Journal of Alzheimer's Disease - Volume 72, issue 4

Authors: Pozueta, Ana | Lage, Carmen | García-Martínez, María | Kazimierczak, Martha | Bravo, María | López-García, Sara | Riancho, Javier | González-Suarez, Andrea | Vázquez-Higuera, José Luis | de Arcocha-Torres, María | Banzo, Ignacio | Jiménez-Bonilla, Julio | Berciano, José | Rodríguez-Rodríguez, Eloy | Sánchez-Juan, Pascual

Article Type: Research Article

Abstract: Background: Semantic dementia (SD) is a subtype of frontotemporal dementia (FTD) characterized by semantic memory loss and preserved abilities of other cognitive functions. The clinical manifestations of SD require a differential diagnosis with Alzheimer’s disease (AD), especially those with early onset, and behavioral variant FTD (bvFTD). Objective: The present study aimed to compare cognitive performances and neuropsychiatric symptoms in a population of AD, bvFTD, and left and right SD defined with the support of molecular imaging (amyloid and 2-[18 F] fluoro-2-deoxy-D-glucose positron emission tomography) and assessed the accuracy of different neuropsychological markers in distinguishing these neurodegenerative diseases. …Methods: Eighty-seven participants (32 AD, 20 bvFTD, and 35 SD (17 Left-SD and 18 Right-SD) completed a comprehensive neuropsychological battery that included memory, language, attention and executive functions, visuospatial function, visuoconstructional skills, and tasks designed specifically to evaluate prosopagnosia and facial emotions recognition. The Neuropsychiatric Inventory was administered to assess neuropsychiatric symptoms. Results: An episodic memory test that included semantic cues, a visuospatial test (both impaired in AD), a naming test and a prosopagnosia task (both impaired in SD) were the four most valuable cognitive metrics for the differential diagnosis between groups. Several behavioral abnormalities were differentially present, of which aggression, self-care (both more frequent in bvFTD), and eating habits, specifically overeating and altered dietary preference (more frequent in SD), were the most valuable in group discrimination. Conclusion: Our study highlights the value of a comprehensive neuropsychological and neuropsychiatric evaluation for the differential diagnosis between FTD syndromes and AD. Show more

Keywords: Alzheimer’s disease, behavior, behavioral variant frontotemporal dementia, cognition, semantic dementia

DOI: 10.3233/JAD-190877

Citation: Journal of Alzheimer's Disease, vol. 72, no. 4, pp. 1129-1144, 2019

Authors: Li, Suyun | Sun, Wenjun | Zhang, Dongfeng

Article Type: Research Article

Abstract: Background: The association of zinc, iron, copper, and selenium intakes with cognitive function is poorly understood so far. Objective: To examine the associations of dietary and total zinc, iron, copper, and selenium intakes with low cognitive performance. Methods: Cross-sectional study data from the National Health and Nutrition Examination Survey (NHANES) 2011–2014 was used. Zinc, iron, copper, and selenium intakes from foods and supplements were estimated from two non-consecutive 24-hour diet recalls. Cognitive function was measured by the Consortium to Establish a Registry for Alzheimer’s disease (CERAD) Word Learning sub-test, Animal Fluency test, and Digit Symbol Substitution …test (DSST). For each cognitive measurement, people whose score were lower than the age group stratified lowest quartile were defined as low cognitive performance. Logistic regression and restricted cubic spline models were applied to examine the associations of dietary and total zinc, iron, copper, and selenium intakes with different measures of low cognitive performance. Results: A total of 2,332 adults aged 60 years or older were included. The association between zinc, iron, copper, and selenium intake and low cognitive performance was significant in different test. Compared with the lowest quartile of total copper intake, the weighted multivariate adjusted ORs (95% CI) of the highest quartile were 0.34 (0.16–0.75) for low cognitive performance in DSST. L-shaped associations between total copper or selenium and low cognitive performance in DSST and animal fluency were found. Conclusion: Dietary and total zinc, copper, and selenium intakes might be inversely associated with the prevalence of low cognitive performance. Show more

