Journal of Alzheimer's Disease - Volume 74, issue 3

Authors: Grøntvedt, Gøril Rolfseng | Lauridsen, Camilla | Berge, Guro | White, Linda R. | Salvesen, Øyvind | Bråthen, Geir | Sando, Sigrid Botne

Article Type: Research Article

Abstract: Background: The unbiased amyloid, tau, and neurodegeneration (A/T/N) classification is designed to characterize individuals in the Alzheimer continuum and is currently little explored in clinical cohorts. Objective: A retrospective comparison of the A/T/N classification system with the results of a two-year clinical study, with extended follow-up up to 10 years after inclusion. Methods: Patients (n  = 102) clinically diagnosed as Alzheimer’s disease (AD) with dementia or amnestic mild cognitive impairment (MCI), and 61 cognitively healthy control individuals were included. Baseline cerebrospinal fluid core biomarkers for AD (Aβ42 , phosphorylated tau, and total tau) were applied to the …A/T/N classification using the final clinical diagnosis at extended follow-up as the gold standard. Results: A + T + N+ was a strong predictor for AD dementia, even among cognitively healthy individuals. Amnestic MCI was heterogenous, considering both clinical outcome and distribution within A/T/N. Some individuals with amnestic MCI progressed to clinical AD dementia within all four major A/T/N groups. The highest proportion of progression was among triple positive cases, but progression was also common in individuals with suspected non-Alzheimer pathophysiology (A-T + N+), and those with triple negative status. A-T-N- individuals who were cognitively healthy overwhelmingly remained cognitively intact over time, but in amnestic MCI the clinical outcome was heterogenous, including AD dementia, other dementias, and recovery. Conclusion: The A/T/N framework accentuates biomarkers over clinical status. However, when selecting individuals for research, a combination of the two may be necessary since the prognostic value of the A/T/N framework depends on clinical status. Show more

Keywords: Alzheimer’s disease, amyloid, biomarkers, cerebrospinal fluid, classification, mild cognitive impairment, tau

DOI: 10.3233/JAD-191227

Citation: Journal of Alzheimer's Disease, vol. 74, no. 3, pp. 829-837, 2020

Authors: Atayde, Adrienne L. | Fischer, Corinne E. | Schweizer, Tom A. | Munoz, David G.

Article Type: Research Article

Abstract: Background: The relationship between sleep, neuropathology, and clinical manifestations of Alzheimer’s disease (AD) remains controversial. Objective: To determine whether nighttime behaviors (NTB) are associated with the development of AD histopathology or cognitive decline. Methods: We compared NTB prevalence in subjects with or without AD lesions, and with or without progressive cognitive decline. Subjects with either absent or severe plaques and tangles were identified from the National Alzheimer’s Disease Coordinating Center data sets and classified as cognitively declining if the standard deviation from their individual mean Mini-Mental Status Examination score was ≥2, and stable if <2 regardless …of their initial score. NTB was assessed using the Neuropsychiatric Inventory Questionnaire Quick Version (NPI-Q). Results: NTB was significantly greater in decliners than stable subjects in the group with severe histopathology as determined by frequent plaques (p  = 0.003) or high Braak stage (p  = 0.002). A similar significant trend was observed in subjects with absent plaques (p  = 0.019) or tangles (p  = 0.006). The prevalence of NTB was comparable between stable AD and non-AD subjects. NTB severity scores showed a similar pattern. Conclusion: The development of NTB as assessed by NPI-Q in subjects with or without AD lesions occurred concurrently with cognitive decline. Among cognitively stable subjects, the presence of AD histopathology did not alter NTB prevalence. Thus, NTB disruptions at the gross granularity level assessed by NPI-Q were much more closely related to cognitive decline than the formation of pathological lesions. Factors other than AD histopathology may mediate the association between NTB and cognitive decline. Show more

Keywords: Alzheimer’s disease, amyloid plaque, cognitive decline, neurofibrillary tangles, sleep

DOI: 10.3233/JAD-190907

Citation: Journal of Alzheimer's Disease, vol. 74, no. 3, pp. 839-850, 2020

Authors: Zhang, Jin | Hua, Xue-feng | Gu, Jinhua | Chen, Feng | Gu, Jianlan | Gong, Cheng-Xin | Liu, Fei | Dai, Chun-Ling

