CJD and AD. Furthermore, the finding of reduced CSF t-PrP levels in CJD patients suggest that, likewise Aβ42 in AD, CSF t-PrP levels reflect the extent of PrPc conversion into abnormal PrP (PrPSc ) and the burden of PrPSc deposition in CJD. Show more

Keywords: Alzheimer’s disease, amyloid-β, biomarker, cerebrospinal fluid, Creutzfeldt-Jakob disease, prion protein, tau protein

DOI: 10.3233/JAD-160740

Citation: Journal of Alzheimer's Disease, vol. 55, no. 4, pp. 1471-1480, 2017

Authors: Igase, Michiya | Ohara, Maya | Igase, Keiji | Kato, Takeaki | Okada, Yoko | Ochi, Masayuki | Tabara, Yasuharu | Kohara, Katsuhiko | Ohyagi, Yasumasa

Article Type: Research Article

Abstract: Background: Accumulation of advanced glycation endproducts (AGEs) is thought to be involved in the pathogenesis of dementia, especially Alzheimer’s disease. Tissue AGE accumulation can be estimated using the relative simple noninvasive measurement of skin autofluorescence (SAF), a method based on the fluorescent properties of some AGEs. However, possible involvement of tissue AGE accumulation in mild cognitive impairment (MCI) has not been fully investigated. Objective: We investigated whether tissue AGE accumulation estimated by SAF is associated with mild cognitive impairment. Methods: We analyzed 226 community-dwelling subjects. In addition to several atherosclerosis-related clinical parameters, MCI screening test, …assessment of brain atrophy, and SAF were performed on people aged > 40 years. MCI was assessed using the Japanese version of the MCI screening method. Atrophy of the brain was assessed by examining the temporal horn area (THA) by brain MRI. Results: SAF was significantly higher in participants with MCI than in those with normal cognitive function (2.56±0.55 versus 2.10±0.41; p  < 0.001). Logistic regression analyses with adjustment for confounding factors including age and THA showed that high SAF > 2.27 was significantly related to the presence of MCI (odds, 6.402; 95% CI, 1.590–25.773, p  = 0.009). Conclusion: We found an association between SAF and MCI, which was independent of brain atrophy, in healthy subjects. Show more

Keywords: Advanced glycation endproducts, brachial ankle pulse wave velocity, brain natriuretic peptide, estimated glomerular filtration rate, mild cognitive impairment, skin auto fluorescence, temporal horn area

DOI: 10.3233/JAD-160917

Citation: Journal of Alzheimer's Disease, vol. 55, no. 4, pp. 1481-1487, 2017

Authors: Carmona-Iragui, María | Santos, Telma | Videla, Sebastián | Fernández, Susana | Benejam, Bessy | Videla, Laura | Alcolea, Daniel | Blennow, Kaj | Blesa, Rafael | Lleó, Alberto | Fortea, Juan

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is the main medical problem in older adults with Down syndrome (DS). Studies of cerebrospinal fluid (CSF) AD biomarkers are limited and the feasibility of lumbar puncture (LP) is controversial in this population. Objective: To analyze the frequency of complications after a LP in DS. Methods: We collected data from 80 adults with DS that underwent a LP within the Down Alzheimer Barcelona Neuroimaging Initiative. Demographics, cognitive status, headache history, and presence of complications after the LP were recorded in every subject. In 53 of them (active group), this information …was collected following a semi-structured and validated protocol that actively looks for complications. Other variables related to the LP procedure were also recorded. A telephone interview to the caregiver was performed 5–7 days after the procedure to ask about complications. Data from 27 subjects (clinical practice group), from whom the presence of complications was obtained in a medical follow-up visit within the three months after the LP, were also included. Results: There were no adverse events in 90% of our participants. The most frequent complication was headache (6.25%); only one subject reported a typical post-lumbar puncture headache with moderate severity that required analgesic treatment. Dizziness (3.75%) and back pain (1.25%) were also reported. All the participants that reported complications belonged to the active group. Conclusion: LP can be safely performed to study CSF biomarkers in DS. The reported complications are qualitatively similar to the general population, but are less frequently reported, even when actively searched for. Show more

Keywords: Alzheimer’s disease, biomarkers, cerebrospinal fluid, Down syndrome, complications, lumbar puncture

DOI: 10.3233/JAD-160827

Citation: Journal of Alzheimer's Disease, vol. 55, no. 4, pp. 1489-1496, 2017