Journal of Alzheimer's Disease - Volume 60, issue 3

Authors: de Jager, Celeste A. | Msemburi, William | Pepper, Katy | Combrinck, Marc I.

Article Type: Research Article

Abstract: Background: Dementia is a growing concern for low- and middle-income countries where longevity is increasing and service provision is poor. Global prevalence estimates vary from 2% to 8.5% for those aged 60 years and older. There have been few dementia studies in sub-Saharan Africa, and prevalence data are lacking for South Africa. Objective: To conduct a large dementia prevalence study in a low income rural population in South Africa. Methods: 1,394 Xhosa-speaking community dwellers, aged ≥60 y (mean age±sd 71.3±8.3 y), in three clinic catchment areas, were screened at home. Trained community health workers administered the brief Community …Screening Instrument for Dementia (CSID) to participants and informants to assess cognitive and functional capacity. Depressive symptoms were assessed with three questions from the EURO-D. Results: The prevalence estimate using published CSID sensitivity/specificity values was 0.8 (95% CI: 0.06–0.09). Using CSID cut-off scores the estimated prevalence was 0.12 (95% CI: 0.10–0.13), with 161 screen-positives. Both methods gave a rate of 0.11 (95% CI: 0.09–0.13) for those over 65 years (n  = 1051). 68.6% of participants were female and 69.8% had less than 7 years of education. Dementia risk was associated with older age and symptoms of depression, but not with sex. The association with education was not significant when controlled for by age. Conclusions: Dementia prevalence estimates were higher than expected for this low-income rural community. There is a need for increased dementia awareness and feasible support interventions. We also need further studies of regional prevalences, dementia subtypes, and modifiable risk factors in South Africa. Show more

Keywords: Community Screening Instrument for Dementia, dementia screening, epidemiology, low- and middle-income country, older people, population

DOI: 10.3233/JAD-170325

Citation: Journal of Alzheimer's Disease, vol. 60, no. 3, pp. 1087-1096, 2017

Authors: Palmieri, Gianna | Cocca, Ennio | Gogliettino, Marta | Valentino, Roberta | Ruvo, Menotti | Cristofano, Gloria | Angiolillo, Antonella | Balestrieri, Marco | Rossi, Mosè | Di Costanzo, Alfonso

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is a progressive, multifactorial neurodegenerative disorder that is the main cause of dementia. To date, there are no definitive diagnostic tests that can predict or assess onset and progression of the disease. Blood biomarkers for AD are being sought for many years but their identification remains a challenging task. In this study, we investigated the potential relationship between AD and levels of acyl-peptide hydrolase (APEH) and proteasome in erythrocyte samples of 52 participants (26 AD and 26 cognitively healthy controls). A statistically significant decrease in proteasome and exopeptidase/endopeptidase APEH activities was found in AD samples compared to …those of healthy controls. Moreover, in contrast to what was observed for proteasome transcripts, APEH activities reduction in AD patients was unrelated to its gene expression levels, suggesting the occurrence of posttranslational modifications or the expression of endogenous inhibitors that might impair enzyme activity. These preliminary data further support a relationship between the APEH-proteasome system and AD molecular players, providing the first evidence of its potential use as a novel blood-based indicator for the routine detection of AD. Show more

Keywords: Alzheimer’s disease, APEH, blood-based indicator system, oxidized peptide hydrolase activity, proteasome, protein quality control

DOI: 10.3233/JAD-170389

Citation: Journal of Alzheimer's Disease, vol. 60, no. 3, pp. 1097-1106, 2017

Authors: Mise, Ayano | Yoshino, Yuta | Yamazaki, Kiyohiro | Ozaki, Yuki | Sao, Tomoko | Yoshida, Taku | Mori, Takaaki | Mori, Yoko | Ochi, Shinichiro | Iga, Jun-ichi | Ueno, Shu-ichi

