Journal of Alzheimer's Disease - Volume Pre-press, issue Pre-press

Authors: Clark, Lindsay R. | Norton, Derek | Berman, Sarah E. | Johnson, Sterling C. | Bendlin, Barbara B. | Wieben, Oliver | Turski, Patrick | Carlsson, Cynthia | Asthana, Sanjay | Gleason, Carey E. | Johnson, Heather M.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) has a higher prevalence among African Americans. Targeting cardiovascular and metabolic risk factors may be potential mechanisms to modify AD risk and address racial/ethnic disparities in AD dementia. Objective: This study investigated relationships among cardiovascular and metabolic risk factors, APOE genotype, AD biomarkers, and intracranial arterial blood flow in Whites and African Americans enriched for AD risk. Methods: 399 cognitively unimpaired adults from the Wisconsin Alzheimer’s Disease Research Center completed physical and neuroimaging examinations. A 4D Flow MRI sequence (phase-contrast vastly under sampled isotropic projection imaging) measured intracranial arterial flow in …the Circle of Willis. Linear mixed-effects regression models estimated relationships between risk factors and intracranial arterial flow and tested interactions with racial group, APOE genotype, and AD biomarkers, with separate models per risk factor. Results: Higher fasting glucose was associated with lower intracranial arterial flow; no additional relationships between flow and risk factors were observed. Main effects of racial group were observed, without an interaction, indicating lower flow in African Americans compared to Whites. In race-stratified analyses, higher glucose and triglycerides were associated with lower flow for African Americans, but not for Whites. No main effects or interactions among risk factors, APOE , or AD biomarkers, and flow were observed. Conclusion: Elevated fasting glucose and triglycerides were associated with lower intracranial arterial flow; these relationships were more prominent in African Americans. Targeting metabolic risk factors may impact intracranial arterial health. Additional research is needed to determine if this will impact disparities in dementia prevalence. Show more

Keywords: African Americans, aging, Alzheimer’s disease, Apolipoprotein E4, cerebrovascular circulation, glucose, metabolic syndrome, neuroimaging, risk factors

DOI: 10.3233/JAD-190645

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2019

Article Type: Correction

DOI: 10.3233/JAD-199010

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-1, 2019

Authors: Fuchsberger, Tanja | Yuste, Raquel | Martinez-Bellver, Sergio | Blanco-Gandia, Mari-Carmen | Torres-Cuevas, Isabel | Blasco-Serra, Arantxa | Arango, Román | Miñarro, Jose | Rodríguez-Arias, Marta | Teruel-Marti, Vicent | Lloret, Ana | Viña, Jose

Article Type: Research Article

Abstract: Glutamate excitotoxicity has long been related to Alzheimer’s disease (AD) pathophysiology, and it has been shown to affect the major AD-related hallmarks, amyloid-β peptide (Aβ) accumulation and tau phosphorylation (p-tau). We investigated whether oral administration of monosodium glutamate (MSG) has effects in a murine model of AD, the double transgenic mice APP/PS1. We found that AD pathogenic factors appear earlier in APP/PS1 when supplemented with MSG, while wildtype mice were essentially not affected. Aβ and p-tau levels were increased in the hippocampus in young APP/PS1 animals upon MSG administration. This was correlated with increased Cdk5-p25 levels. Furthermore, in these mice, …we observed a decrease in the AMPA receptor subunit GluA1 and they had impaired long-term potentiation. The Hebb-Williams maze revealed that they had memory deficits. We show here for the first time that oral MSG supplementation can accelerate AD-like pathophysiology in a mouse model of AD. Show more

Keywords: Alzheimer’s disease, amyloid-β, glutamate excitotoxicity, long-term potentiation, memory, p-tau

DOI: 10.3233/JAD-190274

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-19, 2019

Authors: Schelter, Bjoern O. | Shiells, Helen | Baddeley, Thomas C. | Rubino, Christopher M. | Ganesan, Harish | Hammel, Jeffrey | Vuksanovic, Vesna | Staff, Roger T. | Murray, Alison D. | Bracoud, Luc | Riedel, Gernot | Gauthier, Serge | Jia, Jianping | Bentham, Peter | Kook, Karin | Storey, John M.D. | Harrington, Charles R. | Wischik, Claude M.

Article Type: Research Article

Abstract: Background: Although hydromethylthionine is a potent tau aggregation inhibitor, no difference was found in either of two Phase III trials in mild to moderate Alzheimer’s disease (AD) comparing doses in the range 150–250 mg/day with 8 mg/day intended as a control. Objective: To determine how drug exposure is related to treatment response. Methods: A sensitive plasma assay for the drug was used in a population pharmacokinetic analysis of samples from 1,162 of the 1,686 patients who participated in either of the Phase III trials with available samples and efficacy outcome data. Results: There are steep concentration-response …relationships for steady state plasma levels in the range 0.3–0.8 ng/ml at the 8 mg/day dose. Using a threshold based on the lower limit of quantitation of the assay on Day 1, there are highly significant differences in cognitive decline and brain atrophy in patients with above threshold plasma levels, both for monotherapy and add-on therapy, but with effect sizes reduced by half as add-on. Plasma concentrations in the range 4–21 ng/ml produced by the high doses are not associated with any additional benefit. Conclusions: Hydromethylthionine has pharmacological activity on brain structure and function at the 8 mg/day dose as monotherapy or as add-on to symptomatic treatments. This combined with a plateau at higher doses is consistent with the lack of dose-response seen in the Phase III trials. Treatment benefit is predicted to be maximal at 16 mg/day as monotherapy. A placebo-controlled trial in mild/moderate AD is now ongoing to confirm efficacy at this dose. Show more

Keywords: Acetylcholinesterase inhibitor, Alzheimer’s disease, clinical trials, drug interaction, leucomethylthioninium, population pharmacokinetics

DOI: 10.3233/JAD-190772

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2019

Article Type: Correction

DOI: 10.3233/JAD-199009

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-1, 2019

Authors: Ji, Yangfei | Wang, Dan | Zhang, Boai | Lu, Hong

Article Type: Research Article

Abstract: Background: Parkinson’s disease (PD) is the second most prevalent progressive neurodegenerative disease with motor disorders and cognitive impairment. Bergenin (Berg), extracted from the herb of Saxifrage stolonifera Curt. (Hu-Er-Cao), has anti-tumor, anti-inflammation, anti-oxidative stress, and neuroprotective properties. Objective: In this study, we wanted to investigate the effects of Berg on PD and the underlying mechanisms. Methods: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was used to introduce PD symptoms in mice. The expression levels of tyrosine hydroxylase, dopamine, and Iba-1 were examined. The levels of a series of inflammatory mediators were measured by qPCR. In addition, the PI3K/Akt signaling pathway …was investigated to illustrate the underlying mechanism. In vitro , PC12 cells subjected to lipopolysaccharide (LPS) were treated with Berg. Results: We found that MPTP injection introduced motor deficits, apoptosis of neurons and inflammation, as well as inhibited the PI3K/Akt signaling pathway. However, Berg treatment suppressed the MPTP-induced alterations. In vitro , Berg attenuated the cytotoxic effects on PC12 cells induced by the culture supernatants derived from LPS-induced microglial cells. Conclusion: Berg attenuated the PD symptoms via activating the PI3K/Akt signaling pathway in vivo and in vitro . Show more

Keywords: Bergenin, 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP), Parkinson’s disease, PI3K/Akt signaling pathway

DOI: 10.3233/JAD-190870

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2019

Authors: Geier, David A. | Kern, Janet K. | Homme, Kristin G. | Geier, Mark R.

Article Type: Research Article

Abstract:  Cognitive health is an emerging public health concern for the aging American population. Mercury (Hg) is a toxic element that can cause nervous system damage. This hypothesis-testing study evaluated the relationship between blood ethyl-Hg levels and cognitive decline in an older adult and elderly American population. A total of 1,821,663 weighted-persons between 60–80 years old with detectable blood ethyl-Hg levels within the 2011–2012 National Health and Nutritional Survey were examined. Those persons with blood ethyl-Hg levels greater than the median were deemed the higher ethyl-Hg exposure group and those with ethyl-Hg levels less than the median were deemed the lower …ethyl-Hg exposure group. Three tests were utilized to measure cognitive function: 1) Consortium to Establish a Registry for Alzheimer’s Disease – Word List Learning (CERAD W-L) delayed recall test, 2) animal fluency test, and 3) Digit Symbol Substitution Test. Each cognitive test score was categorized as higher for those with scores greater than the median and lower for those with scores less than the median. Survey logistic regression modeling with covariates was used to analyze the data for the relationship between blood ethyl-Hg levels and cognitive function scores. Significantly increased risks for lower animal fluency test (odds ratio (OR) = 13.652, p  = 0.0029) and CERAD W-L delayed recall test (OR = 6.401, p  = 0.0433) scores were observed among the higher ethyl-Hg exposure group as compared to the lower ethyl-Hg exposure group. This study supports the hypothesis that increased ethyl-Hg exposure is associated with significant cognitive decline in older adult and elderly Americans. Show more

Keywords: Ethylmercury, merthiolate, methylmercury, thiomersal

DOI: 10.3233/JAD-190894

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2019

Authors: Chen, Bing | Zheng, Weiming

Article Type: Research Article

Abstract: Upregulation of Rho-associated protein kinase 2 (ROCK2) hallmarks the progression of neurodegenerative diseases. However, the molecular mechanisms underlying the regulation of ROCK2 expression are not clear and thus addressed in the current study. We generated a subacute model of Parkinson’s disease in mice with a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) method. The MPTP model was validated by impaired rotational behavior of the mice upon apomorphine exposure, astrocytic activation, and reduction in tyrosine-hydroxylase-positive neurons in the mouse striatum. Moreover, MPTP induced increases in ROCK2 protein but not in ROCK2 mRNA. Further analysis showed that MPTP inhibited the expression of microRNA-291 (miR-291), which suppressed ROCK2 …mRNA via 3’-UTR-binding in neuronal cells to increase ROCK2 protein. Intracranial injection of miR-291 four days before MPTP alleviated the impaired rotational behavior of the mice upon apomorphine exposure, MPTP-induced astrocytic activation, and the reduction in tyrosine-hydroxylase-positive neurons in the mouse striatum. Together, these data suggest that miR-291 has a protective role in neurodegeneration, likely through regulation of ROCK2. Show more

Keywords: MicroRNA-291, neurodegenerative disease, ROCK2

DOI: 10.3233/JAD-190832

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2019

Authors: Richards, Emma | Bayer, Antony | Hanley, Claire | Norris, Jade E. | Tree, Jeremy | Tales, Andrea

