Journal of Alzheimer's Disease - Volume 73, issue 4

Authors: Shaughnessy, Keith A. | Hackney, Kyle J. | Clark, Brian C. | Kraemer, William J. | Terbizan, Donna J. | Bailey, Ryan R. | McGrath, Ryan

Article Type: Review Article

Abstract: Background: Measures of handgrip strength have not only emerged as a clinically viable screening tool for determining risk for morbidity, functional disability, and early mortality, but also for helping to identify cognitive deficits. However, the phenomena that links low handgrip strength with cognitive decline remains unclear. The role of the muscular and neural systems, and their adaptations to muscle strengthening activities over the life course, may provide important information for how age-related changes to muscle mass, strength, and neural capacity influence cognition. Moreover, disentangling how handgrip strength and cognitive function are associated may help to inform healthcare providers working with …aging adults and guide targeted interventions aiming to preserve muscle and cognitive functioning. Objective: To 1) highlight and summarize evidence examining the associations of handgrip strength and cognitive functioning, and 2) provide directions for future research in this area. Methods: Articles from the PubMed database were searched from November 2018-May 2019. The search term algorithm, inclusion and exclusion criteria were pre-specified by investigators. Results: Several cross-sectional and longitudinal studies have revealed that measures of handgrip strength were associated with cognitive declines regardless of age demographics and the presence of comorbidities. Conclusion: Handgrip strength can be used in clinical and epidemiological settings for helping to determine the onset and progression of cognitive impairment. Future research should continue to examine how handgrip strength and cognitive function are linked. Show more

Keywords: Aging, Alzheimer’s disease, cognition, dementia, muscle weakness, sarcopenia

DOI: 10.3233/JAD-190856

Citation: Journal of Alzheimer's Disease, vol. 73, no. 4, pp. 1265-1278, 2020

Authors: Frantellizzi, Viviana | Pani, Arianna | Ricci, Maria | Locuratolo, Nicoletta | Fattapposta, Francesco | De Vincentis, Giuseppe

Article Type: Review Article

Abstract: Cerebrovascular diseases are well established causes of cognitive impairment. Different etiologic entities, such as vascular dementia (VaD), vascular cognitive impairment, subcortical (ischemic) VaD, and vascular cognitive disorder, are included in the umbrella definition of vascular cognitive impairment and dementia (VCID). Because of the variability of VCID clinical presentation, there is no agreement on criteria defining the neuropathological threshold of this disorder. In fact, VCID is characterized by cerebral hemodynamic alteration which ranges from decreased cerebral blood flow to small vessels disease and involves a multifactorial process that leads to demyelination and gliosis, including blood-brain barrier disruption, hypoxia, and hypoperfusion, oxidative …stress, neuroinflammation and alteration on neurovascular unit coupling, cerebral microbleeds, or superficial siderosis. Numerous criteria for the definition of VaD have been described: the National Institute of Neurological Disorders and Stroke Association Internationale pour Recherche'-et-l’Enseignement en Neurosciences criteria, the State of California Alzheimer’s Disease Diagnostic and Treatment Centers criteria, DSM-V criteria, the Diagnostic Criteria for Vascular Cognitive Disorders (a VASCOG Statement), and Vascular Impairment of Cognition Classification Consensus Study. Neuroimaging is fundamental for definition and diagnosis of VCID and should be used to assess the extent, location, and type of vascular lesions. MRI is the most sensible technique, especially if used according to standardized protocols, even if CT plays an important role in several conditions. Functional neuroimaging, in particular functional MRI and PET, may facilitate differential diagnosis among different forms of dementia. This systematic review aims to explore the state of the art and future perspective of non-invasive diagnostics of VCID. Show more

Keywords: Brain vascular disorders, functional neuroimaging, MRI, neuroimaging, PET, vascular dementia