Article Type: Research Article

Abstract: Background: TOMM40 is located on chromosome 19, is in linkage disequilibrium with apolipoprotein E (APOE ), andis reported in several genome-wide association studies to be associated with Alzheimer’s disease (AD). Objective: Assess APOE and TOM40 and mitochondrial genes as blood biomarkers for AD. Methods: We examined TOMM40 , PTEN-induced putative kinase 1 (PINK1 ), Parkin RBR E3 ubiquitin protein ligase (PARK2 ), and APOE mRNA expression in relation to the methylation rates of CpG sites in the upstream region of TOMM40 exon 1 in peripheral leukocytes and TOMM40 523 …polyT genotypes in 60 AD and age- and sex-matched control subjects. Results: TOMM40 mRNA expression was significantly lower in AD subjects (0.87±0.18 versus 1.0±0.23, p  = 0.005), and PINK1 mRNA expression was higher in AD subjects (1.5±0.61 versus 1.0±0.52, p  < 0.001). TOMM40 mRNA expression was significantly correlated with the Mini-Mental State Examination total score (r  = 0.290, p  = 0.027). There was no expressional change in peripheral APOE mRNA in either AD or control subjects (p  = 0.32). Methylation rates in the upstream region of TOMM40 exon 1 were not different between AD and control subjects (average rate: 1.37±0.99 versus 1.39±1.20, p  = 0.885), and TOMM40 523 polyT genotypes were also not different between AD and control subjects (p  = 0.67). Conclusion: TOMM40 mRNA expression was lower in AD subjects and was correlated with cognitive decline. Significant changes in both TOMM40 and PINK1 mRNA may be related to mitochondrial dysfunction. Show more

Keywords: Alzheimer’s disease, apolipoprotein E (ApoE), methylation, mitochondria, mRNA expression, Parkin RBR E3 ubiquitin protein ligase (PARK2), PTEN-induced putative kinase 1 (PINK1), translocase of outer mitochondrial membrane 40 (TOMM40)

DOI: 10.3233/JAD-170361

Citation: Journal of Alzheimer's Disease, vol. 60, no. 3, pp. 1107-1117, 2017

Authors: Reijs, Babette L.R. | Ramakers, Inez H.G.B. | Köhler, Sebastian | Teunissen, Charlotte E. | Koel-Simmelink, Marleen | Nathan, Pradeep J. | Tsolaki, Magda | Wahlund, Lars-Olof | Waldemar, Gunhild | Hausner, Lucrezia | Vandenberghe, Rik | Johannsen, Peter | Blackwell, Andrew | Vanderstichele, Hugo | Verhey, Frans | Visser, Pieter Jelle

Article Type: Research Article

Abstract: Background: Performance on episodic, semantic, and working memory tests is impaired in Alzheimer’s disease (AD)-type dementia, but it is unclear which type of memory test is most strongly associated with early AD biomarkers in cerebrospinal fluid (CSF), and most useful for monitoring disease progression. Objective: To examine the association between amyloid-β 1-42 (Aβ42 ) and tau in CSF with performance on different memory domains at baseline, and how these CSF markers are related with memory decline. Methods: We included 263 individuals with normal cognition, mild cognitive impairment, AD-type dementia, and non-AD dementia from the European EDAR …study. Assessment included CSF Aβ42 and t-tau analyses with INNO-BIA AlzBio3 Luminex assay, the CERAD wordlist learning and delayed recall, animal fluency test, and the CANTAB Paired Associates Learning (PAL) and Spatial Working Memory tasks. Follow-up assessments were performed within 3 years after baseline. Results: At baseline, decreased CSF Aβ42 correlated most strongly with the PAL total errors adjusted and the wordlist delayed recall and increased CSF t-tau with the wordlist delayed recall. Over time, decreased CSF Aβ42 was associated with decline on the wordlist learning, whereas increased CSF t-tau were associated with decline in scores on the wordlist learning, wordlist delayed recall, and animal fluency. Associations were independent of baseline diagnosis. Conclusion: Tests assessing episodic verbal and visuospatial memory are most useful for detection of AD pathology. Tests for episodic verbal memory and semantic memory are most useful for tracking memory decline. Show more

