Journal of Alzheimer's Disease - Volume 72, issue 2

Authors: Sugimoto, Taiki | Ono, Rei | Kimura, Ai | Saji, Naoki | Niida, Shumpei | Toba, Kenji | Sakurai, Takashi

Article Type: Research Article

Abstract: Background: Cognitive frailty (CF) is defined as simultaneous presence of physical frailty (PF) and cognitive impairment among older adults without dementia. Although white matter hyperintensities (WMH) as expressions of cerebral small vessel disease are associated with physical and cognitive decline and could manifest as CF, this association remains yet to be clarified. Objects: To clarify the association between CF and WMH among memory clinic patients. Methods: The subjects of this cross-sectional study were 121 cognitively normal (CN) and 212 mildly cognitively impaired (MCI) patients who presented to the Memory Clinic at the National Center for Geriatrics …and Gerontology of Japan. PF status was defined based on the definition proposed by Fried and colleagues. CF was defined as simultaneous presence of pre-PF or PF and MCI. WMH volumes were measured using an automatic segmentation application. Multiple liner regression analyses with adjustment for cardiovascular risk factors were performed. Results: Of all subjects, 77 (63.6%) and 22 (18.2%) CN patients and 132 (62.3%) and 65 (30.7%) MCI patients were categorized into pre-PF and PF, respectively. Multiple liner regression analysis showed that those with CF had higher WMH volumes than those without (β= 0.23). When categorized into six groups according to PF and cognitive status, the PF/CN (β= 0.15), pre-PF/MCI (β= 0.41), and PF/MCI (β= 0.34) groups had higher WMH volumes than the non-PF/CN group. Conclusions: This study showed increased WMH volumes in CF and PF, indicating that WMH could be one of the key underlying brain pathologies of CF. Show more

Keywords: Cognitive frailty, frailty syndrome, mild cognitive impairment, physical frailty, white matter hyperintensity

DOI: 10.3233/JAD-190622

Citation: Journal of Alzheimer's Disease, vol. 72, no. 2, pp. 605-612, 2019

Authors: Turriziani, Patrizia | Smirni, Daniela | Mangano, Giuseppa Renata | Zappalà, Giuseppe | Giustiniani, Andreina | Cipolotti, Lisa | Oliveri, Massimiliano

Article Type: Research Article

Abstract: Background: The lack of effective pharmacological or behavioral interventions for memory impairments associated with Alzheimer’s disease (AD) emphasizes the need for the investigation of approaches based on neuromodulation. Objective: This study examined the effects of inhibitory repetitive transcranial magnetic stimulation (rTMS) of prefrontal cortex on recognition memory in AD patients. Methods: In a first experiment, 24 mild AD patients received sham and real 1Hz rTMS over the left and right dorsolateral prefrontal cortex (DLPFC), in different sessions, between encoding and retrieval phases of a non-verbal recognition memory task. In a second experiment, another group of 14 …AD patients underwent sham controlled repeated sessions of 1Hz rTMS of the right DLPFC across a two week treatment. Non-verbal recognition memory task was performed at baseline, at the end of the two weeks period and at a follow up of 1 month. Results: Right real rTMS significantly improved memory performance compared to right sham rTMS (p  = 0.001). Left real rTMS left the memory performance unchanged as compared with left sham rTMS (p  = 0.46). The two sham conditions did not differ between each other (p  = 0.24). In the second experiment, AD patients treated with real rTMS showed an improvement of memory performance at the end of the two weeks treatment (p  = 0.0009), that persisted at 1-month follow-up (p  = 0.002). Conclusion: These findings provide evidence that inhibitory rTMS over the right DLPFC can improve recognition memory function in AD patients. They also suggest the importance of a new approach of non-invasive brain stimulation as a promising treatment in AD. Show more

Keywords: Alzheimer’s disease, prefrontal cortex, recognition memory, repetitive transcranial magnetic stimulation

