Journal of Alzheimer's Disease - Volume 83, issue 2

Authors: Whitehouse, Peter J.

Article Type: Editorial

DOI: 10.3233/JAD-215215

Citation: Journal of Alzheimer's Disease, vol. 83, no. 2, pp. 487-490, 2021

Authors: Subramaniam, Saravanan | Blake, David T. | Constantinidis, Christos

Article Type: Review Article

Abstract: Memory and cognitive impairment as sequelae of neurodegeneration in Alzheimer’s disease and age-related dementia are major health issues with increasing social and economic burden. Deep brain stimulation (DBS) has emerged as a potential treatment to slow or halt progression of the disease state. The selection of stimulation target is critical, and structures that have been targeted for memory and cognitive enhancement include the Papez circuit, structures projecting to the frontal lobe such as the ventral internal capsule, and the cholinergic forebrain. Recent human clinical and animal model results imply that DBS of the nucleus basalis of Meynert can induce a …therapeutic modulation of neuronal activity. Benefits include enhanced activity across the cortical mantle, and potential for amelioration of neuropathological mechanisms associated with Alzheimer’s disease. The choice of stimulation parameters is also critical. High-frequency, continuous stimulation is used for movement disorders as a way of inhibiting their output; however, no overexcitation has been hypothesized in Alzheimer’s disease and lower stimulation frequency or intermittent patterns of stimulation (periods of stimulation interleaved with periods of no stimulation) are likely to be more effective for stimulation of the cholinergic forebrain. Efficacy and long-term tolerance in human patients remain open questions, though the cumulative experience gained by DBS for movement disorders provides assurance for the safety of the procedure. Show more

Keywords: Acetylcholine, basal forebrain, prefrontal cortex, working memory

DOI: 10.3233/JAD-210425

Citation: Journal of Alzheimer's Disease, vol. 83, no. 2, pp. 491-503, 2021

Authors: Luckey, Alison M. | Robertson, Ian H. | Lawlor, Brian | Mohan, Anusha | Vanneste, Sven

Article Type: Review Article

Abstract: This article aims to reevaluate our approach to female vulnerability to Alzheimer’s disease (AD) and put forth a new hypothesis considering how sex differences in the locus coeruleus-noradrenaline (LC-NA) structure and function could account for why females are more likely to develop AD. We specifically focus our attention on locus coeruleus (LC) morphology, the paucity of estrogens, neuroinflammation, blood-brain barrier permeability, apolipoprotein ɛ 4 polymorphism (APOE ɛ 4), and cognitive reserve. The role of the LC-NA system and sex differences are two of the most rapidly emerging topics in AD research. Current literature either investigates the LC due to …it being one of the first brain areas to develop AD pathology or acknowledges the neuroprotective effects of estrogens and how the loss of these female hormones have the capacity to contribute to the sex differences seen in AD; however, existing research has neglected to concurrently examine these two rationales and therefore leaving our hypothesis undetermined. Collectively, this article should assist in alleviating current challenges surrounding female AD by providing thought-provoking connections into the interrelationship between the disruption of the female LC-NA system, the decline of estrogens, and AD vulnerability. It is therefore likely that treatment for this heterogeneous disease may need to be distinctly developed for females and males separately, and may require a precision medicine approach. Show more

Keywords: Blood-brain barrier, cognitive reserve, dementia, estrogen, locus coeruleus-noradrenaline, neuroinflammation

DOI: 10.3233/JAD-210404

Citation: Journal of Alzheimer's Disease, vol. 83, no. 2, pp. 505-522, 2021

Authors: Samkaria, Avantika | Punjabi, Khushboo | Sharma, Shallu | Joon, Shallu | Sandal, Kanika | Dasgupta, Tirthankar | Sharma, Pooja | Mandal, Pravat K.

