Journal of Alzheimer's Disease - Volume 86, issue 3

Authors: Diaz-Pacheco, Valeria | Vargas-Medrano, Javier | Tran, Eric | Nicolas, Meza | Price, Diamond | Patel, Richa | Tonarelli, Silvina | Gadad, Bharathi S.

Article Type: Review Article

Abstract: Mild traumatic brain injury (mTBI) is the most prevalent type of TBI (80–90%). It is characterized by a loss consciousness for less than 30 minutes, post-traumatic amnesia for less than 24 hours, and Glasgow Coma Score of 13–15. Accurately diagnosing mTBIs can be a challenge because the majority of these injuries do not show noticeable or visible changes on neuroimaging studies. Appropriate determination of mTBI is tremendously important because it might lead in some cases to post-concussion syndrome, cognitive impairments including attention, memory, and speed of information processing problems. The scientists have studied different methods to improve mTBI diagnosis and …enhanced approaches that would accurately determine the severity of the trauma. The present review focuses on discussing the role of biomarkers as potential key factors in diagnosing mTBI. The present review focuses on 1) protein based peripheral and CNS markers, 2) genetic biomarkers, 3) imaging biomarkers, 4) neurophysiological biomarkers, and 5) clinical trials in mTBI. Each section provides information and characteristics on different biomarkers for mTBI. Show more

Keywords: Biomarkers, genetics, mild traumatic brain injury, neuroimaging, neurophysiology, proteomics

DOI: 10.3233/JAD-215158

Citation: Journal of Alzheimer's Disease, vol. 86, no. 3, pp. 943-959, 2022

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: Huang, Yu-Yuan | Chen, Shi-Dong | Leng, Xin-Yi | Kuo, Kevin | Wang, Zuo-Teng | Cui, Mei | Tan, Lan | Wang, Kai | Dong, Qiang | Yu, Jin-Tai

Article Type: Review Article

Abstract: Stroke, characterized as a neurological deficit of cerebrovascular cause, is very common in older adults. Increasing evidence suggests stroke contributes to the risk and severity of cognitive impairment. People with cognitive impairment following stroke often face with quality-of-life issues and require ongoing support, which have a profound effect on caregivers and society. The high morbidity of post-stroke cognitive impairment (PSCI) demands effective management strategies, in which preventive strategies are more appealing, especially those targeting towards modifiable risk factors. In this review article, we attempt to summarize existing evidence and knowledge gaps on PSCI: elaborating on the heterogeneity in current definitions, …reporting the inconsistent findings in PSCI prevalence in the literature, exploring established or less established predictors, outlining prevention and treatment strategies potentially effective or currently being tested, and proposing promising directions for future research. Show more

Keywords: Cognitive dysfunction, epidemiology, prevention, screening, stroke, treatment

DOI: 10.3233/JAD-215644

Citation: Journal of Alzheimer's Disease, vol. 86, no. 3, pp. 983-999, 2022

Authors: Rice, Michaela | Davalos, Deana | Thomas, Michael L.

Article Type: Systematic Review

Abstract: Background: There is a critical need to develop effective interventions for cognitive impairments associated with dementia-related disorders (i.e., Alzheimer’s disease, frontotemporal dementia, mild cognitive impairment). Prospective memory (PM), or the ability to create and carry out future intentions, is one cognitive domain that is impaired in individuals with dementia-related disorders. Effective treatment of PM could significantly improve daily functioning, level of independence, and quality of life. Objective: To date, there have been a number of studies investigating potential interventions, but these interventions have not been comprehensively reviewed and compared across the stages of dementia-related disorders, as is the …aim of the current review. Methods: This review examined 21 studies on the success of intervention strategies for prospective memory in patients with dementia-related disorders. Results: All the studies demonstrated positive effects of intervention on PM abilities, but there are questions concerning ecological validity, length of positive effects on PM, and a lack of diversity of interventions across the different stages of dementia-related disorders. Conclusion: Future research should address these issues by incorporating daily functioning activities and caregiver support into the intervention process, as well as investigating these interventions at more severe stages of dementia-related disorders. Show more

Keywords: Alzheimer’s disease, dementia, intervention, mild cognitive impairment, prospective memory

