Journal of Alzheimer's Disease - Volume Pre-press, issue Pre-press

Authors: Monacelli, Fiammetta | Pizzonia, Monica | Signori, Alessio | Nencioni, Alessio | Gianotti, Chiara | Minaglia, Cecilia | Granello di Casaleto, Tommaso | Podestà, Silvia | Santolini, Federico | Odetti, Patrizio

Article Type: Research Article

Abstract: Background: Hip fracture is a major health problem and a patient’s biological age, comorbidity, and cognitive vulnerability have an impact on its related outcomes. Length of stay (LOS) for these highly vulnerable patients is rather long and the possible causes have not been clearly identified yet. Objective: We aimed to assess the main clinical factors associated with protracted LOS, focusing on delirium with or without dementia in older age hip fractured patients. Methods: 218 subjects (mean age 86.70±6.18 years), admitted to the Orthogeriatric Unit of the Ospedale Policlinico San Martino (Italy), were recruited. …All patients received physical and comprehensive geriatric assessment. Days to surgery, days from surgery to rehabilitation, and LOS were recorded. In-hospital and three months’ mortality were reported. Results: Prevalent delirium at hospital admission was of 3.1%. 35% of patients developed incident delirium. 56.4% were affected by dementia of Alzheimer-type. In addition, 52% of patients developed delirium superimposed to dementia. Mean LOS was 13.5±4.99 days. Namely, delirium, time to surgery, and complication rate disproportionally affected LOS. The analysis with 3 months mortality, based on cognitive vulnerability profiles, showed how delirium mainly affect short-term mortality in patients with dementia. Conclusion: Our exploratory study originally pointed out the high incidence of delirium superimposed to dementia in orthogeriatric wards and how delirium turns to be a moderator of LOS. The results meet the need for additional research by virtue of a deeper understanding of the impact of delirium and dementia on orthogeriatric clinical management and outcomes. Show more

Keywords: Cognitive vulnerability, dedicated orthogeriatric pathway, hip fracture, length of stay

DOI: 10.3233/JAD-180153

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2018

Authors: Nakajima, Madoka | Miyajima, Masakazu | Ogino, Ikuko | Akiba, Chihiro | Kawamura, Kaito | Kamohara, Chihiro | Fusegi, Keiko | Harada, Yoshinao | Hara, Takeshi | Sugano, Hidenori | Tange, Yuichi | Karagiozov, Kostadin | Kasuga, Kensaku | Ikeuchi, Takeshi | Tokuda, Takahiko | Arai, Hajime

Article Type: Research Article

Abstract: Background: Idiopathic normal pressure hydrocephalus (iNPH) is commonly treated by cerebrospinal fluid (CSF) shunting. However, the long-term efficacy of shunt intervention in the presence of comorbid Alzheimer’s disease (AD) pathology is debated. Objective: To identify AD-associated CSF biomarkers predictive of shunting surgery outcomes in patients with iNPH. Methods: Preoperative levels of total and phosphorylated Tau (p-Tau) were measured in 40 patients with iNPH divided into low (<30 pg/mL) and high (≥30 pg/mL) p-Tau groups and followed up for three years following lumboperitoneal shunting. The modified Rankin Scale (mRS), Mini-Mental State Examination (MMSE), Frontal …Assessment Battery, and iNPH Grading Scale scores were compared between the age-adjusted low (n  = 24; mean age 75.7 years [SD 5.3]) and high (n  = 11; mean age 76.0 years [SD 5.6]) p-Tau groups. Results: Cognitive function improved early in the low p-Tau group and was maintained thereafter (p  = 0.005). In contrast, the high p-Tau group showed a gradual decline to baseline levels by the third postoperative year (p  = 0.040). Although the p-Tau concentration did not correlate with the preoperative MMSE score, a negative correlation appeared and strengthened during follow-up (R2  = 0.352, p  <  0.001). Furthermore, the low p-Tau group showed rapid and sustained mRS grade improvement, whereas mRS performance gradually declined in the high p-Tau group. Conclusions: Preoperative CSF p-Tau concentration predicted some aspects of cognitive function after shunt intervention in patients with iNPH. The therapeutic effects of shunt treatment were shorter-lasting in patients with coexisting AD pathology. Show more

Keywords: Alzheimer’s disease, cerebrospinal fluid shunt, normal pressure hydrocephalus, phosphorylation, prognosis, tau proteins

DOI: 10.3233/JAD-180557

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2018

Authors: Ohtani, Ryo | Nirengi, Shinsuke | Nakamura, Michikazu | Murase, Nagako | Sainouchi, Makoto | Kuwata, Yasuhiro | Takata, Masaki | Masuda, Yuuichi | Kotani, Kazuhiko | Sakane, Naoki