DOI: 10.3233/JAD-190888

Citation: Journal of Alzheimer's Disease, vol. 72, no. 2, pp. 613-622, 2019

Authors: Zhou, Guoyu | Zhao, Xinjing | Lou, Zhiyin | Zhou, Shengnian | Shan, Peiyan | Zheng, Ning | Yu, Xiaolin | Ma, Lin

Article Type: Research Article

Abstract: Background: Vasculature changes have been observed in Alzheimer’s disease (AD). AD-related vascular pathology might impair cerebral autoregulation (CA). Objective: This study was designed to evaluate CA of AD patients by using transcranial doppler (TCD). Methods: A total of 61 participants were included in the study, including 31 AD patients and 30 controls. The trend curves of cerebral blood flow velocities (CBFV), pulsatility index, and resistance index were obtained using TCD during supine-to-standing posture changes. CA was measured by the changes of CBFV curves during supine-to-standing test. Results: There were two spikes named X spike …and W spike that appeared in the CBFV curve when the subjects stood abruptly. The slope of the X spike descending branch, the slope of the W spike ascending branch, and the angle between X and W spikes (α angle), showed significant differences between the experimental and control groups (2.34±0.99 versus 3.15±1.61 cm/s2 , p  = 0.021; 2.31±0.81 versus 3.38±1.18 cm/s2 , p  < 0.001; and 52.71±20.26 versus 41.4±12.87 degrees, p  = 0.012, respectively). ROC analysis showed that AUCα angle is 0.664 (p  = 0.028) and that AUCSAB and AUCadjustedSAB are 0.775 and 0.738, respectively (both p  < 0.001). Conclusions: Our study demonstrated that supine-to-standing TCD test is a valuable tool for the evaluation of CA in AD patients. Impaired CA in AD patients manifested as decreased efficiency of changes in the CBFV curve. Neurovascular units were involved in the pathogenesis of AD. Show more

Keywords: Alzheimer’s disease, cerebral autoregulation, supine-to-standing test, transcranial Doppler

DOI: 10.3233/JAD-190296

Citation: Journal of Alzheimer's Disease, vol. 72, no. 2, pp. 623-631, 2019

Authors: Liu, Xi-Xi | Jiao, Bin | Liao, Xin-Xin | Guo, Li-Na | Yuan, Zhen-Hua | Wang, Xin | Xiao, Xue-Wen | Zhang, Xin-Yue | Tang, Bei-Sha | Shen, Lu

Article Type: Research Article

Abstract: Recent studies found that poor oral hygiene was associated with increased risk of dementia, and the number of oral bacteria significantly increased in the brain tissues of patients with Alzheimer’s disease (AD), suggesting that the oral microbiota may play an important role in the pathogenesis of AD. However, the actual composition of oral bacteria communities in patients with AD and whether these oral bacteria are associated with disease severity remain largely unknown. Also, the APOE ɛ 4 polymorphism is a strong risk factor for sporadic AD, and it would be pertinent to see if the bacterial flora was different …in those patients who were APOE ɛ 4 positive. A total of 78 subjects were recruited in this study, including 39 patients with AD and 39 healthy controls. Saliva was collected from each subject. 16S ribosomal RNA (16S rRNA) sequencing was conducted to analyze the salivary microbiota, and Sanger sequencing was performed to analyze the APOE genotype. There was a significantly lower richness and diversity of saliva microbiota detected in AD patients than healthy controls. The relative abundance of Moraxella , Leptotrichia , and Sphaerochaeta in the saliva of AD patients greatly increased, whereas that of Rothia was significantly reduced. Compared with APOE ɛ 4 (–) patients, the level of Abiotrophia and Desulfomicrobium was comparatively abundant, while Actinobacillus and Actinomyces decreased significantly in patients carrying the APOE ɛ 4. No bacteria were found to be associated with the severity of AD. This is the first study to analyze the salivary microorganisms in patients with AD, and we discovered that the composition of salivary microbiome was altered in AD, providing further support for the role of the oral microbiome in AD development. Show more