Article Type: Research Article

Abstract: Slowed behavioral reaction time is associated with pathological brain changes, including white matter lesions, the common clinical characteristic of subcortical ischemic vascular cognitive impairment (SIVCI). In the present study, reaction time (RT) employing Trails B of the Trail Making Test, with responses capped at 300 s, was investigated in SIVCI (n  = 27) compared to cognitively healthy aging (CH) (n  = 26). RT was significantly slowed in SIVCI compared to CH (Cohen’s d effect size = 1.26). Furthermore, failure to complete Trails B within 300 s was also a characteristic of SIVCI although some ostensibly cognitively healthy older adults also failed to complete within this time …limit. Within the SIVCI group, RT did not differ significantly with respect to whether the patients were classified as having moderate/severe or mild, periventricular white matter changes visible on their diagnostic CT/MRI scans. This, together with the high degree of overlap in RT between the two SIVCI subgroups, raises the possibility that using visible ratings scales in isolation may lead to the underestimation of disease level. Show more

Keywords: Methodology, reaction time, subcortical ischemic vascular cognitive impairment, Trail Making Test

DOI: 10.3233/JAD-190823

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2019

Authors: Boccardi, Virginia | Paolacci, Lucia | Remondini, Daniel | Giampieri, Enrico | Poli, Giulia | Curti, Nico | Cecchetti, Roberta | Villa, Alfredo | Ruggiero, Carmelinda | Brancorsini, Stefano | Mecocci, Patrizia

Article Type: Research Article

Abstract: Background: Elevated peripheral levels of different cytokines and chemokines in subjects with Alzheimer’s disease (AD), as compared with healthy controls (HC), have emphasized the role of inflammation in such a disease. Considering the cross-talking between the central nervous system and the periphery, the inflammatory analytes may provide utility as biomarkers to identify AD at earlier stages. Objective: Using an advanced statistical approach, we can discriminate the interactive network of cytokines/chemokines and propose a useful tool to follow the progression and evolution of AD, also in light of sex differences. Methods: A cohort of 289 old-age subjects …was screened for cytokine and chemokine profiling, measured in plasma, after a thorough clinical and neuropsychological evaluation. A custom algorithm based on Fisher linear discriminant analysis was applied to ascertain a classification signature able to discriminate HC from mild cognitive impairment (MCI) and AD. Results: We observed that a joint expression of three proteins (a “signature” composed by IFN-α 2, IL-1α , TNFα ) can discriminate HC from AD with an accuracy of 65.24%. Using this signature on MCI samples, 84.93% of them were classified as “non-HC”. Stratifying MCI samples by sex, we observed that 87.23% of women were classified as “non-HC”, and only 57.69% of males. Indeed, in a scatter plot of IFN-α 2 and IL-1α , the HC group was better separated from MCI and AD in women as compared with men. Conclusion: These findings suggest that AD is accompanied by a peripheral inflammatory response that can already be present in MCI subjects, thus providing a mean for detecting this at-risk status and allow an anticipated intervention. Show more

Keywords: Cytokines, dementia, inflammation, markers, sex

DOI: 10.3233/JAD-190480

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2019

Authors: Yokokawa, Kazuki | Iwahara, Naotoshi | Hisahara, Shin | Emoto, Miho C. | Saito, Taro | Suzuki, Hiromi | Manabe, Tatsuo | Matsumura, Akihiro | Matsushita, Takashi | Suzuki, Syuuichirou | Kawamata, Jun | Sato-Akaba, Hideo | Fujii, Hirotada G. | Shimohama, Shun

Article Type: Research Article

Abstract: Mesenchymal stem cells (MSC) are increasingly being studied as a source of cell therapy for neurodegenerative diseases, and several groups have reported their beneficial effects on Alzheimer’s disease (AD). In this study using AD model mice (APdE9), we found that transplantation of MSC via the tail vein improved spatial memory in the Morris water maze test. Using electron paramagnetic resonance imaging to evaluate the in vivo redox state of the brain, we found that MSC transplantation suppressed oxidative stress in AD model mice. To elucidate how MSC treatment ameliorates oxidative stress, we focused on amyloid-β (Aβ) pathology and microglial …function. MSC transplantation reduced Aβ deposition in the cortex and hippocampus. Transplantation of MSC also decreased Iba1-positive area in the cortex and reduced activated ameboid shaped microglia. On the other hand, MSC transplantation accelerated accumulation of microglia around Aβ deposits and prompted microglial Aβ uptake and clearance as shown by higher frequency of Aβ-containing microglia. MSC transplantation also increased CD14-positive microglia in vivo , which play a critical role in Aβ uptake. To confirm the effects of MSC on microglia, we co-cultured the mouse microglial cell line MG6 with MSC. Co-culture with MSC enhanced Aβ uptake by MG6 cells accompanied by upregulation of CD14 expression. Additionally, co-culture of MG6 cells with MSC induced microglial phenotype switching from M1 to M2 and suppressed production of proinflammatory cytokines. These data indicate that MSC treatment has the potential to ameliorate oxidative stress through modification of microglial functions, thereby improving Aβ pathology in AD model mice. Show more

Keywords: Alzheimer’s disease, CD14, electron paramagnetic resonance imaging, mesenchymal stem cells, microglia, oxidative stress

DOI: 10.3233/JAD-190817

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-18, 2019

Authors: Bermejo-Guerrero, Laura | Sánchez-Tejerina, Daniel | Sánchez-Tornero, Mario | Sánchez-Sánchez, María del Carmen | Gómez-Grande, Adolfo | Villarejo-Galende, Alberto | Martín, Alejandro Octavio Herrero-San | González-Sánchez, Marta

Article Type: Short Communication

Abstract: Hereditary cerebral amyloid angiopathies (CAA) are rare disorders of early onset and severe course. We describe a 47-year-old patient with Iowa-type amyloid precursor protein (APP ) mutation-related hereditary CAA that manifested with concomitant lobar hemorrhage and venous sinus thrombosis. To analyze the cerebral amyloid-β burden, an amyloid-PET was performed, demonstrating low cortical retention except for the calcarine cortex. High amyloid retention was also found in the thalamus and pallidum. The co-occurrence of CAA and venous thrombosis has not been previously reported in Iowa CAA and its mechanism is yet to be elucidated. Low cortical florbetapir-PET uptake does not rule out …CAA in young patients, who may benefit from genetic testing to reach diagnosis when suspicion is strong. Show more

Keywords: Amyloid PET, cerebral amyloid angiopathy, cerebral hemorrhage, cerebral venous thrombosis, Iowa APP mutation

DOI: 10.3233/JAD-190800

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-5, 2019

Authors: Pathak, Gita A. | Silzer, Talisa K. | Sun, Jie | Zhou, Zhengyang | Daniel, Ann A. | Johnson, Leigh | O’Bryant, Sid | Phillips, Nicole R. | Barber, Robert C.

Article Type: Research Article

Abstract: The Mexican American population is among the fastest growing aging population and has a younger onset of cognitive decline. This group is also heavily burdened with metabolic conditions such as hypertension, diabetes, and obesity. Unfortunately, limited research has been conducted in this group. Understanding methylation alterations, which are influenced by both genetic and lifestyle factors, is key to identifying and addressing the root cause for mild cognitive impairment, a clinical precursor for dementia. We conducted an epigenome-wide association study on a community-based Mexican American population using the Illumina EPIC array. Following rigorous quality control measures, we identified 10 CpG sites …to be differentially methylated between normal controls and individuals with mild cognitive impairment annotated to PKIB, KLHL29, SEPT9, OR2C3, CPLX3, BCL2L2-PABPN1 , and CCNY . We found four regions to be differentially methylated in TMEM232, SLC17A8, ALOX12 , and SEPT8 . Functional gene-set analysis identified four gene-sets, RIN3, SPEG, CTSG , and UBE2L3 , as significant. The gene ontology and pathway analyses point to neuronal cell death, metabolic dysfunction, and inflammatory processes. We found 1,450 processes to be enriched using empirical Bayes gene-set enrichment. In conclusion, the functional overlap of differentially methylated genes associated with cognitive impairment in Mexican Americans implies cross-talk between metabolically-instigated systemic inflammation and disruption of synaptic vesicular transport. Show more

Keywords: Alzheimer’s disease, cognitive dysfunction, epigenetics, Mexican Americans, SEPT8 protein

DOI: 10.3233/JAD-190634

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2019

Authors: Matías-Guiu, Jordi A. | Gómez-Pinedo, Ulises | Forero, Lucía | Pytel, Vanesa | Cano, Fátima | Moreno-Ramos, Teresa | Cabrera-Martín, María Nieves | Matías-Guiu, Jorge | González-Rosa, Javier J.

Article Type: Research Article

Abstract: Background: Primary progressive aphasia (PPA) is a heterogeneous syndrome that is difficult to diagnose at early stages. Plasma neurofilament light chain (NFL) has been proposed as a potential biomarker for PPA. Objective: To examine the diagnostic properties of plasma NFL in PPA and to evaluate its association with clinical stages of the disease and brain metabolism. Methods: Our study included 80 participants (13 with non-fluent, 12 with semantic, and 16 with logopenic variant PPA; 13 with amnestic Alzheimer’s disease [AD]; 13 with behavioral variant frontotemporal dementia; and 13 healthy controls). Plasma NFL concentration was measured using …a high-sensitivity enzyme-linked immunosorbent assay (ELISA) kit. PET imaging was performed in a subgroup of patients. Results: NFL discriminated patients from controls with an area under the curve of 0.914 (95% CI, 0.843–0.984; p  <  0.001) (cut-off: 76.46 pg/mL; 94% sensitivity, 76.9% specificity). There were no significant differences between clinical syndromes (PPA subtypes), the main clinical forms of dementia (frontotemporal dementia and AD), or the expected pathological groups (frontotemporal lobar degeneration-tau [FTLD-tau], FTLD-TDP43, and AD). NFL levels showed weak to moderate correlations with age and functional scale score. We found no significant correlation with the extent of hypometabolism observed on FDG-PET images. Conclusion: Plasma NFL is a non-specific marker of neurodegeneration, and may be helpful in the diagnosis of PPA. However, NFL does not permit differential diagnosis between PPA subtypes and is not correlated with the extent of neurodegeneration. Show more

Keywords: Alzheimer’s disease, biomarkers, frontotemporal dementia, neurofilament, positron emission tomography, primary progressive aphasia

DOI: 10.3233/JAD-190838

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2019

Authors: Poptsi, Eleni | Tsardoulias, Emmanouil | Moraitou, Despina | Symeonidis, Andreas L. | Tsolaki, Magda

