Journal of Alzheimer's Disease - Volume 60, issue 1

Authors: Ighodaro, Eseosa T. | Nelson, Peter T. | Kukull, Walter A. | Schmitt, Frederick A. | Abner, Erin L. | Caban-Holt, Allison | Bardach, Shoshana H. | Hord, Derrick C. | Glover, Crystal M. | Jicha, Gregory A. | Van Eldik, Linda J. | Byrd, Alexander X. | Fernander, Anita

Article Type: Review Article

Abstract: Blacks/African Americans have been reported to be ∼2–4 times more likely to develop clinical Alzheimer’s disease (AD) compared to Whites. Unfortunately, study design challenges (e.g., recruitment bias), racism, mistrust of healthcare providers and biomedical researchers, confounders related to socioeconomic status, and other sources of bias are often ignored when interpreting differences in human subjects categorized by race. Failure to account for these factors can lead to misinterpretation of results, reification of race as biology, discrimination, and missed or delayed diagnoses. Here we provide a selected historical background, discuss challenges, present opportunities, and suggest considerations for studying health outcomes among racial/ethnic …groups. We encourage neuroscientists to consider shifting away from using biologic determination to interpret data, and work instead toward a paradigm of incorporating both biological and socio-environmental factors known to affect health outcomes with the goal of understanding and improving dementia treatments for Blacks/African Americans and other underserved populations. Show more

Keywords: Autopsy, epidemiology, ethnicity, neurodegenerative, neuropathology

DOI: 10.3233/JAD-170242

Citation: Journal of Alzheimer's Disease, vol. 60, no. 1, pp. 1-10, 2017

Authors: Ben Jemaa, Sonia | Attia Romdhane, Neila | Bahri-Mrabet, Amel | Jendli, Adel | Le Gall, Didier | Bellaj, Tarek

Article Type: Research Article

Abstract: The Alzheimer’s Disease Assessment Scale’s cognitive subscale (ADAS-Cog) is the most widely used instrument for screening cognitive dysfunction in Alzheimer’s disease. The aim of the present study was to develop an Arabic version of this scale (A-ADAS-Cog), examine its psychometric properties (reliability and validity), and provide normative data. The A-ADAS-Cog), an Arabic version of the Mini-Mental State Examination (A-MMSE), and a Standardized Clinical Dementia Rating Scale (CDR) were administered to three Tunisian groups: 124 normal controls (NC), 33 patients with non-Alzheimer dementia (N-AD), and 25 patients with Alzheimer’s disease (AD). The A-ADAS-Cog scores were significantly affected by age and education. …A correction table was constructed to control these effects. The results showed that the A-ADAS-Cog has good internal consistency and reliability (α = 0.82 for AD). The test-retest reliability of the A-ADAS-Cog was stable over time (r  = 0.97). An evaluation of the construct validity of the A-ADAS-Cog using principal component analysis led to a solution with three factors (memory, language and praxis), which explained 72% of the variance. The concurrent validity of the A-ADAS-Cog was established using the A-MMSE score (r  = –0.86), CDR Sum of Boxes score (CDR-SB; r  = 0.87), and global CDR score (CDR-Global; r  = 0.74). Finally, the A-ADAS-Cog has an excellent discriminating power in the diagnosis of AD (ROC area = 0.92). A cut-off score of 10 (sensitivity = 84% and specificity = 91%) is indicated for the screening of the AD. Overall, the results indicated that the A-ADAS-Cog is psychometrically reliable and valid and provides promising results for screening of dementia in Arabic speaking patients. Show more

Keywords: Alzheimer’s disease, Alzheimer’s Disease Assessment Scale-Cognitive (ADAS-Cog), Arabic version, culture, normative data, reliability, test adaptation, validity

DOI: 10.3233/JAD-170222

Citation: Journal of Alzheimer's Disease, vol. 60, no. 1, pp. 11-21, 2017

Authors: Le Page, Aurélie | Lamoureux, Julie | Bourgade, Karine | Frost, Eric H. | Pawelec, Graham | Witkowski, Jacek M. | Larbi, Anis | Dupuis, Gilles | Fülöp, Tamàs