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is the most common cause of dementia. Studies indicate that neuroinflammation plays an important role in the pathophysiology of AD. High-mobility group box 1 (HMGB1) is an important chromatin protein. It can be secreted by immune cells and passively released from damaged cells to promote inflammation. HMGB1 also can recruit stem cells and promote their proliferation and tissue repairing. However, the role of HMGB1 in the progression of AD is currently unknown. Objective: The aims were to investigate the effect of HMGB1 on the AD-related pathologies and cognitive function using 3×Tg-AD mouse model. …Methods: Female 5-month-old 3×Tg-AD mice were intracerebroventricularly injected with 4.5 μg of HMGB1 or with saline as a control. The levels of interesting protein were assessed by western blots or immunofluorescence. The effect of HMGB1 on the cognitive function was evaluated by one-trial novel object recognition test and Morris water maze. Results: Intracerebroventricular injection of recombinant HMGB1 ameliorated cognitive impairment in 5–6-month-old 3×Tg-AD mice. The levels of synapsin 1, synaptophysin, MAP2, NeuN, and phosphorylated CREB were increased in HMGB1-treated 3×Tg-AD mouse brains. HMGB1 decreased intracellular amyloid-β level but did not affect tau phosphorylation. HMGB1 treatment also promoted neurogenesis in the dentate gyrus and increased the level of GFAP in the 3×Tg-AD mouse brains. Conclusion: These results reveal a novel function of HMGB1 in enhancing neuroplasticity and improving cognitive function in 3×Tg-AD mice. Show more

Keywords: Alzheimer’s disease, amyloid-β , cognition, HMGB1, inflammation, neurogenesis, tau

DOI: 10.3233/JAD-191110

Citation: Journal of Alzheimer's Disease, vol. 74, no. 3, pp. 851-864, 2020

Authors: Arnaldi, Dario | Donniaquio, Andrea | Mattioli, Pietro | Massa, Federico | Grazzini, Matteo | Meli, Riccardo | Filippi, Laura | Grisanti, Stefano | Famà, Francesco | Terzaghi, Michele | Girtler, Nicola | Brugnolo, Andrea | Doglione, Elisa | Pardini, Matteo | Villani, Flavio | Nobili, Flavio

Article Type: Research Article

Abstract: Background: Seizures are common in patients with dementia but precise epidemiologic data of epilepsy in neurodegenerative dementia is lacking. Objective: The first aim of the study was to investigate prevalence and clinical characteristics of epilepsy in a large cohort of patients with neurodegenerative dementias. Subsequently, we explored clinical, neuropsychological, and quantitative electroencephalogram (qEEG) data of Alzheimer’s disease (AD) patients with epilepsy (AD-EPI) as compared to AD patients without epilepsy (AD-CTR). Methods: We retrospectively evaluated consecutive patients with a diagnosis of a neurodegenerative dementia and a clinically diagnosed epilepsy that required antiepileptic drugs (AED). All patients underwent …baseline comprehensive neuropsychological assessment. A follow-up of at least one year was requested to confirm the dementia diagnosis. In AD patients, qEEG power band analysis was performed. AD-CTR and AD-EPI patients were matched for age, Mini-Mental State Examination score, and gender. Results: Thirty-eight out of 2,054 neurodegenerative dementia patients had epilepsy requiring AED. The prevalence of epilepsy was 1.82% for AD, 1.28% for the behavioral variant of frontotemporal dementia (bvFTD), 2.47% for dementia with Lewy bodies (DLB), and 12% for primary progressive aphasia. Epilepsy were more drug-responsive in AD than in non-AD dementias. Finally, no significant differences were found in neuropsychological and qEEG data between AD-EPI and AD-CTR patients. Conclusion: In our cohort, AD, FTD, and DLB dementias have similar prevalence of epilepsy, even if AD patients were more responsive to AED. Moreover, AD-EPI patients did not have significant clinical, neuropsychological qEEG differences compared with AD-CTR patients. Show more