Article Type: Research Article

Abstract: Background: High-density lipoprotein (HDL) containing apolipoprotein A-I is associated with the pathogenesis of Alzheimer’s disease (AD). HDL particle size is modified in the presence of pathological conditions, while the significance of the HDL particle size remains controversial. Objective: The aim of this study was to investigate the HDL lipoprotein subclasses in mild cognitive impairment (MCI) and AD. Methods: This cross-sectional study included 20 AD patients, 17 MCI patients, and 17 age-matched controls without cognitive impairment, selected from the database of the Study of Outcome and aPolipoproteins in Dementia (STOP-Dementia) registry. The diagnoses of …AD and MCI were performed by expert neurologists according to the Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition criteria. Serum HDL subclasses were measured by electrophoretic separation of lipoproteins using the Lipoprint System. The neutrophil-lymphocyte ratio (NLR), a marker of inflammation, was calculated by dividing the neutrophil count by the lymphocyte count. Results: Small-sized HDL particle levels in the MCI group were significantly higher than in the control group, although there was no difference in serum HDL-cholesterol levels between MCI and control groups. NLR in the MCI group was higher than in the control group, but this difference was non-significant (p  = 0.09). There was no difference in HDL subclasses or NLR between the AD and control groups. Conclusion: These findings suggest that HDL subclasses might be associated with the development of MCI. Show more

Keywords: Alzheimer’s disease, HDL subfraction, high-density lipoprotein, inflammation, mild cognitive impairment

DOI: 10.3233/JAD-180135

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2018

Authors: Ávila-Villanueva, Marina | Maestú, Fernando | Fernández-Blázquez, Miguel A.

Article Type: Research Article

Abstract: Background: Early intervention to prevent, or delay, the transition from healthy cognition to cognitive impairment in older adults is an important goal. In this way, it is critical to find sensitive, reproducible, and early markers to use low cost methods for the detection of that transition. One of those early markers for symptomatic manifestation of AD is subjective cognitive decline (SCD). Objective: To examine the internal consistency of the concept of SCD and to evaluate its clinical significance on the progression through the continuum of AD. Methods: 1,091 cognitively healthy individuals from the Vallecas Project cohort …were followed for three years. Cognitive complaints were systematically collected and analyzed along with clinical data. All participants were classified in three groups at every visit based on specific features of their complaints. Results: Concordance analyses showed a good agreement in longitudinal classification of SCD. The Multi-state Markov Model highlighted a unidirectional transition from the status of no cognitive complaints to SCD. Interestingly, a more severe condition of SCD, namely SCD Plus, showed the highest risk of progression to mild cognitive impairment. Conclusions: The concept of SCD is stable over time when it is operationally defined and consistently assessed. It provides not only a fast identification of individuals at higher risk of future mild cognitive impairment, but also it allows us to track longitudinal trajectories. Show more

Keywords: Aging, Alzheimer’s disease, cognitive symptoms, dementia, mild cognitive impairment, subjective cognitive decline

DOI: 10.3233/JAD-180307

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2018

Authors: Wirth, Klaus J.

Article Type: Research Article

Abstract: Background: Cerebral hypoperfusion and degeneration of the noradrenergic locus coeruleus (LC) occur early in Alzheimer’s disease (AD). Cerebral blood vessels are densely innervated by noradrenergic projections from the LC suggesting a functional role for the regulation of cerebral blood flow (CBF). Experimental LC stimulation, however, has provided no clarity as decreases or increases in CBF were reported from different experimental settings and investigators. Objective: To find out with pharmacological methods whether endogenously released norepinephrine (NE) increases or decreases carotid artery blood flow (CABF) in anesthetized pigs by investigating the effect of centrally acting alpha-2 adrenergic drugs, which increase …(atipamezole) or decrease (xylazine) NE in the brain. Methods: CABF was measured by a Doppler-flow probe placed around the left carotid artery in pentobarbital anesthetized young pigs. Results: Neither current antihypertensive drugs nor pharmacological stimulation of dopamine, histamine, serotonin or acetylcholine receptors changed CABF. The alpha-2 adrenergic-receptor agonist xylazine decreased, while the antagonist atipamezole raised CABF. This rise was abolished by a combined treatment with endothelial NO-synthase inhibitor Nω -Nitro-L-arginine methyl ester (L-NAME) and the non-selective β -receptor antagonist propranolol. Propranolol alone did not decrease CABF in contrast to L-NAME but decreased CABF after L-NAME, surprisingly. Conclusion: Pharmacological evidence suggests that NE released in the brain of anesthetized pigs raises CABF involving β -adrenergic mechanisms and nitric oxide. If in awake humans, NE released from the LC had vasodilator effects; early LC degeneration could be involved in early cerebral hypoperfusion of AD. Moreover, a cerebral adrenergic vascular innervation deficit, possibly resulting from LC degeneration, and systemic endothelial dysfunction together may act synergistically to reduce CBF. Show more