Article Type: Research Article

Abstract: The mechanisms of neurodegeneration in Alzheimer’s disease (AD) remain under investigation. Alterations in the blood-brain barrier facilitate exchange of inflammatory mediators and immune cells between the brain and the periphery in AD. Here, we report analysis of phenotype and functions of polymorphonuclear neutrophils (PMN) in peripheral blood from patients with amnestic mild cognitive impairment (aMCI, n  = 13), patients with mild AD (mAD, n  = 15), and healthy elderly controls (n  = 13). Results showed an increased expression of CD177 in mAD but not in healthy or aMCI patients. IL-8 stimulated increased expression of the CD11b integrin in PMN of healthy subjects in …vitro but PMN of aMCI and mAD patients failed to respond. CD14 and CD16 expression was lower in PMN of mAD but not in aMCI individuals relative to controls. Only PMN of aMCI subjects expressed lower levels of CD88. Phagocytosis toward opsonized E. coli was differentially impaired in PMN of aMCI and mAD subjects whereas the capacity to ingest Dextran particles was absent only in mAD subjects. Killing activity was severely impaired in aMCI and mAD subjects whereas free radical production was only impaired in mAD patients. Inflammatory cytokine (TNFα, IL-6, IL-1β, IL-12p70) and chemokine (MIP-1α, MIP-1β, IL-8) production in response to LPS stimulation was very low in aMCI and nearly absent in mAD subjects. TLR2 expression was low only in aMCI. Our data showed a differentially altered capacity of PMN of aMCI and mAD subjects to respond to pathological aggression that may impact impaired responses associated with AD development. Show more

Keywords: Alzheimer’s disease, aMCI patients, polymorphonuclear neutrophils

DOI: 10.3233/JAD-170124

Citation: Journal of Alzheimer's Disease, vol. 60, no. 1, pp. 23-42, 2017

Authors: Adams, Stephanie L. | Benayoun, Laurent | Tilton, Kathy | Chavez, Olivia R. | Himali, Jayandra J. | Blusztajn, Jan Krzysztof | Seshadri, Sudha | Delalle, Ivana

Article Type: Research Article

Abstract: Genome-wide association studies (GWAS) identified susceptibility loci associated with decreased hippocampal volume, and found hippocampal subfield-specific effects at MSRB3 (methionine sulfoxide reductase-B3). The MSRB3 locus was also linked to increased risk for late onset Alzheimer’s disease (AD). In this study, we uncovered novel sites of MsrB3 expression in CA pyramidal layer and arteriolar walls by using automated immunohistochemistry on hippocampal sections from 23 individuals accompanied by neuropathology reports and clinical dementia rating scores. Controls, cognitively intact subjects with no hippocampal neurofibrillary tangles, exhibited MsrB3 signal as distinct but rare puncta in CA1 pyramidal neuronal somata. In CA3, however, …MsrB3-immunoreactivity was strongest in the neuropil of the pyramidal layer. These patterns were replicated in rodent hippocampi where ultrastructural and immunohistofluorescence analysis revealed MsrB3 signal associated with synaptic vesicles and colocalized with mossy fiber terminals. In AD subjects, the number of CA1 pyramidal neurons with frequent, rather than rare, MsrB3-immunoreactive somatic puncta increased in comparison to controls. This change in CA1 phenotype correlated with the occurrence of AD pathological hallmarks. Moreover, the intensity of MsrB3 signal in the neuropil of CA3 pyramidal layer correlated with the signal pattern in neurons of CA1 pyramidal layer that was characteristic of cognitively intact individuals. Finally, MsrB3 signal in the arteriolar walls in the hippocampal white matter decreased in AD patients. This characterization of GWAS-implicated MSRB3 protein expression in human hippocampus suggests that patterns of neuronal and vascular MsrB3 protein expression reflect or underlie pathology associated with AD. Show more

Keywords: Alzheimer’s disease, CA1, CA3, hippocampal arterioles, MsrB3, synaptic vesicles

