Journal of Alzheimer's Disease - Volume 82, issue 2

Authors: Delazer, Margarete | Zamarian, Laura | Djamshidian, Atbin

Article Type: Research Article

Abstract: Background: Agraphia is a typical feature in the clinical course of Alzheimer’s disease (AD). Objective: Assess the differences between AD and normal aging as regards kinematographic features of handwriting and elucidate writing deficits in AD. Methods: The study included 23 patients with AD (78.09 years/SD = 7.12; MMSE 21.39/SD = 3.61) and 34 healthy controls (75.56 years/SD = 5.85; MMSE 29.06/SD = 0.78). Both groups performed alphabetical and non-alphabetical writing tasks. The kinematographic assessment included the average number of inversions per stroke (NIV; number of peaks in the velocity profile in a single up or down stroke), percentage of automated segments, frequency (average number …of strokes per second), writing pressure, and writing velocity on paper. Results: A total of 14 patients showed overt writing difficulties reflected by omissions or substitutions of letters. AD patients showed less automated movements (as measured by NIV), lower writing velocity, and lower frequency of up-and-down strokes in non-alphabetical as well as in alphabetical writing. In the patient group, Spearman correlation analysis between overt writing performance and NIV was significant. That means patients who had less errors in writing a sentence showed a higher automaticity in handwriting. The correctness of alphabetical writing and some kinematographic measures in writing non-alphabetical material reached excellent diagnostic values in ROC analyses. There was no difference in the application of pressure on the pen between patients and controls. Conclusion: Writing disorders are multi-componential in AD and not strictly limited to one processing level. The slow and poorly automated execution of motor programs is not bound to alphabetical material. Show more

Keywords: Agraphia, dementia, inversions, kinematographic analysis, writing velocity

DOI: 10.3233/JAD-210279

Citation: Journal of Alzheimer's Disease, vol. 82, no. 2, pp. 727-735, 2021

Authors: Callahan, Brandy L. | McLaren-Gradinaru, Michael | Burles, Ford | Iaria, Giuseppe

Article Type: Research Article

Abstract: Background: Older adults with bipolar disorder (BD) have increased dementia risk, but signs of dementia are difficult to detect in the context of pre-existing deficits inherent to BD. Objective: To identify the emergence of indicators of early dementia in BD. Methods: One hundred and fifty-nine non-demented adults with BD from the National Alzheimer’s Coordinating Center (NACC) data repository underwent annual neuropsychological assessment up to 14 years (54.0 months average follow-up). Cognitive performance was examined longitudinally with linear mixed-effects models, and yearly differences between incident dementia cases and controls were examined in the six years prior to …diagnosis. Results: Forty participants (25.2%) developed dementia over the follow-up period (‘incident dementia cases’). Alzheimer’s disease was the most common presumed etiology, though this was likely a result of sampling biases within NACC. Incident dementia cases showed declining trajectories in memory, language, and speeded attention two years prior to dementia onset. Conclusion: In a sample of BD patients enriched for Alzheimer’s type dementia, prodromal dementia in BD can be detected up to two years before onset using the same cognitive tests used in psychiatrically-healthy older adults (i.e., measures of verbal recall and fluency). Cognition in the natural course of BD is generally stable, and impairment or marked decline on measures of verbal episodic memory or semantic retrieval may indicate an early neurodegenerative process. Show more

Keywords: Aging, cognitive dysfunction, neuropsychology, psychiatry

DOI: 10.3233/JAD-201240

Citation: Journal of Alzheimer's Disease, vol. 82, no. 2, pp. 737-748, 2021

Authors: Ben Ayed, Ines | Castor-Guyonvarch, Naomie | Amimour, Souad | Naija, Salma | Aouichaoui, Chirine | Ben Omor, Sana | Tabka, Zouhair | El Massioui, Farid

