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

Authors: Lövheim, Hugo | Gustafsson, Maria | Isaksson, Ulf | Karlsson, Stig | Sandman, Per-Olof

Article Type: Research Article

Abstract: Background: For research purposes, there is a need for tools to assess an individual’s level of cognitive function. For survey-based investigations in nursing home contexts, proxy ratings allow the assessment also of individuals with severe cognitive impairment. Objective: The aim of this study was to describe the feasibility and psychometric properties of Gottfries’ cognitive scale when used in a nursing home context for proxy rating of cognitive function. Method: The psychometric properties of Gottfries’ cognitive scale were investigated in a sample of 8,492 nursing home residents in Västerbotten County, Sweden, using item response theory and classic …scale theory-based approaches. Results: Cognitive function could be scored in 97.1% of the assessed individuals. The scale had a negligible floor effect, it had items with a large spread in difficulties, it appeared linear, and it distributed the assessed individuals equally over the scale. Internal consistency (Cronbach’s alpha) was 0.967, and an exploratory factor analysis revealed three factors of the scale – interpreted to represent orientation to time, to place, and to person. Conclusion: Gottfries’ cognitive scale is a feasible tool for grading cognitive function among nursing home residents using staff proxy ratings. The scale has excellent psychometric properties with a very high internal consistency, a favorable distribution of item difficulties producing an almost rectangular distribution of scores, and a negligible floor effect. The scale thus can be recommended for use in survey-based investigations in nursing home contexts. Show more

Keywords: Assessment, cognitive function, cognitive impairment, dementia, measurement, nursing home, scale, survey

DOI: 10.3233/JAD-190599

Citation: Journal of Alzheimer's Disease, vol. 72, no. 4, pp. 1251-1260, 2019

Authors: Choo, IL Han | Chong, Ari | Chung, Ji Yeon | Kim, Hoowon

Article Type: Research Article

Abstract: Background: Subjective memory complaints (SMC) are a risk factor for Alzheimer’s disease. Objective: We aimed to explore the association between SMC and regional amyloid-β (Aβ) deposition in mild cognitive impairment (MCI). Methods: Sixty-eight individuals with MCI were recruited. [18 F]Florbetaben PET scans were performed. T1-weighted 3D volumes were also acquired for co-registration with PET and for defining the regions of interest (ROI). Two step exploratory partial correlation analyses between SMC and Aβ deposition were performed with covariates of age, sex, education, and depression. Furthermore, for the priori ROI that had the most significant partial correlation, we …investigated the correlation between the SMC and regional Aβ burden using a multiple linear regression model controlling for depression, age, sex, and education. Results: Significant positive correlations between the SMC and Aβ burden was found in the medial temporal ROI (first step) and in the left parahippocampus ROI (second step). In the priori left parahippocampus, we found significant correlation between the SMC and Aβ burden (R2  = 0.473, p  = 0.014). Conclusions: Our study suggested that the SMC was associated with amyloid accumulation, especially in the left parahippocampus, in individuals with MCI. Show more

Keywords: Amyloid burden, mild cognitive impairment, subjective memory complaints

DOI: 10.3233/JAD-190816

Citation: Journal of Alzheimer's Disease, vol. 72, no. 4, pp. 1261-1268, 2019

Authors: Ording, Anne G. | Veres, Katalin | Horváth-Puhó, Erzsébet | Glymour, M. Maria | Rørth, Mikael | Henderson, Victor W. | Sørensen, Henrik T.

