Journal of Alzheimer's Disease - Volume 63, issue 1

Authors: Galbiati, Andrea | Carli, Giulia | Hensley, Michael | Ferini-Strambi, Luigi

Article Type: Review Article

Abstract: Rapid eye movement (REM) sleep behavior disorder (RBD) is a REM sleep parasomnia characterized by the loss of the typical muscular atonia present during healthy REM sleep. RBD can occur in the absence of other neurological conditions or in association with a neurodegenerative disorder. It is now well established that RBD is a strong predictor of neurodegeneration, in particular synucleinopathies, such as Parkinson’s disease, Lewy body dementia (LBD), or multiple system atrophy. However, some longitudinal studies report that a minority of patients develop either overlapping form of dementia or Alzheimer disease’s (AD). Although AD is reported as a possible development …in patients with RBD, it is in a limited number of cases and there are concerns about the accuracy of the diagnostic criteria. Neuropsychological impairments identified in cross-sectional studies of RBD patients describe a profile similar to that observed in dementia related to synucleinopathies. However, only deficits in executive function predict the development of neurodegeneration. Longitudinal studies reported the development of AD in RBD patients in about 7% of cases with variability ranging from 3% and 11%. Since the majority of longitudinal investigations do not report AD as a possible development for RBD patients the proportion may be overestimated. The study of the relationship between RBD and AD may be confounded by two factors that lead to misdiagnosis: the use of clinical criteria alone and the overlap between the clinical features and neuropathology of AD and LBD. Future studies to investigate this association must use updated diagnostic criteria incorporating ancillary investigations. Show more

Keywords: Alzheimer’s disease, cognition, neurodegeneration, REM sleep behavior disorder

DOI: 10.3233/JAD-171164

Citation: Journal of Alzheimer's Disease, vol. 63, no. 1, pp. 1-11, 2018

Authors: Quinn, James P. | Corbett, Nicola J. | Kellett, Katherine A. B. | Hooper, Nigel M.

Article Type: Review Article

Abstract: With predictions showing that 131.5 million people worldwide will be living with dementia by 2050, an understanding of the molecular mechanisms underpinning disease is crucial in the hunt for novel therapeutics and for biomarkers to detect disease early and/or monitor disease progression. The metabolism of the microtubule-associated protein tau is altered in different dementias, the so-called tauopathies. Tau detaches from microtubules, aggregates into oligomers and neurofibrillary tangles, which can be secreted from neurons, and spreads through the brain during disease progression. Post-translational modifications exacerbate the production of both oligomeric and soluble forms of tau, with proteolysis by a range of …different proteases being a crucial driver. However, the impact of tau proteolysis on disease progression has been overlooked until recently. Studies have highlighted that proteolytic fragments of tau can drive neurodegeneration in a fragment-dependent manner as a result of aggregation and/or transcellular propagation. Proteolytic fragments of tau have been found in the cerebrospinal fluid and plasma of patients with different tauopathies, providing an opportunity to develop these fragments as novel disease progression biomarkers. A range of therapeutic strategies have been proposed to halt the toxicity associated with proteolysis, including reducing protease expression and/or activity, selectively inhibiting protease-substrate interactions, and blocking the action of the resulting fragments. This review highlights the importance of tau proteolysis in the pathogenesis of tauopathies, identifies putative sites during tau fragment-mediated neurodegeneration that could be targeted therapeutically, and discusses the potential use of proteolytic fragments of tau as biomarkers for different tauopathies. Show more