Article Type: Research Article

Abstract: Background: Many studies have shown the impact of acute aerobic exercises (AAE) on cognition in healthy adults or at a pre-dementia stage. Few studies, however, have explored the positive effects of AAE in moderate Alzheimer’s disease (ADM) patients. Objective: Evaluating the effect of AAE on cognitive functions in ADM patients. Methods: Overall, 79 (age: 69.62±0.99) ADM patients were recruited. Participants were divided into three groups according to the task: aerobic exercises done alone or combined with cognitive games presented on a screen, and a control group who performed a reading task. The aerobic exercise protocol consisted …of a 20-min cycling exercise of moderate intensity, corresponding to 60%of the individual target maximal heart rate recorded in a 6-minute walking test. The participants’ cognition was monitored before and after the intervention using the Tower of Hanoi, Digit Span, and Stroop tasks. Results: After the exercise, the participants’ attention in both the physical and combined groups improved for the Stroop, the forward and backward Digit Span tasks, as well as the time taken to solve the Tower of Hanoi, although no significant differences were found in the number of moves taken in the latter. By contrast, the control group did not show any significant improvement for most of the cognitive tasks after the reading session. Conclusion: Current evidence suggests that AAE may help to improve cognitive functions in ADM patients. This improvement is enhanced when the exercise is combined with cognitive games. Safe and progressive types of exercises should be promoted among ADM patients. Show more

Keywords: Aerobic exercises, Alzheimer disease, attention, solving problem, working memory

DOI: 10.3233/JAD-201317

Citation: Journal of Alzheimer's Disease, vol. 82, no. 2, pp. 749-760, 2021

Authors: Korpioja, Anita | Krüger, Johanna | Koivuluoma, Susanna | Pylkäs, Katri | Moilanen, Virpi | Helisalmi, Seppo | Hiltunen, Mikko | Remes, Anne M.

Article Type: Research Article

Abstract: Background: Rare variants of SORL1 have been associated with an increased risk of early-onset or late-onset Alzheimer’s disease (AD). However, a lot remains to be clarified about their significance in the pathogenesis of the disease. Objective: To evaluate the role of SORL1 variants among Finnish patients with early-onset AD (EOAD). Methods: The rare SORL1 variants were screened in a cohort of 115 Finnish EOAD patients (mean age at onset 58.3 years, range 46–65 years) by using the whole-exome sequencing. Results: We found one novel nonsense variant (p.Gln290* ) and eight missense variants …in SORL1 . This is the first study reporting the SORL1 variants p.Lys80Arg, p.Ala789Val and p.Arg866Gln in EOAD patients. Furthermore, two of these three missense variants were overrepresented in EOAD patients compared to gnomAD non-neuro Finnish samples. Conclusion: This study strengthens the earlier findings, that the rare variants in SORL1 are associated with EOAD. Show more

Keywords: Dementia, early onset Alzheimer’s disease, gene, human, mutation, neurodegenerative disease, single nucleotide polymorphism, SORL1

DOI: 10.3233/JAD-210207

Citation: Journal of Alzheimer's Disease, vol. 82, no. 2, pp. 761-770, 2021

Authors: Sewell, Margaret C. | Neugroschl, Judith | Umpierre, Mari | Chin, Shehan | Zhu, Carolyn W. | Velasco, Nelly | Gonzalez, Sabrina | Acabá-Berrocal, Alexandra | Bianchetti, Luca | Silva, Gabriela | Collazo, Alma | Sano, Mary