Article Type: Research Article

Abstract:  Observational studies have shown inverse associations between neurological diseases, particularly dementia, and subsequent cancer risk, but is unknown whether this association is valid or arises from bias. We conducted a Danish nationwide cohort study using population-based health registries (1980–2012). The study included patients with dementia (n  = 173,434) and with Parkinson’s disease (n  = 28,835). We followed patients for 10 years to assess subsequent cancer diagnoses. We computed absolute reduction in cancer risk attributable to dementia or Parkinson’s disease (expected minus the observed number of cancer cases divided by the person time) and standardized incidence rate ratios (SIRs) as the observed to …expected number of cancers, based on sex-, age-, and calendar year-standardized national incidence rates. During 10 years, the reduction in cancer cases were 79.9 per 10,000 person-years for Alzheimer’s disease [SIR = 0.68 (95% CI: 0.66, 0.70)], 74.4 per 10,000 person-years for vascular dementia [SIR = 0.71 (95% CI: 0.67, 0.74)], 55.8 per 10,000 person-years [SIR = 0.77 (95% CI: 0.75, 0.78)] for all-cause dementia, and 4.0 per 10,000 person-years [SIR = 0.98 (95% CI: 0.95, 1.02) for Parkinson’s disease. Associations were nearly similar for solid tumors diagnosed at localized, regional, or distant stages. We found an inverse association between dementia and cancer risk, with similar associations when considering only cancers diagnosed at distant stage. The cancer risk varied by type of dementia, with a gradient toward a stronger protective effect associated with Alzheimer’s disease and vascular dementia, which may favor a biological explanation. Overall results do not show an inverse association between Parkinson’s disease and cancer. Show more

Keywords: Alzheimer’s disease, dementia, epidemiology, neoplasms, Parkinson’s disease, risk

DOI: 10.3233/JAD-190867

Citation: Journal of Alzheimer's Disease, vol. 72, no. 4, pp. 1269-1277, 2019

Authors: Ułamek-Kozioł, Marzena | Czuczwar, Stanisław J. | Kocki, Janusz | Januszewski, Sławomir | Bogucki, Jacek | Bogucka-Kocka, Anna | Pluta, Ryszard

Article Type: Research Article

Abstract:  There is currently no knowledge about the expression profile of the autophagy (BECN1 ), mitophagy (BNIP3 ), and apoptosis (CASP3 ) genes in the CA3 region of the hippocampus after cerebral ischemia. In addition, it is unknown whether genes for BECN1 , BNIP3 , and CASP3 have any effect on the neuronal death in the CA3 area of the hippocampus due to ischemia. In this study, for the first time, we present, by means of a quantitative PCR protocol with reverse transcriptase, the expression of BECN1 and CASP3 genes in the neuronal CA3 region of the hippocampus …with the co-expression of the mitochondrial BNIP3 gene, which genes are associated with Alzheimer’s disease, in the ischemic model of Alzheimer’s disease in the rat. The present study showed that after ischemia, the CASP3 gene was significantly expressed within 7–30 days, the BECN1 gene was significantly overexpressed on the thirtieth day, and the BINP3 gene was lowered below control values during post-ischemic follow-up period. The caspase-dependent neuronal death in the CA3 region of the hippocampus after ischemia is not accompanied by overexpression of the BNIP3 gene. Our data may therefore suggest a new insight into the BNIP3 gene in the regulation of neuronal mitophagy in neurodegeneration in the CA3 region of the hippocampus after ischemia. This indicates no involvement of the BNIP3 gene along with the CASP3 gene in the CA3 region of the hippocampus in delayed neuronal death after brain ischemia. Show more

Keywords: Alzheimer’s disease, apoptosis, autophagy, brain ischemia, cardiac arrest, genes, mitophagy

DOI: 10.3233/JAD-190966

Citation: Journal of Alzheimer's Disease, vol. 72, no. 4, pp. 1279-1286, 2019

Authors: Valech, Natalia | Sánchez-Benavides, Gonzalo | Tort-Merino, Adrià | Coll-Padrós, Nina | Olives, Jaume | León, María | Falcon, Carles | Molinuevo, José Luis | Rami, Lorena