Keywords: Cognition, copper intake, eating, selenium intake, zinc intake

DOI: 10.3233/JAD-190263

Citation: Journal of Alzheimer's Disease, vol. 72, no. 4, pp. 1145-1157, 2019

Authors: Bussè, Cinzia | Pettenuzzo, Ilaria | Pompanin, Sara | Roiter, Beatrice | di Bernardo, Gian Antonio | Zorzi, Giovanni | Fragiacomo, Federica | Gazzola, Gianmarco | Cecchin, Diego | Pigato, Giorgio | Cagnin, Annachiara

Article Type: Research Article

Abstract: Behavioral and cognitive variables predicting behavioral frontotemporal dementia (bvFTD) versus primary psychiatric disorders mimicking bvFTD (phenocopy syndrome: bvFTD-PS) were studied. Forty-one probable/definite bvFTD and 16 bvFTD-PS patients were evaluated with cognitive battery, Neuropsychiatric Inventory, and Stereotypic and Ritualistic Behavior-revised questionnaires. Twenty-seven healthy subjects served as control. Severity of cognitive impairment/behavioral symptoms and profile of cognitive deficits were similar, with bvFTD-PS showing impaired executive abilities and memory. However, phonemic fluency was impaired only in bvFTD (p  < 0.001). Depression was worse in bvFTD-PS, while apathy, disinhibition, and dietary changes characterized bvFTD. Phonemic fluency and depression accounted for the best predictive diagnostic model. …A structured psychiatric screening of bvFTD mimickers may often yield a psychiatric diagnosis with predominant depressive symptoms and therefore a potentially treatable condition. Show more

Keywords: Frontotemporal dementia, phenocopy, psychiatric diseases

DOI: 10.3233/JAD-190332

Citation: Journal of Alzheimer's Disease, vol. 72, no. 4, pp. 1159-1164, 2019

Authors: Abdullah, Mohammad | Kimura, Noriyuki | Akatsu, Hiroyasu | Hashizume, Yoshio | Ferdous, Taslima | Tachita, Takuto | Iida, Shinsuke | Zou, Kun | Matsubara, Etsuro | Michikawa, Makoto

Article Type: Research Article

Abstract: Currently, best-characterized indicators for Alzheimer’s disease (AD) diagnosis are the decreased levels of amyloid-β protein 42 and increased levels of phosphorylated tau in cerebrospinal fluid (CSF). The positron emission tomography (PET) imaging with Pittsburgh compound B (PiB) is also used in AD diagnosis by visualizing amyloid deposition in the brain. These methods are invasive or expensive; therefore, less invasive and easily detectable blood biomarkers are required. Because our previous study showed that flotillin release, a marker of exosomes, was attenuated by Aβ, we designed the present study to determine whether flotillin level could be reduced in CSF and/or serum of …patients with AD. In this study, we analyzed flotillin levels in CSF and serum of non-AD controls, patients with AD and mild cognitive impairment (MCI) by western blotting. Flotillin levels in cerebroventricular fluid (CVF) and serum of AD, vascular dementia (VaD), and non-AD autopsy cases were also analyzed. Flotillin levels significantly decreased in the CSF and serum of AD patients compared with those of non-AD controls, respectively. Moreover, in patients with MCI due to AD determined by PiB-PET, CSF and serum flotillin levels significantly decreased compared with those of patients with MCI due to non-AD. Flotillin levels remained unchanged in CVF and serum of autopsy cases diagnosed as VaD. Serum flotillin level is negatively associated with brain amyloid deposition indicated as PiB uptake. These results demonstrate that serum flotillin level can serve as one of the blood markers for estimation of brain amyloid deposition and early diagnosis of AD. Show more

Keywords: Alzheimer’s disease, blood diagnostic marker, cerebrospinal fluid, cerebroventricular fluid, flotillin, mild cognitive impairment