Keywords: Alpha-2 adrenergic drugs, Alzheimer’s disease, atipamezole, carotid artery blood flow, cerebral blood flow, cerebral hypoperfusion, degeneration, locus coeruleus, pigs, propranolol, xylazine

DOI: 10.3233/JAD-180340

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2018

Authors: Nagata, Tomoyuki | Shinagawa, Shunichiro | Nakajima, Shinichiro | Mimura, Masaru | Shigeta, Masahiro

Article Type: Research Article

Abstract: Background/Objective: To assess associations between improvements in neuropsychiatric symptoms (NPS) and neurocognitive change in patients with Alzheimer’s disease (AD) during treatment using the Clinical Antipsychotic Trials of Intervention Effectiveness– Alzheimer Disease (CATIE-AD) dataset. Methods: AD outpatients with NPS who needed pharmacological treatment (n  = 421) were followed up with antipsychotics, citalopram, or placebo for up to 36 weeks (mean±SD = 252±52 days). The study aim was to investigate associations between improvement in each NPS evaluating scale (by Clinical Global Impression of Change [CGI-C], Neuropsychiatric Inventory [NPI], or Brief Psychiatric Scale [BPRS]) at endpoint (week 36 or early termination [ET], …n  = 340) and neurocognitive change (change score in the Mini-Mental State Examination [MMSE] between endpoint and baseline during the treatment). Multiple logistic regression analyses were performed on the associations between each NPS improvement and neurocognitive change as well as socio-clinico-demographic variables of interest. Results: At endpoint, NPS improvement rates were 76.1%, 70.8%, and 58.1% in CGI-C, NPI, and BPRS, respectively, while MMSE score change was – 2.3±3.8. NPS improvement was significantly related to more severe psychotic symptoms at baseline and preserved levels of neurocognition (smaller MMSE score change) among several variables. Conclusions: Our findings suggested that neurocognitive preservation may be associated with attaining optimal benefits from any treatment against NPSs in a longitudinal treatment course of patients with AD. Show more

Keywords: Alzheimer’s disease, antipsychotic, CATIE-AD, neurocognitive impairment, neuropsychiatric symptom

DOI: 10.3233/JAD-180304

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2018

Authors: Jütten, Linda H. | Mark, Ruth E. | Wicherts, Jelte M. | Sitskoorn, Margriet M.

Article Type: Research Article

Abstract: Background: Many psychosocial and behavioral interventions have been developed for informal dementia caregivers. Because existing meta-analyses only focused on a limited number of interventions and outcomes, how effective these interventions are overall and which interventions components are associated with larger effects has yet to be explored. Objective: To provide a comprehensive meta-analysis of the effectiveness of psychosocial and behavioral interventions on burden, depression, anxiety, quality of life, stress, and sense of competence in informal dementia caregivers. In addition, we examined if interventions which utilized more sessions and/or were delivered personally (face-to-face) had larger effect sizes. In …exploratory meta-regressions, we examined seven additional moderators. Methods: The protocol was registered with PROSPERO, number CRD42017062555. We systematically searched the literature to identify controlled trials assessing the effect of psychosocial and behavioral interventions on the six outcome measures, for informal dementia caregivers. We performed six random effects meta-analyses, to assess the pooled effect sizes of the interventions. In addition, we performed separate meta-regressions, for each outcome, for each moderator. Results: The sample consisted of 60 studies. For all outcomes except anxiety, the pooled effects were small and in favor of the intervention group. No moderator was found to systematically predict these effects. There were no indications for publication bias or selection bias based on significance. Conclusion: Overall, the interventions yield significant (small) effects, independent of intervention characteristics. Future research should explore options to enhance the effectiveness of interventions aimed at assisting informal caregivers. Show more

Keywords: Burden, dementia, depression, informal caregivers, interventions, meta-analysis, meta-regression, psychobehavioral, psychosocial

DOI: 10.3233/JAD-180508

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-24, 2018

Authors: Zupanic, Eva | Kåreholt, Ingemar | Norrving, Bo | Secnik, Juraj | von Euler, Mia | Winblad, Bengt | Religa, Dorota | Kramberger, Milica Gregoric | Johnell, Kristina | Eriksdotter, Maria | Garcia-Ptacek, Sara

