Journal of Alzheimer's Disease - Volume 70, issue 2

Article Type: Editorial

DOI: 10.3233/JAD-199004

Citation: Journal of Alzheimer's Disease, vol. 70, no. 2, pp. 315-316, 2019

Authors: Akpan, Asangaedem | Tabue-Teguo, Maturin | Fougère, Bertrand

Article Type: Review Article

Abstract:  Neurocognitive disorders create important challenges for patients, their families, and clinicians who provide their health care. Early/timely detection in daily clinical practice allows for diagnosis and adequate treatment, psychosocial support, education, and engagement in shared decision-making related to health care, life planning, involvement in research, and financial matters. However, neurocognitive disorders, when present, are not detected or not diagnosed and not documented, in more than half of patients seen by primary care physicians. The aim of this paper is to highlight the strategies and the perspectives to improve the early/timely detection of neurocognitive disorders in daily clinical practice.

Keywords: Daily clinical practice, detection, neurocognitive disorders, older people, prevention, tools

DOI: 10.3233/JAD-180381

Citation: Journal of Alzheimer's Disease, vol. 70, no. 2, pp. 317-322, 2019

Authors: El-Hayek, Youssef H. | Wiley, Ryan E. | Khoury, Charles P. | Daya, Ritesh P. | Ballard, Clive | Evans, Alison R. | Karran, Michael | Molinuevo, José Luis | Norton, Matthew | Atri, Alireza

Article Type: Review Article

Abstract: While it is generally understood that Alzheimer’s disease (AD) and related dementias (ADRD) is one of the costliest diseases to society, there is widespread concern that researchers and policymakers are not comprehensively capturing and describing the full scope and magnitude of the socioeconomic burden of ADRD. This review aimed to 1) catalogue the different types of AD-related socioeconomic costs described in the literature; 2) assess the challenges and gaps of existing approaches to measuring these costs; and 3) analyze and discuss the implications for stakeholders including policymakers, healthcare systems, associations, advocacy groups, clinicians, and researchers looking to improve the ability …to generate reliable data that can guide evidence-based decision making. A centrally emergent theme from this review is that it is challenging to gauge the true value of policies, programs, or interventions in the ADRD arena given the long-term, progressive nature of the disease, its insidious socioeconomic impact beyond the patient and the formal healthcare system, and the complexities and current deficiencies (in measures and real-world data) in accurately calculating the full costs to society. There is therefore an urgent need for all stakeholders to establish a common understanding of the challenges in evaluating the full cost of ADRD and define approaches that allow us to measure these costs more accurately, with a view to prioritizing evidence-based solutions to mitigate this looming public health crisis. Show more

Keywords: Alzheimer’s disease, caregivers, cost of illness, dementia, disease progression, health care costs, health policy, long-term care, resource allocation

DOI: 10.3233/JAD-190426

Citation: Journal of Alzheimer's Disease, vol. 70, no. 2, pp. 323-341, 2019

Authors: Calderón-Garcidueñas, Lilian | González-Maciel, Angélica | Kulesza, Randy J. | González-González, Luis Oscar | Reynoso-Robles, Rafael | Mukherjee, Partha S. | Torres-Jardón, Ricardo

Article Type: Review Article

Abstract: Exposures to fine particulate matter (PM2.5 ) and ozone (O3 ) ≥US EPA standards are associated with Alzheimer’s disease (AD) risk. The projection of 13.8 million AD cases in the US by the year 2050 obligate us to explore early environmental exposures as contributors to AD risk and pathogenesis. Metropolitan Mexico City children and young adults have lifetime exposures to PM2.5 and O3 , and AD starting in the brainstem and olfactory bulb is relentlessly progressing in the first two decades of life. Magnetite combustion and friction-derived nanoparticles reach the brain and are associated with early and progressive damage …to the neurovascular unit and to brain cells. In this review: 1) we highlight the interplay environment/genetics in the AD development in young populations; 2) comment upon ApoE ɛ 4 and the rapid progression of neurofibrillary tangle stages and higher suicide risk in youth; and 3) discuss the role of combustion-derived nanoparticles and brain damage. A key aspect of this review is to show the reader that air pollution is complex and that profiles change from city to city with common denominators across countries. We explore and compare particulate matter profiles in Mexico City, Paris, and Santiago in Chile and make the point of why we should invest in decreasing PM2.5 to at least our current US EPA standard. Multidisciplinary intervention strategies are critical for prevention or amelioration of cognitive deficits and AD progression and risk of suicide in young individuals. AD pathology evolving from childhood is threating the wellbeing of future generations. Show more