Article Type: Research Article

Abstract: Background: Subjective cognitive decline (SCD) and mild cognitive impairment (MCI) are acknowledged stages of the clinical spectrum of Alzheimer’s disease (AD), and cognitive control seems to be among the first neuropsychological predictors of cognitive decline. Existing tests are usually affected by educational level, linguistic abilities, cultural differences, and social status, constituting them error-prone when differentiating between the aforementioned stages. Creating robust neuropsychological tests is therefore prominent. Objective: The design of a novel psychometric battery for the cognitive control and attention assessment, free of demographic effects, capable to discriminate cognitively healthy aging, SCD, MCI, and mild Dementia (mD). …Methods: The battery initial hypothesis was tuned using iterations of administration on random sampling healthy older adults and people with SCD, MCI, and mD, from the area of Thessaloniki, Greece. This resulted in the first release of the REflexes MEasurement DEviceS for Alzheimer battery (REMEDES for Alzheimer-R4Alz). Results: The first release lasts for almost an hour. The battery was design to assess working memory (WM) including WM storage, processing, and updating, enriched by episodic buffer recruitment. It was also designed to assess attention control abilities comprising selective, sustained, and divided attention subtasks. Finally, it comprises an inhibitory control, a task/rule switching or set-shifting, and a cognitive flexibility subtask as a combination of inhibition and task/rule switching abilities. Conclusion: The R4Alz battery is an easy to use psychometric battery with increasing difficulty levels and assumingly ecological validity, being entertaining for older adults, potentially free of demographic effects, and promising as a more accurate and early diagnosis tool of neurodegeneration. Show more

Keywords: Attentional control, cognitive control, dementia, healthy aging, mild cognitive impairment, psychometric assessment, subjective cognitive decline

DOI: 10.3233/JAD-190798

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-19, 2019

Authors: Franchini, Flaminia | Musicco, Massimo | Ratto, Federica | Storti, Gabriele | Shofany, Jacob | Caltagirone, Carlo | Di Santo, Simona Gabriella

Article Type: Research Article

Abstract: Background: Alzheimer’s disease is the principal cause of dementia and is determined, in at least one third cases, by modifiable risk factors (MRF). The “Lifestyle for Brain Health (LIBRA)” index was recently developed to quantify the individual risk of progression to dementia ascribable to MRF. Objective: The aim of this study was to investigate the association between LIBRA scores and markers of cognitive performance, functional independence, and psycho-behavioral symptoms in a community-based sample of Italian elders. Methods: 308 senior participants with mild cognitive impairment (MCI) or subjective cognitive decline (SCD) were evaluated with a complete neuropsychological …battery and semi-structured interviews for the assessment of depression, apathy, and functional autonomy. All the 12 LIBRA MRF were available for the calculation of LIBRA scores. A modified version of the index (LIBRA-2) was calculated by removing depression weight from the LIBRA index. Partial correlation analyses, controlling for age and education, assessed the association between LIBRA indices and cognitive, functional, and behavioral outcomes. Separate analyses were repeated in the MCI and SCD subgroups. Results: In participants with SCD (SCDp), significant correlations existed between LIBRA and markers of impairment in global cognition, visuo-spatial attention, and semantic fluency. LIBRA-2 associated with psycho-behavioral symptoms in the whole sample and in SCDp. LIBRA-2 only associated with apathy in the MCI subgroup. Conclusions: The LIBRA index might be useful to determine the lifestyle-attributable risk of cognitive and psycho-behavioral decline in Italian seniors at risk, while in those with overt cognitive impairment, these outcomes are presumably mainly associated with non-modifiable factors. Show more

Keywords: Alzheimer’s disease, apathy, depression, LIBRA Index, modifiable risk factors, mild cognitive impairment, neuropsychological tests, subjective cognitive decline

DOI: 10.3233/JAD-190495

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2019

Authors: Wan, Yu | Liang, Yingxia | Liang, Feng | Shen, Nolan | Shinozuka, Kenneth | Yu, Jin-Tai | Ran, Chongzhao | Quan, Qimin | Tanzi, Rudolph E. | Zhang, Can

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is a devastating neurodegenerative disease with no cure currently available. A pathological hallmark of AD is accumulation and deposition of amyloid-β protein (Aβ), a ∼4 kDa peptide generated through serial cleavage of the amyloid-β protein precursor (AβPP) by β- and γ -secretases. Curcumin is a natural compound primarily found in the widely used culinary spice, turmeric, which displays therapeutic potential for AD. Recently, we reported the development of curcumin analogs and identified a lead compound, curcumin-like compound-R17 (CLC-R17), that significantly attenuates Aβ deposition in an AD transgenic mouse model. Here, we elucidated the mechanisms of this analog …on Aβ levels and AβPP processing using cell models of AD. Using biochemical methods and our recently developed nanoplasmonic fiber tip probe technology, we showed that the lead compound potently lowers Aβ levels in conditioned media and reduces oligomeric amyloid levels in the cells. Furthermore, like curcumin, the lead compound attenuates the maturation of AβPP in the secretory pathway. Interestingly, it upregulated α -secretase processing of AβPP and inhibited β-secretase processing of AβPP by decreasing BACE1 protein levels. Collectively, our data reveal mechanisms of a promising curcumin analog in reducing Aβ levels, which strongly support its development as a potential therapeutic for AD. Show more

Keywords: Alzheimer’s disease, amyloid-β , amyloid-β protein precursor, autophagy, curcumin, curcumin analog, oligomerization

DOI: 10.3233/JAD-190562

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2019

Authors: Giudice, Maria Lo | Mihalik, Balázs | Turi, Zsófia | Dinnyés, András | Kobolák, Julianna

Article Type: Research Article

Abstract: Despite numerous efforts and studies over the last three decades, Alzheimer’s disease (AD) remains a disorder not fully understood and incurable so far. Development of induced pluripotential stem cell (iPSC) technology to obtain terminally differentiated neurons from adult somatic cells revolutionized the study of AD, providing a powerful tool for modelling the disease and for screening candidate drugs. Indeed, iPSC reprogramming allowed generation of neurons from both sporadic and familial AD patients with the promise to recapitulate the early pathological mechanisms in vitro and to identify novel targets. Interestingly, NPS 2143, a negative allosteric modulator of the calcium sensing …receptor, has been indicated as a possible therapeutic for AD. In the present study, we assessed the potential of our iPSC-based familial AD cellular model as a platform for drug testing. We found that iPSC-derived neurons respond to treatment with γ -secretase inhibitor, modifying the physiological amyloid-β protein precursor (AβPP) processing and amyloid-β (Aβ) secretion. Moreover, we demonstrated the expression of calcium sensing receptor (CaSR) protein in human neurons derived from healthy and familial AD subjects. Finally, we showed that calcilytic NPS 2143 induced a changing of Aβ and sAβPPα secreted into conditioned media and modulation of CaSR and PSEN1 expression at the plasma membrane of AD neurons. Overall, our findings suggest that NPS 2143 affects important AD processes in a relevant in vitro system of familial AD. Show more

Keywords: Alzheimer’s disease, amyloid, calcium-sensing receptor, calcilytic, induced pluripotential stem cell-derived neurons, sAβPPα

DOI: 10.3233/JAD-190602

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2019

Authors: Trumbore, Conrad N. | Paik, Jennie | Fay, David | Vachet, Richard W.

Article Type: Research Article

Abstract:  Amyloid-β (Aβ) solution injections into an aqueous mobile phase moving through narrow bore stainless-steel capillary tubing results in adsorption of at least 99% Aβ within the tubing or injection valve. However, if flow is stopped for a period of 5–10 minutes, then started, wall desorption yields Aβ-containing molecules in the new effluent. The amount of desorbed Aβ-containing effluent depends on flow rate, period of flow cessation, and number of successive Aβ injections into the same tube without cleaning between injections. Unexpected multiple chromatographic peaks in these experiments seem to imply “separation” of released, previously adsorbed Aβ-containing products in the empty …capillary tubing. These preliminary experiments raise questions about possible errors in Alzheimer’s disease (AD) spinal tap analyses, which use stainless-steel needles of approximately the same inner diameter and encounter similar flow rates as those in our capillary experiments. Microliter syringes and HPLC connectors also contain stainless-steel tubing that have similar inner diameter dimensions and similar flow rates. The capillary system involved in these experiments has previously been proposed as a model system for studying the effects of shear on Aβ within the brain because it offers a research environment that provides highly restrictive flow through very small dimension channels. A suggestion is made for the use of this system in exploratory anti-amyloid drug studies in which both the drug and Aβ are injected in the same solution so that both drug and Aβ are subjected to the same shear environment. Reduction in adsorbed Aβ is suggested as an indicator of effective anti-Aβ drugs. Show more

Keywords: Amyloid aggregation, amyloid-β, cerebrospinal fluid, chromatography, glymphatic pathway, HPLC, interstitial fluid, shear energy

DOI: 10.3233/JAD-190522

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2019

Authors: Wong, Matthew Wai Kin | Braidy, Nady | Crawford, John | Pickford, Russell | Song, Fei | Mather, Karen A. | Attia, John | Brodaty, Henry | Sachdev, Perminder | Poljak, Anne

Article Type: Research Article

Abstract:  Apolipoprotein E (APOE ) genotype is an established genetic risk factor for sporadic Alzheimer’s disease (AD) but the extent to which APOE genotype influences the plasma lipidome is unknown, even though lipids are potential diagnostic or prognostic biomarkers for AD. We quantified plasma lipids using untargeted liquid chromatography coupled mass spectrometry in a total of 152 non-demented participants aged 65–100 years carrying at least one ɛ 2 or ɛ 4 allele (ɛ 2/ɛ 2 or ɛ 2/ɛ 3, n  = 38: ɛ 4/ɛ 3 or ɛ 4/ɛ 4, n  = 38), who were roughly matched to an ɛ 3/ɛ 3 control …by age, sex, and lipid-lowering medication (n  = 76). Low density lipoprotein cholesterol levels were genotype dependent (ɛ 4/ɛ 4> ɛ 4/ɛ 3> ɛ 3/ɛ 3> ɛ 2/ɛ 3> ɛ 2/ɛ 2). The greatest variation in lipids was related to the ɛ 2 isoform, where various lysophosphatidylcholines and all phosphatidylethanolamine (PE) subclasses were elevated relative to ɛ 3/ɛ 3 and ɛ 4 carriers. APOE ɛ 4 carriers had reduced phosphatidylinositol relative to ɛ 3/ɛ 3 and ɛ 2 carriers. Logistic regression revealed that ɛ 2 carriers were at least 4 times higher odds of being in the highest tertile of PE lipid level relative to ɛ 3/ɛ 3. The elevation in PE and other phospholipids in ɛ 2 carriers may indicate the protective effect of ɛ 2 is linked to these phospholipids. Additionally, high baseline PE in cognitively normal participants predicted protection against cognitive decline six years later. Our data suggest substantial modulation of plasma lipids by APOE genotype and therefore indicates possible lipid targets and pathomechanisms involved in AD risk. Show more

Keywords: Alzheimer’s disease, apolipoproteins, lipids, lipidomics, liquid chromatography-mass spectrometry, plasma

DOI: 10.3233/JAD-190524

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2019

Authors: Nakanishi, Miharu | Yamasaki, Syudo | Nishida, Atsushi | Richards, Marcus