Keywords: Alzheimer’s disease, dementia, EEG, epilepsy, seizure

DOI: 10.3233/JAD-191315

Citation: Journal of Alzheimer's Disease, vol. 74, no. 3, pp. 865-874, 2020

Authors: Yang, Aimin | Wang, Hongwei | Zuo, Xiaoxiao | Yang, Jianjun

Article Type: Research Article

Abstract: Persistent neuropathic pain (NP) causes future development of neurodegenerative diseases, e.g., Alzheimer’ disease, and thus needs to be optimally treated. Surgically-induced neuropathic pain (SNPP) is a persistent pain that occurs in nearly half of the individuals after common operations. Here, we showed that specific activation of 5-hydroxytryptamine (5-HT) type 2A receptors by systemic administration of TCB-2 [(4-bromo-3,6-dimethoxybenzocyclobuten-1-yl) methylamine hydrobromide] improved the function of potassium chloride cotransporter 2 (KCC2), resulting in reduction in neuropathic pain after chronic constriction injury (CCI), a rat model that mimics SNPP. Moreover, TCB-2 administration attenuated both mechanical and thermal hyperalgesia, likely through augmentation of dorsal horn …KCC2 levels, since this effect was abolished by intrathecal provision of dihydroindenyl oxy alkanoic acid (DIOA), which blocked the effects of KCC2. Furthermore, TCB-2-mediated re-activation of KCC2 likely reduces future development of neurodegeneration in rats. Together, our data support further studies on the possibility of using this strategy to reduce postoperative pain and future neurodegenerative disorders in clinic. Show more

Keywords: Alzheimer’ disease, neurodegeneration, potassium chloride cotransporter 2 (KCC2), surgically-induced neuropathic pain

DOI: 10.3233/JAD-200027

Citation: Journal of Alzheimer's Disease, vol. 74, no. 3, pp. 875-881, 2020

Authors: Almansoub, Hasan A.M.M. | Tang, Hui | Wu, Ying | Wang, Ding-Qi | Mahaman, Yacoubou Abdoul Razak | Salissou, Maibouge Tanko Mahamane | Lu, Youming | Hu, Fan | Zhou, Lan-Ting | Almansob, Yusra A.M. | Liu, Dan

Article Type: Research Article

Abstract: Neurotoxicity is one of the major pathological changes in multiple neurological disorders, including Alzheimer’s disease (AD) and Parkinson’s disease (PD), the second popular neurodegenerative disease in aged people. It is known that the AD and PD share the similar neuropathological hallmarks, such as the oxidative stress, loss of specific neurons, and aggregation of specific proteins. However, there are no effective therapeutic drugs for both AD and PD yet. Oxytocin (OXT) is a small peptide with 9 amino acids that is neuroprotective to many neurological disorders. Whether OXT administration confers neuroprotection to 1-methyl-4-phenyl-1, 2, 3, 6- tetrahydropyridine (MPTP)-induced neurotoxicity in mice …are still not known. In this study, we first found that the OXT levels are decreased in MPTP mice. Supplementation with OXT effectively rescues the locomotor disabilities and anxiety-like behaviors in MPTP mice. OXT also alleviates the hyperphosphorylation of α -synuclein at S129 site and the loss of dopaminergic neurons in the substantia nigra pars compacta, as well as the oxidative stress in the MPTP mice, and alleviates both oxidative stress and cell cytotoxicity in vitro . Furthermore, we found that OXT could inhibit the miR-26a/DAPK1 signal pathway in MPTP mice. In summary, our study demonstrates protective effects of OXT in MPTP mice and that miR-26a/DAPK1 signaling pathway may play an important role in mediating the protection of OXT. Show more

Keywords: Alpha-synuclein, behavior deficit, MPTP, neurotoxicity, oxidative stress, oxytocin, Parkinson’s disease

DOI: 10.3233/JAD-191091

Citation: Journal of Alzheimer's Disease, vol. 74, no. 3, pp. 883-901, 2020

Authors: Marelli, Cecilia | Hourregue, Claire | Gutierrez, Laure-Anne | Paquet, Claire | Menjot de Champfleur, Nicolas | De Verbizier, Delphine | Jacob, Melissa | Dubois, Jonathan | Maleska, Aleksandra Maceski | Hirtz, Christophe | Navucet, Sophie | Bennys, Karim | Dumurgier, Julien | Cognat, Emmanuel | Berr, Claudine | Magnin, Eloi | Lehmann, Sylvain | Gabelle, Audrey