DOI: 10.3233/JAD-190908

Citation: Journal of Alzheimer's Disease, vol. 72, no. 4, pp. 1165-1176, 2019

Authors: Gatt, Ariana | Whitfield, David R. | Ballard, Clive | Doherty, Patrick | Williams, Gareth

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is an incurable complex neurodegenerative condition with no new therapies licensed in the past 20 years. AD progression is characterized by the up- and downregulation of distinct biological processes that can be followed through the expression level changes of associated genes and gene networks. Objective: Our study aims to establish a multiplex gene expression tracking platform to follow disease progression in an animal model facilitating the study of treatment paradigms. Methods: We have established a multiplex platform covering 47 key genes related to immunological, neuronal, mitochondrial, and autophagy cell types and processes …that capture disease progression in the 5×FAD mouse model. Results: We show that the immunological response is the most pronounced change in aged 5×FAD mice (8 months and above), and in agreement with early stage human disease samples, observe an initial downregulation of microglial genes in one-month-old animals. The less dramatic downregulation of neuronal and mitochondrial gene sets is also reported. Conclusion: This study provides the basis for a quantitative multi-dimensional platform to follow AD progression and monitor the efficacy of treatments in an animal model. Show more

Keywords: Alzheimer’s disease, biomarker, 5×FAD mouse, transcriptional profiling

DOI: 10.3233/JAD-190805

Citation: Journal of Alzheimer's Disease, vol. 72, no. 4, pp. 1177-1191, 2019

Authors: Massa, Federico | Farotti, Lucia | Eusebi, Paolo | Capello, Elisabetta | Dottorini, Massimo E. | Tranfaglia, Cristina | Bauckneht, Matteo | Morbelli, Silvia | Nobili, Flavio | Parnetti, Lucilla

Article Type: Research Article

Abstract: Background: In Alzheimer’s disease (AD) diagnosis, both cerebrospinal fluid (CSF) biomarkers and FDG-PET sometimes give inconclusive results. Objective: To evaluate the incremental diagnostic value of FDG-PET over CSF biomarkers, and vice versa, in patients with mild cognitive impairment (MCI) and suspected AD, in which the first biomarker resulted inconclusive. Methods: A consecutive series of MCI patients was retrospectively selected from two Memory Clinics where, as per clinical routine, either the first biomarker choice is FDG-PET and CSF biomarkers are only used in patients with uninformative FDG-PET, or vice versa. We defined criteria of uncertainty in interpretation …of FDG-PET and CSF biomarkers, according to current evidence. The final diagnosis was established according to clinical-neuropsychological follow-up of at least one year (mean 4.4±2.2). Results: When CSF was used as second biomarker after FDG-PET, 14 out of 36 (39%) received informative results. Among these 14 patients, 11 (79%) were correctly classified with respect to final diagnosis, thus with a relative incremental value of CSF over FDG-PET of 30.6%. When FDG-PET was used as second biomarker, 26 out of 39 (67%) received informative results. Among these 26 patients, 15 (58%) were correctly classified by FDG-PET with respect to final diagnosis, thus with a relative incremental value over CSF of 38.5%. Conclusion: Our real-world data confirm the added values of FDG-PET (or CSF) in a diagnostic pathway where CSF (or FDG-PET) was used as first biomarkers in suspected AD. These findings should be replicated in larger studies with prospective enrolment according to a Phase III design. Show more

Keywords: Alzheimer’s disease, cerebrospinal fluid biomarkers, FDG-PET, mild cognitive impairment

DOI: 10.3233/JAD-190539

Citation: Journal of Alzheimer's Disease, vol. 72, no. 4, pp. 1193-1207, 2019

Authors: Ochiai, Ryuji | Saitou, Katsuyoshi | Suzukamo, Chika | Osaki, Noriko | Asada, Takashi