Article Type: Research Article

Abstract: Background: Exploring the relationship between Alzheimer’s disease (AD) biomarkers and subjective cognitive decline (SCD) is needed for better defining its clinical meaning in preclinical AD (preAD). Objective: To assess the association between the Subjective Cognitive Decline Questionnaire (SCD-Q), gray matter (GM), and cerebrospinal fluid amyloid-β (Aβ). Methods: 56 cognitively healthy older adults and their informants answered the SCD-Q. Correlations between GM and SCD-Q scores were explored using structural voxel-based morphometry models including Aβ levels. SCD-Q* Aβ vectors were calculated with higher scores reflecting higher SCD and cerebral amyloid, simultaneously. Subjects were classified according to their perception …of cognitive worsening in the last two years, exploring for GM differences between-groups. Results: Higher self-reported SCD-Q scores correlated with reduced GM in the right frontal lobe and increased volumes in the occipital lobe, calcarine sulcus, fusiform gyrus, and cerebellum, while higher informant’s scores correlated with increased GM in the right middle temporal gyrus. Correlations were more significant for SCD-Q language items, self-complaints, and more positive than negative correlations were found. The SCD-Q* Aβ vectors were negatively associated with GM both in self and informant’s reports. Finally, lower Aβ levels related to lower GM in subjects who noticed cognitive worsening, but related to higher GM in subjects who have not noticed this decline. Conclusions: Our results suggest that SCD-Q scores relate with incipient brain changes that may be due to preAD. Independent studies are needed to confirm our observations. Show more

Keywords: Amyloid-β, gray matter, preclinical Alzheimer’s disease, subjective cognitive decline, subjective cognitive decline-questionnaire

DOI: 10.3233/JAD-190624

Citation: Journal of Alzheimer's Disease, vol. 72, no. 4, pp. 1287-1302, 2019

Authors: Douglass, Amanda | Walterfang, Mark | Velakoulis, Dennis | Abel, Larry

Article Type: Research Article

Abstract: Background: Changes to visual search have shown specific patterns in a number of dementia subtypes. The cortical regions involved in the control of visual search overlap with the regions affected in behavioral variant frontotemporal dementia (bvFTD). Previous literature has examined visual search in bvFTD with smaller array sizes. Objective: To examine the pattern of behavior shown by bvFTD patients while undertaking visual search in the presence of larger numbers of distractors to model increased cognitive load. Methods: 15 bvFTD and 17 control participants undertook three visual search tasks: color, orientation, and conjunction searches. A wide range …of array sizes was used, from 16 to 100 items arranged as a square. Behavior was quantified using accuracy, response time, and eye movements. Results: BvFTD participants displayed a reduction in accuracy and an increased response time across all task types. BvFTD participants displayed an increase in number of objects examined and number of fixations made for color and conjunction tasks. Fixation duration was increased for orientation and conjunction (the more difficult tasks) but not color search. Results indicated the increase in time to response to be due to an increased intercept, with no significant difference in slope for the different tasks. Conclusion: BvFTD participants display a pattern of visual search behavior consisting of a decrease in accuracy, an increase in response time, and a corresponding increase in the number and length of eye movements made during visual search. The pattern seen corresponds to studies of frontal lobe damage, while differing in pattern from that seen in a range of other cognitive conditions. Show more

Keywords: Eye movements, frontotemporal dementia, search, visual scan-paths

DOI: 10.3233/JAD-190981

Citation: Journal of Alzheimer's Disease, vol. 72, no. 4, pp. 1303-1312, 2019

Authors: Jia, Jianping | Ji, Yong | Feng, Tao | Ye, Qinyong | Peng, Dantao | Kuang, Weihong | Ning, Yuping | Liang, Zhihou | Fan, Dongsheng | Wei, Wenshi | Li, Yansheng | Xiao, Shifu