Article Type: Research Article

Abstract: Background: There is growing interest in public health strategies to modify dementia risk in midlife to reduce the burden of cognitive impairment in subsequent decades. Risk reduction messages should include key recommendations for women in response to the high prevalence of dementia observed in this population. Midlife is a critical period for dementia-related brain changes and psychosocial crises. Psychological well-being can improve resilience to crises, yet it is not well understood with respect to dementia risk reduction. Objective: This study aimed to examine the association between midlife psychological well-being and cognitive function in later life in women. …Methods: The study included 703 women from the British 1946 birth cohort in the Medical Research Council’s National Survey of Health and Development. Psychological well-being at 52 years was assessed using the Ryff Scales of Psychological Well-being over six dimensions: autonomy, environmental mastery, personal growth, positive relations with others, purpose in life, and self-acceptance. Cognitive function at 69 years was measured using the Addenbrooke’s Cognitive Examination, Third Edition. Results: After controlling for cognitive ability at eight years, educational attainment by 26 years, occupational attainment and marital status by 53 years, depression, smoking, and physical exercise at 60–64 years, there was a significant association between greater personal growth and lower self-acceptance at 52 years, and better cognition at 69 years. However, there was no association between cognition and the other four Ryff scales. Conclusion: Most aspects of midlife psychological well-being, except for personal growth and self-acceptance, were not prospectively associated with cognition. Show more

Keywords: Cohort studies, dementia, psychological well-being, risk factors, women

DOI: 10.3233/JAD-190590

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2019

Authors: Kim, Hong-Bae | Park, Byoungjin | Shim, Jae-Yong

Article Type: Research Article

Abstract: Background: Prevalence of both anemia and cognitive impairment tends to increase with age. Individual studies have recently shown that anemia could be associated with cognitive impairment. Objective: To investigate the association between anemia and cognitive impairment including dementia. Methods: Two of the authors systematically searched PubMed, EMBASE, and the Cochrane library to retrieve observational studies reporting a relationship between anemia and cognitive impairment from 1964 to July 10, 2019. Case-control and cohort studies were included, and odds ratios (ORs) or relative risks (RRs) with 95% confidence intervals (CIs) for the risk of cognitive impairment were calculated …using a random-effects model. Results: In total, 16 observational studies including eight case-control studies and eight cohort studies were included in the final analysis. Anemia was significantly linked to cognitive impairment (OR or RR 1.51; 95% CI: 1.32–1.73) in a random-effects meta-analysis, albeit with medium heterogeneity (I2  = 47.8%). Meta-estimates of dementia from prospective population-based cohort studies were similar (RR 1.46; 95% CI: 1.22–1.76) without substantial heterogeneity (I2  = 23.2%). Conclusion: Our meta-analysis indicates that anemia is associated with cognitive impairment. Further prospective research is warranted to determine the cause-effect relationship of anemia with cognitive impairment and whether treatment of anemia might reduce the risk of dementia. Show more

Keywords: Anemia, cognitive impairment, dementia, meta-analysis, observational study, systematic review

DOI: 10.3233/JAD-190521

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2019

Authors: Pepperberg, David R.

Article Type: Research Article

Abstract: Cerebral hypoperfusion-induced hypoxia, a condition that impairs oxygen utilization and thus ATP production by mitochondrial oxidative phosphorylation (oxphos), is thought to contribute to neural degeneration in Alzheimer’s disease. However, hypoxia upregulates the generation of amyloid-β (Aβ), a group of peptides known to impair/inhibit the electron transport chain (ETC) of reactions that support oxphos in the inner mitochondrial membrane (IMM). This is a hypothesis paper that reconciles the hypoxia-induced upregulation of Aβ with Aβ’s ETC-inhibiting action and, specifically, posits an oxphos-enhancing effect of this inhibition under conditions of newly developing or otherwise mild hypoxia. This effect is typically transient; that is, …under conditions of prolonged or severe hypoxia, the oxphos-enhancing activity is overwhelmed by Aβ’s well-known toxic actions on mitochondria and other cellular components. The hypothesis is motivated by evidence that the IMM transmembrane potential Ψ m , an important determinant of ETC activity, exhibits heterogeneity, i.e., a range of values, among a given local population of mitochondria. It specifically proposes that during oxygen limitation, Aβ selectively inactivates ETC complexes in mitochondria that exhibit relatively low absolute values of Ψ m , thereby suppressing oxygen binding and consumption by complex IV of the ETC in these mitochondria. This effect of Aβ on low-Ψ m mitochondria is hypothesized to spare hypoxia-limited oxygen for oxphos-enabling utilization by the ETC of the remaining active, higher-Ψ m local mitochondria, and thereby to increase overall ATP generated collectively by the local mitochondrial population, i.e., to ameliorate hypoxia-induced oxphos reduction. The protective action of Aβ hypothesized here may slow the early development of hypoxia-associated cellular deterioration/loss in Alzheimer’s disease and perhaps other neurodegenerative diseases. Show more

Keywords: Alzheimer’s disease, amyloid-β, hypoxia, mitochondrial transmembrane potential, neurodegeneration, oxidative phosphorylation

DOI: 10.3233/JAD-190476

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2019

Authors: Nitzan, Keren | Benhamron, Sandrine | Valitsky, Michael | Kesner, Eyal | Lichtenstein, Michal | Ben-Zvi, Ayal | Ella, Ezra | Segalstein, Yehudit | Saada, Ann | Lorberboum-Galski, Haya | Rosenmann, Hanna

Article Type: Research Article

Abstract: Pathogenesis of neurodegenerative diseases involves dysfunction of mitochondria, one of the most important cell organelles in the brain, with its most prominent roles in producing energy and regulating cellular metabolism. Here we investigated the effect of transferring active intact mitochondria as a potential therapy for Alzheimer’s disease (AD), in order to correct as many mitochondrial functions as possible, rather than a mono-drug related therapy. For this purpose, AD-mice (amyloid-β intracerebroventricularly injected) were treated intravenously (IV) with fresh human isolated mitochondria. One to two weeks later, a significantly better cognitive performance was noticed in the mitochondria treated AD-mice relative to vehicle …treated AD-mice, approaching the performance of non-AD mice. We also detected a significant decrease in neuronal loss and reduced gliosis in the hippocampus of treated mice relative to untreated AD-mice. An amelioration of the mitochondrial dysfunction in brain was noticed by the increase of citrate-synthase and cytochrome c oxidase activities relative to untreated AD-mice, reaching activity levels of non-AD-mice. Increased mitochondrial activity was also detected in the liver of mitochondria treated mice. No treatment-related toxicity was noted. Thus, IV mitochondrial transfer may possibly offer a novel therapeutic approach for AD. Show more

Keywords: Alzheimer’s disease, amyloid-ICV model, cognition, mitochondria, mitochondrial-transfer

DOI: 10.3233/JAD-190853

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-18, 2019

Authors: Seblova, Dominika | Brayne, Carol | Machů, Vendula | Kuklová, Marie | Kopecek, Miloslav | Cermakova, Pavla

Article Type: Research Article

Abstract: Background: Studies from North America and Western Europe suggest stable or declining trends in impaired cognition across birth cohorts. Objective: We aimed to examine changes in the age-specific prevalence of cognitive impairment in the Czech Republic. Methods: The study used two samples from the population-based Czech Survey on Health, Ageing and Retirement in Europe. Age-specific prevalence of cognitive impairment (defined based on scores in verbal fluency, immediate recall, delayed recall, and temporal orientation) was compared between participants in wave 2 (2006/2007; n  = 1,107) and wave 6 (2015; n  = 3,104). Logistic regression was used to estimate the …association between the wave and cognitive impairment, step-wise adjusting for sociodemographic and clinical characteristics. Multiple sensitivity analyses, focusing on alternative operationalizations of relative cognitive impairment, impact of missing cognitive data, and survival bias, were carried out. Results: The most conservative estimate suggested that the age-specific prevalence of cognitive impairment declined by one fifth, from 11% in 2006/2007 to 9% in 2015. Decline was observed in all sensitivity analyses. The change was associated with differences in physical inactivity, management of high blood cholesterol, and increases in length education. Conclusion: Older adults in the Czech Republic, a country situated in the Central and Eastern European region, have achieved positive developments in cognitive aging. Longer education, better management of cardiovascular factors, and reduced physical inactivity seem to be of key importance. Show more

Keywords: Cognitive impairment, Czech Republic, epidemiology, prevalence, trends

DOI: 10.3233/JAD-190688

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2019

Authors: Castellani, Rudy J. | Smith, Margaret | Bailey, Kristi | Perry, George | deJong, Joyce L.

Article Type: Research Article

Abstract: Traumatic brain injury (TBI) is widely assumed to be causal in neurodegenerative disease, based on epidemiological surveys demonstrating an increased risk of Alzheimer disease (AD) following TBI, and on recent theories surrounding repetitive head movement. We tested this assumption by evaluating 30 consecutive forensic examinations in which neuropathology consultation was sought, and in which a history of remote TBI was uncovered during the course of the investigation. In this series, there was a high frequency of psychiatric co-morbidities (100%), remote contusion (90%), and seizures (63%). Extent of proteinopathy showed no differences with age-matched controls. A subset of the cases showed …focal geographic tauopathy that correlated with older age at autopsy, but had no correlation with clinical signs, and was minimal in comparison with the encephalomalacia secondary to trauma. The results suggest that cerebral contusion and post-traumatic epilepsy may be over-represented in civilian TBI, while structural brain damage from trauma is the predominant cause of morbidity following TBI. We found no evidence that TBI initiates a progressive proteinopathy. Show more

Keywords: Amyloid-β, contusion, epilepsy, neurodegenerative disease, phosphorylated tau, traumatic brain injury

DOI: 10.3233/JAD-190782

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2019

Authors: Elshatoury, Heba | Avots, Egils | Anbarjafari, Gholamreza | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: In this research work, machine learning techniques are used to classify magnetic resonance imaging brain scans of people with Alzheimer’s disease. This work deals with binary classification between Alzheimer’s disease and cognitively normal. Supervised learning algorithms were used to train classifiers in which the accuracies are being compared. The database used is from The Alzheimer’s Disease Neuroimaging Initiative (ADNI). Histogram is used for all slices of all images. Based on the highest performance, specific slices were selected for further examination. Majority voting and weighted voting is applied in which the accuracy is calculated and the best result is 69.5% for …majority voting. Show more

Keywords: Alzheimer’s disease, computer vision, feature extraction, individual grey matter, machine learning, magnetic resonance imaging

DOI: 10.3233/JAD-190704

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2019

Authors: Turriziani, Patrizia | Smirni, Daniela | Mangano, Giuseppa Renata | Zappalà, Giuseppe | Giustiniani, Andreina | Cipolotti, Lisa | Oliveri, Massimiliano