DOI: 10.3233/JAD-215473

Citation: Journal of Alzheimer's Disease, vol. 86, no. 3, pp. 1001-1024, 2022

Authors: Cipriano, Lorenzo | Saracino, Dario | Oliva, Mariano | Campana, Vito | Puoti, Gianfranco | Conforti, Renata | Fulgione, Ludovica | Signoriello, Elisabetta | Bonavita, Simona | Coppola, Cinzia

Article Type: Systematic Review

Abstract: Background: Cerebral microbleeds (CMBs) are small round/oval lesions seen in MRI-specific sequences. They are divided in deep and lobar according to their location. Lobar CMBs (L-CMBs) are commonly associated with amyloid angiopathy. Although CMBs have been considered clinically silent for a long time, a growing body of evidence has shown that they could play a crucial role in cognitive functioning. Objective: The aim of this systematic review was to estimate the role of L-CMBs in cognitive performance. Methods: We selected, from the Cochrane Library, Embase, PubMed, and ScienceDirect databases, clinical studies, published from January 2000 to …January 2020 and focused on the association between L-CMBs and cognitive functions. The inclusion criteria were: 1) participants grouped according to presence or absence of CMBs, 2) extensive neuropsychological examination, 3) CMBs differentiation according to topographical distribution, and 4) MRI-based CMB definition (< 10 mm and low signal in T2* /SWI). The impact of L-CMBs was separately assessed for executive functions, visuospatial skills, language, and memory. Results: Among 963 potentially eligible studies, six fulfilled the inclusion criteria. Four studies reported a greater reduction in executive performances in participants with L-CMB and two studies showed a statistically significant association between visuospatial dysfunction and L-CMBs. No association was found between hippocampal memory or language abilities and L-CMBs. Conclusion: Lobar CMBs are associated with a reduction of processing speed and visuospatial performances, thus suggesting the contribution of vascular amyloid deposition to this cognitive profile. This occurrence enables us to suspect an underlying Alzheimer’s disease pathology even in absence of typical hippocampal memory impairment. Show more

Keywords: Alzheimer’s disease, cerebral microbleeds, cognitive impairment, executive functions, hippocampal memory

DOI: 10.3233/JAD-215323

Citation: Journal of Alzheimer's Disease, vol. 86, no. 3, pp. 1025-1035, 2022

Authors: Kelberman, Michael A. | Anderson, Claire R. | Chlan, Eli | Rorabaugh, Jacki M. | McCann, Katharine E. | Weinshenker, David

Article Type: Research Article

Abstract: Background: The locus coeruleus (LC) is one of the earliest brain regions to accumulate hyperphosphorylated tau, but a lack of animal models that recapitulate this pathology has hampered our understanding of its contributions to Alzheimer’s disease (AD) pathophysiology. Objective: We previously reported that TgF344-AD rats, which overexpress mutant human amyloid precursor protein and presenilin-1, accumulate early endogenous hyperphosphorylated tau in the LC. Here, we used TgF344-AD rats and a wild-type (WT) human tau virus to interrogate the effects of endogenous hyperphosphorylated rat tau and human tau in the LC on AD-related neuropathology and behavior. Methods: Two-month-old …TgF344-AD and WT rats received bilateral LC infusions of full-length WT human tau or mCherry control virus driven by the noradrenergic-specific PRSx8 promoter. Rats were subsequently assessed at 6 and 12 months for arousal (sleep latency), anxiety-like behavior (open field, elevated plus maze, novelty-suppressed feeding), passive coping (forced swim task), and learning and memory (Morris water maze and fear conditioning). Hippocampal microglia, astrocyte, and AD pathology were evaluated using immunohistochemistry. Results: In general, the effects of age were more pronounced than genotype or treatment; older rats displayed greater hippocampal pathology, took longer to fall asleep, had reduced locomotor activity, floated more, and had impaired cognition compared to younger animals. TgF344-AD rats showed increased anxiety-like behavior and impaired learning and memory. The tau virus had negligible influence on most measures. Conclusion: Effects of hyperphosphorylated tau on AD-like neuropathology and behavioral symptoms were subtle. Further investigation of different forms of tau is warranted. Show more

Keywords: Alzheimer’s disease, behavior, cognition, locus coeruleus, rat, tau, transgenic

DOI: 10.3233/JAD-215546

Citation: Journal of Alzheimer's Disease, vol. 86, no. 3, pp. 1037-1059, 2022

Authors: Gallucci, Maurizio | Cenesi, Leandro | White, Céline | Antuono, Piero | Quaglio, Gianluca | Bonanni, Laura