Article Type: Research Article

Abstract: Background: Previous studies have shown that patients with dementia receive less testing and treatment for stroke. Objectives: Our aim was to investigate hospital management of acute ischemic stroke in patients with and without dementia. Methods: Retrospective analysis of prospectively collected data 2010–2014 from the Swedish national dementia registry (SveDem) and the Swedish national stroke registry (Riksstroke). Patients with dementia who suffered an acute ischemic stroke (AIS) (n  = 1,356) were compared with matched non-dementia AIS patients (n  = 6,755). Outcomes included length of stay in a stroke unit, total length of hospitalization, and utilization of …diagnostic tests and assessments. Results: The median age at stroke onset was 83 years. While patients with dementia were equally likely to be directly admitted to a stroke unit as their non-dementia counterparts, their stroke unit and total hospitalization length were shorter (10.5 versus 11.2 days and 11.6 versus 13.5, respectively, p  <  0.001). Dementia patients were less likely to receive carotid ultrasound (OR 0.36, 95% CI [0.30–0.42]) or undergo assessments by the interdisciplinary team members (physiotherapists, speech therapists, occupational therapists; p  <  0.05 for all adjusted models). However, a similar proportion of patients received CT imaging (97.4% versus 98.6%, p  = 0.001) and a swallowing assessment (90.7% versus 91.8%, p  = 0.218). Conclusions: Patients with dementia who suffer an ischemic stroke have equal access to direct stroke unit care compared to non-dementia patients; however, on average, their stay in a stroke unit and total hospitalization are shorter. Dementia patients are also less likely to receive specific diagnostic tests and assessments by the interdisciplinary stroke team. Show more

Keywords: Cohort studies, dementia, hospital management, ischemic stroke

DOI: 10.3233/JAD-180653

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2018

Authors: Emmerzaal, Tim L. | Rodenburg, Richard J. | Tanila, Heikki | Verweij, Vivienne | Kiliaan, Amanda J. | Kozicz, Tamas

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is a severe neurodegenerative disorder for which the exact etiology is largely unknown. An increasingly recognized and investigated notion is the pathogenic role of mitochondrial dysfunction in AD. We assessed mitochondrial oxidative-phosphorylation (OXPHOS) enzyme activities in the APPswe/PS1Δ E9 mouse model from 4.5 to 14 months of age. We show an age-dependent decrease in mitochondrial complex-II activity starting at 9 months in APP/PS1 mice. Other enzymes of the OXPHOS do not show any alterations. Since amyloid-β (Aβ ) plaques are already present from 4 months of age, mitochondrial dysfunction likely occurs downstream of Aβ …pathology in this mouse model. Show more

Keywords: Alzheimer’s disease, amyloid beta-peptides, electron transport complex II, electron transport complex IV, mice, mitochondria

DOI: 10.3233/JAD-180337

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2018

Authors: Yeo, Si Ning | Lee, Tih Shih | Sng, Wei Theng | Heo, Min Quan | Bautista, Dianne | Cheung, Yin Bun | Zhang, Hai Hong | Wang, Chuanchu | Chin, Zheng Yang | Feng, Lei | Zhou, Juan | Chong, Mei Sian | Ng, Tze Pin | Krishnan, K. Ranga | Guan, Cuntai

Article Type: Research Article

Abstract: Background: Cognitive training has been demonstrated to improve cognitive performance in older adults. To date, no study has explored personalized training that targets the brain activity of each individual. Objective: This is the first large-scale trial that examines the usefulness of personalized neurofeedback cognitive training. Methods: We conducted a randomized-controlled trial with participants who were 60–80 years old, with Clinical Dementia Rating (CDR) score of 0–0.5, Mini-Mental State Examination (MMSE) score of 24 and above, and with no neuropsychiatric diagnosis. Participants were randomly assigned to the Intervention or Waitlist-Control group. The training system, BRAINMEM, has attention, …working memory, and delayed recall game components. The intervention schedule comprised 24 sessions over eight weeks and three monthly booster sessions. The primary outcome was the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) total score after the 24-session training. Results: There were no significant between-subjects differences in overall cognitive performance post-intervention. However, a sex moderation effect (p = 0.014) was present. Men in the intervention group performed better than those in the waitlist group (mean difference, +4.03 (95% CI 0.1 to 8.0), p = 0.046. Among females, however, both waitlist-control and intervention participants improved from baseline, although the between-group difference in improvement did not reach significance. BRAINMEM also received positive appraisal and intervention adherence from the participants. Conclusion: A personalized neurofeedback intervention is potentially feasible for use in cognitive training for older males. The sex moderation effect warrants further investigation and highlights the importance of taking sex into account during cognitive training. Show more

Keywords: Brain-computer interface, cognitive training, older adults, personalized neurofeedback

DOI: 10.3233/JAD-180450

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2018