Journal of Alzheimer's Disease - Volume 62, issue 1

Authors: Schweda, Mark | Kögel, Anna | Bartels, Claudia | Wiltfang, Jens | Schneider, Anja | Schicktanz, Silke

Article Type: Research Article

Abstract: Background: Biomarker-supported testing for preclinical and prodromal Alzheimer’s disease (AD) finds its way into clinical practice. Professional attitudes and practices regarding disclosure and ethical issues are controversial in many countries. Objectives: Against this background, the objective was to survey the actual practice and the attitudes of physicians in German hospitals and memory clinics in order to explore possible practical insecurities and ethical concerns. Methods: A detailed survey with 37 items was conducted among medical professionals at German hospitals and memory clinics (n  = 108). Analyses were performed using SPSS 21.0 (IBM). Findings were based on frequency and …percentage distribution. Results: Nearly half of the respondents stated that persons with mild cognitive impairment and pathological cerebrospinal fluid biomarkers were informed they had or would soon develop AD. While 81% acknowledged a ‘right not to know’, 75% said that results were always communicated. A majority agreed there was a benefit of prediction or later life planning [end-of-life, financial, family, housing (73–75%)] but also expected high psychological stress (82%) and self-stigmatization (70%) for those tested. Conclusions: There is considerable heterogeneity and insecurity regarding prediction and early detection in the context of AD in Germany. Information of professionals and standardization of professional testing and disclosure practices are needed. Show more

Keywords: Alzheimer’s disease, dementia, disclosure, ethics, Germany, questionnaires, surveys

DOI: 10.3233/JAD-170443

Citation: Journal of Alzheimer's Disease, vol. 62, no. 1, pp. 145-155, 2018

Authors: Corvol, Aline | Netter, Alix | Campeon, Arnaud | Somme, Dominique

Article Type: Research Article

Abstract: Background: The French National Alzheimer Plan 2008-2012 created specialized Alzheimer teams, which provide up to 15 sessions of cognitive rehabilitation in the patient’s home for 3 months. Sessions are conducted by an occupational therapist and a gerontological nursing assistant. Objectives: As the patient’s experience is one determinant of successful implementation, we explored the usefulness of these teams as viewed by the patient and his or her main caregiver. Methods: Thirteen patients and their caregiver, previously assisted by a specialized Alzheimer team, were individually given semi-structured interviews (n  = 26, duration 20 to 180 minutes). Results: …Our study showed that although patients and caregiver had no initial expectations, most of them appreciated the support provided by the specialized Alzheimer teams. Patients valued the “human” component, and favored interventions that improved quality of life over those intended to maintain functional capacities. Caregivers observed improved mood and behavior in patients. Those involved in sessions felt empowered by contact with a specialized Alzheimer team. We discuss how patients’ and caregivers’ feedback influenced the implementation process through comprehensive use of the five dimensions of the RE-AIM framework. Conclusion: Whereas intervention by specialized Alzheimer teams was largely accepted by health care professionals, patients, and caregivers, its effectiveness is questioned in view of its deviation from the evidence-based model. Interviews with patients and caregivers shed light on some reasons for this deviation, as what they value in the intervention differs from the functional focus of the model. Show more

Keywords: Alzheimer’s disease, occupational therapy, patient acceptance of health care, public health systems research, qualitative research

DOI: 10.3233/JAD-170765

Citation: Journal of Alzheimer's Disease, vol. 62, no. 1, pp. 157-164, 2018

Authors: Haapalinna, Fanni | Kokki, Merja | Jääskeläinen, Olli | Hallikainen, Merja | Helisalmi, Seppo | Koivisto, Anne | Kokki, Hannu | Paajanen, Teemu | Penttinen, Janne | Pikkarainen, Maria | Rautiainen, Minna | Soininen, Hilkka | Solje, Eino | Remes, Anne M. | Herukka, Sanna-Kaisa