Article Type: Research Article

Abstract: Background: The lack of effective pharmacological or behavioral interventions for memory impairments associated with Alzheimer’s disease (AD) emphasizes the need for the investigation of approaches based on neuromodulation. Objective: This study examined the effects of inhibitory repetitive transcranial magnetic stimulation (rTMS) of prefrontal cortex on recognition memory in AD patients. Methods: In a first experiment, 24 mild AD patients received sham and real 1Hz rTMS over the left and right dorsolateral prefrontal cortex (DLPFC), in different sessions, between encoding and retrieval phases of a non-verbal recognition memory task. In a second experiment, another group of 14 …AD patients underwent sham controlled repeated sessions of 1Hz rTMS of the right DLPFC across a two week treatment. Non-verbal recognition memory task was performed at baseline, at the end of the two weeks period and at a follow up of 1 month. Results: Right real rTMS significantly improved memory performance compared to right sham rTMS (p  = 0.001). Left real rTMS left the memory performance unchanged as compared with left sham rTMS (p  = 0.46). The two sham conditions did not differ between each other (p  = 0.24). In the second experiment, AD patients treated with real rTMS showed an improvement of memory performance at the end of the two weeks treatment (p  = 0.0009), that persisted at 1-month follow-up (p  = 0.002). Conclusion: These findings provide evidence that inhibitory rTMS over the right DLPFC can improve recognition memory function in AD patients. They also suggest the importance of a new approach of non-invasive brain stimulation as a promising treatment in AD. Show more

Keywords: Alzheimer’s disease, prefrontal cortex, recognition memory, repetitive transcranial magnetic stimulation

DOI: 10.3233/JAD-190888

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2019

Authors: D’Cunha, Nathan M. | McKune, Andrew J. | Isbel, Stephen | Kellett, Jane | Georgousopoulou, Ekavi N. | Naumovski, Nenad

Article Type: Research Article

Abstract: The use of existing public spaces by people living with dementia, such as museums and art galleries, are becoming popular due to their ability to facilitate programs which promote social engagement and inclusion. However, few studies have investigated physiological outcomes of art gallery-based programs. Using a quasi-experimental design, the present study aimed to investigate the levels of salivary biomarkers of cortisol and interleukin-6, quality of life (QoL), depressive symptoms, cognition, and wellbeing, after attending the National Gallery of Australia (NGA) Art and Dementia program. Twenty-eight people living with dementia, each supported by a carer or family member, were recruited for …a six-week program and were followed up at twelve weeks. In total, 25 participants (17 female; mean age 84.6±7.27 years) completed the study, and 22 provided viable saliva samples. The waking to evening salivary cortisol ratio was higher post-intervention (p  = 0.033), and returned to baseline levels at follow-up (p  = 1.00), indicating a more dynamic salivary cortisol rhythm in response to the six-week program. Interleukin-6 levels remained unchanged (p  = 0.664). No improvements in QoL (DEMQOL-Carer) were observed between baseline and post-intervention (p  = 0.076). However, self-reported depressive symptoms decreased post-intervention compared with baseline (p  = 0.015), and memory (immediate recall) (p  = 0.009) and verbal fluency (p  = 0.027) improved between the same timepoints. The NGA Art and Dementia program appears to have quantifiable benefits, including improved hypothalamic-pituitary-adrenal axis function, justifying a need for longer controlled trial inclusive of physiological outcomes. Show more

Keywords: Alzheimer’s disease, art, cognitive function, cortisol, dementia, psychophysiology, quality of life

DOI: 10.3233/JAD-190784

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2019

Authors: Orgeta, Vasiliki | Tuijt, Remco | Leung, Phuong | Verdaguer, Elisabet Sole | Gould, Rebecca L. | Jones, Rebecca | Livingston, Gill

Article Type: Research Article

Abstract: Engaging in meaningful and enjoyable activities is an important contributor to well-being and maintaining good quality of life. There is a paucity of randomized controlled trials of interventions supporting people with mild dementia to engage in meaningful and purposeful activity. The aim of this study was to assess whether Behavioral Activation (BA) is an acceptable psychological intervention for people with mild dementia and whether a large-scale trial is feasible. Participants were randomly assigned to BA (n  = 42) or treatment as usual (TAU) (n  = 21). BA aimed at increasing engagement in enjoyable and meaningful activity, and preventing low mood. Follow-up was …at 3 and 6 months. Assessors were blind to treatment allocation (trial registration number: ISRCTN75503960). Retention rate was above 80% at both assessment time points. Treatment acceptability and credibility were high. Depressive symptoms remained unchanged in both groups. There was evidence of improvement associated with BA for every day function (–3.92, 95% Confidence Interval (CI) –6.87 to –0.97), and engagement in meaningful and enjoyable activity (5.08, 95% CI 0.99 to 9.16) post-treatment (3 months) in comparison to TAU. Both carer-rated patient health-related quality of life (0.16, 95% CI 0.04 to 0.28) and physical health (11.31, 95% CI 2.03 to 20.59) showed evidence of improvement at 3 months. Improvements in meaningful and enjoyable activity were maintained at 6 months. BA for people with mild dementia is feasible and acceptable and may be associated with clinically significant changes in function and quality of life. A full scale randomized controlled trial of clinical effectiveness is now needed. Show more

Keywords: Acceptability, activity scheduling, behavioral activation, behavioral therapy, dementia, feasibility, low mood, pleasant events, randomized controlled trial

DOI: 10.3233/JAD-190696

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2019

Authors: van Husen, Lea S. | Schedin-Weiss, Sophia | Trung, Minh Nguyen | Kazmi, Manija A. | Winblad, Bengt | Sakmar, Thomas P. | Elsässer, Simon J. | Tjernberg, Lars O.

Article Type: Research Article

Abstract: The amyloid-β protein precursor (AβPP) is critical in the pathophysiology of Alzheimer’s disease (AD), since two-step proteolytic processing of AβPP generates the neurotoxic amyloid-β peptide (Aβ). We developed a dual fluorescence labeling system to study the exact subcellular location of γ -secretase cleavage of AβPP. The C-terminal tail of AβPP was fluorescently labeled using a SNAP-tag, while the Aβ region of AβPP was fluorescently tagged with a dye at a genetically-encoded noncanonical amino acid (ncAA). The ncAA was introduced at specific positions in AβPP using a genetic code expansion strategy and afterwards, the reactive side-chain of the ncAA was coupled …to the dye using a bioorthogonal labeling chemistry. In proof-of-concept experiments, HEK293T cells were transfected with plasmids containing engineered AβPP harboring an amber mutation and an amber codon suppression system with an evolved tRNA synthetase/tRNA pair and grown in the presence of a lysine-derived ncAA. Processing of the AβPP variants was validated with ELISA and immunoblotting, and seven AβPP mutants that showed similar cleavage pattern as wild-type AβPP were identified. The AβPP mutant was fluorescently labeled with 6-methyl-tetrazine-BDP-FL and TMR-Star at the ncAA and SNAP-tag, respectively. Using this approach, AβPP was fluorescently labeled at two sites in living cells with minimal background to allow monitoring of Aβ and C-terminal cleavage products simultaneously. The method described provides a powerful tool to label Aβ with minimal perturbations of its processing, thus enabling studies of the trafficking of the cleavage products of AβPP. Show more

Keywords: Alzheimer’s disease, amber codon, amyloid-β precursor protein, cell biology, click chemistry, confocal microscopy, γ-secretase

DOI: 10.3233/JAD-190898

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2019

Authors: Aulston, Brent | Liu, Qing | Mante, Michael | Florio, Jazmin | Rissman, Robert A. | Yuan, Shauna H.

Article Type: Research Article

Abstract: Extracellular vesicles (EVs) are a heterogeneous group of secreted particles consisting of microvesicles, which are released by budding of the cellular membrane, and exosomes, which are secreted through exocytosis from multivesicular bodies. EV cargo consists of a wide range of proteins and nucleic acids that can be transferred between cells. Importantly, EVs may be pathogenically involved in neurodegenerative diseases such as Alzheimer’s disease (AD). While EVs derived from AD neurons have been found to be neurotoxic in vitro , little is known about the pathological consequences of AD EVs in vivo . Furthermore, although all known familial AD (fAD) mutations …involve either amyloid-β protein precursor (AβPP) or the machinery that processes AβPP, hyperphosphorylation of the microtubule associated protein tau appears to play a critical role in fAD-associated neurodegeneration, and previous reports suggest EVs may propagate tau pathology in the AD brain. Therefore, we hypothesized that fAD EVs may have a mechanistic involvement in the development of fAD-associated tau pathology. To test this, we isolated EVs from iPSC-derived neuronal cultures generated from an fAD patient harboring a A246E mutation to presenilin-1 and stereotactically injected these EVs into the hippocampi of wild-type C57BL/6 mice. Five weeks after injection, mice were euthanized and pathology evaluated. Mice injected with fAD EVs displayed increased tau phosphorylation at multiple sites relative to PBS and non-disease control EV injected groups. Moreover, fAD EV injected hippocampi contained significantly more tau inclusions in the CA1 hippocampal neuronal field than controls. In total, these findings identify EVs as a potential mediator of fAD-associated tau dysregulation and warrant future studies to investigate the therapeutic potential of EV-targeted treatments for fAD. Show more

Keywords: Alzheimer’s disease, C57BL/6, extracellular vesicles induced pluripotent stem cells, tau, tauopathy

DOI: 10.3233/JAD-190656

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2019

Authors: Vonk, Jet M.J. | Rentería, Miguel Arce | Medina, Valerie M. | Pericak-Vance, Margaret A. | Byrd, Goldie S. | Haines, Jonathan | Brickman, Adam M. | Manly, Jennifer J.

