Journal of Alzheimer's Disease - Volume 68, issue 2

Authors: Lee, Cecilia S. | Larson, Eric B. | Gibbons, Laura E. | Latimer, Caitlin S. | Rose, Shannon E. | Hellstern, Leanne L. | Keene, C. Dirk | Crane, Paul K. | for the Adult Changes in Thought (ACT) Study

Article Type: Research Article

Abstract: Background: The aging eye offers unique opportunities to study and understand the aging brain, in particular related to Alzheimer’s disease (AD) and dementia. However, little is known about relationships between eye diseases and dementia-related neurodegeneration. Objective: To determine the potential association between three age-related eye diseases and AD and dementia-related neuropathology. Methods: We reviewed autopsy data from the prospective longitudinal Adult Changes in Thought (ACT) cohort. ICD-9 codes were used to identify diagnoses of diabetic retinopathy, glaucoma, and age-related macular degeneration. Multivariate regression models were used to determine odds ratios (OR) of neuropathology features associated with …dementia, including Braak stage, Consortium to Establish a Registry for AD (CERAD score), Lewy bodies, hippocampal sclerosis, and microvascular brain injury, in addition to quantitative paired helical filament (PHF)-tau levels for people with and without each eye condition. We also evaluated interactions between eye conditions and dementia related neuropathologic findings were evaluated. Results: 676 autopsies were included. Diabetic retinopathy was significantly associated with increased risk of deep cerebral microinfarcts (OR = 1.91 [95% confidence interval (CI) 1.11, 3.27], p  = 0.02). No other significant association or interaction between eye diseases and neuropathology was found. When PHF-tau quantity was evaluated in 124 decedents, the OR for the association between PHF-tau in the occipital cortex and glaucoma was 1.36 (95% CI 0.91, 2.03, p  = 0.13). No statistical correction was made for multiple comparisons. Conclusion: Increased risk of deep cerebral microinfarcts was found in participants diagnosed with diabetic retinopathy. Eye diseases such as glaucoma may increase susceptibility to neurofibrillary tangles in the occipital cortex. Show more

Keywords: Alzheimer’s disease, diabetic retinopathy, glaucoma, macular degeneration, neuropathology

DOI: 10.3233/JAD-181087

Citation: Journal of Alzheimer's Disease, vol. 68, no. 2, pp. 647-655, 2019

Authors: de la Monte, Suzanne M. | Tong, Ming | Daiello, Lori A. | Ott, Brian R.

Article Type: Research Article

Abstract: Background: Brain insulin resistance is a well-recognized abnormality in Alzheimer’s disease (AD) and the likely mediator of impaired glucose utilization that emerges early and progresses with disease severity. Moreover, the rates of mild cognitive impairment (MCI) or AD are significantly greater in people with diabetes mellitus or obesity. Objective: This study was designed to determine whether systemic and central nervous system (CNS) insulin resistant disease states emerge together and thus may be integrally related. Methods: Insulin-related molecules were measured in paired human serum and cerebrospinal fluid (CSF) samples from 19 with MCI or early AD, and …21 controls using a multiplex ELISA platform. Results: In MCI/AD, both the CSF and serum samples had significantly elevated mean levels of C-peptide and an incretin, and reduced expression of Visfatin, whereas only CSF showed significant reductions in insulin and leptin and only serum had increased glucagon, PAI-1, and ghrelin. Although the overall CSF and serum responses reflected insulin resistance together with insulin deficiency, the specific alterations measured in CSF and serum were different. Conclusion: In MCI and early-stage AD, CNS and systemic insulin-related metabolic dysfunctions, including insulin resistance, occur simultaneously, suggesting that they are integrally related and possibly mediated similar pathogenic factors. Show more

Keywords: Alzheimer’s disease, cerebrospinal fluid, insulin resistance, mild cognitive impairment, neurodegeneration, serum

DOI: 10.3233/JAD-180906

Citation: Journal of Alzheimer's Disease, vol. 68, no. 2, pp. 657-668, 2019

Authors: Nunes, Paula Villela | Schwarzer, Monise Caroline | Leite, Renata Elaine Paraizo | Ferretti-Rebustini, Renata Eloah de Lucena | Pasqualucci, Carlos Augusto | Nitrini, Ricardo | Rodriguez, Roberta Diehl | Nascimento, Camila Fernandes | Oliveira, Katia Cristina de | Grinberg, Lea Tenenholz | Jacob-Filho, Wilson | Lafer, Beny | Suemoto, Claudia Kimie