Article Type: Research Article

Abstract: Background: Mild cognitive impairment (MCI) is a global-scale issue, due in large part to the rapidly growing elderly population. The main polyphenol contained in coffee beans, chlorogenic acid (CGA), improves attention in healthy individuals. The utility of CGAs for treating MCI, however, has not been evaluated. Objective: To determine the effects of continuous CGA intake on cognitive function, especially attention, in patients diagnosed with MCI. Methods: The study was a randomized controlled crossover trial including 34 patients with MCI. Participants were randomly divided into two groups: Those who first ingested a placebo beverage and those who …first ingested an active beverage containing CGAs (553.6 mg/bottle) twice daily for 12 weeks. After a 4-week washout period, the subjects ingested the other beverage (i.e., placebo or active beverage) in the same manner. Endpoint measures included scores on the Japanese version of the Mini-Mental State Examination (MMSE), the Japanese version of the Alzheimer’s Disease Assessment Scale-cognitive component (ADAS-cog) testing overall cognitive function, and the Japanese version of the Trail Making Test (TMT-A, TMT-B) testing attention, along with the results of blood tests to evaluate safety. Results: In the TMT-B test, participants had a significantly reduced number of errors while ingesting the CGA beverage as compared with the placebo beverage (p  < 0.05), although there was no difference in test completion time. Scores in the MMSE, ADAS-cog, and TMT-A did not differ significantly between conditions. Conclusion: Continuous intake of CGAs appears to improve attention and executive function among cognitive functions in MCI. Show more

Keywords: Attention, chlorogenic acid, coffee, crossover studies, mild cognitive impairment, polyphenol, trail making test

DOI: 10.3233/JAD-190757

Citation: Journal of Alzheimer's Disease, vol. 72, no. 4, pp. 1209-1216, 2019

Authors: Wang, Zhao-Jun | Zhao, Fang | Wang, Chen-Fang | Zhang, Xiu-Min | Xiao, Yi | Zhou, Fang | Wu, Mei-Na | Zhang, Jun | Qi, Jin-Shun | Yang, Wei

Article Type: Research Article

Abstract: Exaggerated Ca2+ signaling might be one of primary causes of neural dysfunction in Alzheimer’s disease (AD). And the intracellular Ca2+ overload has been closely associated with amyloid-β (Aβ)-induced endoplasmic reticulum (ER) stress and memory impairments in AD. Here we showed for the first time the neuroprotective effects of Xestospongin C (XeC), a reversible IP3 receptor antagonist, on the cognitive behaviors and pathology of APP/PS1 AD mice. Male APP/PS1-AD mice (n  = 20) were injected intracerebroventricularly with XeC (3μ mol) via Alzet osmotic pumps for four weeks, followed by cognition tests, Aβ plaque examination, and ER stress-related protein measurement. …The results showed that XeC pretreatment significantly improved the cognitive behavior of APP/PS1-AD mice, raising the spontaneous alteration accuracy in Y maze, decreasing the escape latency and increasing the target quadrant swimming time in Morris water maze; XeC pretreatment also reduced the number of Aβ plaques and the overexpression of ER stress proteins 78 kDa glucose-regulated protein (GRP-78), caspase-12, and CAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP) in the hippocampus of APP/PS1 mice. In addition, in vitro experiments showed that XeC effectively ameliorated Aβ1 - 42 -induced early neuronal apoptosis and intracellular Ca2+ overload in the primary hippocampal neurons. Taken together, IP3 R-mediated Ca2+ disorder plays a key role in the cognitive deficits and pathological damages in AD mice. By targeting the IP3  R, XeC might be considered as a novel therapeutic strategy in AD. Show more

Keywords: Amyloid-β, APP/PS1-AD mice, calcium overload, cognitive behavior, endoplasmic reticulum stress Xestospongin C

DOI: 10.3233/JAD-190796

Citation: Journal of Alzheimer's Disease, vol. 72, no. 4, pp. 1217-1231, 2019

Authors: Unger, Robert H. | Flanigan, Patrick M. | Khosravi, Mitra | Leverenz, James B. | Tousi, Babak