Article Type: Research Article

Abstract: Background: The neuropathology of Alzheimer’s disease (AD) has previously been shown to be rather common among the elderly. Objective: The aim of this study was to inspect the associations between cerebrospinal fluid (CSF) AD biomarker concentrations, age, the APOE ɛ 4 allele, cardiovascular diseases, diabetes, and cognitive performance in a cohort of a neurologically healthy population. Methods: This study included 93 subjects (42 men, mean age 67 years) without previous neurological symptoms or subjective cognitive complaints. Their cognition was assessed, and CSF biomarkers and APOE ɛ 4 status were analyzed. …Results: Of the studied subjects, 8.6% (n  = 8) had a pathological CSF AD biomarker profile. An increase in age correlated positively with CSF tau pathology and negatively with global cognitive performance. Conclusion: AD-type pathological changes in CSF and subtle cognitive impairment are common within a population with no previous memory complaints. Age was the main risk factor for the changes. Show more

Keywords: Aging, Alzheimer’s disease, apolipoprotein E4, cerebrospinal fluid, cognition

DOI: 10.3233/JAD-170534

Citation: Journal of Alzheimer's Disease, vol. 62, no. 1, pp. 165-174, 2018

Authors: Wezyk, Michalina | Szybinska, Aleksandra | Wojsiat, Joanna | Szczerba, Marcelina | Day, Kelly | Ronnholm, Harriet | Kele, Malin | Berdynski, Mariusz | Peplonska, Beata | Fichna, Jakub Piotr | Ilkowski, Jan | Styczynska, Maria | Barczak, Anna | Zboch, Marzena | Filipek-Gliszczynska, Anna | Bojakowski, Krzysztof | Skrzypczak, Magdalena | Ginalski, Krzysztof | Kabza, Michal | Makalowska, Izabela | Barcikowska-Kotowicz, Maria | Wojda, Urszula | Falk, Anna | Zekanowski, Cezary

Article Type: Research Article

Abstract:  The BRCA1 protein, one of the major players responsible for DNA damage response has recently been linked to Alzheimer’s disease (AD). Using primary fibroblasts and neurons reprogrammed from induced pluripotent stem cells (iPSC) derived from familial AD (FAD) patients, we studied the role of the BRCA1 protein underlying molecular neurodegeneration. By whole-transcriptome approach, we have found wide range of disturbances in cell cycle and DNA damage response in FAD fibroblasts. This was manifested by significantly increased content of BRCA1 phosphorylated on Ser1524 and abnormal ubiquitination and subcellular distribution of presenilin 1 (PS1). Accordingly, the iPSC-derived FAD neurons showed increased content …of BRCA1(Ser1524) colocalized with degraded PS1, accompanied by an enhanced immunostaining pattern of amyloid-β. Finally, overactivation of BRCA1 was followed by an increased content of Cdc25C phosphorylated on Ser216, likely triggering cell cycle re-entry in FAD neurons. This study suggests that overactivated BRCA1 could both influence PS1 turnover leading to amyloid-β pathology and promote cell cycle re-entry-driven cell death of postmitotic neurons in AD. Show more

Keywords: Alzheimer’s disease, BRCA1, DNA damage response, cell cycle re-entry, presenilin 1, ubiquitination

DOI: 10.3233/JAD-170830

Citation: Journal of Alzheimer's Disease, vol. 62, no. 1, pp. 175-202, 2018

Authors: Vogelgsang, Jonathan | Wedekind, Dirk | Bouter, Caroline | Klafki, Hans-W. | Wiltfang, Jens

Article Type: Research Article

Abstract: Analysis of cerebrospinal fluid (CSF) is one of the key tools for the state-of-the-art differential diagnosis of dementias. Dementia due to Alzheimer’s disease (AD) is characterized by elevated CSF levels of total Tau (tTau) and phospho-181-Tau (pTau) and low CSF amyloid-β42 (Aβ42 ). Discrepancies in the laboratory analysis of human materials are well known and much effort has been put into harmonization procedures. In this study, we measured CSF biomarkers of more than 100 patients obtained under clinical routine conditions in two different clinical laboratories. The CSF biomarker levels obtained from the two different sites were significantly correlated: R2 … = 0.7129 (tTau, p  < 0.001), 0.7914 (pTau, p  < 0.001), 0.5078 (Aβ42 , p  < 0.001), 0.5739 (Aβ40 , p  < 0.001), and 0.4308 (Aβ42/40 , p  < 0.001). However, the diagnostic classifications of the Aβ42 , tTau, and pTau levels of identical subjects into normal versus pathological range made by the two different sites showed substantial discrepancies (31.5%, 29.6%, and 25.0% discordant cases, respectively). Applying Aβ42/40 , instead of CSF Aβ42 alone, lead to a reduction of the discordant cases to 16.8%. Our findings suggest that CSF Aβ42/40 can outperform Aβ42 as a biomarker for AD neuropathology, not only under well-controlled study conditions but also in real life clinical routine. Thus, we recommend the inclusion of Aβ42/40 as a CSF biomarker in the diagnostic procedure. Show more