Article Type: Research Article

Abstract: Background: Rivastigmine is a cholinesterase inhibitor, approved for the treatment of mild-to-moderate dementia of Alzheimer’s type. Objective: To explore the efficacy and safety of the maximal tolerated dose of rivastigmine capsules in Chinese patients with mild-to-moderate Alzheimer’s disease (AD). Methods: The study was a multicenter, open-label, single-arm, phase IV clinical study in mild-to-moderate drug-naïve AD patients treated with rivastigmine capsules. The primary endpoint was the changes in the total scores of Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS-Cog) from baseline to week 16. Secondary endpoints included changes in the scores of the following assessment scales and safety: …Alzheimer’s Disease Cooperative Study; Activities of Daily Living; Mini-Mental Status Examination (MMSE); Neuropsychiatry Index (NPI), and Caregiver Burden Inventory. Results: 222 patients were enrolled. Of these, 136 (75.1%) patients received and maintained the effective dose (≥6 mg/d) of rivastigmine for at least 4 weeks. The ADAS-Cog scale score improved in rivastigmine-treated patients at week 16 compared with baseline (p  < 0.001) by 2.0 (95% CI: –3.0 to –1.1) points, which met the pre-defined superiority criteria. NPI-10 and NPI-12 scores improved by 3.6 and 4.0 points at week 16 (p  = 0.001, p  < 0.001), respectively. A total of 107 patients (59.1%) experienced adverse effects (AEs) during the study; common AEs included nausea (20.5%), vomiting (16.6%), anorexia (7.8%), dizziness (7.7%), and diarrhea (7.2%). Conclusion: This was the first phase IV study on rivastigmine in mainland China. The study preliminarily demonstrated that rivastigmine capsules showed good tolerability and efficacy in mild-to-moderate AD patients with the maximal tolerated dose. Show more

Keywords: Alzheimer’s disease, capsule, Chinese population, rivastigmine

DOI: 10.3233/JAD-190791

Citation: Journal of Alzheimer's Disease, vol. 72, no. 4, pp. 1313-1322, 2019

Authors: Ali, Farhan | Baringer, Stephanie L. | Neal, Arianna | Choi, Esther Y. | Kwan, Alex C.

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) has several hallmark features including amyloid-β (Aβ) plaque deposits and neuronal loss. Here, we characterized Aβ plaque aggregation and parvalbumin-positive (PV) GABAergic neurons in 6–9-month-old 5xFAD mice harboring mutations associated with familial AD. We used immunofluorescence staining to compare three regions in the frontal cortex—prelimbic (PrL), cingulate (Cg, including Cg1 and Cg2), and secondary motor (M2) cortices—along with primary somatosensory (S1) cortex. We quantified the density of Aβ plaques, which showed significant laminar and regional vulnerability. There were more plaques of larger sizes in deep layers compared to superficial layers. Total plaque burden was higher in frontal …regions compared to S1. We also found layer- and region-specific differences across genotype in the density of PV interneurons. PV neuron density was lower in 5xFAD mice than wild-type, particularly in deep layers of frontal regions, with Cg (–50%) and M2 (–39%) exhibiting the largest reduction. Using in vivo two-photon imaging, we longitudinally visualized the loss of frontal cortical PV neurons across four weeks in the AD mouse model. Overall, these results provide information about Aβ deposits and PV neuron density in a widely used mouse model for AD, implicating deep layers of frontal cortical regions as being especially vulnerable. Show more

Keywords: 5xFAD, amyloid-β , cingulate cortex, familial Alzheimer’s disease, frontal cortex, parvalbumin-positive neurons, plaques, secondary motor cortex

DOI: 10.3233/JAD-181190

Citation: Journal of Alzheimer's Disease, vol. 72, no. 4, pp. 1323-1339, 2019

Authors: Liechti, Caroline | Caviezel, Marco P. | Müller, Stephan | Reichert, Carolin F. | Calabrese, Pasquale | Linnemann, Christoph | Melcher, Tobias | Leyhe, Thomas

Article Type: Research Article

Abstract: The hippocampus plays an indispensable role in episodic memory, particularly during the consolidation process. However, its precise role in retrieval of episodic memory is still ambiguous. In this study, we investigated the correlation of hippocampal morphometry and the performance in an autobiographical memory task in 27 healthy controls and 24 patients suffering from Alzheimer’s disease (AD). Most importantly, correlations were defined separately and comparatively for memory contents with different retrieval frequency in the past. In healthy subjects, memory performance for seldom retrieved autobiographical events was significantly associated with gray matter density in the bilateral hippocampus, whereas this correlation was not …present for events with high retrieval frequency. This pattern of findings confirms that retrieval frequency plays a critical role in the consolidation of episodic autobiographical memories, thereby making them more independent of the hippocampal system. In AD patients, on the other hand, successful memory retrieval appeared to be related to hippocampal morphometry irrespective of the contents’ retrieval frequency, comprising events with high retrieval frequency, too. The observed differences between patients and control subjects suggest that AD-related neurodegeneration not only impairs the function, but also decreases the functional specialization of the hippocampal memory system, which, thus, may be considered as marker for AD. Show more