Article Type: Research Article

Abstract: Background: Color vision impairment (CVI) has been reported in dementia with Lewy bodies (DLB) and prodromal Lewy body disease (pro-LBD). Objective: In order to better characterize the diagnostic value of CVI testing, we compared the prevalence of CVI in patients with with Lewy body disease compared to Alzheimer’s disease (AD), and we examined clinical and imaging characteristics associated with CVI in patients with DLB and suspected pro-LBD. Methods: We retrospectively reviewed medical records, dopamine transporter (DaT-SPECT) imaging, and volumetric MRI from patients with AD, DLB, and suspected pro-LBD who underwent an online Farnsworth D-15 color vision …test. Results: 111 patients (62 DLB, 25 pro-LBD, and 24 AD) were included with a median age of 75 years. Newly diagnosed CVI was present in 67% of patients with DLB, 44% of patients with pro-LBD, and 18% of patients with AD. In patients with DLB, CVI was associated with lower Montreal Cognitive Assessment (MoCA) scores and lower sub-scores in visuospatial/executive function, naming, and language. In a multivariable logistic regression model, a diagnosis of DLB or pro-LBD compared to AD, and a lower composite MoCA score in visuospatial/executive function, naming, and language were associated with CVI controlling for age and gender. Among 17 DLB patients who underwent volumetric MRI, patients with CVI (n  = 9) demonstrated lower normative volumetric percentiles in the right transverse superior temporal lobe. Conclusion: We provide further evidence that CVI can help differentiate DLB from AD, and we suggest that CVI may be an indicator of cognitive decline and disease progression in DLB. Show more

Keywords: Alzheimer’s disease, biomarkers, color vision, Lewy body disease, presenile dementia

DOI: 10.3233/JAD-190727

Citation: Journal of Alzheimer's Disease, vol. 72, no. 4, pp. 1233-1240, 2019

Authors: Danese, Alessandra | Federico, Angela | Martini, Alice | Mantovani, Elisa | Zucchella, Chiara | Tagliapietra, Matteo | Tamburin, Stefano | Cavallaro, Tiziana | Marafioti, Vincenzo | Monaco, Salvatore | Turri, Giulia

Article Type: Research Article

Abstract: The QTc interval is the electrocardiographic manifestation of ventricular depolarization and repolarization. This marker is often prolonged in acute and chronic neurological conditions. The cause of the cerebrogenic QT prolongation remains unclear. The aim of the study was to analyze the relation between QTc interval and the degree of cognitive impairment and structural brain imaging changes in patients with dementia and mild cognitive impairment (MCI). To this aim, 269 patients were screened, of whom 61 met one or more exclusion criteria. The remaining 208 patients (56 control subjects, 44 patients with MCI, and 108 with dementia) were recruited. Eighty-five patients …using drugs causing prolongation of QT interval were further excluded. The QT interval was measured manually in all 12 leads by a single blinded observer, assuming the longest QT value adjusted for heart rate by using the Bazett’s formula. All patients underwent a structural brain imaging and the following measures were obtained: the bicaudate ratio and the periventricular hyperintensity and deep white matter hyperintensity using the modified Fazekas scale. Prolonged QTc interval was prevalent in 1) patients with dementia, especially in those with moderate-severe degree; 2) subjects with impairment of praxis and attention, low functional status, and behavioral symptoms; 3) patients with global and temporal atrophy and with higher scores on the Fazekas or leukoaraiosis scales. Degenerative and vascular processes might play a main role in QTc interval prolongation because of the damage to brain areas involved in the control of the autonomic cardiac nervous system. Show more

Keywords: Autonomic cardiac system, dementia, mild cognitive impairment, QT interval

DOI: 10.3233/JAD-190632

Citation: Journal of Alzheimer's Disease, vol. 72, no. 4, pp. 1241-1249, 2019