Keywords: Air pollution, Alzheimer’s disease continuum, ApoE ɛ4, combustion and friction derived nanoparticles, Mexico City, Paris, PM2.5, Santiago de Chile, suicide, tauopathies

DOI: 10.3233/JAD-190331

Citation: Journal of Alzheimer's Disease, vol. 70, no. 2, pp. 343-360, 2019

Authors: Wolf, Dominik | Fischer, Florian U. | Fellgiebel, Andreas | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: The present study aims at investigating if the association between amyloid-β and longitudinal cognitive decline in cognitively healthy elderly is modulated by resilience capacity. Resilience capacity was quantified by education, which is a common proxy of resilience and has been shown to be related to a wide range of behaviors promoting resilience. Analyses were conducted with longitudinal cognitive data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). 276 cognitively healthy older individuals (≥56 years) were included in the study. Baseline amyloid pathology was quantified using CSF amyloid-β 1–42 measurements. Longitudinal cognitive decline was assessed using ADAS13, Clinical Dementia Rating – Sum …of Boxes, and ADNI-Memory composite scores. Duration of follow-up was 10 years (mean follow-up: 2.6 years). Linear mixed effects models demonstrated stronger cognitive decline over time with increasing baseline amyloid. Subsequent mixed-effects analyses showed that this amyloid-related cognitive decline is stronger in individuals with lower resilience capacity (i.e., lower levels of education). Of note, this effect was not an artifact of differences in neurodegeneration patterns between individuals with lower and higher resilience. Results suggest that resilience capacity has high potential to counteract early amyloid pathology and to significantly slow cognitive decline. Show more

Keywords: Amyloid-β, cognitive decline, healthy older adults, preclinical Alzheimer’s disease, resilience

DOI: 10.3233/JAD-190370

Citation: Journal of Alzheimer's Disease, vol. 70, no. 2, pp. 361-370, 2019

Authors: Kelly, Sarah C. | McKay, Erin C. | Beck, John S. | Collier, Timothy J. | Dorrance, Anne M. | Counts, Scott E.

Article Type: Research Article

Abstract: Noradrenergic locus coeruleus (LC) neuron loss is a significant feature of mild cognitive impairment and Alzheimer’s disease (AD). The LC is the primary source of norepinephrine in the forebrain, where it modulates attention and memory in vulnerable cognitive regions such as prefrontal cortex (PFC) and hippocampus. Furthermore, LC-mediated norepinephrine signaling is thought to play a role in blood-brain barrier (BBB) maintenance and neurovascular coupling, suggesting that LC degeneration may impact the high comorbidity of cerebrovascular disease and AD. However, the extent to which LC projection system degeneration influences vascular pathology is not fully understood. To address this question in vivo …, we stereotactically lesioned LC projection neurons innervating the PFC of six-month-old Tg344-19 AD rats using the noradrenergic immunotoxin, dopamine-β-hydroxylase IgG-saporin (DBH-sap), or an untargeted control IgG-saporin (IgG-sap). DBH-sap-lesioned animals performed significantly worse than IgG-sap animals on the Barnes maze task in measures of both spatial and working memory. DBH-sap-lesioned rats also displayed increased amyloid and inflammation pathology compared to IgG-sap controls. However, we also discovered prominent parenchymal albumin extravasation with DBH-sap lesions indicative of BBB breakdown. Moreover, microvessel wall-to-lumen ratios were increased in the PFC of DBH-sap compared to IgG-sap rats, suggesting that LC deafferentation results in vascular remodeling. Finally, we noted an early emergence of amyloid angiopathy in the DBH-sap-lesioned Tg344-19 AD rats. Taken together, these data indicate that LC projection system degeneration is a nexus lesion that compromises both vascular and neuronal function in cognitive brain areas during the prodromal stages of AD. Show more

Keywords: Alzheimer’s disease, blood-brain barrier, cerebral amyloid angiopathy, locus coeruleus, vascular remodeling

DOI: 10.3233/JAD-190090

Citation: Journal of Alzheimer's Disease, vol. 70, no. 2, pp. 371-388, 2019

Authors: van de Beek, Marleen | van Steenoven, Inger | Ramakers, Inez H.G.B. | Aalten, Pauline | Koek, Huiberdina L. | Olde Rikkert, Marcel G.M. | Manniën, Judith | Papma, Janne M. | de Jong, Frank Jan | Lemstra, Afina W. | van der Flier, Wiesje M.

