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Authors: Midorikawa, Akira | Leyton, Cristian E. | Foxe, David | Landin-Romero, Ramon | Hodges, John R. | Piguet, Olivier

Article Type: Research Article

Abstract: Background: Anecdotal evidence indicates that some patients with dementia exhibit novel or increased positive behaviors, such as painting or singing, after the disease onset. Due to the lack of objective measures, however, the frequency and nature of these changes has not been formally investigated. Objective: This study aimed to systematically identify changes in these behaviors in the two most common younger-onset dementia syndromes: Alzheimer’s disease (AD) and behavioral-variant frontotemporal dementia (bvFTD). Methods: Sixty-three caregivers of patients with dementia (32 caregivers of AD patients and 31 caregivers of bvFTD patients) participated in the study. Caregivers rated the presence and frequency of …positive and negative behavior changes after the onset of dementia using the Hypersensory and Social/Emotional Scale (HSS) questionnaire, focusing on three domains: sensory processing, cognitive skills, and social/emotional processing. Six composites scores were obtained reflecting these three domains (two composite scores for each domain). Differences across scores and ratios of increased and decreased behaviors were analyzed between AD and bvFTD, at different disease severity levels. Results: After disease onset, significant changes in the sensory processing domain were observed across disease severity levels, particularly in AD. Composite scores of the other domains did not change significantly. Importantly, however, some novel or increased positive behaviors were present in between 10% (Music activities) and 70% (Hypersensitivity) of AD and bvFTD patients, regardless of disease severity. Conclusions: We provide the first systematic investigation of positive behaviors in AD and bvFTD. The newly developed HSS questionnaire is a valid measure to characterize changes and progression of positive behaviors in patients with dementia. Show more

Keywords: Alzheimer’s disease, behavioral symptoms, caregivers, factor analysis, frontotemporal dementia, progression, questionnaire development

DOI: 10.3233/JAD-160440

Citation: Journal of Alzheimer's Disease, vol. 54, no. 2, pp. 549-558, 2016

Authors: Saarelainen, Laura | Taipale, Heidi | Koponen, Marjaana | Tanskanen, Antti | Tolppanen, Anna-Maija | Tiihonen, Jari | Hartikainen, Sirpa

Article Type: Research Article

Abstract: Background: Benzodiazepines and related drugs (BZDR) are occasionally used to treat certain symptoms of Alzheimer’s disease (AD). However, the risks related to BZDR use are high in older persons. Although frequent BZDR use has been reported in persons with AD, no previous study has focused specifically on the incidence of BZDR use in this population. Objective: We investigated the incidence of BZDR use in persons with and without AD during a five-year follow-up. Methods: The Finnish nationwide, register-based MEDALZ cohort includes all AD cases who received a clinically verified AD diagnosis in 2005–2011 (n  = 70,718) and their matched comparison persons. …Incidence of BZDR, including benzodiazepines (lorazepam, oxazepam, temazepam, alprazolam, chlordiazepoxide, diazepam, and nitrazepam) and Z-drugs (zolpidem and zopiclone), use was investigated in the cohort from two years before to three years after the diagnosis of AD. Further, initial BZDRs were investigated. Results: The incidence of BZDR use was higher in persons with AD starting from 12 months before the diagnosis and peaked at six months after the diagnosis of AD (incidence rate ratio [IRR] = 2.6, 95% confidence interval [CI] = 2.5–2.8). Benzodiazepines were more frequently initiated by persons with AD, with the incidence peaking at six months after the diagnosis (IRR = 4.5, 95% CI = 4.1–4.9) and remaining over three times higher than in comparison persons until three years after the diagnosis. Conclusion: Early symptomatic treatment with BZDRs is contrary to AD treatment guidelines. As BZDRs impair cognition, the observed early treatment with BZDRs may complicate the monitoring of AD treatment effectiveness. Show more