Keywords: Biomarkers, dementia, proteases, proteolysis, tau, tauopathies

DOI: 10.3233/JAD-170959

Citation: Journal of Alzheimer's Disease, vol. 63, no. 1, pp. 13-33, 2018

Authors: de la Torre, Jack

Article Type: Research Article

Abstract: The vascular hypothesis of Alzheimer’s disease (VHAD) was proposed 24 years ago from observations made in our laboratory using aging rats subjected to chronic brain hypoperfusion. In recent years, VHAD has become a mother-lode to numerous neuroimaging studies targeting cerebral hemodynamic changes, particularly brain hypoperfusion in elderly patients at risk of developing Alzheimer’s disease (AD). There is a growing consensus among neuroradiologists that brain hypoperfusion is likely involved in the pathogenesis of AD and that disturbed cerebral blood flow (CBF) can serve as a key biomarker for predicting conversion of mild cognitive impairment to AD. The use of cerebral hypoperfusion …as a preclinical predictor of AD is becoming decisive in stratifying low and high risk patients that may develop cognitive decline and for assessing the effectiveness of therapeutic interventions. There is currently an international research drive from neuroimaging groups to seek new perspectives that can broaden our understanding of AD and improve lifestyle. Diverse neuroimaging methods are currently being used to monitor normal and dyscognitive brain activity. Some techniques are very powerful and can detect, diagnose, quantify, prognose, and predict cognitive decline before AD onset, even from a healthy cognitive state. Multimodal imaging offers new insights in the treatment and prevention of cognitive decline during advanced aging and better understanding of the functional and structural organization of the human brain. This review discusses the impact the VHAD and CBF are having on the neuroimaging technology that can usher practical strategies to help prevent AD. Show more

Keywords: Alzheimer’s disease, amyloid cascade hypothesis, brain hypoperfusion, cerebral blood flow, cognitive impairment, dementia prediction, neuroimaging, vascular hypothesis of Alzheimer’s disease

DOI: 10.3233/JAD-180004

Citation: Journal of Alzheimer's Disease, vol. 63, no. 1, pp. 35-52, 2018

Authors: Guzik-Makaruk, Ewa M. | Pływaczewski, Emil W. | Mroczko, Piotr | Olesiuk-Okomska, Magda | Kulczyńska-Przybik, Agnieszka

Article Type: Review Article

Abstract: According to the projections of the statistical office of the European Union, Eurostat, nearly one third of EU citizens will be at least 65 in 2060. The U.S. population age 65 and older continues to increase and is projected to nearly double from 48 million to 88 million by 2050. Elderly people are especially exposed to neurodegenerative diseases (NDs). The most common ND is Alzheimer’s disease (AD), a chronic and progressive disorder with a variety of pathological changes within neuronal tissue, which begin even 10–15 years before the onset of cognitive impairment symptoms. AD is perceived as a disease continuum …and considered to include three basic phases: preclinical (asymptomatic) stage, mild cognitive impairment (MCI), and dementia due to AD. A very important issue, from medical and legal perspectives, is the NDs patient’s consent to medical procedures, including diagnostic procedures, such as lumber puncture. NDs patients are not always able to express their consent and do not always understand the information provided by a physician. This applies to a group of patients in the final stages of NDs. This paper presents legal regulations of selected European countries and signalizes the U.S. legal solutions on the issue of NDs patients’ informed consent to medical procedures. Show more

Keywords: Alzheimer’s disease, consent to treatment, legal regulations, neurodegenerative diseases

DOI: 10.3233/JAD-171176

Citation: Journal of Alzheimer's Disease, vol. 63, no. 1, pp. 53-67, 2018

Authors: Høilund-Carlsen, Poul F. | Barrio, Jorge R. | Gjedde, Albert | Werner, Thomas J. | Alavi, Abass

Article Type: Editorial

Abstract: Referring to recent international articles stating that amyloid imaging or detection has a high additive value in making a diagnosis of Alzheimer’s disease (AD) when previous investigations are inconclusive, the authors of this editorial argue that this statement is based on circular reasoning and, hence, misleading. Since autopsy findings and other potential indicators fit poorly with amyloid PET, they conclude that this examination has no role in the diagnosis of AD.