Article Type: Research Article

Abstract: Background: Quality of Life (QoL) is an important outcome measure in dementia, particularly in the context of interventions. Research investigating longitudinal QoL in dementia with Lewy bodies (DLB) is currently lacking. Objective: To investigate determinants and trajectories of QoL in DLB compared to Alzheimer’s disease (AD) and controls. Methods: QoL was assessed annually in 138 individuals, using the EQ5D-utility-score (0–100) and the health-related Visual Analogue Scale (VAS, 0–100). Twenty-nine DLB patients (age 69±6), 68 AD patients (age 70±6), and 41 controls (age 70±5) were selected from the Dutch Parelsnoer Institute-Neurodegenerative diseases and Amsterdam Dementia Cohort. We …examined clinical work-up over time as determinants of QoL, including cognitive tests, neuropsychiatric inventory, Geriatric Depression Scale (GDS), and disability assessment of dementia (DAD). Results: Mixed models showed lower baseline VAS-scores in DLB compared to AD and controls (AD : β±SE = -7.6±2.8, controls: β±SE = -7.9±3.0, p  < 0.05). An interaction between diagnosis and time since diagnosis indicated steeper decline on VAS-scores for AD patients compared to DLB patients (β±SE = 2.9±1.5, p  < 0.1). EQ5D-utility-scores over time did not differ between groups. Higher GDS and lower DAD-scores were independently associated with lower QoL in dementia patients (GDS : VAS β±SE = -1.8±0.3, EQ5D-utility β±SE = -3.7±0.4; DAD : VAS = 0.1±0.0, EQ5D-utility β±SE = 0.1±0.1, p  < 0.05). No associations between cognitive tests and QoL remained in the multivariate model. Conclusion: QoL is lower in DLB, while in AD QoL shows steeper decline as the disease advances. Our results indicate that non-cognitive symptoms, more than cognitive symptoms, are highly relevant as they impact QoL. Show more

Keywords: Alzheimer’s disease, dementia, dementia with Lewy Bodies, quality of Life

DOI: 10.3233/JAD-190041

Citation: Journal of Alzheimer's Disease, vol. 70, no. 2, pp. 389-397, 2019

Authors: Sun, Bin-Lu | Li, Wei-Wei | Wang, Jun | Xu, Ya-Li | Sun, Hao-Lun | Tian, Ding-Yuan | Wang, Yan-Jiang | Yao, Xiu-Qing

Article Type: Research Article

Abstract: Emerging evidence suggests that gut microbiota dysbiosis plays a role in neurodegenerative disorders. However, whether the composition and diversity of the gut microbiota are altered in tauopathies remains largely unknown. This study was aimed to examine the diversity and composition of the gut microbiota in tauopathies, as well as the correlation with pathological changes in the brain. We collected fecal samples from 32 P301L tau transgenic mice and 32 age- and gender-matched littermate mice at different ages. The 16S ribosomal RNA sequencing technique was used to analyze the microbiota composition in feces. Brain tau pathology levels were measured by immunohistochemistry. …The diversity and composition of the gut microbiota significantly changed with aging. At the phylum level, the relative abundance of Bacteroidetes was increased, while Firmicutes were decreased in P301L mice compared with that in Wt mice after 3 months of age. In addition, Actinobacteria was decreased in P301L mice at 3 and 6 months of age, meanwhile Tenericutes was decreased in P301L mice at 10 months of age. Moreover, several specific macrobiota were highly associated with the levels of AT8-tau or pT231-tau protein in the brain. Our findings suggest that gut microbiota changed with aging, as well as in the tauopathy mice model. Modulation of the gut microbiota may be a potential strategy for treatment of tauopathy. Show more