Article Type: Research Article

Abstract: Background: Latinx elders are underrepresented in dementia research. In a previous study we assessed research attitudes in urban minority elders and found a significant minority expressed neutral to negative attitudes relating to trust, safety, and personal responsibility to help research. Objective: To assess the impact of a composite intervention on attitudes toward research and research participation among elderly Latinx. The intervention was a collaboratively produced research participation video shown during presentations with our elderly community advisory board (CAB) as co-presenters. Methods: The video was created by the ADRC and CAB. All senior center attendees were eligible …to participate. Afterwards, the Research Attitudes Questionnaire (RAQ) and a brief questionnaire on the impact of the video were administered. Using Wilcoxon Rank Sum Tests, Chi Square, and OLS regressions, RAQ responses were compared to those from a historical cohort from similar centers. Results: 74 in the “Historical Cohort 1” and 104 in “Intervention Cohort 2” were included. RAQ total score was higher in Cohort 2 than Cohort 1 (28.5 versus 26.1, p  < 0.05) after controlling for age, education, and country of origin. In response to the question “Has the video influenced your willingness and interest to participate in research”, 88.7%of the participants in Cohort 2 reported being “more” or “much more” interested in research. Conclusion: Tailoring community research recruitment programs to include relatable peers using novel recruitment techniques may have positive implications for improving enrollment of diverse elderly individuals in research. Show more

Keywords: Attitudes towards research, diversity, elder minorities, minorities in research, research participation

DOI: 10.3233/JAD-210027

Citation: Journal of Alzheimer's Disease, vol. 82, no. 2, pp. 771-779, 2021

Authors: Svensson, Johan | Blomqvist, Maria | Kettunen, Petronella | Eckerström, Carl | Henricsson, Marcus | Jonsson, Michael | Bjerke, Maria | Månsson, Jan-Eric | Wallin, Anders

Article Type: Research Article

Abstract: Background: Sulfatides (STs) in cerebrospinal fluid (CSF), as well as magnetic resonance imaging (MRI)-detected white matter hyperintensities (WMHs), may reflect demyelination. Here, we investigated the diagnostic utility of CSF ST levels in the subcortical small vessel type of dementia (SSVD), which is characterized by the presence of brain WMHs. Objective: To study the diagnostic utility of CSF ST levels in SSVD. Methods: This was a mono-center, cross-sectional study of SSVD (n  = 16), Alzheimer’s disease (n  = 40), mixed dementia (n  = 27), and healthy controls (n  = 33). Totally, 20 ST species were measured in CSF by liquid chromatography-mass …spectrometry (LC-MS/MS). Results: CSF total ST levels, as well as CSF levels of hydroxylated and nonhydroxylated ST species, did not differ across the study groups. In contrast, CSF neurofilament light chain (NFL) levels separated the patient groups from the controls. CSF total ST level correlated with CSF/serum albumin ratio in the total study population (r  = 0.64, p  < 0.001) and in all individual study groups. Furthermore, CSF total ST level correlated positively with MRI-estimated WMH volume in the total study population (r  = 0.30, p  < 0.05), but it did not correlate with CSF NFL level. Conclusion: Although there was some relation between CSF total ST level and WMH volume, CSF ST levels were unaltered in all dementia groups compared to the controls. This suggests that CSF total ST level is a poor biomarker of demyelination in SSVD. Further studies are needed to investigate the mechanisms underlying the marked correlation between CSF total ST level and CSF/serum albumin ratio. Show more

Keywords: Alzheimer’s disease, cerebrospinal fluid, mixed dementia, sulfatide species, sulfatides, subcortical small vessel type of dementia, white matter hyperintensities

DOI: 10.3233/JAD-201552

Citation: Journal of Alzheimer's Disease, vol. 82, no. 2, pp. 781-790, 2021

Authors: Greco, Frank A. | McKee, Ann C. | Kowall, Neil W. | Hanlon, Eugene B.