Keywords: Alzheimer’s disease, amyloid PET, circular inference, dementia

DOI: 10.3233/JAD-180050

Citation: Journal of Alzheimer's Disease, vol. 63, no. 1, pp. 69-73, 2018

Authors: Tabira, Takeshi | Kawamura, Nobutoshi

Article Type: Short Communication

Abstract: Extracts from Huperzia serrata (HS) function as a cholinesterase inhibitor and a glutamic acid receptor antagonist. We tested a supplement containing HS extracts, curcumin, and others in dementia patients and individuals with mild cognitive impairment (MCI) in an open label study. Most patients with Alzheimer’s disease, dementia with Lewy bodies, and MCI individuals exhibited improvements in cognitive functions, as assessed by the Alzheimer’s Disease Assessment Scale-cognitive subscale Japanese version. The scores were significantly improved at 6–12 weeks compared with baseline scores (p  = 0.007) and at 22–28 weeks (p  = 0.004). Thus, this supplement may be administered to dementia patients …as well as MCI individuals. Show more

Keywords: Alzheimer’s disease, curcumin, dementia with Lewy bodies, huperzine A, mild cognitive impairment

DOI: 10.3233/JAD-171154

Citation: Journal of Alzheimer's Disease, vol. 63, no. 1, pp. 75-78, 2018

Authors: Scheinin, Noora M. | Gardberg, Maria | Röyttä, Matias | Rinne, Juha O.

Article Type: Short Communication

Abstract: Our aim was to assess whether in vivo 11 C-PIB negative memory-impaired subjects may nonetheless exhibit brain Alzheimer’s disease (AD) pathology. We re-evaluated the PET images and systematically characterized the postmortem neuropathology of six individuals who had undergone clinically indicated amyloid PET. The single case with negligible amyloid-β (Aβ) pathology had Lewy body disease, where concomitant AD changes are often seen. Further, the subject’s plaques were predominantly diffuse. The predictive value of a negative 11 C-PIB scan appears to be good, even in memory-impaired populations. Our results suggest that considerable neuritic Aβ plaque pathology in the absence of specific/cortical …11 C-PIB binding upon PET is unlikely. Show more

Keywords: Aβ, amyloid, immunohistochemistry, neuritic plaque, neuropathology, PIB, positron emission tomography

DOI: 10.3233/JAD-170569

Citation: Journal of Alzheimer's Disease, vol. 63, no. 1, pp. 79-85, 2018

Authors: Julian, Adrien | Rioux-Bilan, Agnès | Ragot, Stéphanie | Krolak-Salmon, Pierre | Berrut, Gilles | Dantoine, Thierry | Hommet, Caroline | Hanon, Olivier | Page, Guylène | Paccalin, Marc

Article Type: Short Communication

Abstract: Peripheral inflammatory processes are involved in Alzheimer’s disease (AD). We aimed to determine whether plasma inflammatory mediator levels at diagnosis are associated with cognitive decline through a 2-year follow-up in AD patients. Patients (n  = 109, mean age 79.44 (6.82) years) were included at diagnosis with MMSE scores between 16 and 25, with C-reactive protein <10 mg/L, and without any acute or chronic inflammation status. Plasma IL-1β, IL-6, TNF-α, and CCL5 were measured using Luminex X-MAP technology at baseline, and after one year and two years of follow-up. The mean values of IL-1β, IL-6, TNF-α, and CCL5 at diagnosis were 0.3, 1.94, …6.57, and 69,615.81 pg/mL, respectively. Mean cognitive decline in MMSE was 3.35 points. No correlation between plasmatic value of IL-1β, IL-6, TNF-α, or CCL5 at diagnosis and cognitive decline during the two years of follow-up was found. Cognitive decline in AD does not appear to be predictable by the tested inflammatory mediators. Show more

Keywords: Alzheimer’s disease, cognitive decline, cytokines, inflammation

DOI: 10.3233/JAD-171131

Citation: Journal of Alzheimer's Disease, vol. 63, no. 1, pp. 87-92, 2018

Authors: Cardillo, Giancarlo de Mattos | De-Paula, Vanessa de Jesus Rodrigues | Ikenaga, Eliza Hiromi | Costa, Luciana Rodrigues | Catanozi, Sergio | Schaeffer, Evelin Lisete | Gattaz, Wagner Farid | Kerr, Daniel Shikanai | Forlenza, Orestes Vicente