Keywords: Alzheimer’s disease, amyloid-β, biomarkers, cerebrospinal fluid, episodic memory, spatial memory, working memory

DOI: 10.3233/JAD-160766

Citation: Journal of Alzheimer's Disease, vol. 60, no. 3, pp. 1119-1128, 2017

Authors: Garrido, Sandra | Dunne, Laura | Chang, Esther | Perz, Janette | Stevens, Catherine J. | Haertsch, Maggie

Article Type: Research Article

Abstract: The use of pre-recorded music to ease behavioral and psychological symptoms associated with dementia is popular in health-care contexts in both formal music therapy settings and in non-therapist led interventions. However, further understanding of how non-therapist led interventions compare to therapist led interventions is needed. This paper reviews 28 studies that used pre-recorded music with people with dementia using a critical interpretive synthesis model. Results revealed that pre-recorded music can be effective in reducing a variety of affective and behavioral symptoms, in particular agitation, even where a trained music therapist is not present. However, the results are not universally positive, …suggesting the need for further clarification of protocols for music use and closer investigation of variables that influence individual responseto music. Show more

Keywords: Alzheimer’s disease, critical synthesis, dementia, music, music interventions, music therapy, review

DOI: 10.3233/JAD-170612

Citation: Journal of Alzheimer's Disease, vol. 60, no. 3, pp. 1129-1142, 2017

Authors: Ahmed, Mohammad Ejaz | Iyer, Shankar | Thangavel, Ramasamy | Kempuraj, Duraisamy | Selvakumar, Govindhasamy Pushpavathi | Raikwar, Sudhanshu P. | Zaheer, Smita | Zaheer, Asgar

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by the presence of intracellular neurofibrillary tangles (NFTs) containing hyperphosphorylated tau, and the extracellular deposition of amyloid plaques (APs) with misfolded amyloid-β (Aβ) peptide. Glia maturation factor (GMF), a highly conserved pro-inflammatory protein, isolated and cloned in our laboratory, has been shown to activate glial cells leading to neuroinflammation and neurodegeneration in AD. We hypothesized that inflammatory reactions promoted by NLRP3-Caspase-1inflammasome pathway trigger dysfunction in autophagy and accumulation of Aβ which is amplified and regulated by GMF in AD. In this study, using immunohistochemical techniques we analyzed components of the NLRP3 …inflammasome and autophagy- lysosomal markers in relation to Aβ, p-tau and GMF in human postmortem AD and age-matched non-AD brains. Tissue sections were prepared from the temporal cortex of human postmortem brains. Here, we demonstrate an increased expression of the inflammasome components NLRP3 and Caspase-1 and the products of inflammasome activation IL-1β and IL-18 along with GMF in the temporal cortex of AD brains. These inflammasome components and the pro-inflammatory cytokines co-localized with GMF in the vicinity and periphery of the APs and NFTs. Moreover, using double immunofluorescence staining, AD brain displayed an increase in the autophagy SQSTM1/p62 and LC3 positive vesicles and the lysosomal marker LAMP1 that also co-localized with GMF, Aβ and hyperphosphorylated p-tau. Our results indicate that in AD, the neuroinflammation promoted by the NLRP3 inflammasome may be amplified and regulated by GMF, which further impairs clearance of protein aggregates mediated by the auto-phagosomal pathway. Show more

Keywords: Alzheimer’s disease, amyloid plaques, autophagy, glia maturation factor, inflammasome, neurofibrillary tangles, pro-inflammatory cytokine