Article Type: Research Article

Abstract: Background: The APOE ɛ 4 allele is a well-known risk factor for Alzheimer’s disease (AD). Previous research argues that higher education helps to preserve cognition in older adults with AD pathology because of its key role in cognitive reserve and resilience. Objective: To test if higher educational level buffers the effect of APOE ɛ 4 on cognition among older non-Hispanic Blacks. Methods: Participants were 849 non-demented older non-Hispanic Blacks (38.3% APOE ɛ 4 +), who underwent a comprehensive neuropsychological evaluation. Multiple linear regression models tested the relationship between APOE ɛ …4 status and twelve cognitive measures with education (up to high school and beyond high school) as a moderator. Results: Education buffered the effects of the APOE ɛ 4 allele, such that there was no impact of APOE ɛ 4 status on word-list memory retention and working memory among participants with more than a high school degree. This pattern was not observed for ten other cognitive measures of verbal and visual episodic memory, semantic memory, executive function, and processing speed—although a similar trend was observed for switching ability in executive functioning. The buffering effect of education was stronger among women than men. Conclusion: Our findings suggest that genetic effects on late-life cognition may be modified by environmental factors such as educational attainment. These results are consistent with the framework of cognitive reserve such that engaging in cognitively enriching activities and acquiring skills and knowledge with more years of education may increase the capacity to maintain cognitive function despite high genetic risk for impairment. Show more

Keywords: African American, Alzheimer’s disease, APOE, cognitive reserve, educational attainment, episodic memory, genetic risk, neuropsychological evaluation

DOI: 10.3233/JAD-190415

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2019

Authors: Sugimoto, Taiki | Ono, Rei | Kimura, Ai | Saji, Naoki | Niida, Shumpei | Toba, Kenji | Sakurai, Takashi

Article Type: Research Article

Abstract: Background: Cognitive frailty (CF) is defined as simultaneous presence of physical frailty (PF) and cognitive impairment among older adults without dementia. Although white matter hyperintensities (WMH) as expressions of cerebral small vessel disease are associated with physical and cognitive decline and could manifest as CF, this association remains yet to be clarified. Objects: To clarify the association between CF and WMH among memory clinic patients. Methods: The subjects of this cross-sectional study were 121 cognitively normal (CN) and 212 mildly cognitively impaired (MCI) patients who presented to the Memory Clinic at the National Center for Geriatrics …and Gerontology of Japan. PF status was defined based on the definition proposed by Fried and colleagues. CF was defined as simultaneous presence of pre-PF or PF and MCI. WMH volumes were measured using an automatic segmentation application. Multiple liner regression analyses with adjustment for cardiovascular risk factors were performed. Results: Of all subjects, 77 (63.6%) and 22 (18.2%) CN patients and 132 (62.3%) and 65 (30.7%) MCI patients were categorized into pre-PF and PF, respectively. Multiple liner regression analysis showed that those with CF had higher WMH volumes than those without (β= 0.23). When categorized into six groups according to PF and cognitive status, the PF/CN (β= 0.15), pre-PF/MCI (β= 0.41), and PF/MCI (β= 0.34) groups had higher WMH volumes than the non-PF/CN group. Conclusions: This study showed increased WMH volumes in CF and PF, indicating that WMH could be one of the key underlying brain pathologies of CF. Show more

Keywords: Cognitive frailty, frailty syndrome, mild cognitive impairment, physical frailty, white matter hyperintensity

DOI: 10.3233/JAD-190622

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2019

Authors: Kehoe, Patrick G. | Al Mulhim, Noura | Zetterberg, Henrik | Blennow, Kaj | Miners, James S.

Article Type: Research Article

Abstract: Observations in autopsied brain tissue indicate that overactivation of the classical renin-angiotensin system (cRAS) and underactivity within regulatory RAS pathways (rRAS) are associated with pathology in Alzheimer’s disease (AD). The primary aim of this study was to investigate whether cerebrospinal fluid (CSF) markers of RAS are altered in AD in relation to established CSF markers of disease pathology (lower Aβ42 and elevated tau) and CSF markers of capillary dysfunction. We studied 40 controls and 40 AD cases grouped according to a biomarker profile (i.e., AD cases t-tau>400 pg/mL, pTau >60 pg/mL, and Aβ42 <550 pg/mL). Angiotensin-II converting enyme-1 …(ACE1) and ACE2 enzyme activity was measured using fluorogenic peptide substrates; sPDGFRβ and albumin level by sandwich ELISA and angiotensin-I (Ang-I), Ang-II, and Ang-(1-7) by direct ELISA. CSF Aβ42 , total, and phosphorylated tau levels were previously measured by INNOTEST sandwich ELISA. CSF ACE1 activity was significantly elevated in AD (p  = 0.008) and positively correlated with ACE2 in AD (r  = 0.420, p  = 0.007). CSF ACE1 weakly correlated with t-tau (r  = 0.294, p  = 0.066) and p-tau (r  = 0.329, p  = 0.038) but not with Aβ42 in the controls but not in AD. ACE1 correlated positively with sPDGFRβ (r  = 0.426, p  = 0.007), a marker of pericyte injury, and ACE2 correlated positively with albumin (r  = 0.422, p  = 0.008), a marker of blood-brain barrier integrity. CSF Ang-I, Ang-II, and Ang-(1-7) levels were unchanged in AD. This cross-sectional CSF study indicates RAS dysfunction in relation to capillary damage in AD. Show more

Keywords: Alzheimer’s disease, angiotensin-II, angiotensin-(1-7), angiotensin-II converting enyme-1 (ACE1), angiotensin-II converting enyme-2 (ACE2), cerebrospinal fluid, renin-angiotensin system

DOI: 10.3233/JAD-190721

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2019

Authors: Tian, Jing | Wang, Tienju | Wang, Qi | Guo, Lan | Du, Heng

Article Type: Research Article

Abstract: Hippocampal lesions including synaptic injury, neuroinflammation, and impaired neurogenesis are featured pathology closely associated with neuronal stress and cognitive impairment in Alzheimer’s disease (AD). Previous studies suggest that ghrelin and its receptor, growth hormone secretagogue receptor 1α (GHSR1α ), promote hippocampal synaptic function and neurogenesis. GHSR1α activation thus holds the potential to be a therapeutic avenue for the treatment of hippocampal pathology in AD; however, a comprehensive study on the preventive effect of MK0677 on hippocampal lesions in AD-related conditions is still lacking. In this study, we treated a transgenic mouse model of AD-like amyloidosis (5xFAD mice) at …the asymptomatic stage with MK0677, a potent ghrelin mimetic. We found that MK0677 fostered hippocampal neurogenesis in 5xFAD mice but observed little preventive function with regards to the development of hippocampal amyloid-β (Aβ) deposition, synaptic loss, microglial activation, or cognitive impairment. Furthermore, MK0677 at a dose of 3 mg/kg significantly increased 5xFAD mouse mortality. Despite enhanced hippocampal neurogenesis, MK0677 treatment has little beneficial effect to prevent hippocampal lesions or cognitive deficits against Aβ toxicity. This study, together with a failed large-scale clinical trial, suggests the ineffectiveness of MK0677 alone for AD prevention and treatment. Show more

Keywords: Alzheimer’s disease, amyloid-β, growth hormone secretagogue receptor 1α, hippocampus, MK0677

DOI: 10.3233/JAD-190779

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2019

Authors: Zhou, Guoyu | Zhao, Xinjing | Lou, Zhiyin | Zhou, Shengnian | Shan, Peiyan | Zheng, Ning | Yu, Xiaolin | Ma, Lin

Article Type: Research Article

Abstract: Background: Vasculature changes have been observed in Alzheimer’s disease (AD). AD-related vascular pathology might impair cerebral autoregulation (CA). Objective: This study was designed to evaluate CA of AD patients by using transcranial doppler (TCD). Methods: A total of 61 participants were included in the study, including 31 AD patients and 30 controls. The trend curves of cerebral blood flow velocities (CBFV), pulsatility index, and resistance index were obtained using TCD during supine-to-standing posture changes. CA was measured by the changes of CBFV curves during supine-to-standing test. Results: There were two spikes named X spike …and W spike that appeared in the CBFV curve when the subjects stood abruptly. The slope of the X spike descending branch, the slope of the W spike ascending branch, and the angle between X and W spikes (α angle), showed significant differences between the experimental and control groups (2.34±0.99 versus 3.15±1.61 cm/s2 , p  = 0.021; 2.31±0.81 versus 3.38±1.18 cm/s2 , p  < 0.001; and 52.71±20.26 versus 41.4±12.87 degrees, p  = 0.012, respectively). ROC analysis showed that AUCα angle is 0.664 (p  = 0.028) and that AUCSAB and AUCadjustedSAB are 0.775 and 0.738, respectively (both p  < 0.001). Conclusions: Our study demonstrated that supine-to-standing TCD test is a valuable tool for the evaluation of CA in AD patients. Impaired CA in AD patients manifested as decreased efficiency of changes in the CBFV curve. Neurovascular units were involved in the pathogenesis of AD. Show more

Keywords: Alzheimer’s disease, cerebral autoregulation, supine-to-standing test, transcranial Doppler

DOI: 10.3233/JAD-190296

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2019

Authors: Yoshida, Koji | Hata, Yukiko | Ichimata, Shojiro | Nishida, Naoki

Article Type: Research Article

Abstract: Background: Aggregation of abnormal phosphorylated tau in brain stem areas may be a possible early pathological manifestation of Alzheimer’s disease (AD). Objective: This study aimed to explore the prevalence of cases with AD-related pathology in subjects <40 years of age and to explore the association of such pathology, neuropsychiatric symptoms, and APOE genotype. Method: We conducted brain immunohistochemistry for 189 cases <40 years of age (mean±standard deviation age 25.3±13.1 years). Tau positive cases were then assessed for the distribution of tau pathology in the locus ceruleus (LC), raphe nucleus (RN), and entorhinal cortex (ErC), and …the distinction between neuronal threads and cellular inclusions. Apolipoprotein E (APOE ) genotype was also examined. Results: Tau pathology was detected in 135 cases (71.4%; 13–39 years; only LC, 23 cases; only RN, 4 cases; only ErC, 35 cases; LC+RN, 3 cases; LC+ErC, 57 cases; all three regions, 10 cases). The prevalence of thread pathology was higher than that of cellular inclusions. Significantly higher prevalence of the APOE ɛ 2 allele were found in 10–39 years of age natural death cases (p  < 0.05). Amyloid-β deposition was found in only 7 cases, along with a significantly high frequency of the ɛ 4 allele (p  < 0.05). While a past history of psychiatric disease was a significant risk factor for suicide, AD-related pathology was not associated with suicide. Conclusions: Both the brain stem and entorhinal cortex was the initial site of tau pathology in many younger subjects. AD-related pathology may not be a significant accelerating factor for suicide in younger subjects. Show more

Keywords: Alzheimer’s disease, amyloid-β, ApoE, neuropathology, suicide, tau

DOI: 10.3233/JAD-190196

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2019

Authors: Liu, Xi-Xi | Jiao, Bin | Liao, Xin-Xin | Guo, Li-Na | Yuan, Zhen-Hua | Wang, Xin | Xiao, Xue-Wen | Zhang, Xin-Yue | Tang, Bei-Sha | Shen, Lu

Article Type: Research Article

Abstract: Recent studies found that poor oral hygiene was associated with increased risk of dementia, and the number of oral bacteria significantly increased in the brain tissues of patients with Alzheimer’s disease (AD), suggesting that the oral microbiota may play an important role in the pathogenesis of AD. However, the actual composition of oral bacteria communities in patients with AD and whether these oral bacteria are associated with disease severity remain largely unknown. Also, the APOE ɛ 4 polymorphism is a strong risk factor for sporadic AD, and it would be pertinent to see if the bacterial flora was different …in those patients who were APOE ɛ 4 positive. A total of 78 subjects were recruited in this study, including 39 patients with AD and 39 healthy controls. Saliva was collected from each subject. 16S ribosomal RNA (16S rRNA) sequencing was conducted to analyze the salivary microbiota, and Sanger sequencing was performed to analyze the APOE genotype. There was a significantly lower richness and diversity of saliva microbiota detected in AD patients than healthy controls. The relative abundance of Moraxella , Leptotrichia , and Sphaerochaeta in the saliva of AD patients greatly increased, whereas that of Rothia was significantly reduced. Compared with APOE ɛ 4 (–) patients, the level of Abiotrophia and Desulfomicrobium was comparatively abundant, while Actinobacillus and Actinomyces decreased significantly in patients carrying the APOE ɛ 4. No bacteria were found to be associated with the severity of AD. This is the first study to analyze the salivary microorganisms in patients with AD, and we discovered that the composition of salivary microbiome was altered in AD, providing further support for the role of the oral microbiome in AD development. Show more