Keywords: Alzheimer’s disease, benzodiazepines, drug utilization, registries

DOI: 10.3233/JAD-150630

Citation: Journal of Alzheimer's Disease, vol. 49, no. 3, pp. 809-818, 2016

Authors: Ihara, Masafumi | Washida, Kazuo

Article Type: Review Article

Abstract: Many studies have shown a relationship between atrial fibrillation (AF) and vascular dementia. AF is a major risk factor for stroke, and stroke is the greatest risk factor for vascular dementia. However, the relationship between Alzheimer’s disease (AD), the leading cause of dementia, and AF remains unclear. At least four epidemiological studies have reported AF significantly raises the risk of AD 1.5- to 2.5-fold. Chronic cerebral hypoperfusion, resulting from persistent AF, could explain the link as hypoperfusion may mechanistically exacerbate amyloid-β (Aβ) neuropathology, such as senile plaques and amyloid angiopathy, by upregulating Aβ-producing enzymes and lowering Aβ clearance efficiency. In …addition, hypoperfusion may exacerbate tau pathology directly through upregulation of tau-phosphorylating enzymes and indirectly via the amyloid cascade. However, most neuropathological studies do not support the direct link between AD pathology and AF but rather suggests vascular neuropathology is related to, or coexistent with, AF and lowers the threshold for clinically-evident AD. Vascular neuropathology may thus mediate the link between AD and AF. From a treatment perspective, an observational study has shown that catheter ablation is associated with less incidence of AD in AF patients, suggesting rhythm-control suppresses hypoperfusion-induced AD neuropathology. In addition, rate-control may lower the rate of cognitive decline in cognitively impaired elderly subjects with AF. Further studies are warranted to clarify the mechanisms underlying the linkage between AF and AD. However, anticoagulation and rhythm-/rate-control against AF may hold promise even for AD patients. Show more

Keywords: Alzheimer’s disease, anticoagulant, atrial fibrillation, catheter ablation, dementia, hypoperfusion, rhythm control

DOI: 10.3233/JAD-170970

Citation: Journal of Alzheimer's Disease, vol. 62, no. 1, pp. 61-72, 2018

Authors: Ho, Lap | Legere, Marc | Li, Tongbin | Levine, Samara | Hao, Ke | Valcarcel, Breanna | Pasinetti, Giulio M.

Article Type: Research Article

Abstract: Autonomic dysfunction is very common in patients with dementia, and its presence might also help in differential diagnosis among dementia subtypes. Various central nervous system structures affected in Alzheimer’s disease (AD) are also implicated in the central autonomic nervous system (ANS) regulation. For example, deficits in central cholinergic function in AD could likely lead to autonomic dysfunction. We recently developed a simple, readily applicable evaluation for monitoring ANS disturbances in response to traumatic brain injury (TBI). This ability to monitor TBI allows for the possible detection and targeted prevention of long-term, detrimental brain responses caused by TBI that lead to …neurodegenerative diseases such as AD. We randomly selected and extracted de-identified medical record information from subjects who have been assessed using the ANS evaluation protocol. Using machine learning strategies in the analysis of information from individual as well as a combination of ANS evaluation protocol components, we identified a novel prediction model that is effective in correctly segregating between cases with or without a documented history of TBI exposure. Results from our study support the hypothesis that trauma-induced ANS dysfunctions may contribute to clinical TBI features. Because autonomic dysfunction is very common in AD patients it is possible that TBI may also contribute to AD and/or other forms of dementia through these novel mechanisms. This study provides a novel prediction model to physiologically assess the likelihood of subjects with prior history of TBI to develop clinical TBI complications, such as AD. Show more

Keywords: Alzheimer’s disease, autonomic nervous system, biomarker, neurodegenerative disorders, risk factor, traumatic brain injury

DOI: 10.3233/JAD-160948

Citation: Journal of Alzheimer's Disease, vol. 56, no. 1, pp. 305-315, 2017

Authors: Novais, Filipa | Starkstein, Sergio

Article Type: Review Article

Abstract: Depression is among the most frequent psychiatric comorbid conditions in dementia. There is no strong consensus as to what criteria should be used to diagnose depression in AD. This is at least partially explained by the overlap between symptoms of depression and symptoms of AD. Recent studies using latent class analysis provided clarification to this diagnostic dilemma. All nine DSM-IV symptoms of major depression were found to characterize a class with a high chance (96% ) of having a clinical diagnosis of major depression, and symptoms of anxiety were also frequent. Other psychiatric symptoms may also be included under the …construct of depression in AD, since both apathy and anxiety are among the most frequent comorbid conditions for major depression in AD. Subtypes of depression should also be validated in this condition. For instance, increased awareness of cognitive and functional deficits is significantly associated with dysthymia but not with major depression, suggesting that different depressive syndromes in AD may have different etiology. Show more

Keywords: Alzheimer’s disease, anxiety, apathy, delusions, dementia, depression

DOI: 10.3233/JAD-148004

Citation: Journal of Alzheimer's Disease, vol. 47, no. 4, pp. 845-855, 2015

Authors: Ticinesi, Andrea | Mancabelli, Leonardo | Carnevali, Luca | Nouvenne, Antonio | Meschi, Tiziana | Del Rio, Daniele | Ventura, Marco | Sgoifo, Andrea | Angelino, Donato