Article Type: Research Article

Abstract: Coronavirus (COVID-19) has emerged as a human catastrophe worldwide, and it has impacted human life more detrimentally than the combined effect of World Wars I and II. Various research studies reported that the disease is not confined to the respiratory system but also leads to neurological and neuropsychiatric disorders suggesting that the virus is potent to affect the central nervous system (CNS). Moreover, the damage to CNS may continue to rise even after the COVID-19 infection subsides which may further induce a long-term impact on the brain, resulting in cognitive impairment. Neuroimaging techniques is the ideal platform to detect and …quantify pathological manifestations in the brain of COVID-19 survivors. In this context, a scheme based on structural, spectroscopic, and behavioral studies could be executed to monitor the gradual changes in the brain non-invasively due to COVID-19 which may further help in quantifying the impact of COVID-19 on the mental health of the survivors. Extensive research is required in this direction for identifying the mechanism and implications of COVID-19 in the brain. Cohort studies are urgently required for monitoring the effects of this pandemic on individuals of various subtypes longitudinally. Show more

Keywords: Brain, cognition, COVID-19, gamma-aminobutyric acid, glutathione, magnetic resonance spectroscopy, mental health, psychiatry

DOI: 10.3233/JAD-210287

Citation: Journal of Alzheimer's Disease, vol. 83, no. 2, pp. 523-530, 2021

Authors: Funayama, Michitaka | Nakajima, Asuka | Kurose, Shin | Takata, Taketo

Article Type: Short Communication

Abstract: Diagnosis of frontotemporal dementia is challenging in the early stages. Various psychiatric and neurological diseases are misdiagnosed as frontotemporal dementia and vice versa. Here we present a case with right temporal variant of frontotemporal dementia who presented with alcohol dependency and remarkable behavioral symptoms and was first misdiagnosed as having alcohol-related dementia. He then revealed symptoms related to right temporal variant of frontotemporal dementia, such as prosopagnosia, difficulty recognizing his housemates, loss of empathy, ritualistic behaviors, and difficulty finding and comprehending words. Retrospectively, his alcohol dependency itself was considered an early manifestation of right temporal variant of frontotemporal dementia.

Keywords: Alcohol-related dementia, alcohol dependency, alcohol use disorder, behavioral variant frontotemporal dementia, reward, right temporal, semantic dementia

DOI: 10.3233/JAD-210501

Citation: Journal of Alzheimer's Disease, vol. 83, no. 2, pp. 531-537, 2021

Authors: Cárcamo, Jasmine | Kociolek, Anton J. | Fernández, Kayri K. | Gu, Yian | Zhu, Carolyn W. | Stern, Yaakov | Cosentino, Stephanie

Article Type: Short Communication

Abstract: To assess the predictive value of neuropsychological tests for severe dependency in Alzheimer’s disease as defined by the Equivalent Institutional Care Rating Scale, in a multiethnic, community cohort. The sample included 146 elders from the Predictors 3 cohort. Cox proportional hazard models tested the predictive value of each neuropsychological test at baseline on relative risk of meeting severe dependency. Higher semantic processing and memory test scores at baseline were associated with lower risk of meeting severe dependency in the adjusted Cox models. The integrity of semantic processing and memory abilities in dementia appears to predict time to severe functional dependency.

Keywords: Alzheimer’s disease, cognition, dementia, memory, neuropsychological tests

DOI: 10.3233/JAD-210019

Citation: Journal of Alzheimer's Disease, vol. 83, no. 2, pp. 539-544, 2021

Authors: Park, Mincheol | Baik, Kyoungwon | Lee, Young-gun | Kang, Sung Woo | Jung, Jin Ho | Jeong, Seong Ho | Lee, Phil Hyu | Sohn, Young H. | Ye, Byoung Seok