Article Type: Research Article

Abstract: Background: The most significant biomarkers that are included in the Alzheimer’s disease (AD) research framework are amyloid-β plaques deposition, p-tau, t-tau, and neurodegeneration. Although cerebrospinal fluid (CSF) biomarkers are included in the most recent AD research criteria, their use is increasing in the routine clinical practice and is applied also to the preclinical phases of AD, including mild cognitive impairment. The role of these biomarkers is still unclear concerning the preclinical stage of AD diagnosis, the CSF methodology, and the costs-benefits of the biomarkers’ tests. The controversies regarding the use of biomarkers in the clinical practice are related to …the concepts of analytical validity, clinical validity, and clinical utility and to the question of whether they are able to diagnose AD without the support of AD clinical phenotypes. Objective: The objective of the present work is to expose the strengths and weaknesses of the use of CSF biomarkers in the diagnosis of AD in a clinical context. Methods: We used PubMed as main source for articles published and the final reference list was generated on the basis of relevance to the topics covered in this work. Results: The use of CSF biomarkers for AD diagnosis is certainly important but its indication in routine clinical practice, especially for prodromal conditions, needs to be regulated and also contextualized considering the variety of possible clinical AD phenotypes. Conclusion: We suggest that the diagnosis of AD should be understood both as clinical and pathological. Show more

Keywords: Alzheimer’s disease, analytical validity, ATN model, clinical utility, clinical validity, CSF biomarkers, diagnosis, mild cognitive impairment, probabilistic model

DOI: 10.3233/JAD-215432

Citation: Journal of Alzheimer's Disease, vol. 86, no. 3, pp. 1061-1072, 2022

Authors: de Paula França Resende, Elisa | Ketelle, Robin | Karydas, Anna | Allen, Isabel | Grinberg, Lea T. | Spina, Salvatore | Seeley, William W. | Perry, David C. | Miller, Bruce | Naasan, Georges

Article Type: Research Article

Abstract: Background: The association between lifetime alcohol abuse and a higher risk to develop dementia is well known. However, it is unknown whether older adults who begin abusing alcohol late in life have an underlying neurodegenerative disease. Objective: Identify the frequency of lifelong alcohol abuse (L-AA), late-onset alcohol abuse (LO-AA), and alcohol abuse as a first symptom of dementia (AA-FS) in patients with neurodegenerative diseases. Methods: Cross-sectional retrospective study of patients evaluated at an academic referral center with a clinical diagnosis of behavioral variant frontotemporal dementia (bvFTD), Alzheimer-type dementia (AD), and semantic variant primary progressive aphasia (svPPA) …(n  = 1,518). The presence of alcohol abuse was screened with the National Alzheimer’s Coordinating Center questionnaire. L-AA was defined as onset < 40 years, LO-AA as onset ≥40 years, and AA-FS was defined when the abuse started within the first three years from symptom onset. Results: The frequency of LO-AA was 2.2% (n  = 33/1,518). LO-AA was significantly more frequent in patients with bvFTD than AD (7.5%, n  = 13/173 versus 1.3%, n  = 16/1,254, CI:1.0;11.4%), but not svPPA (4.4%, n  = 4/91, CI: –4.4;10.7%). Similarly, AA-FS was more frequent in bvFTD patients than AD (5.7%, n  = 10/173 versus 0.7%, n  = 9/1,254, CI:0.5%;9.5%), but not svPPA (2.2%, n  = 2/91, CI:–2.4;9.1%). Conclusion: LO-AA can be a presenting symptom of dementia, especially bvFTD. Alcohol abuse onset later in life should prompt a clinical investigation into the possibility of an underlying neurodegenerative process because delay in diagnosis and treatment may increase patient and caregiver burden. The results need to be interpreted with caution due to the limitations of the study. Show more

Keywords: Alcohol-related problems, Alzheimer’s dementia, dementia, frontotemporal dementia

DOI: 10.3233/JAD-215369

Citation: Journal of Alzheimer's Disease, vol. 86, no. 3, pp. 1073-1080, 2022

Authors: Yassi, Nawaf | Pase, Matthew P. | Buckley, Rachel F. | Rosenich, Emily | Watson, Rosie | Maruff, Paul | Lim, Yen Ying