Keywords: Alzheimer’s disease, amyloid-β, biomarker, cerebrospinal fluid, clinical diagnostics

DOI: 10.3233/JAD-170793

Citation: Journal of Alzheimer's Disease, vol. 62, no. 1, pp. 203-212, 2018

Authors: Watremez, William | Jackson, Joshua | Almari, Bushra | McLean, Samantha L. | Grayson, Ben | Neill, Joanna C. | Fischer, Nicolas | Allouche, Ahmad | Koziel, Violette | Pillot, Thierry | Harte, Michael K.

Article Type: Research Article

Abstract: Background: With current treatments for Alzheimer’s disease (AD) only providing temporary symptomatic benefits, disease modifying drugs are urgently required. This approach relies on improved understanding of the early pathophysiology of AD. A new hypothesis has emerged, in which early memory loss is considered a synapse failure caused by soluble amyloid-β oligomers (Aβo). These small soluble Aβo, which precede the formation of larger fibrillar assemblies, may be the main cause of early AD pathologies. Objective: The aim of the current study was to investigate the effect of acute administration of stabilized low-n amyloid-β1-42 oligomers (Aβo1-42 ) on cognitive, …inflammatory, synaptic, and neuronal markers in the rat. Methods: Female and male Lister Hooded rats received acute intracerebroventricular (ICV) administration of either vehicle or 5 nmol of Aβo1-42 (10μ L). Cognition was assessed in the novel object recognition (NOR) paradigm at different time points. Levels of inflammatory (IL-1β, IL-6, TNF-α), synaptic (PSD-95, SNAP-25), and neuronal (n-acetylaspartate, parvalbumin-positive cells) markers were investigated in different brain regions (prefrontal and frontal cortex, striatum, dorsal and ventral hippocampus). Results: Acute ICV administration of Aβo1-42 induced robust and enduring NOR deficits. These deficits were reversed by acute administration of donepezil and rolipram but not risperidone. Postmortem analysis revealed an increase in inflammatory markers, a decrease in synaptic markers and parvalbumin containing interneurons in the frontal cortex, with no evidence of widespread neuronal loss. Conclusion: Taken together the results suggest that acute administration of soluble low-n Aβo may be a useful model to study the early mechanisms involved in AD and provide us with a platform for testing novel therapeutic approaches that target the early underlying synaptic pathology. Show more

Keywords: Alzheimer’s disease, amyloid-β oligomers, cognition, parvalbumin interneurons

DOI: 10.3233/JAD-170489

Citation: Journal of Alzheimer's Disease, vol. 62, no. 1, pp. 213-226, 2018

Authors: Taragano, Fernando E. | Allegri, Ricardo F. | Heisecke, Silvina L. | Martelli, María I. | Feldman, Mónica L. | Sánchez, Viviana | García, Virginia A. | Tufro, Graciela | Castro, Diego M. | Leguizamón, Patricio Perez | Guelar, Verónica | Ruotolo, Eva | Zegarra, Cecilia | Dillon, Carol