Article Type: Research Article

Abstract: Background: Small vessel disease (SVD) magnetic resonance imaging (MRI) markers including deep and periventricular white matter hyperintensities (PWMH), lacunes, and microbleeds are frequently observed in Alzheimer’s disease (AD) and Lewy body disease (LBD), but their implication has not been clearly elucidated. Objective: To investigate the implication of SVD MRI markers in cognitively impaired patients with AD and/or LBD. Methods: We consecutively recruited 57 patients with pure AD-related cognitive impairment (ADCI), 49 with pure LBD-related cognitive impairment (LBCI), 45 with mixed ADCI/LBCI, and 34 controls. All participants underwent neuropsychological tests, brain MRI, and amyloid positron emission tomography. …SVD MRI markers including the severity of deep and PWMH and the number of lacunes and microbleeds were visually rated. The relationships among vascular risk factors, SVD MRI markers, ADCI, LBCI, and cognitive scores were investigated after controlling for appropriate covariates. Results: LBCI was associated with more severe PWMH, which was conversely associated with an increased risk of LBCI independently of vascular risk factors and ADCI. PWMH was associated with attention and visuospatial dysfunction independently of vascular risk factors, ADCI, and LBCI. Both ADCI and LBCI were associated with more lobar microbleeds, but not with deep microbleeds. Conclusion: Our findings suggest that PWMH could reflect degenerative process related with LBD, and both AD and LBD independently increase lobar microbleeds. Show more

Keywords: Alzheimer’s disease, Lewy body disease, mixed disease, periventricular white matter hyperintensity, small vessel disease, white matter hyperintensity

DOI: 10.3233/JAD-210669

Citation: Journal of Alzheimer's Disease, vol. 83, no. 2, pp. 545-556, 2021

Authors: Zhao, Xuhao | Chong, Eddie Jun Yi | Qi, Wei | Pang, Ting | Xu, Xin | Chen, Christopher

Article Type: Research Article

Abstract: Background: Long-term post-stroke cognitive impairment (PSCI) has often been overlooked, especially among patients with minor stroke or transient ischemic attack (TIA). Objective: To assess 6-year domain-specific cognitive trajectories among survivors of minor stroke or TIA and to identify possible indicators associated with cognitive trajectories, as well as long-term and incident PSCI. Methods: Eligible participants completed cognitive and clinical assessments at baseline (2 weeks after stroke) and up to 5 follow-up visits in 6 years. Mixed linear models and generalized estimating equations were adopted to analyze longitudinal data and survival analysis to explore incident PSCI, controlling for …demographic, clinical, and vascular indicators. Results: The prevalence of PSCI and mortality rate ranged from 34.6% to 53.7%, and 0 to 7.7% respectively, among 244 patients. Incidence of PSCI was 21.9%. While visual memory demonstrated a significant improvement (p  < 0.05), other cognitive domains showed a fluctuating yet stable pattern across visits (all ps > 0.05). Besides age, baseline IQCODE (attention: –0.218 SD/y, executive function: –0.238 SD/y, visual memory: –0.266 SD/y), and MoCA improvement within 1 year (visuoconstruction: 0.007 SD/y, verbal memory: 0.012 SD/y) were associated with longitudinal cognitive changes. Baseline MoCA (OR = 0.66, 95% CI = [0.59–0.74]), MoCA improvement within 3–6 months (OR = 0.79, 95% CI = [0.71–0.89], and within 1 year (OR = 0.86, 95% CI = [0.76–0.96]) were associated with long-term PSCI, while baseline MoCA (OR = 0.76, 95% CI = [0.61–0.96]) was also associated with incident PSCI. Conclusion: While most domains remained stable across-time, visual memory demonstrated an overall improvement. Short-term cognitive improvement could be an early indicator of long-term cognitive trajectory to identify individuals who may be resilient to PSCI. Show more

Keywords: Cognitive impairment, cognitive trajectory, domain-specific cognition, minor stroke, risk factor, transient ischemic attack