Article Type: Research Article

Abstract: Background: Behavioral and psychological symptoms (BPSD) can be a prodrome of dementia, and the Neuropsychiatric Inventory (NPI) is widely used for BPSD evaluation. Objective: To compare the prevalence of BPSD according to cognitive status, and to determine NPI cutoffs that best discern individuals with mild cognitive impairment (MCI) and dementia from those without dementia. Methods: We included 1,565 participants (mean age = 72.7±12.2 years, 48% male). BPSD and cognitive status were assessed with the NPI and the Clinical Dementia Rating (CDR). We used multivariable logistic regression models to investigate the association of BPSD with cognitive status. The area …under the curve (AUC) was used to assess model discrimination, and to determine the best NPI cutoff for MCI and dementia. Results: Participants were cognitively normal (CDR = 0; n  = 1,062), MCI (CDR = 0.5; n  = 145), or dementia (CDR≥1.0, n  = 358). NPI symptoms were more frequent in dementia and MCI when compared to cognitively normal. Higher odds for delusions, hallucinations, disinhibition, and psychomotor alterations were found among participants with dementia and MCI than in those who were cognitively normal. The best NPI cutoff to discern participants with dementia from those cognitively normal was 11 (AUC = 0.755). Poor discrimination (AUC = 0.563) was found for the comparison of MCI and those cognitively normal. Conclusions: We found an increase in BPSD frequencies across the continuum of cognitive impairment. BPSD severity and frequency in MCI was more similar to individuals cognitively normal than with dementia. NPI scores≥to 11 in individuals with no diagnosis of dementia can support the decision for further investigation of dementia. Show more

Keywords: Behavioral and psychological symptoms, dementia, mild cognitive impairment, Neuropsychiatric Inventory

DOI: 10.3233/JAD-180641

Citation: Journal of Alzheimer's Disease, vol. 68, no. 2, pp. 669-678, 2019

Authors: Boccia, Maddalena | Di Vita, Antonella | Diana, Sofia | Margiotta, Roberta | Imbriano, Letizia | Rendace, Lidia | Campanelli, Alessandra | D’Antonio, Fabrizia | Trebbastoni, Alessandro | de Lena, Carlo | Piccardi, Laura | Guariglia, Cecilia

Article Type: Research Article

Abstract: Spatial navigation tasks reveal small differences between normal and pathological aging and may thus disclose potential neuropsychological predictors of neurodegenerative diseases. The aim of our study was to investigate which navigational skills are compromised in the early phase of pathological aging as well as the extent to which they are compromised. We performed an extensive neuropsychological evaluation based on working memory and learning tasks (i.e., Corsi Block-Tapping Test and Walking Corsi Test) involving both reaching and navigational vista spaces. We also assessed spatial navigation skills in the real world by asking participants to perform route-learning and landmark-recognition tasks. We conducted …a cross-sectional study on nineteen patients with a diagnosis of mild cognitive impairment (MCI) who displayed either an isolated memory deficit (single-domain amnestic MCI, MCIsd; N = 3) or a memory deficit associated with deficits in other cognitive functions (multi-domain MCI, MCImd; N = 16) as well as on nineteen healthy control participants. The groups’ performances were compared by means of mixed factorial ANOVA and two-sample t -tests. We found that patients with MCI performed worse than controls, especially when they were required to learn spatial positions within the navigational vista space. Route-learning within the real environment was also impaired whereas landmark-recognition was spared. The same pattern of results emerged in the MCImd subgroup. Moreover, single case analyses on MCIsd patients revealed a dissociation between learning of spatial positions within navigational vista space and within reaching space. These results suggest that topographical learning is compromised in the early phase of MCIsd and MCImd and that spatial navigation tasks may be used to better characterize topographical disorientation in MCI patients as well as for the early diagnosis of pathological aging. Show more