Keywords: Alzheimer’s disease, autobiographical memory, cognitive impairment, episodic memory, gray matter, hippocampus, historic events, magnetic resonance imaging, medial temporal lobe, voxel-based morphometry

DOI: 10.3233/JAD-190047

Citation: Journal of Alzheimer's Disease, vol. 72, no. 4, pp. 1341-1352, 2019

Authors: Wang, Shao-Yang | Chen, Wei | Xu, Wei | Li, Jie-Qiong | Hou, Xiao-He | Ou, Ya-Nan | Yu, Jin-Tai | Tan, Lan

Article Type: Research Article

Abstract: Background: Neurofilament light chain (NFL) as a potential biomarker of neurodegenerative diseases has been studied in a number of studies. Thus, a comprehensive meta-analysis is warranted to assess NFL performance in neurodegenerative diseases. Objective: To assess the performance of NFL in blood and cerebrospinal fluid (CSF) as a biomarker for neurodegenerative diseases. Methods: A total of 36 studies with comparison of NFL level between individuals with neurodegenerative diseases and controls were retrieved from PubMed, Web of Science and Science Direct, and the ratio of means method and delta method based on the random-effect model were used …to analyze the differentiation of NFL between patients and controls. Results: Differentiation of CSF NFL between patients with neurodegenerative diseases and controls showed significant results. Although a few studies on blood NFL available were included in the meta-analysis, the results still showed a distinct possibility that NFL could be a potential biomarker for neurodegenerative diseases. NFL levels were increased significantly in dementias, amyotrophic lateral sclerosis, Creutzfeldt-Jakob disease, and Huntington’s disease. By contrast, NFL levels were not increased in Parkinson’s disease (PD), although they were increased significantly in PD-related disorders (multiple system atrophy and progressive supranuclear palsy). Conclusions: In our study, in addition to PD, NFL was suggested to be a global diagnostic biomarker for neurodegenerative diseases. Moreover, it could be used in differential diagnosis of PD and PD-related disorders. However, it was worth noting that NFL was not appropriate for diagnosis or differential diagnosis without clinical symptoms and other auxiliary examinations. Show more

Keywords: Biomarkers, blood, cerebrospinal fluid, meta-analysis, neurodegenerative diseases, neurofilament light chain

DOI: 10.3233/JAD-190615

Citation: Journal of Alzheimer's Disease, vol. 72, no. 4, pp. 1353-1361, 2019

Authors: Lennon, Jack C.

Article Type: Book Review

Abstract: This review of Dementia Reimagined: Building a Life of Joy and Dignity from Beginning to End by Dr. Tia Powell describes its unique, scientifically-informed approach to the topics of caring for family members with dementia within the confines of the current United States healthcare system and preparing for their long-term care. Her book serves to provide an important account of many difficulties confronted along the course of dementia, ultimately seeking compassionate, dignified care for a loved one during the many years following diagnosis that allow for the experiencing of life’s joys that are unique to each individual. This book …is tailored to a broad readership, providing information for all individuals caring for people with dementia, and maintains a candid voice as it relates to our pursuit of curative treatments for an incurable illness. This review raises further questions related to how autonomy and beneficence can be amplified when interdisciplinary conflicts arise, as well as how education reform may improve patient care. Show more

Keywords: Aging, Alzheimer’s disease, dementia, ethics, healthcare

DOI: 10.3233/JAD-190611

Citation: Journal of Alzheimer's Disease, vol. 72, no. 4, pp. 1363-1365, 2019

Article Type: Other

DOI: 10.3233/JAD-199011

Citation: Journal of Alzheimer's Disease, vol. 72, no. 4, pp. 1367-1379, 2019