DOI: 10.3233/JAD-191046

Citation: Journal of Alzheimer's Disease, vol. 73, no. 4, pp. 1279-1294, 2020

Authors: Turchetta, Chiara Stella | De Simone, Maria Stefania | Perri, Roberta | Fadda, Lucia | Caruso, Giulia | De Tollis, Massimo | Caltagirone, Carlo | Carlesimo, Giovanni Augusto

Article Type: Research Article

Abstract:  Amnestic mild cognitive impairment has a greater risk of progressing to Alzheimer’s disease (AD). Consistent with AD patients’ distinctive deficit in consolidating new memory traces, in a recent study we demonstrated that the forgetting rate on the recency portion of a word list differentiates AD from other forms of dementia. In line with this finding, the aim of this study was to investigate whether increased recency forgetting could be a reliable index for predicting amnestic mild cognitive impairment (MCI) patients’ conversion to AD. For this purpose, we compared accuracy in immediate and delayed recall from different portions of a word …list in a group of patients with amnestic MCI who converted (C-MCI) or did not convert (S-MCI) to AD during a three-year follow-up period and in a group of normal controls. The results of the present study show that the forgetting from the recency portion of the list (operationalized as a ratio between immediate and delayed recall) was significantly larger in C-MCI than in S-MCI patients. Consistently, the hierarchical logistic regression analyses demonstrated that the recency ratio is a strong predictor of group membership. Similar to what occurs in full-blown AD patients, the results of our study suggest that the increased forgetting rate from the recency portion of the list in C-MCI patients is due to severely reduced efficiency in converting transitory short-term memory representations into stable long-term memory traces. This is consistent with prominent involvement of neuropathological changes in the cortical areas of the medial-temporal lobes and suggests that the recency ratio is a cognitive marker able to identify MCI patients who have a greater likelihood of progressing to AD. Show more

Keywords: Alzheimer’s disease, forgetting rate, memory disorders, mild cognitive impairment, recency effect

DOI: 10.3233/JAD-190509

Citation: Journal of Alzheimer's Disease, vol. 73, no. 4, pp. 1295-1304, 2020

Authors: Xu, Chenjia | Apostolova, Liana G. | Oblak, Adrian L. | Gao, Sujuan

Article Type: Research Article

Abstract: Background: Animal studies have shown that diet-induced hypercholesterolemia (HC) increases amyloid-β (Aβ) accumulation and accelerates Alzheimer’s disease (AD) pathology. However, the association of HC with AD in human studies has not been consistently established. Objective: We aimed to investigate the relationship between HC and risk of AD neuropathology in a large national sample with autopsies. Methods: This study used neuropathological and clinical data from 3,508 subjects from the National Alzheimer’s Coordinating Center (NACC) who underwent autopsies from 2005 to 2017. Demographic and clinical characteristics, as well as neuropathological outcomes were compared between subjects with and without …HC. Associations between HC and AD neuropathology were examined by multivariate ordinal logistic regressions adjusting for potential confounders. Results: HC was not associated with any AD neuropathology in a model only adjusting for demographic variables. However, HC was significantly associated with higher CERAD neuritic and diffuse plaque burden, higher Braak stage, and more severe cerebral amyloid angiopathy when analyzed in a multivariate model controlling for comorbidities. Additional adjusting for cerebrovascular conditions did not diminish these associations. The association between HC and increased risk of neuritic plaques weakened but remained significant even after controlling for ApoE genotype. Conclusion: This study suggested that HC was associated with increased severity of AD pathology, which could only be partially accounted for by ApoE genotype. The associations were not mediated by cerebrovascular conditions. Show more

Keywords: Alzheimer’s disease, ApoE genotype, cerebral amyloid angiopathy, hypercholesterolemia, neuropathology

DOI: 10.3233/JAD-191023

Citation: Journal of Alzheimer's Disease, vol. 73, no. 4, pp. 1305-1311, 2020

Authors: Han, Ji Hyun | Lee, Hyo-Jung | Han, Ji Won | Suh, Seung Wan | Lee, Ju Ri | Byun, Seonjeong | Kim, Keun Suh | Kim, Sung Yeol | Lee, Jung-Tae | Yoo, Eunha | Chang, Na-Hee | Kim, Tae Hui | Kim, Ki Woong