Keywords: Alzheimer’s disease, APOE , oral microbiome, 16S rRNA

DOI: 10.3233/JAD-190587

Citation: Journal of Alzheimer's Disease, vol. 72, no. 2, pp. 633-640, 2019

Authors: Yoshida, Koji | Hata, Yukiko | Ichimata, Shojiro | Nishida, Naoki

Article Type: Research Article

Abstract: Background: Aggregation of abnormal phosphorylated tau in brain stem areas may be a possible early pathological manifestation of Alzheimer’s disease (AD). Objective: This study aimed to explore the prevalence of cases with AD-related pathology in subjects <40 years of age and to explore the association of such pathology, neuropsychiatric symptoms, and APOE genotype. Method: We conducted brain immunohistochemistry for 189 cases <40 years of age (mean±standard deviation age 25.3±13.1 years). Tau positive cases were then assessed for the distribution of tau pathology in the locus ceruleus (LC), raphe nucleus (RN), and entorhinal cortex (ErC), and …the distinction between neuronal threads and cellular inclusions. Apolipoprotein E (APOE ) genotype was also examined. Results: Tau pathology was detected in 135 cases (71.4%; 13–39 years; only LC, 23 cases; only RN, 4 cases; only ErC, 35 cases; LC+RN, 3 cases; LC+ErC, 57 cases; all three regions, 10 cases). The prevalence of thread pathology was higher than that of cellular inclusions. Significantly higher prevalence of the APOE ɛ 2 allele were found in 10–39 years of age natural death cases (p  < 0.05). Amyloid-β deposition was found in only 7 cases, along with a significantly high frequency of the ɛ 4 allele (p  < 0.05). While a past history of psychiatric disease was a significant risk factor for suicide, AD-related pathology was not associated with suicide. Conclusions: Both the brain stem and entorhinal cortex was the initial site of tau pathology in many younger subjects. AD-related pathology may not be a significant accelerating factor for suicide in younger subjects. Show more

Keywords: Alzheimer’s disease, amyloid-β, APOE, neuropathology, suicide, tau

DOI: 10.3233/JAD-190196

Citation: Journal of Alzheimer's Disease, vol. 72, no. 2, pp. 641-652, 2019

Authors: Forbes, Harriet J. | Wong, Angel Y.S. | Morton, Caroline | Bhaskaran, Krishnan | Smeeth, Liam | Richards, Marcus | Schmidt, Sigrun A.J. | Langan, Sinéad M. | Warren-Gash, Charlotte

Article Type: Research Article

Abstract: Background: In the UK, an estimated one third of people with dementia have not received a diagnosis. Good evidence suggests that dementia risk is increased among widowed individuals; however, it is not clear if they are being diagnosed in routine primary care. Objective: This study aimed to investigate if bereavement influenced the probability of having received a dementia diagnosis. Methods: A population-based cohort study using UK electronic health records, between 1997 and 2017, among 247,586 opposite-sex partners. Those experiencing partner bereavement were matched (age, sex, and date of bereavement) to a non-bereaved person living in a …partnership. Multivariate cox regression was performed. Results: Partner bereavement was associated with an increased risk of receiving a diagnosis of dementia in the first three months (hazard ratio (HR) 1.43, 95% CI 1.20–1.71) and first six months (HR 1.24, 95% CI 1.09–1.41), while there was a small reduced risk of getting a dementia diagnosis over all follow-up (HR 0.94, 95% CI 0.89–0.98). Conclusions: Partner bereavement appears to lead to a short-term increased risk of the surviving partner receiving a diagnosis of dementia, suggesting that bereavement unmasks existing undiagnosed dementia. Over the longer term, however, bereaved individuals are less likely to have a diagnosis of dementia in their health records than non-bereaved individuals. Show more

Keywords: Bereavement, Clinical Practice Research Datalink, dementia, diagnosis, epidemiology

DOI: 10.3233/JAD-190571

Citation: Journal of Alzheimer's Disease, vol. 72, no. 2, pp. 653-662, 2019