Article Type: Research Article

Abstract: Background: Memory troubles and hippocampal atrophy are considered more frequent and focal atrophy less severe in late-onset (>65 years) than in presenile behavioral variant of frontotemporal dementia (bvFTD). Objective: To compare cerebrospinal fluid (CSF) and plasma biomarkers in late-onset and presenile bvFTD. Methods: Multicentric retrospective study (2007-2017) on patients with clinical diagnosis of bvFTD. Results: This study included 44 patients (67%) with presenile and 22 (33%) with late-onset bvFTD (comparable mean disease duration; n  = 11 with causal mutations). Hippocampal atrophy was more frequent (80% versus 25.8%) and severe in late-onset bvFTD (median Scheltens score: …3 [0–4] versus 1 [0–3]), without difference after adjustment for age. Lobar atrophy and focal hypometabolism/hypoperfusion were not different between groups. The median CSF Aβ1-42 and phosphorylated tau (P-tau) concentrations were in the normal range and comparable between groups. Axonal neurodegeneration biomarkers were within the normal range (CSF T-tau; plasma T-tau in late-onset bvFTD) or higher (plasma neurofilament light chain (NFL); plasma T-tau in presenile bvFTD) than the normal values, but globally not different between bvFTD groups. Plasma glial fibrillary acid protein (GFAP) was strongly increased in both bvFTD groups compared with the values in controls of the same age. Conclusion: The CSF and plasma biomarker profiles did not suggest a more aggressive neurodegeneration in the presenile group (comparable T-tau, NFL, and GFAP levels) or the co-existence of Alzheimer’s disease in the late-onset group (comparable and within normal range CSF Aβ1-42 and P-tau). The severity of the neurodegenerative process seems comparable in presenile and late-onset bvFTD. Show more

Keywords: Biomarkers, cerebrospinal fluid, frontotemporal dementia, glial fibrillary acid protein, late-onset, neurofilament light chain

DOI: 10.3233/JAD-190378

Citation: Journal of Alzheimer's Disease, vol. 74, no. 3, pp. 903-911, 2020

Authors: Arroyo-Anlló, Eva M. | Sánchez, Jorge Chamorro | Ventola, Alejandra R. Melero | Ingrand, Pierre | Neau, Jean-Philippe | Gil, Roger

Article Type: Research Article

Abstract: Background: Multiple sclerosis (MS) is considered a neurodegenerative disease and an inflammatory demyelinating neuropathology in young population. Procedural memory has been poorly investigated in MS. Objective: We assessed whether the MS group was able to develop a motor-cognitive skill, using a procedural task (PLSC) developed in our laboratory, applying a manual and serial reaction time (RT) paradigm to semantic categorization. Methods: We evaluated 26 MS patients and 26 socio-demographic matched control participants using the PLSC task. Results: Using non-parametric statistical analyses, we observed a significant improvement of semantic categorization RTs with practice (p  = 0.002), …even with new verbal material to categorize in MS patients (p  = 0.006), despite their motor and executive moderate deficits. This same profile of semantic procedural learning in MS was observed in previous studies carried out with Alzheimer’s and Parkinson’s diseases. Moreover, the visual-motor RTs remained stable or slightly improved over the five blocks in both groups, as well as in the AD groups of previous studies. The MS group showed longer visual-motor reaction times than those of the control group (p  < 0.042), except in motor initiation aspect (p  = 0.064). Both groups showed no significant differences for any type of error. Additionally, disability level and cognitive performances were not associated with the ratio of semantic procedural learning. Conclusion: The present results support the notion that MS patients may be capable of acquiring semantic skill, despite their motor disabilities and executive troubles. This work also addresses the possibilities to improve motor-cognitive skill RTs in neurodegenerative diseases. Show more

Keywords: Alzheimer’s disease, dementia, language, multiple sclerosis, neurodegenerative diseases, Parkinson’s disease, procedural memory, reaction time, skill

DOI: 10.3233/JAD-191083

Citation: Journal of Alzheimer's Disease, vol. 74, no. 3, pp. 913-924, 2020

Authors: Pasha, Evan P. | Rutjes, Elmer | Tomoto, Tsubasa | Tarumi, Takashi | Stowe, Ann | Claassen, Jurgen A.H.R. | Munro Cullum, C. | Zhu, David C. | Zhang, Rong