DOI: 10.3233/JAD-170459

Citation: Journal of Alzheimer's Disease, vol. 60, no. 1, pp. 43-56, 2017

Authors: Radakovic, Ratko | Starr, John M. | Abrahams, Sharon

Article Type: Research Article

Abstract: Background: Apathy is a complex multidimensional syndrome frequently reported in Alzheimer’s disease (AD) and is associated with impaired awareness. Here we present a psychometrically robust method to profile apathy in AD. Objectives: To determine the validity and reliability of a multidimensional apathy measure, the Dimensional Apathy Scale (DAS), and explore the apathy subtype profile and its associations in AD. Methods: 102 people with AD and 55 healthy controls were recruited. Participants completed the DAS, the Apathy Evaluation Scale (AES), Geriatric Depression Short form (GDS-15), and Lawton Instrumental Activities of Daily Living (LIADL). Psychometric properties of the …DAS were determined. AD-Control comparison was performed to explore group differences on the DAS. Latent Class Analysis (LCA) was used to explore the profile of apathy in AD. Results: The DAS had a good to excellent Cronbach’s standardized alpha (self-rated = 0.85, informant/carer-rated = 0.93) and good convergent and divergent validity against standard apathy (AES) and depression (GDS-15) measures. Group comparison showed people with AD were significantly higher for all apathy subtypes than controls (p  < 0.001), and lacking in awareness over all apathy subtype deficits. LCA showed three distinct AD subgroups, with 42.2% in the Executive-Initiation apathy, 28.4% in the Global apathy, and 29.4% in the Minimal apathy group. Conclusions: The DAS is a psychometrically robust method of assessing multidimensional apathy in AD. The apathy profiles in AD are heterogeneous, with additional specific impairments relating to awareness dependent on apathy subtype. Show more

Keywords: Alzheimer’s disease, apathy, awareness, behavior rating scale, psychometrics, syndrome

DOI: 10.3233/JAD-170292

Citation: Journal of Alzheimer's Disease, vol. 60, no. 1, pp. 57-67, 2017

Authors: Thibeau, Sherilyn | McFall, G. Peggy | Camicioli, Richard | Dixon, Roger A.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) risk-reduction strategies (e.g., increasing physical activity, improving mobility) have garnered increasing attention in the literature. However, the effect of such modifiable factors on the preclinical trajectories of brain and cognitive health may be moderated by non-modifiable biomarkers associated with AD. Objective: In a longitudinal sample of non-demented older adults, we examine the independent predictors everyday physical activity (EPA) and mobility on executive function (EF) performance and change. Next, we test whether these predictions are modified by interactions between age and AD genetic risk. Methods: This accelerated longitudinal design included adults (n  = 532, …M age = 70.4, age range 53–95) from the Victoria Longitudinal Study. We tested the independent effects of EPA and Mobility (i.e., gait, balance), moderation by Apolipoprotein E (i.e., APOE ɛ 4+, ɛ 4–) and age (young-old, middle-old, old-old), and interactions between APOE and age on performance and 9-year change in an EF latent variable. Results: First, higher levels of both EPA and Mobility were associated with better EF performance and less decline. Second, the interaction between age and APOE showed that low EPA and older age was associated with poorer EF performance and steeper EF decline for APOE ɛ 4 + carriers, and low mobility was associated with poorer EF performance and steeper EF decline for APOE ɛ 4 + carriers than the non-risk carriers. Conclusion: In non-demented older adults, age moderated the effects of both EPA and Mobility on EF performance and change. However, this moderation occurs differentially across APOE4 status. Show more

Keywords: Apolipoprotein E, everyday physical activity, executive function, mobility, Victoria Longitudinal Study

DOI: 10.3233/JAD-170130

Citation: Journal of Alzheimer's Disease, vol. 60, no. 1, pp. 69-86, 2017

Authors: Zhang, Nan | Zhang, Liling | Li, Yan | Gordon, Marc L. | Cai, Li | Wang, Ying | Xing, Mengya | Cheng, Yan