Keywords: Alzheimer’s disease, environmental navigation, mild cognitive impairment, topographical memory

DOI: 10.3233/JAD-180890

Citation: Journal of Alzheimer's Disease, vol. 68, no. 2, pp. 679-693, 2019

Authors: Strunz, Maximilian | Jarrell, Juliet T. | Cohen, David S. | Rosin, Eric R. | Vanderburg, Charles R. | Huang, Xudong

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is an age-related progressive form of dementia that features neuronal loss, intracellular tau, and extracellular amyloid-β (Aβ) protein deposition. Neurodegeneration is accompanied by neuroinflammation mainly involving microglia, the resident innate immune cell population of the brain. During AD progression, microglia shift their phenotype, and it has been suggested that they express matricellular proteins such as secreted protein acidic and rich in cysteine (SPARC) and Hevin protein, which facilitate the migration of other immune cells, such as blood-derived dendritic cells. We have detected both SPARC and Hevin in postmortem AD brain tissues and confirmed significant alterations in transcript …expression using real-time qPCR. We suggest that an infiltration of myeloid-derived immune cells occurs in the areas of diseased tissue. SPARC is highly expressed in AD brain and collocates to Aβ protein deposits, thus contributing actively to cerebral inflammation and subsequent tissue repair, and Hevin may be downregulated in the diseased state. However, further research is needed to reveal the exact roles of SPARC and Hevin proteins and associated signaling pathways in AD-related neuroinflammation. Nevertheless, normalizing SPARC/Hevin protein expression such as interdicting heightened SPARC protein expression may confer a novel therapeutic opportunity for modulating AD progression. Show more

Keywords: Alzheimer’s disease, amyloid-β , dendritic cells, Hevin/SPARCL1 protein, macrophages, microglia, SPARC protein

DOI: 10.3233/JAD-181032

Citation: Journal of Alzheimer's Disease, vol. 68, no. 2, pp. 695-710, 2019

Authors: Ngabirano, Laure | Samieri, Cecilia | Feart, Catherine | Gabelle, Audrey | Artero, Sylvaine | Duflos, Claire | Berr, Claudine | Mura, Thibault

Article Type: Research Article

Abstract: Background: The links between diet and the risk of dementia have never been studied considering the possibility of protopathic bias (i.e., reverse causation). Objective: We aimed to examine the relationship between consumption frequency of meat, fish, fruits, and vegetables and long-term risk of dementia and Alzheimer’s disease (AD), by taking into account this possibility. Methods: We analyzed data of 5,934 volunteers aged 65 and over from the Three-city study who were followed every 2 to 4 years for 12 years. Dietary habits were assessed at inclusion using a brief food frequency questionnaire. The presence of symptoms …of dementia was investigated at each follow-up visit. To limit the risk of protopathic bias, a 4-year lag window between exposure and disease assessment was implemented by excluding from the analyses all dementia cases that occurred during the first four years after inclusion. Analyses were performed using a Cox proportional hazard model and were adjusted for socio-demographic, lifestyle, and health factors. Results: The average follow-up time was 9.8 years. During this period, 662 cases of dementia, including 466 of AD, were identified. After adjustment, only low meat consumption (≤1 time/week) was associated with an increased risk of dementia and AD compared with regular consumption (≥4 times/week) (HR = 1.58 95% CI = [1.17–2.14], HR = 1.67 95% CI = [1.18–2.37], respectively). No association was found between the consumption of fish, raw fruits, or cooked fruits and vegetables and the risk of dementia or AD. Conclusion: These findings suggest very low meat consumption increases the long-term risk of dementia and AD, and that a protopathic bias could have impacted finding from previous studies. Show more

Keywords: Cohort, dementia, fish, meat, protopathic bias, reverse causation

DOI: 10.3233/JAD-180919

Citation: Journal of Alzheimer's Disease, vol. 68, no. 2, pp. 711-722, 2019

Authors: Abu-Rumeileh, Samir | Giannini, Giulia | Polischi, Barbara | Albini-Riccioli, Luca | Milletti, David | Oppi, Federico | Stanzani-Maserati, Michelangelo | Capellari, Sabina | Mantovani, Paolo | Palandri, Giorgio | Cortelli, Pietro | Cevoli, Sabina | Parchi, Piero