DOI: 10.3233/JAD-210619

Citation: Journal of Alzheimer's Disease, vol. 83, no. 2, pp. 557-568, 2021

Authors: Sung, Pi-Shan | Lee, Kang-Po | Lin, Po-Yu | Su, Hui-Chen | Yu, Rwei-Ling | Tsai, Kuen-Jer | Lin, Sheng-Hsiang | Chen, Chih-Hung

Article Type: Research Article

Abstract: Background: Differences exist regarding post-stroke cognitive outcomes. Objective: The aim of this study investigates the potential factors associated with post-stroke cognitive performance and trajectories. Methods: We performed a prospective cohort study using serial monitoring of cognitive function over a 1-year period after a first-ever ischemic stroke. Small vessel disease (SVD) burden and hippocampal atrophy (HA) were evaluated using the modified cerebral small vessel disease scores (mCSVD) and medial temporal atrophy score (MTA) scores. A generalized estimating equation (GEE) model and a group-based trajectory model (GBTM) was used to analyze the potential factors associated with post-stroke cognitive …outcomes. Results: A total of 112 patients were enrolled. The GEE model showed that all patients, regardless of initial cognitive performance, had a tendency to show an increase in the Montreal Cognitive Assessment over time. The cognitive performance was better in male patients with higher education levels (p  = 0.046 and p  < 0.001, respectively), but tended to be worse in patients with higher SVD burden and HA. The GBTM model grouped patients into low, intermediate, and high performance (LP, IP, and HP) after stroke. A higher SVD burden, rather than HA and initial stroke severity and location, independently predicted a higher odds of poor post-stroke cognitive trajectory (being in the LP group) after stroke (adjusted odds ratio 2.74, 95%CI 1.09–6.86). Conclusion: In patients with first-ever mild stroke, cognitive improvement over time was evident. The detrimental impact of the SVD burden may outweigh the effect of HA or acute stroke insult on the post-stroke cognitive trajectory during the 1-year follow-up. Show more

Keywords: Cerebral small vessel diseaseburden, hippocampal atrophy, post-stroke cognitivetrajectory, post-stroke dementia

DOI: 10.3233/JAD-210587

Citation: Journal of Alzheimer's Disease, vol. 83, no. 2, pp. 569-579, 2021

Authors: Amini, Samad | Zhang, Lifu | Hao, Boran | Gupta, Aman | Song, Mengting | Karjadi, Cody | Lin, Honghuang | Kolachalama, Vijaya B. | Au, Rhoda | Paschalidis, Ioannis Ch.

Article Type: Research Article

Abstract: Background: Widespread dementia detection could increase clinical trial candidates and enable appropriate interventions. Since the Clock Drawing Test (CDT) can be potentially used for diagnosing dementia-related disorders, it can be leveraged to develop a computer-aided screening tool. Objective: To evaluate if a machine learning model that uses images from the CDT can predict mild cognitive impairment or dementia. Methods: Images of an analog clock drawn by 3,263 cognitively intact and 160 impaired subjects were collected during in-person dementia evaluations by the Framingham Heart Study. We processed the CDT images, participant’s age, and education level using a …deep learning algorithm to predict dementia status. Results: When only the CDT images were used, the deep learning model predicted dementia status with an area under the receiver operating characteristic curve (AUC) of 81.3% ± 4.3%. A composite logistic regression model using age, level of education, and the predictions from the CDT-only model, yielded an average AUC and average F1 score of 91.9% ±1.1% and 94.6% ±0.4%, respectively. Conclusion: Our modeling framework establishes a proof-of-principle that deep learning can be applied on images derived from the CDT to predict dementia status. When fully validated, this approach can offer a cost-effective and easily deployable mechanism for detecting cognitive impairment. Show more

Keywords: Alzheimer’s disease, artificial intelligence, clock test, deep learning, dementia

DOI: 10.3233/JAD-210299

Citation: Journal of Alzheimer's Disease, vol. 83, no. 2, pp. 581-589, 2021