Keywords: Alzheimer’s disease, APOE , oral microbiome, 16S rRNA

DOI: 10.3233/JAD-190587

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2019

Authors: Rossini, Paolo Maria | Cappa, Stefano F. | Lattanzio, Fabrizia | Perani, Daniela | Spadin, Patrizia | Tagliavini, Fabrizio | Vanacore, Nicola

Article Type: Research Article

Abstract: Alzheimer’s disease is the most common age-related neurodegenerative disorder and its burden on patients, families, and society grows significantly with lifespan. Early modifications of risk-enhancing lifestyles and treatment initiation expand personal autonomy and reduce management costs. Many clinical trials with potentially disease-modifying drugs are devoted to mild cognitive impairment (MCI) prodromal-to-Alzheimer’s disease. The identification of biomarkers for early diagnosis may thus be crucial for early intervention and identification of high-risk subjects, the most appropriate target of new drugs as soon as they will be discovered. INTERCEPTOR is a strategic project by the Italian Ministry of Health and the Italian Medicines …Agency (AIFA), aiming to validate the best combination (highly accurate, non-invasive, available on the whole national territory and financially sustainable) of biomarkers and organizational model for early diagnosis. 500 MCI subjects will be enrolled at baseline and followed-up for 3 years for at least 400 of them in order to define a “hub & spoke” nationwide model with recruiting (spokes) centers for MCI identification and expert (hubs) centers for risk diagnosis. Show more

Keywords: Alzheimer’s disease, biomarkers, early diagnosis, healthcare organizational models, mild cognitive impairment, prodromal Alzheimer’s disease, public health

DOI: 10.3233/JAD-190670

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2019

Authors: Richards, Emma | Bayer, Antony | Tree, Jeremy | Hanley, Claire | Norris, Jade | Tales, Andrea

Article Type: Research Article

Abstract: In this study, reaction time (RT), intraindividual variability (IIV), and errors, and the effects of practice and processing load upon such function, were compared in patients with subcortical ischemic vascular cognitive impairment (SIVCI) [n  = 27] and cognitively healthy older adults (CH) [n  = 26]. Compared to CH aging, SIVCI was characterized by a profile of significantly slowed RT, raised IIV, and higher error levels, particularly in the presence of distracting stimuli, indicating that the integrity and/or accessibility of the additional functions required to support high processing load, serial search strategies, are reduced in SIVCI. Furthermore, although practice speeded RT in SIVCI, …unlike CH, practice did not lead to an improvement in IIV. This indicates that improvement in RT in SIVCI can in fact mask an abnormally high degree of IIV. Because IIV appears more related to disease, function, and health than RT, its status and potential for change may represent a particularly meaningful, and relevant, disease characteristic of SIVCI. Finally, a high level of within-group variation in the above measures was another characteristic of SIVCI, with such processing heterogeneity in patients with ostensibly the same diagnosis, possibly related to individual variation in pathological load. Detailed measurement of RT, IIV, errors, and practice effects therefore reveal a degree of functional impairment in brain processing not apparent by measuring RT in isolation. Show more

Keywords: Intra-individual variability, methodology, reaction time, subcortical ischemic vascular cognitive impairment

DOI: 10.3233/JAD-190889

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2019

Authors: Forbes, Harriet J. | Wong, Angel Y.S. | Morton, Caroline | Bhaskaran, Krishnan | Smeeth, Liam | Richards, Marcus | Schmidt, Sigrun A.J. | Langan, Sinéad M. | Warren-Gash, Charlotte

Article Type: Research Article

Abstract: Background: In the UK, an estimated one third of people with dementia have not received a diagnosis. Good evidence suggests that dementia risk is increased among widowed individuals; however, it is not clear if they are being diagnosed in routine primary care. Objective: This study aimed to investigate if bereavement influenced the probability of having received a dementia diagnosis. Methods: A population-based cohort study using UK electronic health records, between 1997 and 2017, among 247,586 opposite-sex partners. Those experiencing partner bereavement were matched (age, sex, and date of bereavement) to a non-bereaved person living in a …partnership. Multivariate cox regression was performed. Results: Partner bereavement was associated with an increased risk of receiving a diagnosis of dementia in the first three months (hazard ratio (HR) 1.43, 95% CI 1.20–1.71) and first six months (HR 1.24, 95% CI 1.09–1.41), while there was a small reduced risk of getting a dementia diagnosis over all follow-up (HR 0.94, 95% CI 0.89–0.98). Conclusions: Partner bereavement appears to lead to a short-term increased risk of the surviving partner receiving a diagnosis of dementia, suggesting that bereavement unmasks existing undiagnosed dementia. Over the longer term, however, bereaved individuals are less likely to have a diagnosis of dementia in their health records than non-bereaved individuals. Show more

Keywords: Bereavement, Clinical Practice Research Datalink, dementia, diagnosis, epidemiology

DOI: 10.3233/JAD-190571

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2019

Authors: Krolak-Salmon, Pierre | Maillet, Audrey | Vanacore, Nicola | Selbaek, Geir | Rejdak, Konrad | Traykov, Latchezar | Politis, Antonios | Georges, Jean | Borson, Soo | Leperre-Desplanques, Armelle

Article Type: Review Article

Abstract: Neurocognitive disorders causing progressive cognitive, functional, and behavioral impairment remain underdiagnosed. The needs for a timely diagnosis are now widely acknowledged since person-centered care helps to preserve life quality and prevent crises. One powerful barrier to detection in primary care is the lack of an easy-to-follow stepwise approach, grounded in evidence and consistent with high-quality specialty practice. To help fill this gap, the current European Joint Action proposes a graduated diagnosis strategy tailored to the patients’ needs and wills, clarifying appropriate components for primary and specialty care. This strategy considers a first evaluation in primary care that may detect a …neurocognitive disorder, that would lead to a second evaluation step allowing etiological diagnosis hypotheses performed mostly by the specialist. A third evaluation stage considering some biological, electrophysiological, or neuroimaging complementary techniques would be proposed to atypical cases or patients willing to consider access to research. Show more

Keywords: Alzheimer’s disease, detection, diagnosis, general practitioner, memory, neurocognitive disorder

DOI: 10.3233/JAD-190461

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2019

Authors: Goldstein, Felicia C. | Loring, David W. | Thomas, Tiffany | Saleh, Sabria | Hajjar, Ihab

Article Type: Research Article

Abstract: Background: The utility of recognition memory for identifying persons with biomarker evidence of Alzheimer’s disease (AD) is unclear since prior studies of mild cognitive impairment (MCI) relied only on clinical diagnosis and did not include simultaneous measures of central amyloidosis and tauopathy. Objective: We evaluated whether recognition memory and associated indices, including discriminability and response bias from signal detection theory, differentiate persons with amnestic MCI (aMCI) due to prodromal AD from non-prodromal AD. Method: Sixty older adults with aMCI were classified as prodromal AD (n  = 28) or non-prodromal AD (n  = 32) based upon cerebrospinal fluid levels …of amyloid-β and tau. Memory was assessed using the Hopkins Verbal Learning Test-Revised which includes free recall and recognition. Results: ANCOVAs adjusting for age indicated comparable (all p  > 0.05) performances between prodromal and non-prodromal MCI groups respectively on traditional HVLT-R recognition measures of hits (mean±SD: 9.5±3.0 versus 10.9±1.7), false alarms (1.8±1.8 versus 1.5±1.5), and hits minus false alarms (7.7±3.0 versus 9.2±2.6). In contrast, discriminability (d’), which reflects how easily targets and distractors are distinguished, was significantly (p  = 0.009) poorer in the prodromal versus non-prodromal groups (3.1±1.9 versus 4.8±2.0, effect size = 0.87). In addition, only d’ significantly predicted group membership (OR = 0.66, CI = 0.48–0.92, p  = 0.04). Response bias, the tendency to report that a target did or did not appear, was comparable between groups (0.08±1.1 versus –0.04±1.3). Conclusion: Recognition discriminability is significantly poorer in aMCI with biomarker evidence of prodromal AD. In contrast to traditional recognition indices, discriminability from signal detection theory may be superior in identifying aMCI due to AD versus non-AD etiologies. Show more

Keywords: Alzheimer’s disease, amyloid-β , amyloidosis, biomarkers, mild cognitive impairment, prodromal Alzheimer’s disease, recognition memory, signal detection, tau

DOI: 10.3233/JAD-190468

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2019

Authors: Nie, Ran | Wu, Zhou | Ni, Junjun | Zeng, Fan | Yu, Weixian | Zhang, Yufeng | Kadowaki, Tomoko | Kashiwazaki, Haruhiko | Teeling, Jessica L. | Zhou, Yanmin

Article Type: Research Article

Abstract: Abnormal accumulation of amyloid-β (Aβ) in the brain is the most significant pathological hallmark of Alzheimer’s disease (AD). We have found that chronic systemic exposure to lipopolysaccharide of Porphyromonas gingivalis (P. gingivalis ) induces the accumulation of Aβ in the brain of middle-aged mice. On the other hand, recent research has shown that circulating Aβ is transferred into the brain; however, the involvement of chronic systemic P. gingivalis infection in the peripheral Aβ metabolism is unknown. We hypothesized that chronic P. gingivalis infection expands Aβ pools in peripheral inflammatory tissues and thereby contributes to the accumulation of …Aβ in the brain of patients with periodontitis. We showed that the increased expression of IL-1β, AβPP770 , CatB, Aβ1-42 , and Aβ3-42 was mainly co-localized with macrophages in the liver of P. gingivalis infected mice. Blocking CatB and NF-κ B significantly inhibited the P. gingivalis- induced expression of IL-1β, AβPP770 , Aβ1-42 , and Aβ3-42 in RAW264.7 cells. Aβ3-42 , but not Aβ1-42 , induced the significant death of macrophages, and the reduction of phagocytic abilities induced by Aβ3-42 tended to be higher than that induced by Aβ1-42 . Additionally, the expression of AβPP770 , CatB, Aβ1-42 , and Aβ3-42 was determined in the macrophages of gingival tissues from periodontitis patients. These findings indicate that chronic systemic P. gingivalis infection induces the Aβ accumulation in inflammatory monocytes/macrophages via the activation of CatB/NF-κ B signaling, thus suggesting monocytes/macrophages serve as a circulating pool of Aβ in patients with periodontitis. Taken together, CatB may be a novel therapeutic target for preventing the periodontitis-related AD initiation and pathological progression. Show more