Article Type: Research Article

Abstract: Cerebrospinal fluid (CSF) biomarkers have been extensively investigated in idiopathic normal pressure hydrocephalus (iNPH) with the aim of a better differential diagnosis, but the pathophysiological mechanisms underlying CSF biomarker changes and the relationship between biomarker levels and clinical variables are still a matter of debate. We evaluated CSF amyloid-β (Aβ)42 and Aβ40 , total (t)-tau, phosphorylated (p)-tau, total prion protein (t-PrP), and neurofilament light chain protein (NfL) in healthy controls (n  = 50) and subjects with iNPH (n  = 71), Alzheimer’s disease (AD) (n  = 60), and several other subtypes of dementia (n  = 145). Patients with iNPH showed significantly lower levels of …Aβ42 , Aβ40 , t-tau, and p-tau compared to controls. Similarly, t-PrP values showed a trend toward lower levels in iNPH patients than in controls. At variance, NfL levels were increased in iNPH as in all other neurodegenerative dementias, with no significant difference between “pure” iNPH cases and those with vascular or AD comorbidities. The Aβ42 /Aβ40 ratio showed higher diagnostic value than Aβ42 alone in the differential diagnosis between iNPH and AD. There were no clinically relevant associations between neuroimaging markers, scores at clinical and cognitive scales/tests, or rates of response at tap test and CSF biomarker results. In summary, the CSF biomarker signature in patients with iNPH is mainly characterized by reduced CSF concentrations of Aβ- and tau-related proteins. The assessment of CSF neurodegenerative biomarker profile in iNPH, including the Aβ42 /Aβ40 ratio, contributes to the differential diagnosis with AD and other dementias but shows poor associations with clinical variables. Show more

Keywords: Aβ42/Aβ40 ratio, Alzheimer’s disease, amyloid, dementia with Lewy bodies, frontotemporal dementia, neurofilament light chain protein, prion protein, tau, vascular dementia

DOI: 10.3233/JAD-181012

Citation: Journal of Alzheimer's Disease, vol. 68, no. 2, pp. 723-733, 2019

Authors: Nakajima, Madoka | Kuriyama, Nagato | Miyajima, Masakazu | Ogino, Ikuko | Akiba, Chihiro | Kawamura, Kaito | Kurosawa, Michiko | Watanabe, Yoshiyuki | Fukushima, Wakaba | Mori, Etsuro | Kato, Takeo | Sugano, Hidenori | Tange, Yuichi | Karagiozov, Kostadin | Arai, Hajime

Article Type: Research Article

Abstract: Background: Patients with idiopathic normal-pressure hydrocephalus (iNPH) are typically older adults with multiple comorbidities that are associated with a reduction in the efficacy of iNPH treatment via cerebrospinal fluid (CSF) shunt placement. Objective: The present study aimed to investigate the effectiveness of CSF shunt for iNPH using data from a nationwide epidemiological survey in Japan. Methods: We examined 1,423 patients (581 women) aged ≥60 years (median age [25%–75%]: 77 [73–80] years) who were diagnosed with iNPH following a hospital visit in 2012. Patients who experienced an improvement of at least one modified Rankin Scale (mRS) grade …after the CSF shunt were classified as “improvement” while the remaining patients were classified as “non-improvement.” The efficacy of the shunt intervention (n  = 842) was analyzed using a binomial logistic regression analysis. Results: An analysis of risk factors associated with shunt placement in patients with mRS grade 2 revealed an association between comorbid chronic ischemic lesions (odds ratio [OR], 2.28; 95% confidence interval [CI], 1.11–4.67; p  = 0.025) and cervical spondylosis (OR, 3.62; 95% CI, 1.15–11.34; p  = 0.027). Patients with mRS grade 3 at study entry had an association with comorbid Alzheimer’s disease (OR, 3.02; 95% CI, 1.44–6.31; p  = 0.003). Conclusions: The results presented here showed that any age-related risk is minimal and should not be cause for rejection of surgical treatment options. Clinical decisions regarding CSF shunt should be individualized to each patient, with adequate consideration of the relative risks and benefits, including maximizing a healthy life expectancy. Show more