Article Type: Research Article

Abstract: Background: There is insufficient available information on behavioral changes in the absence of cognitive impairment as factors increasing the risk of conversion to dementia. Objective: To observe and analyze patients with mild behavioral impairment (MBI), mild cognitive impairment (MCI), and a psychiatry group (PG) to compare the risk of progression to dementia. Methods: From 677 initially assessed ≥60-year-old patients, a series of 348 patients was studied for a five-year period until censoring or conversion to dementia: 96 with MBI, 87 with MCI, and 165 with general psychiatry disorders, including 4 subgroups: Anxiety, Depression, Psychosis and Others. …All patients were assessed with clinical, psychiatric, neurological, neuropsychological, and neuroimaging studies. Results: From 348 patients, 126 evolved to dementia (36.2%). Conversion was significantly higher in MBI (71.5%), followed by the MCI-MBI overlap (59.6%) and MCI (37.8%) groups, compared to PG (13.9%) (Log-rank p  < 0.001). MCI patients mostly converted to Alzheimer’s dementia, while MBI converted to frontotemporal dementia and Lewy body dementia. Patients in PG converted to Lewy body dementia and frontotemporal dementia. Conclusion: Conversion to dementia is significantly higher in patients with neuropsychiatric symptoms. The MBI concept generates a new milestone in the refining of diagnosis of neurodegenerative diseases and the possibility of creating neuropsychiatric profiles. Its earlier identification will allow new possibilities for therapeutic intervention. Show more

Keywords: Alzheimer’s disease, conversion to dementia, follow-up, frontotemporal disease, Lewy body disease, mild behavioral impairment, mild cognitive impairment, pre-dementia

DOI: 10.3233/JAD-170632

Citation: Journal of Alzheimer's Disease, vol. 62, no. 1, pp. 227-238, 2018

Authors: Shoda, Chiho | Kitagawa, Yorihisa | Shimada, Hiroyuki | Yuzawa, Mitsuko | Tateno, Amane | Okubo, Yoshiro

Article Type: Research Article

Abstract: Background: Histopathological studies have confirmed that soft drusen contains amyloid-β (Aβ). Objective: To examine the relationship between the area of soft drusen in the macular area and cerebral Aβ accumulation or plasma Aβ level in elderly persons without dementia. Methods: Fourteen consecutive patients (18 eyes) aged ≥50 years with macular soft drusen were studied prospectively. From color fundus photographs, the area of soft drusen (pixel) within a 6,000 μm diameter with the macula as center was measured. Standard uptake value ratio (SUVR) was obtained from positron emission tomography using florbetapir, which indicates the ratio of cerebral …cortical-to-cerebellar Aβ accumulation. Ratio of plasma Aβ1-42 to Aβ1-40 level was calculated. Results: Mean age was 73.3±7.6 years. The soft drusen area was 4.32±2.42 mm2 . The SUVR was 1.08±0.15. Plasma Aβ1-42 /Aβ1-40 ratio was 0.17±0.08. When SUVR ≥1.10 was defined as positive and <1.10 as negative, the soft drusen area in SUVR-positive patients (6.19±1.14 mm2 ) was significantly (p  = 0.0043) larger than that in SUVR-negative patients (3.13±2.27 mm2 ). Multivariate regression analysis showed that SUVR positivity correlated with soft drusen area (p  = 0.0484) and with Voxel-based Specific Regional Analysis System for Alzheimer’s Disease score (p  = 0.0360). However, there was no correlation with gender (p  = 0.1921), age (p  = 0.2361), Alzheimer’s Disease Assessment Scale score (p  = 0.6310), Mini-Mental State Examination score (p  = 0.4246), or plasma Aβ1-42 /Aβ1-40 ratio (p  = 0.8398). Conclusion: Among elderly persons without dementia, the area of soft drusen was larger in those with more extensive cerebral Aβ accumulation. The area of soft drusen may be a biomarker of cerebral Aβ accumulation. Show more

Keywords: Alzheimer’s disease, amyloid, dementia, florbetapir, macular degeneration, positron-emission tomography

DOI: 10.3233/JAD-170956

Citation: Journal of Alzheimer's Disease, vol. 62, no. 1, pp. 239-245, 2018

Authors: Babiloni, Claudio | Del Percio, Claudio | Lizio, Roberta | Noce, Giuseppe | Lopez, Susanna | Soricelli, Andrea | Ferri, Raffaele | Pascarelli, Maria Teresa | Catania, Valentina | Nobili, Flavio | Arnaldi, Dario | Famà, Francesco | Aarsland, Dag | Orzi, Francesco | Buttinelli, Carla | Giubilei, Franco | Onofrj, Marco | Stocchi, Fabrizio | Vacca, Laura | Stirpe, Paola | Fuhr, Peter | Gschwandtner, Ute | Ransmayr, Gerhard | Garn, Heinrich | Fraioli, Lucia | Pievani, Michela | Frisoni, Giovanni B. | D’Antonio, Fabrizia | De Lena, Carlo | Güntekin, Bahar | Hanoğlu, Lutfu | Başar, Erol | Yener, Görsev | Emek-Savaş, Derya Durusu | Triggiani, Antonio Ivano | Franciotti, Raffaella | Taylor, John Paul | De Pandis, Maria Francesca | Bonanni, Laura