Article Type: Research Article

Abstract: Background: Midlife cardiovascular risk factors (CVRF) are associated with reduced cognition and an increased risk of dementia. Objective: To further investigate this association using remote unsupervised online assessment of cognition and cardiovascular risk in middle-aged adults; and to explore the extent to which the association is altered by carriage of the APOE ɛ4 allele. Methods: The Healthy Brain Project is an online cohort of middle-aged cognitively unimpaired adults (40–70 years) who have undergone cognitive assessment and provided self-reports of demographic and health history. Cardiovascular risk was determined by ascertaining history of hypertension, hypercholesterolemia, diabetes mellitus, …overweight (body mass index≥25), and current cigarette smoking. Participants (n  = 2,480) were then grouped based on the number of reported CVRF into no CVRF, 1, 2, and≥3 CVRF. Associations between the number of CVRF as a continuous variable, CVRF group, and each individual CVRF with composite measures of attention, memory and subjective cognitive function were investigated. Results: Higher number of CVRF was associated with poorer attention (β= –0.042, p  = 0.039) and memory (β= –0.080, p  < 0.001), but not with subjective cognitive function. When considered individually, current smoking (β= –0.400, p  = 0.015), diabetes (β= –0.251, p  = 0.023), and hypercholesterolemia (β= –0.109, p  = 0.044) were independently associated with poorer memory performance. APOE ɛ4 carriers with≥1 CVRF performed worse on memory than ɛ4 carriers with no CVRFs (β(SE) = 0.259(0.077), p  = 0.004). This was not observed in ɛ4 non-carriers. Conclusion: In cognitively normal middle-aged adults, CVRF were associated with poorer cognition, particularly in the memory domain. These results support feasibility of online assessment of cardiovascular risk for cognitive impairment. Show more

Keywords: Alzheimer’s disease, cardiovascular risk factors, diabetes mellitus, dyslipidemias, smoking

DOI: 10.3233/JAD-215375

Citation: Journal of Alzheimer's Disease, vol. 86, no. 3, pp. 1081-1091, 2022

Authors: Tanaka, Tomotaka | Gyanwali, Bibek | Villaraza, Steven Gayoles | Saridin, Francis N. | Vrooman, Henri | Ihara, Masafumi | Reilhac, Anthonin | Chen, Christopher L.H. | Hilal, Saima

Article Type: Research Article

Abstract: Background: P-wave terminal force in lead V1 (PTFV1) on electrocardiography has been associated with atrial fibrillation and ischemic stroke. Objective: To investigate whether PTFV1 is associated with cerebral small vessel disease (CSVD) markers and etiological subtypes of cognitive impairment and dementia. Methods: Participants were recruited from ongoing memory clinic study between August 2010 to January 2019. All participants underwent physical and medical evaluation along with an electrocardiography and 3 T brain magnetic resonance imaging. Participants were classified as no cognitive impairment, cognitive impairment no dementia, vascular cognitive impairment no dementia, and dementia subtypes (Alzheimer’s …disease and vascular dementia). Elevated PTFV1 was defined as > 4,000μV×ms and measured manually on ECG. Results: Of 408 participants, 78 (19.1%) had elevated PTFV1 (37 women [47%]; mean [SD] age, 73.8 [7.2] years). The participants with elevated PTFV1 had higher burden of lacunes, cerebral microbleeds (CMB), and cortical microinfarcts. As for the CMB location, persons with strictly deep CMB and mixed CMB had significantly higher PTFV1 than those with no CMB (p  = 0.005, p  = 0.007). Regardless of adjustment for cardiovascular risk factors and/or heart diseases, elevated PTFV1 was significantly associated with presence of CMB (odds ratio, 2.26; 95% CI,1.33–3.91). Conclusion: Elevated PTFV1 was associated with CSVD, especially deep CMB. PTFV1 in vascular dementia was also higher compared to Alzheimer’s disease. Thus, PTFV1 might be a potential surrogate marker of brain-heart connection and vascular brain damage. Show more

Keywords: Cerebral microbleeds, cerebral small vessel diseases, cognitive impairment, electrocardiography, P-wave

DOI: 10.3233/JAD-215413

Citation: Journal of Alzheimer's Disease, vol. 86, no. 3, pp. 1093-1105, 2022