DOI: 10.3233/JAD-170634

Citation: Journal of Alzheimer's Disease, vol. 60, no. 3, pp. 1143-1160, 2017

Authors: Finger, Elizabeth | Zhang, Jing | Dickerson, Bradford | Bureau, Yves | Masellis, Mario | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Neuropsychiatric symptoms in Alzheimer’s disease are among the most disabling and difficult aspects for caregivers and treating health professionals to manage. Despite the high prevalence of these behaviors, little is known about the factors which lead some patients to develop florid behavioral symptoms while others may progress to severe dementia without such phenomenon. We examined whether regional brain volumes as measured by cortical thickness would predict the presence or absence of disinhibition in patients with Alzheimer’s disease. Using data from the ADNI, we identified 758 patients with caregiver ratings on the Neuropsychiatric Inventory and a volumetric MRI scan with cortical …thickness measurements completed in FreeSurfer by the UCSF core. Of these, 177 patients were found to have disinhibition. Logistic regression models demonstrated that reduced cortical thickness in the right frontal pole was associated with the presence of disinhibition even when controlling for age, disease severity, total intracranial volume, gender, and APOE genotype. The results are considered in the context of leading models of the functions of frontopolar cortex. Show more

Keywords: Alzheimer’s disease, disinhibition, frontopolar cortex

DOI: 10.3233/JAD-170348

Citation: Journal of Alzheimer's Disease, vol. 60, no. 3, pp. 1161-1170, 2017

Authors: Dutzi, Ilona | Schwenk, Michael | Kirchner, Marietta | Bauer, Jürgen M. | Hauer, Klaus

Article Type: Research Article

Abstract: Background: Dementia is a frequent diagnosis in geriatric rehabilitation. Studies in patients with dementia on the development of their cognitive status during rehabilitation and its relation to functional outcomes have been scarce. Objectives: To describe the changes in cognitive status in patients with dementia during inpatient rehabilitation and to determine its association with patient characteristics and rehabilitation outcome. Methods: Cohort study in a geriatric rehabilitation center with data collection at admission and discharge. Outcome measures were change in global and domain-related cognitive functioning and its association with activities of daily living (ADL) and discharge home. …Results: 154 patients (mean age 83.7 years) diagnosed with mild to moderate dementia were included. Cognitive performance significantly improved from admission to discharge for all cognitive variables tested (p  < 0.001 to 0.03). Change in global cognitive functioning, executive functions, and episodic memory were positively associated with ADL recovery. Change in global cognitive functioning predicted ADL improvements (β= 0.32; p  = 0.006). Only 7.8% of patients, characterized by worse ADL and motor abilities as well as higher frailty scores at admission, deteriorated in global cognitive scores. In comparison to patients with stable or improved cognition, these patients showed least improvements in ADL-scores (4.1 versus 12.5) and a trend for higher institutionalization (50% versus 26.5%). Conclusions: The findings highlight the potential of patients with dementia to recover cognitive functioning during rehabilitation. Cognitive change represents an independent rehabilitation outcome and a prognostic factor for successful rehabilitation suggesting that specific interventions are indicated to maintain and enhance cognitive functioning in these highly vulnerable patients. Show more

Keywords: Cognitive development, cognitive impairment, dementia, geriatrics, rehabilitation, rehabilitation outcomes

DOI: 10.3233/JAD-170401

Citation: Journal of Alzheimer's Disease, vol. 60, no. 3, pp. 1171-1182, 2017

Authors: Sánchez, Stella M. | Abulafia, Carolina | Duarte-Abritta, Barbara | de Guevara, M. Soledad Ladrón | Castro, Mariana N. | Drucaroff, Lucas | Sevlever, Gustavo | Nemeroff, Charles B. | Vigo, Daniel E. | Loewenstein, David A. | Villarreal, Mirta F. | Guinjoan, Salvador M.