Article Type: Research Article

Abstract: Background: Although tooth loss is known to increase the risk of cognitive impairment and dementia, few studies have investigated the association between functional teeth including rehabilitated lost teeth and cognitive function Objective: We investigated the associations of the numbers of functional teeth and functional occlusal units with cognitive impairment and cognitive function in late life. Methods: The current study was conducted as a part of the Korean Longitudinal Study on Cognitive Aging and Dementia (KLOSCAD), a community-based elderly cohort study. We analyzed 411 participants who have agreed with the additional dental exam. Geriatric psychiatrists and neuropsychologists …administered the Consortium to Establish a Registry for Alzheimer’s disease Assessment Packet Clinical and Neuropsychological Assessment Battery to all participants, and dentists examined their dental status. Results: Higher number of functional teeth (OR = 0.955, 95% CI = 0.914–0.997, p  = 0.037) and higher number of functional occlusal units (OR = 0.900, 95% CI = 0.813–0.996, p  = 0.042) were associated with lower odds of cognitive impairment. When we analyzed these relationships separated by the location of teeth, only the numbers of functional teeth (OR = 0.566, 95% CI = 0.373–0.857, p  = 0.007) and functional occlusal units (OR = 0.399, 95% CI = 0.213–0.748, p  = 0.004) in the premolar area were associated with lower odds of cognitive impairment. Conclusion: Loss of functional teeth and functional occlusal units (especially in the premolar region) were associated with increased cognitive impairment. Show more

Keywords: Cognitive impairment, dental prosthesis, occlusal unit, tooth

DOI: 10.3233/JAD-190971

Citation: Journal of Alzheimer's Disease, vol. 73, no. 4, pp. 1313-1320, 2020

Authors: Giil, Lasse Melvaer | Aarsland, Dag

Article Type: Research Article

Abstract: Studies indicate more rapid cognitive decline in patients with Lewy body dementia (LBD) compared to Alzheimer’s disease (AD). However, there has been less focus on any difference in the variability of cognitive decline. We assessed Mini-Mental State Examination (MMSE) test performance at baseline and annually for 5 years in 222 patients with mild dementia in the DemVest study who had either AD (137) or LBD (85). We used linear mixed models (LMMs) with random intercepts (variability in MMSE at baseline) and slopes (variability in MMSE decline), with years in study, age, gender, and diagnosis as independent variables. A non-linear (quadratic) …trajectory was selected, interacting with age and diagnosis. To study differences in variance, we compared a regular LMM (i.e., a homoscedastic model), which assumes equal variance across groups, to a heteroscedastic model, assuming unequal intercept and slope variance based on diagnosis. The heteroscedastic model gave a better fit (Likelihood ratio test: χ 2  = 30.3, p  < 0.001), showing overall more variability in LBD. Further, the differences in intercept and slope variances were tested using a modified Wald test. The MMSE intercept variance (AD: 2.78, LBD: 7.75, difference: 4.97, p  = 0.021) and slope variance (AD: 2.62, LBD 7.81, difference: 5.19, p  = 0.004) were both higher in LBD. In conclusion, patients with LBD in the DemVest study have a higher variability in MMSE scores at study inclusion, and in MMSE decline compared to AD. Accordingly, clinical trials on LBD may need a larger sample size compared to AD. Show more

Keywords: Alzheimer’s disease, cognitive decline, dementia with Lewy bodies, heteroscedastic, Lewy body dementia, Lewy body disease, MMSE decline, random effects, trajectory, variability, variance

DOI: 10.3233/JAD-190731

Citation: Journal of Alzheimer's Disease, vol. 73, no. 4, pp. 1321-1330, 2020

Authors: Ano, Yasuhisa | Ohya, Rena | Takaichi, Yuta | Washinuma, Terukatsu | Uchida, Kazuyuki | Takashima, Akihiko | Nakayama, Hiroyuki