Article Type: Research Article

Abstract: Telomere length (TL) is a biomarker of cell aging, and its shortening has been linked to several age-related diseases. In Alzheimer’s disease (AD), telomere shortening has been associated with neuroinflammation and oxidative stress. The majority of studies on TL in AD were based on leucocyte DNA, with little information about its status in the central nervous system. In addition to other neuroprotective effects, lithium has been implicated in the maintenance of TL. The present study aims to determine the effect of chronic lithium treatment on TL in different regions of the mouse brain, using a triple-transgenic mouse model (3xTg-AD). Eighteen …transgenic and 22 wild-type (Wt) male mice were treated for eight months with chow containing 1.0 g (Li1) or 2.0 g (Li2) of lithium carbonate/kg, or standard chow (Li0). DNA was extracted from parietal cortex, hippocampus and olfactory epithelium and TL was quantified by real-time PCR. Chronic lithium treatment was associated with longer telomeres in the hippocampus (Li2, p  = 0.0159) and in the parietal cortex (Li1, p  = 0.0375) of 3xTg-AD compared to Wt. Our findings suggest that chronic lithium treatment does affect telomere maintenance, but the magnitude and nature of this effect depend on the working concentrations of lithium and characteristics of the tissue. This effect was observed when comparing 3xTg-AD with Wt mice, suggesting that the presence of AD pathology was required for the lithium modulation of TL. Show more

Keywords: Alzheimer’s disease, hippocampus, lithium, olfactory epithelium, parietal cortex, telomere, transgenic mice

DOI: 10.3233/JAD-170838

Citation: Journal of Alzheimer's Disease, vol. 63, no. 1, pp. 93-101, 2018

Authors: Ransmayr, Gerhard | Hermann, Philipp | Sallinger, Katharina | Benke, Thomas | Seiler, Stephan | Dal-Bianco, Peter | Marksteiner, Josef | Defrancesco, Michaela | Sanin, Günter | Struhal, Walter | Guger, Michael | Vosko, Milan | Hagenauer, Karin | Lehner, Riccarda | Futschik, Andreas | Schmidt, Reinhold

Article Type: Research Article

Abstract: Background: Comprehensive studies on caregiver burden (CB) of persons caring for dementia patients differ methodologically and show variable results. Objective: Analysis of known and hypothesized factors of CB in home care of dementia patients. Methods: Multicenter longitudinal study comprising 585 persons caring mostly for Alzheimer’s disease patients (age median 77.25 years, Mini-Mental State Examination raw score median 23) using the Zarit Caregiver Burden Interview (CBI). Known patient-related determinants of CB were studied, such as dementia severity (Clinical Dementia Rating, CDR), neuropsychological deficits (CERAD-Plus), neuropsychiatric symptoms (Neuropsychiatric Inventory, NPI), disability (Disability Assessment for Dementia, DAD), dependency (Dependency …Scale, DS), and moreover, unclarified potential factors (age, sex, education of patients; age, sex, occupational status of the caregivers; family relationship). Psychological and somatic effects of CB were analyzed (factor analysis). Results: Caregiver age was median 61. Female caregivers prevailed (67.8%). Median CBI sum score (CBIss) was 16 at baseline. After two years, CBIss was 22 and 37% of the caregivers reported mild to moderate (CBIss 21–40), 16.8% moderate to severe or severe (≥41), and 46.2% absent to little CB (CBIss ≤ 20). CB correlated positively with NPI, CDR, DS scores, disability (DAD), years of education of the patients, and proximity of patient and caregiver sex (female), and negatively with caregiver age. Caregivers reported restrictions of time, health problems, and negative emotions. Conclusion: The findings are applicable to identify persons at risk for substantial CB and its consequences. There is demand for personal, psychological, and medical support of caregivers and increasing male participation. Show more

Keywords: Caregiver burden, dementia, dementia severity, dependency, home care, Zarit Caregiver Burden Interview, neuropsychiatric symptoms

DOI: 10.3233/JAD-170657

Citation: Journal of Alzheimer's Disease, vol. 63, no. 1, pp. 103-114, 2018