Keywords: 16S ribosomal RNA sequencing, gut microbiota, tau, tauopathy

DOI: 10.3233/JAD-181220

Citation: Journal of Alzheimer's Disease, vol. 70, no. 2, pp. 399-412, 2019

Authors: Lian, Teng-Hong | Zhu, Wan-Lin | Li, Shao-Wu | Liu, Ya-Ou | Guo, Peng | Zuo, Li-Jun | Hu, Yang | Yu, Shu-Yang | Li, Li-Xia | Jin, Zhao | Yu, Qiu-Jin | Wang, Rui-Dan | Zhang, Wei

Article Type: Research Article

Abstract:  We explored changes in clinical features and neuropathological mechanisms underlying olfactory dysfunction (OD) in 60 patients with Alzheimer’s disease (AD). Olfactory function was evaluated using the Sniffin’ Sticks test and a threshold discrimination identification (TDI) score. Based on the TDI score, we divided patients according to the presence or absence of OD (AD-OD and AD-NOD, respectively). Cognitive and neuropsychiatric symptoms were evaluated by a series of rating scales. The volumes and cortical thickness of the thalamus, hippocampus, and amygdala were measured using structural magnetic resonance imaging. Neuropathological protein levels in cerebrospinal fluid were measured. The frequency of OD was 50%. …TDI scores were lower in the AD-OD group than in the AD-NOD group (p  < 0.001). Compared with the AD-NOD group, the AD-OD group showed greater cognitive function impairments (p  < 0.001), and daily living activities were more severely compromised (p  = 0.019). The AD-OD group had lower hippocampal and amygdala volumes (p  = 0.025, p  = 0.030, respectively) and a more pronounced reduction in cortical thickness (p  = 0.010). The total tau level was lower in the AD-OD group than the AD-NOD group (p  = 0.040). Lower Mini-Mental State Examination scores and thinner AD-signature cortices were associated with lower TDI scores (OR = 0.826, p  < 0.001; OR = 1.433, p  = 0.008). Overall, in AD patients, the impairments in olfactory discrimination and identification seem to be more correlated with cognitive levels. OD in AD may be an indicator of pathological cognitive decline and structural changes. Show more

Keywords: Alzheimer’s disease, clinical features, neuropathological mechanism, olfactory dysfunctions, structural MRI

DOI: 10.3233/JAD-181217

Citation: Journal of Alzheimer's Disease, vol. 70, no. 2, pp. 413-423, 2019

Authors: D’Antonio, Fabrizia | De Bartolo, Maria Ilenia | Ferrazzano, Gina | Trebbastoni, Alessandro | Amicarelli, Sara | Campanelli, Alessandra | de Lena, Carlo | Berardelli, Alfredo | Conte, Antonella

Article Type: Research Article

Abstract: Background: The temporal processing of sensory information can be evaluated by testing the somatosensory temporal discrimination threshold (STDT), which is defined as the shortest interstimulus interval needed to recognize two sequential sensory stimuli as separate in time. The STDT requires the functional integrity of the basal ganglia and of the somatosensory cortex (S1). Although there is evidence that time processing is impaired in patients with Alzheimer’s disease (AD), no study has yet investigated STDT in patients with various degree of cognitive impairment. Objective: The aim of our study was to understand how cognition and attention deficits affect STDT …values in patients with cognitive abnormalities. Methods: We enrolled 63 patients: 28 had mild-moderate AD, 16 had mild cognitive impairment (MCI), and the remaining 19 had subjective cognitive deficit (SCD). A group of 45 age-matched healthy subjects acted as controls. Paired tactile stimuli for STDT testing consisted of square-wave electrical pulses delivered with a constant current stimulator through surface electrodes over the distal phalanx of the index finger. Results: STDT values were higher in AD and MCI patients than in SCD subjects or healthy controls. Changes in the STDT in AD and MCI were similar in both conditions and did not correlate with disease severity. Conclusions: STDT alterations in AD and MCI may reflect a dysfunction of the dopaminergic system, which signals salient events and includes the striatum and the mesocortical and mesolimbic circuits. Show more

Keywords: Alzheimer’s disease, mild cognitive impairment, somatosensory temporal discrimination threshold, subjective cognitive decline, temporal processing

DOI: 10.3233/JAD-190385

Citation: Journal of Alzheimer's Disease, vol. 70, no. 2, pp. 425-432, 2019