Keywords: Alzheimer’s disease, cerebrospinal fluid shunt, geriatric care, healthy life expectancy, normal pressure hydrocephalus

DOI: 10.3233/JAD-180955

Citation: Journal of Alzheimer's Disease, vol. 68, no. 2, pp. 735-744, 2019

Authors: Nordheim, Johanna | Häusler, Andreas | Yasar, Sevil | Suhr, Ralf | Kuhlmey, Adelheid | Rapp, Michael | Gellert, Paul

Article Type: Research Article

Abstract: Background: Psychosocial interventions may improve the quality of life of both people with dementia (PWD) and their family caregivers. However, research is inconclusive and focused primarily on the quality of life of either the PWD or the caregiver, rather than on both. Objective: Our aim was to evaluate the effect of couple-based interdisciplinary psychosocial intervention in patients with mild-to-moderate dementia on quality of life of both partners. Methods: 108 community-dwelling PWD and their caregiving partners were enrolled in this pragmatic randomized controlled trial. The intervention consisted of 7 sessions at participants’ homes led by a psychotherapist …and a social worker. Quality of life was evaluated at baseline, one, and six-month follow-up for patients and their partners. Mixed effects models have been applied. Results: Intervention allocation was not associated with an improvement in quality of life in either the patients or their partners. In subgroup analyses, intervention was negatively associated with caregiver performance. However, this was only present in those reporting poor relationship quality. Patients in the intervention group who reported good relationship quality were found to have decreased cognitive decline. Conclusion: A couple-based interdisciplinary intervention did not yield improvements in quality of life. This may be the result of a bias caused by an increased awareness due to the intervention. Relationship quality and support in the long-term should be considered when designing and implementing interventions for PWD and their partners. Show more

Keywords: Caregiving, coping with illness/disability, dementia, family, psychosocial intervention, quality of life

DOI: 10.3233/JAD-180812

Citation: Journal of Alzheimer's Disease, vol. 68, no. 2, pp. 745-755, 2019

Authors: Wang, Ya-Juan | Wan, Yu | Wang, Hui-Fu | Tan, Chen-Chen | Li, Jie-Qiong | Yu, Jin-Tai | Tan, Lan | Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Two CD33 common variants, rs3826656 and rs3865444, have been identified to be correlated with Alzheimer’s disease (AD). Our study examined the effects of the two AD-related CD33 common variants (rs3826656 and rs3865444) on the chosen AD-related brain regions (including hippocampus, amygdala, parahippocampus, middle temporal, entorhinal cortex, and total brain volume) in non-demented elders recruited from the Alzheimer’s Disease Neuroimaging Initiative database at baseline and during four-year follow-up. We further tested the effects in an Aβ-positive group (including preclinical and prodromal stage of AD) and an Aβ-negative group. In the total non-demented elderly population, no associations reached significant levels …after FDR correction. In the Aβ-positive group, we found that rs3826656 was associated with hippocampal and amygdala volumes (Hippocampus-R: pc  = 0.0022; Amygdala-L: pc  = 0.0044; Amygdala-R: pc  = 0.0066), and rs3865444 was associated with right entorhinal volume (pc  = 0.0286). The associations of rs3826656 with hippocampal and amygdala volumes in the Aβ-positive group were successfully replicated in the prodromal AD group (Hippocampus-R: pc  = 0.0022; Amygdala-L: pc  = 0.0022; Amygdala-R: pc  = 0.0088). These changes became more obvious over time during four-year follow-up. No associations were found between the two CD33 variants and neuroimaging biomarkers in the Aβ-negative and preclinical AD groups after FDR correction. These results suggested that the two CD33 common variants (rs3826656 and rs3865444) influenced volumes and atrophy rates of AD-related brain regions in non-demented elders. Subgroup analyses showed the effects mainly existed in the Aβ-positive group instead of the Aβ-negative group, and the effects began in the prodromal AD stage. Show more

Keywords: Alzheimer’s disease, brain structure, CD33, neuroimaging, non-demented elders, polymorphism

DOI: 10.3233/JAD-181062

Citation: Journal of Alzheimer's Disease, vol. 68, no. 2, pp. 757-766, 2019