Article Type: Research Article

Abstract: Background: Expression of neuronal thread protein (NTP), which is considered to be related to neuritic sprouting and neuronal death, may be elevated in brain tissue, cerebrospinal fluid, and even urine in patients with Alzheimer’s disease (AD). Objective: In this study, we analyzed the correlation between urine AD-associated NTP (AD7c-NTP) level, and amyloid-β (Aβ) deposition, and clinical symptoms in AD and mild cognitive impairment (MCI). Methods: Twenty-two patients with mild to moderate AD and 8 subjects with MCI were recruited. Aβ deposition was measured with [11 C]-labeled Pittsburgh compound B (PiB)-positron emission tomography (PET) in all participants. …Urine AD7c-NTP levels were measured using enzyme-linked immunosorbent assay. Mini-Mental State Examination (MMSE) and Neuropsychiatric Inventory (NPI) were used to evaluate cognitive function and behavioral psychological symptoms, respectively. Results: Fourteen (63.6%) of AD patients and 2 (25.0%) of MCI subjects were Aβ positive on PiB-PET. There was a significant difference in urine AD7c-NTP level between Aβ positive (2.27±2.22 ng/ml) and negative (0.55±0.60 ng/ml) subjects (p  = 0.018). Using 1.46 ng/ml as a cut-off value, 68.8% of Aβ positive subjects showed elevated urine AD7c-NTP level, and 92.9% of Aβ negative subjects showed normal urine AD7c-NTP level. There were no relationships between urine AD7c-NTP level and MMSE and total NPI scores. However, AD7c-NTP level positively correlated with agitation score on NPI. Conclusions: Urine AD7c-NTP had high specificity and moderate sensitivity in predicting Aβ deposition among patients with cognitive impairment. Furthermore, urine AD7c-NTP level strongly correlated with the symptom of agitation. Show more

Keywords: Agitation, Alzheimer’s disease, amyloid-β, mild cognitive impairment, neuronal thread protein

DOI: 10.3233/JAD-170383

Citation: Journal of Alzheimer's Disease, vol. 60, no. 1, pp. 87-95, 2017

Authors: Fladby, Tormod | Pålhaugen, Lene | Selnes, Per | Waterloo, Knut | Bråthen, Geir | Hessen, Erik | Almdahl, Ina Selseth | Arntzen, Kjell-Arne | Auning, Eirik | Eliassen, Carl Fredrik | Espenes, Ragna | Grambaite, Ramune | Grøntvedt, Gøril Rolfseng | Johansen, Krisztina Kunszt | Johnsen, Stein Harald | Kalheim, Lisa Flem | Kirsebom, Bjørn-Eivind | Müller, Kai Ivar | Nakling, Arne Exner | Rongve, Arvid | Sando, Sigrid Botne | Siafarikas, Nikias | Stav, Ane Løvli | Tecelao, Sandra | Timon, Santiago | Bekkelund, Svein Ivar | Aarsland, Dag

Article Type: Research Article

Abstract: While APOE ɛ 4 is the major genetic risk factor for Alzheimer’s disease (AD), amyloid dysmetabolism is an initial or early event predicting clinical disease and is an important focus for secondary intervention trials. To improve identification of cases with increased AD risk, we evaluated recruitment procedures using pathological CSF concentrations of Aβ42 (pAβ) and APOE ɛ 4 as risk markers in a multi-center study in Norway. In total, 490 subjects aged 40–80 y were included after response to advertisements and media coverage or memory clinics referrals. Controls (n  = 164) were classified as normal controls without first-degree …relatives with dementia (NC), normal controls with first-degree relatives with dementia (NCFD), or controls scoring below norms on cognitive screening. Patients (n  = 301) were classified as subjective cognitive decline or mild cognitive impairment. Subjects underwent a clinical and cognitive examination and MRI according to standardized protocols. Core biomarkers in CSF from 411 and APOE genotype from 445 subjects were obtained. Cases (both self-referrals (n  = 180) and memory clinics referrals (n  = 87)) had increased fractions of pAβ and APOE ɛ 4 frequency compared to NC. Also, NCFD had higher APOE ɛ 4 frequencies without increased fraction of pAβ compared to NC, and cases recruited from memory clinics had higher fractions of pAβ and APOE ɛ 4 frequency than self-referred. This study shows that memory clinic referrals are pAβ enriched, whereas self-referred and NCFD cases more frequently are pAβ negative but at risk (APOE ɛ 4 positive), suitable for primary intervention. Show more

Keywords: Alzheimer’s disease, amyloid, apolipoprotein E4, biomarkers, cerebrospinal fluid, mild cognitive impairment, subjective cognitive decline

DOI: 10.3233/JAD-170231

Citation: Journal of Alzheimer's Disease, vol. 60, no. 1, pp. 97-105, 2017

Authors: Werner, Christian | Wiloth, Stefanie | Lemke, Nele Christin | Kronbach, Florian | Jansen, Carl-Philipp | Oster, Peter | Bauer, Jürgen M. | Hauer, Klaus