Article Type: Review Article

Abstract: Animal studies increasingly indicate that the gut microbiota composition and function can be involved in the pathophysiology and progression of Alzheimer’s disease (AD) at multiple levels. However, few studies have investigated this putative gut-brain axis in human beings, and none of them considered diet as a determinant of intestinal microbiota composition. Epidemiological studies highlight that a high intake of fruit and vegetables, such as that typical of the Mediterranean diet, can modulate AD progression. Thus, nutritional interventions are being increasingly studied as a possible non-pharmacological strategy to slow down the progression of AD. In particular, polyphenols and fibers represent the …nutritional compounds with the higher potential of counterbalancing the pathophysiological mechanisms of dementia due to their antioxidant, anti-inflammatory, and anti-apoptotic properties. These actions are mediated by the gut microbiota, that can transform polyphenols and fibers into biologically active compounds including, among others, phenyl-γ-valerolactones, urolithins, butyrate, and other short-chain fatty acids. In this review, the complex mechanisms linking nutrition, gut microbiota composition, and pathophysiology of cognitive decline in AD are discussed, with a particular focus on the role of polyphenols and fibers. The gaps between pre-clinical and clinical studies are particularly emphasized, as well as the urgent need for studies comprehensively evaluating the link between nutrition, microbiome, and clinical aspects of AD. Show more

Keywords: Aging, butyrate, cognitive impairment, short-chain fatty acids

DOI: 10.3233/JAD-215493

Citation: Journal of Alzheimer's Disease, vol. 86, no. 3, pp. 961-982, 2022

Authors: Rosa, Gianmarco | Giannotti, Chiara | Martella, Lucia | Massa, Federico | Serafini, Gianluca | Pardini, Matteo | Nobili, Flavio Mariano | Monacelli, Fiammetta | for the Disease Management Team on Dementia of the IRCCS Ospedale Policlinico San Martino (Genoa, I)

Article Type: Review Article

Abstract: Dementia is an age-related clinical condition, with higher incidence rates in older ages. However, there is some evidence that a reverse epidemiology is also observed. Namely, the cohort analysis of dementia incidence rates by birth in selected populations demonstrated a decreased incidence of dementia in late life across the last twenty years, possibly due to decreased incidence of cardiovascular disorders and increased education and cognitive reserve. In line with that, age is probably a proxy for other pathophysiological processes rather than a strictly causative factor for the onset of dementia, especially in oldest old persons. The present narrative review provides …an update on the clinical interplay between the spectrum of brain aging, cardiovascular morbidity, dementia pathologies, and their clinical expression in the oldest old patients. Available evidence suggests that vascular prevention in the perspective of dementia largely involve middle ages, with an apparent reverse epidemiology in oldest old. Similarly, the present findings underline how cognitive resilience and frailty may be key relevant mediators in the modulation of the clinical expression of brain mixed neuropathologies in persons over 85 years old, providing a new integrated conceptual framework. Show more

Keywords: Brain aging, brain resilience, cardiovascular comorbidity, frailty, hippocampal sclerosis, mixed dementia, oldest old

DOI: 10.3233/JAD-191075

Citation: Journal of Alzheimer's Disease, vol. 75, no. 4, pp. 1083-1103, 2020

Authors: Mohan, Devi | Yap, Kwong Hsia | Reidpath, Daniel | Soh, Yee Chang | McGrattan, Andrea | Stephan, Blossom C.M. | Robinson, Louise | Chaiyakunapruk, Nathorn | Siervo, Mario | on behalf of DePEC team

Article Type: Research Article

Abstract: Background: A key focus for dementia risk-reduction is the prevention of socio-demographic, lifestyle, and nutritional risk factors. High sodium intake is associated with hypertension and cardiovascular disease (both are linked to dementia), generating numerous recommendations for salt reduction to improve cardiovascular health. Objective: This systematic review aimed to assess, in middle- and older-aged people, the relationship between dietary sodium intake and cognitive outcomes including cognitive function, risk of cognitive decline, or dementia. Methods: Six databases (PubMed, EMBASE, CINAHL, Psych info, Web of Science, and Cochrane Library) were searched from inception to 1 March 2020. Data extraction included information on study …design, population characteristics, sodium reduction strategy (trials) or assessment of dietary sodium intake (observational studies), measurement of cognitive function or dementia, and summary of main results. Risk-of-bias assessments were performed using the National Heart, Lung, and Blood Institute (NHLBI) assessment tool. Results: Fifteen studies met the inclusion criteria including one clinical trial, six cohorts, and eight cross-sectional studies. Studies reported mixed associations between sodium levels and cognition. Results from the only clinical trial showed that a lower sodium intake was associated with improved cognition over six months. In analysis restricted to only high-quality studies, three out of four studies found that higher sodium intake was associated with impaired cognitive function. Conclusion: There is some evidence that high salt intake is associated with poor cognition. However, findings are mixed, likely due to poor methodological quality, and heterogeneous dietary, analytical, and cognitive assessment methods and design of the studies. Reduced sodium intake may be a potential target for intervention. High quality prospective studies and clinical trials are needed. Show more

Keywords: Cognitive dysfunction, dementia, salt, sodium, systematic review

DOI: 10.3233/JAD-191339

Citation: Journal of Alzheimer's Disease, vol. 76, no. 4, pp. 1347-1373, 2020