Article Type: Research Article

Abstract: Background: Vascular dysfunction has been implicated in the onset and progression of Alzheimer’s disease (AD), yet the relationship of arterial stiffening with brain amyloid-β (Aβ) burden in at risk patients is unclear. Objective: We aimed to determine the relationship of aortic and carotid arterial stiffening with Aβ burden in patients with amnestic mild cognitive impairment (aMCI), a proposed transitional stage between normal aging and AD. Methods: Thirty-two older adults with aMCI underwent 18 Florbetapir PET amyloid imaging to ascertain Aβ burden via standardized uptake value ratio (SUVR). Carotid-femoral pulse wave velocity (cfPWV), which reflects aortic stiffness, …and carotid β stiffness index and distensibility, which reflect local cerebral arterial stiffness, thus having direct impact on the cerebral circulation, were measured using applanation tonometry and ultrasonography. Results: Region-of-interest based analysis showed that precuneus and mean cortex Aβ SUVR were correlated positively with carotid β stiffness index and negatively with carotid distensibility after adjusting for age, sex, mean arterial pressure (MAP), pulse pressure (PP), and APOE4 status. Whole-brain voxel-wise analysis showed that Aβ SUVR was positively correlated with carotid β stiffness index, and negatively with carotid distensibility at the precuneus/cingulate gyrus after multiple comparison correction. cfPWV was not correlated with Aβ SUVR. Conclusions: Carotid rather than aortic stiffening was independently associated with brain Aβ burden in patients with aMCI after adjusting for age, sex, MAP, PP, and APOE4 status. These findings provide evidence that arterial stiffening, particularly carotid artery stiffening, may contribute to AD pathology in patients with aMCI. Show more

Keywords: Arterial stiffness, amyloid, mild cognitive impairment, ClinicalTrials.gov identifier: NCT01146717

DOI: 10.3233/JAD-191073

Citation: Journal of Alzheimer's Disease, vol. 74, no. 3, pp. 925-935, 2020

Authors: Watt, Georgia | Shang, Kani | Zieba, Jerzy | Olaya, Juan | Li, Henry | Garner, Brett | Karl, Tim

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is characterized by progressive cognitive decline and pathologically by the accumulation of amyloid-β (Aβ) and tau hyperphosphorylation causing neurodegeneration and neuroinflammation. Current AD treatments do not stop or reverse the disease progression, highlighting the need for more effective therapeutics. The phytocannabinoid cannabidiol (CBD) has demonstrated antioxidant, anti-inflammatory, and neuroprotective properties. Furthermore, chronic CBD treatment (20 mg/kg) reverses social and object recognition memory deficits in the AβPPxPS1 transgenic mouse model with only limited effects on AD-relevant brain pathology. Importantly, studies have indicated that CBD works in a dose-dependent manner. Thus, this study determined the chronic effects of 50 mg/kg …CBD in male AβPPxPS1 mice. 12-month-old mice were treated with 50 mg/kg CBD or vehicle via daily intraperitoneal injections for 3 weeks prior to behavioral testing. A variety of cognitive domains including object and social recognition, spatial and fear-associated memory were evaluated. Pathological brain analyses for AD-relevant markers were conducted using ELISA and western blot. Vehicle-treated male AβPPxPS1 mice demonstrated impaired social recognition memory and reversal spatial learning. These deficits were restored after CBD treatment. Chronic CBD tended to reduce insoluble Aβ40 levels in the hippocampus of AβPPxPS1 mice but had no effect on neuroinflammation, neurodegeneration, or PPARγ markers in the cortex. This study demonstrates that therapeutic-like effects of 50 mg/kg CBD on social recognition memory and spatial learning deficits in AβPPxPS1 mice are accompanied by moderate brain region-specific reductions in insoluble Aβ40 levels. The findings emphasize the clinical relevance of CBD treatment in AD; however, the underlying mechanisms involved require further investigation. Show more

Keywords: Alzheimer’s disease, amyloid-β , BDNF, cannabidiol, cognition, IBA1, neuroinflammation, PPARγ , transgenic AβPPswe/PS1 E9 mice

DOI: 10.3233/JAD-191242

Citation: Journal of Alzheimer's Disease, vol. 74, no. 3, pp. 937-950, 2020