Article Type: Research Article

Abstract:  The prevention of age-related memory decline and dementia has been becoming a high priority because of the rapid growth in aging populations. Accumulating epidemiological and clinical studies indicate that intake of fermented dairy products rich in β-lactolin improves memory retrieval and executive function and attenuates cognitive decline in the elderly. However, the effects of long-term consumption of β-lactolin on Alzheimer’s disease (AD) pathologies have not been investigated. In the present study, we examined the effects of β-lactolin and whey digestion rich in β-lactolin on AD pathology in 5×FAD transgenic mice and PS19 tauopathy mice. Intake of β-lactolin and whey digestion …rich in β-lactolin reduced the levels of inflammatory cytokines, suppressed the infiltration of activated microglia, decreased the levels of amyloid-β, ameliorated impaired long-term object memory, and attenuated decreased synaptophysin, dopamine, brain-derived neurotrophic factor, and insulin-like growth factor 1 levels in the cortex in 5×FAD transgenic mice. In addition, intake of β-lactolin and whey digestion rich in β-lactolin improved behavioral abnormality and reduced the ratio of phosphorylated tau to total tau in the cortex in PS19 tauopathy mice. These findings indicate that consumption with β-lactolin and whey digestion rich in β-lactolin suppresses inflammation and attenuates AD pathology and cognitive impairment. Show more

Keywords: Alzheimer’s disease, amyloid-β , β-lactolin, cognitive function, inflammation, memory, microglia, peptide, tauopathy

DOI: 10.3233/JAD-190997

Citation: Journal of Alzheimer's Disease, vol. 73, no. 4, pp. 1331-1342, 2020

Authors: Boublay, Nawele | Bouet, Romain | Dorey, Jean-Michel | Padovan, Catherine | Makaroff, Zaza | Fédérico, Denis | Gallice, Isabelle | Barrellon, Marie-Odile | Robert, Philippe | Moreaud, Olivier | Rouch, Isabelle | Krolak-Salmon, Pierre | Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Behavioral and psychological symptoms of dementia (BPSD) are frequent and troublesome for patients and caregivers. Considering possible preventive approaches, a better understanding of underlying neural correlates of BPSD is crucial. Objective: The aim is to assess whether brain regional volume predicts behavioral changes in mild AD. Methods: This work took part from the PACO study, a multicenter and prospective study that included 252 patients with mild AD from 2009 to 2014. Fifty-three patients were retained. Forty healthy matched control subjects from the ADNI cohort were included as controls. Voxel-based morphometry analysis was conducted to assess …regional brain volume using baseline MRI scans as a predictor of future behavioral changes over a period of 18 months. Behavior was assessed at baseline and longitudinally at 6-month intervals using the shortened form of the Neuropsychiatric Inventory (NPI). Results: The volume of 23 brain structures in frontal, temporal, parietal, occipital, subcortical regions and cerebellum predicted the evolution of NPI scores. Frontal volume was the most powerful predictor with frontal gyri, anterior cingulate cortex, and orbital gyri being particularly involved. Conclusion: To our knowledge, this is the first study assessing regional brain volumes as predictors of behavioral changes considered at earlier stages of AD. Up to 23 brain structures were associated with an increased risk of developing BPSD. Frontal lobe volume was the strongest predictor of future evolution of NPI. The involvement of multiple structures in the prediction of behavior suggests a role of the main large-scale networks involved in cognition. Show more

Keywords: Alzheimer’s disease, behavioral and psychological symptoms of dementia, Neuropsychiatric Inventory, magnetic resonance imaging, neuroimaging

DOI: 10.3233/JAD-190612

Citation: Journal of Alzheimer's Disease, vol. 73, no. 4, pp. 1343-1353, 2020

Authors: Gmitterova, Karin | Varges, Daniela | Schmitz, Matthias | Zafar, Saima | Maass, Fabian | Lingor, Paul | Zerr, Inga