Article Type: Research Article

Abstract: Background: We have obtained previous evidence of limbic dysfunction in middle-aged, asymptomatic offspring of late-onset Alzheimer’s disease (LOAD) patients, and failure to recover from proactive semantic interference has been shown to be a sensitive cognitive test in other groups at risk for LOAD. Objective: To assess the effects of specific proactive semantic interference deficits as they relate to functional magnetic resonance imaging (fMRI) neocortical and limbic functional connectivity in middle aged offspring of individuals with LOAD (O-LOAD) and age-equivalent controls. Methods: We examined 21 O-LOAD and 20 controls without family history of neurodegenerative disorders (CS) on …traditional measures of cognitive functioning and the LASSI-L, a novel semantic interference test uniquely sensitive to the failure to recover from proactive interference (frPSI). Cognitive tests then were correlated to fMRI connectivity of seeds located in entorhinal cortex and anterodorsal thalamic nuclei among O-LOAD and CS participants. Results: Relative to CS, O-LOAD participants evidenced lower connectivity between entorhinal cortex and orbitofrontal, anterior cingulate, and anterior temporal cortex. In the offspring of LOAD patients, LASSI-L measures of frPSI were inversely associated with connectivity between anterodorsal thalamus and contralateral posterior cingulate. Intrusions on the task related to frPSI were inversely correlated with a widespread connectivity network involving hippocampal, insular, posterior cingulate, and dorsolateral prefrontal cortices, along with precunei and anterior thalamus in this group. Different patterns of connectivity associated with frPSI were observed among controls. Conclusion: The present results suggest that both semantic interference deficits and connectivity abnormalities might reflect limbic circuit dysfunction as a very early clinical signature of LOAD pathology, as previously demonstrated for other limbic phenotypes, such as sleep and circadian alterations. Show more

Keywords: Entorhinal cortex, functional connectivity, late-onset Alzheimer’s disease, limbic, proactive semantic interference, thalamus

DOI: 10.3233/JAD-170491

Citation: Journal of Alzheimer's Disease, vol. 60, no. 3, pp. 1183-1193, 2017

Authors: Buratti, Laura | Viticchi, Giovanna | Baldinelli, Sara | Falsetti, Lorenzo | Luzzi, Simona | Pulcini, Alessandra | Petrelli, Cristina | Provinciali, Leandro | Silvestrini, Mauro

Article Type: Research Article

Abstract: Background: Sleep breathing disorders can affect cognitive performances through complex brain anatomical and functional changes. Objective: Our aim was to evaluate the correlations between cognitive performances and obstructive sleep apnea syndrome (OSAS), as well as the possible influence of vascular factors. Methods: Thirty-four non-demented OSAS patients and 34 controls were submitted to a neuropsychological evaluation and to a vascular screening including the study of cerebrovascular reactivity by means of the breath-holding index (BHI) calculation. After 6 months, polisomnographic, neuropsychologic, and hemodynamics assessment was repeated in patients. Results: At baseline, some cognitive performances involved in …executive and memory functions were significantly lower in patients with respect to controls. Significantly lower values in mean BHI were also detected in patients with respect to controls (p  < 0.0001). At the 6-month evaluation, 18 patients had a reduction in OSAS severity (group 1) and 16 remained stable (group 2). Group 1 patients had a significant improvement in left and mean BHI (p  < 0.001) and in short-term (p  = 0.02) and long-term Rey Auditory Verbal Learning Test (p  < 0.001). No change in cerebrovascular reactivity and cognitive profile was detected in group 2 patients. Conclusions: Patients with OSAS may experience a reduced cognitive efficiency. Improvement of OSAS was associated to favorable hemodynamic changes and increased level of performances in verbal memory tasks so suggesting an involvement of vascular underlying mechanisms in sustaining cognitive dysfunctions in OSAS. Our preliminary data suggest the need for further studies to deepen the knowledge about the relationships between OSAS, cerebral hemodynamic compromise, and cognitive impairment risk. Show more

Keywords: Cerebral hemodynamics, cognitive performances, obstructive sleep apnea

DOI: 10.3233/JAD-170445

Citation: Journal of Alzheimer's Disease, vol. 60, no. 3, pp. 1195-1203, 2017