Keywords: Alzheimer’s disease, Cathepsin B, interleukin 1β, monocytes/macrophages, nuclear factor-kappa B, peripheral amyloid-β, Porphyromonas gingivalis infection, systemic inflammation

DOI: 10.3233/JAD-190298

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2019

Authors: Teipel, Stefan J. | Kuper-Smith, Jan O. | Bartels, Claudia | Brosseron, Frederic | Buchmann, Martina | Buerger, Katharina | Catak, Cihan | Janowitz, Daniel | Dechent, Peter | Dobisch, Laura | Ertl-Wagner, Birgit | Fließbach, Klaus | Haynes, John-Dylan | Heneka, Michael T. | Kilimann, Ingo | Laske, Christoph | Li, Siyao | Menne, Felix | Metzger, Coraline D. | Priller, Josef | Pross, Verena | Ramirez, Alfredo | Scheffler, Klaus | Schneider, Anja | Spottke, Annika | Spruth, Eike J. | Wagner, Michael | Wiltfang, Jens | Wolfsgruber, Steffen | Düzel, Emrah | Jessen, Frank | Dyrba, Martin | the DELCODE study group

Article Type: Research Article

Abstract: Diffusion changes as determined by diffusion tensor imaging are potential indicators of microstructural lesions in people with mild cognitive impairment (MCI), prodromal Alzheimer’s disease (AD), and AD dementia. Here we extended the scope of analysis toward subjective cognitive complaints as a pre-MCI at risk stage of AD. In a cohort of 271 participants of the prospective DELCODE study, including 93 healthy controls and 98 subjective cognitive decline (SCD), 45 MCI, and 35 AD dementia cases, we found reductions of fiber tract integrity in limbic and association fiber tracts in MCI and AD dementia compared with controls in a tract-based analysis …(p  < 0.05, family wise error corrected). In contrast, people with SCD showed spatially restricted white matter alterations only for the mode of anisotropy and only at an uncorrected level of significance. DTI parameters yielded a high cross-validated diagnostic accuracy of almost 80% for the clinical diagnosis of MCI and the discrimination of Aβ positive MCI cases from Aβ negative controls. In contrast, DTI parameters reached only random level accuracy for the discrimination between Aβ positive SCD and control cases from Aβ negative controls. These findings suggest that in prodromal stages of AD, such as in Aβ positive MCI, multicenter DTI with prospectively harmonized acquisition parameters yields diagnostic accuracy meeting the criteria for a useful biomarker. In contrast, automated tract-based analysis of DTI parameters is not useful for the identification of preclinical AD, including Aβ positive SCD and control cases. Show more

Keywords: amyloid, anisotropy, cerebral white matter, cognition, diagnosis, diffusion tensor imaging, mild cognitive impairment, subjective cognitive decline

DOI: 10.3233/JAD-190446

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2019

Authors: La Rosa, Francesca | Saresella, Marina | Marventano, Ivana | Piancone, Federica | Ripamonti, Enrico | Al-Daghri, Nasser | Bazzini, Chiara | Paola Zoia, Chiara | Conti, Elisa | Ferrarese, Carlo | Clerici, Mario

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is associated with the accumulation of amyloid-β (Aβ ) within senile plaques in the brain and neuroinflammation, possibly driven by the activation of the NLRP3 inflammasome. Nucleoside reverse transcriptase inhibitors (NRTI) hamper the NLRP3 inflammasome assembly. Objective: We utilized an in vitro model reproducing the Aβ -driven inflammation seen in AD to analyze whether stavudine (D4T), a prototypical NRTI, modulates Aβ -mediated inflammasome activation and the ability of macrophages to eliminate Aβ via phagocytosis and autophagy. Methods: THP-1-derived macrophages were stimulated in vitro with Aβ 42 …or with Aβ 42 after LPS-priming in the presence/absence of D4T. NLRP3 and TREM2 expression was analyzed by RT-PCR; phagocytosis, as well as ASC-Speck formation, was analyzed by Amnis FlowSight Imaging; NLRP3-produced cytokines were quantified by ELISA and, finally, autophagy was analyzed by measuring p-ERK1/2, p-AKT, beclin, p70-S6Kinase, and Lamp by ELISA and western blot. Results: IL-1β , IL-18, and caspase-1 were increased whereas Aβ phagocytosis and TREM2 were reduced in LPS+Aβ 42 -stimulated cells. D4T reduced NLRP3 assembly as well as IL-18 and caspase-1 production, but did not affect IL-1β production and TREM2 expression. Notably, whereas D4T reduced Aβ phagocytosis, Aβ autophagy by macrophages was stimulated by D4T, as witnessed by the down-modulation of ERK1/2 and AKT phosphorylation and the upregulation of beclin, LAMP, and p70-S6K, their downstream targets. Conclusion: In this in vitro model of AD, D4T reduces NLRP3 inflammasome-associated inflammation and stimulates Aβ autophagy by macrophages. It will be interesting to verify the possibly beneficial effects of D4T in the clinical scenario. Show more

Keywords: Alzheimer’s disease, amyloid-β phagocytosis, autophagy, cytokines, D4T, NLRP3-inflammasome, 0000-0003-3181-9505

DOI: 10.3233/JAD-181259

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2019

Authors: Chen, Guanqun | Yang, Kun | Du, Wenying | Hu, Xiaochen | Han, Ying

Article Type: Research Article

Abstract: Background: Subjective cognitive decline (SCD) refers to the self-perception of cognitive decline among cognitively normal elderly individuals. SCD related worry confers a higher risk of developing cognitive decline. However, the clinical characteristics of SCD patients with worry are not clear. Objective: To explore the clinical characteristics of SCD patients with worry. Methods: A cross-sectional study was carried out, with 270 consecutive participants of the Sino Longitudinal Study on Cognitive Decline (SILCODE) study. Participants were classified as normal controls (n  = 36), SCD patients without worry (n  = 91), or SCD patients with worry (n  = 143) and were comprehensively …compared on 1) their self-perception of cognitive decline, 2) multiple cognitive domains, 3) neuropsychiatric symptoms, and 4) sleep status. Results: SCD patients with worry had significantly more self-perception of cognitive decline (p  <  0.001); increased depression (p  <  0.001) and anxiety (p  <  0.001); decreased sleep quality (p  <  0.001), sleep latency (p  <  0.05), sleep time (p  <  0.01), and sleep efficiency (p  <  0.05); more sleep disorders (p  <  0.05) and daytime dysfunction (p  <  0.05); and a higher global score on the Pittsburgh Sleep Quality Index (p  <  0.001) than normal controls. Although there was a significant increase only in self-perception of cognitive decline (p  <  0.001), anxiety (p  <  0.001), and Pittsburgh Sleep Quality Index scores (p  <  0.05), the severity of the increase in those without worry was between that in SCD patients with worry and normal controls. Conclusion: Our findings show that participants who had SCD with worry showed distinct clinical characteristics compared with normal controls and SCD patients without worry, which could be useful for understanding the higher risk in SCD patients with worry of subsequently developing Alzheimer’s disease. Show more

Keywords: Alzheimer’s disease, clinical characteristic, neuropsychiatric symptoms, prevention trials, sleep disorders, subjective cognitive decline, subjective cognitive decline questionnaire

DOI: 10.3233/JAD-190501

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2019

Authors: Liu, Xiaoguang | Hebron, Michaeline L. | Mulki, Sanjana | Wang, Chen | Lekah, Elizabeth | Ferrante, Dalila | Shi, Wangke | Kurd-Misto, Bahjat | Moussa, Charbel

Article Type: Research Article

Abstract: Ubiquitin Specific Protease-13 (USP13) is a de-ubiquinating enzyme that regulates protein ubiquitination and clearance. The role of USP13 is largely unknown in neurodegeneration. In this study we aim to demonstrate whether tau accumulation and/or clearance depends on ubiquitination/de-ubiquitination via USP-13. We used transgenic animal models of human amyloid precursor protein (APP) or P301L tau mutations and genetically knocked-down USP13 expression via shRNA to determine USP13 effects on tau ubiquitination and levels. We found a two-fold increase of USP13 levels in postmortem Alzheimer’s disease (AD) brains. USP13 knockdown significantly increased the activity of the 20S proteasome and reduced the levels of …hyper-phosphorylated tau (p-tau) in primary cortical neurons. USP13 knockdown also reduced the levels of amyloid and increased p-tau ubiquitination and clearance in transgenic animal models that overexpress murine tau as a result of the expression of familial APP mutations (TgAPP) and the human mutant P301L tau (rTg4510), respectively. Clearance of p-tau appears to be mediated by autophagy in these animal models. Taken together, these data suggest that USP13 knockdown reduces p-tau accumulation via regulation of ubiquitination/de-ubiquitination and mediates its clearance via autophagy and/or the proteasome. These results suggest that USP13 inhibition may be a therapeutic strategy to reduce accumulation of plaques and toxic p-tau in AD and human tauopathies. Show more

Keywords: Alzheimer’s disease, amyloid, tau, ubiquitin, USP13

DOI: 10.3233/JAD-190635

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2019

Authors: Jiang, Juanjuan | Yan, Zhuangzhi | Sheng, Can | Wang, Min | Guan, Qinglan | Yu, Zhihua | Han, Ying | Jiang, Jiehui

Article Type: Research Article

Abstract: Background: Detecting subtle changes in visual attention from electroencephalography (EEG) and the perspective of eye movement in mild cognitive impairment (MCI) patients can be of great significance in screening early Alzheimer’s disease (AD) in a large population at primary care. Objective: We proposed an automatic, non-invasive, and quick MCI detection approach based on multimodal physiological signals for clinical decision-marking. Methods: The proposed model recruited 152 patients with MCI and 184 healthy elderly controls (HC) who underwent EEG and eye movement signal recording under a visual stimuli task, as well as other neuropsychological assessments. Forty features were …extracted from EEG and eye movement signals by linear and nonlinear analysis. The features related to MCI were selected by logistic regression analysis. To evaluate the efficacy of this MCI detection approach, we applied the same procedures to achieve the Clinical model, EEG model, Eye movement model, EEG+ Clinical model, Eye movement+ Clinical model, and Combined model, and compared the classification accuracy between the MCI and HC groups with the above six models. Results: After the penalization of logistic regression analysis, five features from EEG and eye movement features exhibited significant differences (p  <  0.05). In the classification experiment, the combined model resulted in the best accuracy. The average accuracy for the Clinical/EEG/Eye movement/EEG+ Clinical/Eye movement+ Clinical/Combined model was 68.69%, 61.79%, 73.13%, 69.46%, 75.61%, and 81.51%, respectively. Conclusion: These results suggest that the proposed MCI detection tool has the potential to screen MCI patients from HCs and may be a powerful tool for personalized precision MCI screening in the large-scale population under primary care condition. Show more

Keywords: Attention, electroencephalography, eye movement, mild cognitive impairment, multimodal detection, 2017LCSY345

DOI: 10.3233/JAD-190628

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2019