Article Type: Research Article

Abstract: Background: Chromogranin A (CgA) is a general marker of gut endocrine cells, which are part of the “gut-brain axis” in Parkinson’s disease (PD). Objective: We analyzed CgA as a marker of synaptic dysfunction to assess its role in the differential diagnosis across different Lewy body disorders. Methods: We analyzed the CgA levels in the cerebrospinal fluid (CSF) and serum from 54 patients covering the spectrum of Lewy body disorders [13 Parkinson’s disease (PD), 17 Parkinson’s disease dementia (PDD), 24 dementia with Lewy bodies (DLB)] and 14 controls using an ELISA. Results: A positive correlation …was noted between CSF and serum CgA levels (ρ = 0.47, 95% CI: 0.24 to 0.65, p  < 0.0001). The highest values of CgA in CSF and in serum were measured in DLB and there was a significant difference between DLB and PDD (p  = 0.03 and p  = 0.004). The serum levels of CgA in controls achieved lower values compared to DLB (p  = 0.006). There was a gradual increase in serum levels from PD to PDD and DLB. An inverse correlation was seen between the CSF level of CgA and Aβ42 (ρ  = –0.296, 95% CI: –0.51 to –0.04, p  = 0.02). Conclusion: The incorporation of CgA analysis as an additional biomarker may be useful in the diagnostic work-up of Lewy body dementia. CgA analysis may be relevant in distinguishing DLB from PDD patients and presumably early stages of PD. Our data on altered serum levels in DLB pave the way to the development of blood-based parameters for the differential diagnosis, which however needs to be confirmed in a prospective study. Show more

Keywords: Blood biomarker, cerebrospinal fluid, Chromogranin A, Lewy body dementia, Parkinson’s disease

DOI: 10.3233/JAD-191153

Citation: Journal of Alzheimer's Disease, vol. 73, no. 4, pp. 1355-1361, 2020

Authors: Sajjad, Muhammad Umar | Blennow, Kaj | Knapskog, Anne Brita | Idland, Ane-Victoria | Chaudhry, Farrukh Abbas | Wyller, Torgeir Bruun | Zetterberg, Henrik | Watne, Leiv Otto

Article Type: Research Article

Abstract: Background: Delirium is a common and serious complication in geriatric patients. The pathophysiology of delirium is not known. Objective: The objective of the current study was to test the hypothesis that cerebrospinal fluid (CSF) levels of inflammatory markers at the time of spinal anesthesia for hip surgery are associated with delirium. Methods: In total 133 hip fracture patients and 125 cognitively healthy controls undergoing elective surgery, together with 73 Alzheimer’s disease (AD) dementia patients, were recruited at Oslo University Hospital and Diakonhjemmet Hospital, Oslo, Norway. Delirium was evaluated daily in hip fracture patients by the Confusion …Assessment Method (CAM). Depression was evaluated by Cornell Scale for Depression in Dementia (CSDD). Tumor necrosis factor alpha (TNF-α ), interleukin-1beta (IL-1β), and interleukin-8 (IL-8) levels were measured in CSF using a Mesoscale Discovery (MSD) immunoassay. Results: Hip fracture patients had significantly higher IL-8 levels (p  < 0.001) compared to cognitively healthy controls or patients with stable AD dementia. Furthermore, preoperative IL-8 levels were significantly higher (p  = 0.013) in hip fracture patients who developed delirium (incident delirium) after surgery as compared to patients with no delirium. However, subgroup analyses showed that IL-8 levels were only significantly higher in delirium patients without dementia (p  = 0.006). In contrast, depression subgroup analysis showed that IL-8 concentration was significantly higher (p  = 0.002) in delirium patients with depression. Both TNF-α and IL-1β were undetected in most patients. Conclusions: Our study suggests that IL-8 levels are associated with delirium onset and that underlying depression or dementia influences IL-8 levels. Show more

Keywords: Alzheimer’s disease, cytokines, delirium, depression

DOI: 10.3233/JAD-190941

Citation: Journal of Alzheimer's Disease, vol. 73, no. 4, pp. 1363-1372, 2020