Article Type: Research Article

Abstract: Background: A complex motor skill highly relevant to mobility in everyday life (e.g., sit-to-stand [STS] transfer) has not yet been addressed in studies on motor learning in people with dementia (PwD). Objective: To determine whether a dementia-specific motor learning exercise program enables PwD to learn compensatory STS maneuvers commonly taught in geriatric rehabilitation therapy to enhance patients’ STS ability. Methods: Ninety-seven patients with mild-to-moderate dementia (Mini-Mental State Examination: 21.9±2.9 points) participated in a double-blinded, randomized, placebo-controlled trial with 10-week intervention and 3-month follow-up period. The intervention group (IG, n  = 51) underwent a motor learning exercise program …on compensatory STS maneuvers specifically designed for PwD. The control group (CG, n  = 46) performed a low-intensity motor placebo activity. Primary outcomes were scores of the Assessment of Compensatory Sit-to-stand Maneuvers in People with Dementia (ACSID), which covers the number of recalled and initiated, and of effectively performed compensatory STS maneuvers. Secondary outcomes included temporal and kinematic STS characteristics measured by a body-fixed motion sensor (BFS, DynaPort® Hybrid). Results: The IG significantly improved in all ACSID scores compared to the CG (p  < 0.001). Secondary analysis confirmed learning effects for all BFS-based outcomes (p  < 0.001–0.006). Learning gains were sustained during follow-up for most outcomes. Conclusion: People with mild-to-moderate dementia can learn and retain compensatory STS maneuvers in response to a dementia-specific motor learning exercise program. This is the first study that demonstrated preserved motor learning abilities in PwD by using a motor skill highly relevant to everyday life. Show more

Keywords: Dementia, learning, motor skills, movement, randomized controlled trial, rehabilitation

DOI: 10.3233/JAD-170258

Citation: Journal of Alzheimer's Disease, vol. 60, no. 1, pp. 107-120, 2017

Authors: Bloch, Konstantin | Gil-Ad, Irit | Vanichkin, Alexey | Hornfeld, Shay Henry | Koroukhov, Nickolay | Taler, Michal | Vardi, Pnina | Weizman, Abraham

Article Type: Research Article

Abstract: Background: Animal models of dementia associated with metabolic abnormalities play an important role in understanding the bidirectional relationships between these pathologies. Rodent strains develop cognitive dysfunctions without alteration of peripheral metabolism following intracerebroventricular administration of streptozotocin (icv-STZ). Objective: We aimed to estimate the effect of icv-STZ on cognitive functions and peripheral metabolism in Lewis rats, which are rarely used for the induction of cognitive abnormalities. Methods: Inbred adult Lewis rats were treated with single icv-STZ (3 mg/kg). Cognitive functions were assessed using Morris water maze (MWM) test and locomotion by the Open Field test. Metabolic alterations were …studied using histological and biochemical analysis of brain and peripheral tissues. Results: The icv-STZ induced rapid weight decline during the first two weeks. Thereafter, the rats showed an accelerated weight gain. Three months after the icv-STZ treatment, the rats were severely obese and revealed fatty liver, pancreatic islet hypertrophy, significantly elevated levels of blood insulin, leptin, and adiponectin, but intact peripheral glucose homeostasis. The icv-STZ rats expressed amyloid-β deposits in blood vessels of leptomeningeal area, microgliosis, astrogliosis, and spongiosis in fimbria-fornix area of hippocampus. Locomotor activities of icv-STZ treated and sham-operated rats were similar. In the MWM test, the icv-STZ treated rats demonstrated severely impaired spatial learning during both acquisition and reversal phases. Conclusions: Icv-STZ treated Lewis rats develop severe dementia associated with obesity and peripheral metabolic abnormalities. This animal model may be useful for exploring the pathophysiological relationship between obesity and dementia and provides a new tool for development of effective therapy. Show more

Keywords: Animal models, body weight changes, cognitive decline, intracerebroventricular administration of streptozotocin, neuroinflammation, peripheral metabolic dysfunctions

DOI: 10.3233/JAD-161289

Citation: Journal of Alzheimer's Disease, vol. 60, no. 1, pp. 121-136, 2017