Article Type: Research Article

Abstract: The present study tested the hypothesis that cortical sources of resting state eyes-closed electroencephalographic (rsEEG) rhythms reveal different abnormalities in cortical neural synchronization in groups of patients with mild cognitive impairment due to Alzheimer’s disease (ADMCI) and dementia with Lewy bodies (DLBMCI) as compared to cognitively normal elderly (Nold) subjects. Clinical and rsEEG data in 30 ADMCI, 23 DLBMCI, and 30 Nold subjects were available in an international archive. Age, gender, and education were carefully matched in the three groups. The Mini-Mental State Evaluation (MMSE) score was matched between the ADMCI and DLBMCI groups. Individual alpha frequency peak (IAF) was …used to determine the delta, theta, alpha1, alpha2, and alpha3 frequency band ranges. Fixed beta1, beta2, and gamma bands were also considered. eLORETA estimated the rsEEG cortical sources. Receiver operating characteristic curve (ROCC) classified these sources across individuals. Compared to Nold, IAF showed marked slowing in DLBMCI and moderate in ADMCI. Furthermore, the posterior alpha 2 and alpha 3 source activities were more abnormal in the ADMCI than the DLBMCI group, while widespread delta source activities were more abnormal in the DLBMCI than the ADMCI group. The posterior delta and alpha sources correlated with the MMSE score and correctly classified the Nold and MCI individuals (area under the ROCC >0.85). In conclusion, the ADMCI and DLBMCI patients showed different features of cortical neural synchronization at delta and alpha frequencies underpinning brain arousal and vigilance in the quiet wakefulness. Future prospective cross-validation studies will have to test the clinical validity of these rsEEG markers. Show more

Keywords: Exact low resolution brain electromagnetic source tomography (eLORETA), mild cognitive impairment due to Alzheimer’s disease, mild cognitive impairment due to dementia with Lewy bodies, receiver operating characteristic curve, resting state electroencephalographic rhythms

DOI: 10.3233/JAD-170703

Citation: Journal of Alzheimer's Disease, vol. 62, no. 1, pp. 247-268, 2018

Authors: Leskelä, Stina | Takalo, Mari | Marttinen, Mikael | Huber, Nadine | Paananen, Jussi | Mitra, Vikram | Rauramaa, Tuomas | Mäkinen, Petra | Leinonen, Ville | Soininen, Hilkka | Pike, Ian | Remes, Anne M. | Hiltunen, Mikko | Haapasalo, Annakaisa

Article Type: Research Article

Abstract: A subset of C9orf72 repeat expansion-carrying frontotemporal dementia patients display an Alzheimer-like decrease in cerebrospinal fluid amyloid-β (Aβ) biomarker levels. We report that downregulation of C9orf72 in non-neuronal human cells overexpressing amyloid-β protein precursor (AβPP) resulted in increased levels of secreted AβPP fragments and Aβ, while levels of AβPP or its C-terminal fragments (CTFs) remained unchanged. In neuronal cells, AβPP and C83 CTF levels were decreased upon C9orf72 knockdown, but those of secreted AβPP fragments or Aβ remained unchanged. C9orf72 protein levels significantly increased in human brain with advancing neurofibrillary pathology and positively correlated with brain Aβ42 …levels. Our data suggest that altered C9orf72 levels may lead to cell-type specific alterations in AβPP processing, but warrant further studies to clarify the underlying mechanisms. Show more

Keywords: Alzheimer’s disease, amyloid-β, amyloid-β protein precursor, C9orf72, frontotemporal dementia

DOI: 10.3233/JAD-170362

Citation: Journal of Alzheimer's Disease, vol. 62, no. 1, pp. 269-278, 2018