Article Type: Research Article

Abstract: Background: Medical imaging methods such as PET and MRI aid clinical assessment of Alzheimer’s disease (AD). Less expensive, less technically demanding, and more widely deployable technologies are needed to expand objective screening for diagnosis, treatment, and research. We previously reported brain tissue near-infrared optical spectroscopy (NIR) in vitro indicating the potential to meet this need. Objective: To determine whether completely non-invasive, clinical, NIR in vivo can distinguish AD patients from age-matched controls and to show the potential of NIR as a clinical screen and monitor of therapeutic efficacy. Methods: NIR spectra were acquired in …vivo . Three groups were studied: autopsy-confirmed AD, control and mild cognitive impairment (MCI). A feature selection approach using the first derivative of the intensity normalized spectra was used to discover spectral regions that best distinguished “AD-alone” (i.e., without other significant neuropathology) from controls. The approach was then applied to other autopsy-confirmed AD cases and to clinically diagnosed MCI cases. Results: Two regions about 860 and 895 nm completely separate AD patients from controls and differentiate MCI subjects according to the degree of impairment. The 895 nm feature is more important in separating MCI subjects from controls (ratio-of-weights: 1.3); the 860 nm feature is more important for distinguishing MCI from AD (ratio-of-weights: 8.2). Conclusion: These results form a proof of the concept that near-infrared spectroscopy can detect and classify diseased and normal human brain in vivo . A clinical trial is needed to determine whether the two features can track disease progression and monitor potential therapeutic interventions. Show more

Keywords: Alzheimer’s disease, cognitive dysfunction, data analysis, mild cognitive impairment, near-infrared spectroscopy

DOI: 10.3233/JAD-201021

Citation: Journal of Alzheimer's Disease, vol. 82, no. 2, pp. 791-802, 2021

Authors: Zhao, Xuan | Li, Cancan | Ding, Guoyong | Heng, Yuanyuan | Li, An | Wang, Wei | Hou, Haifeng | Wen, Jun | Zhang, Yanbo

Article Type: Research Article

Abstract: Background: The increasing prevalence of Alzheimer’s disease (AD), along with the associated burden on healthcare systems, presents a substantial public health challenge. Objective: This study aimed to investigate trends in AD mortality and the relevant burden across the United States (U.S.) from 1999 to 2018 and to predict mortality trends between 2019 and 2023. Methods: Data on AD-related deaths between 1999 and 2018 were collected from the WONDER database administered by the U.S. Centers for Disease Control and Prevention (CDC). The Joinpoint Regression Program was used to analyze mortality trends due to AD. Years of life …lost (YLL) were calculated to explore the burden of AD deaths. An autoregressive integrated moving average (ARIMA) model was employed to forecast mortality trends from 2019 to 2023. Results: Over a recent 20-year period, the number of AD deaths in the U.S. increased from 44,536 (31,145 females and 13,391 males) to 122,019 (84,062 females and 37,957 males). The overall age-adjusted mortality rate increased from 16.5/100,000 in 1999 to 30.5/100,000 in 2018. AD mortality is projected to reach 42.40/100000 within the year 2023. Overall, AD resulted in 322,773.00 YLL (2.33 per 1000 population) in 1999 and 658,501.87 YLL (3.68 per 1000 population) in 2018. Conclusion: Our findings demonstrate an increase in AD mortality in the U.S. from 1999 to 2018 as well as a rapid increase from 2019 to 2023. The high burden of AD deaths emphasizes the need for targeted prevention, early diagnosis, and hierarchical management. Show more

Keywords: Alzheimer’s disease, mortality, time series analysis, years of life lost

DOI: 10.3233/JAD-210225

Citation: Journal of Alzheimer's Disease, vol. 82, no. 2, pp. 803-813, 2021

Authors: Paradela, Regina Silva | Ferreira, Naomi Vidal | Nucci, Mariana Penteado | Cabella, Brenno | Martino, Luiza Menoni | Torres, Laura Aló | Costa, Danielle Irigoyen da | Consolim-Colombo, Fernanda Marciano | Suemoto, Claudia Kimie | Irigoyen, Maria Claudia

Article Type: Research Article

Abstract: Background: Socioeconomic factors are important contributors to brain health. However, data from developing countries (where social inequalities are the most prominent) are still scarce, particularly about hypertensive individuals. Objective: To evaluate the relationship between socioeconomic index, cognitive function, and cortical brain volume, as well as determine whether white matter hyperintensities are mediators of the association of the socioeconomic index with cognitive function in hypertensive individuals. Methods: We assessed 92 hypertensive participants (mean age = 58±8.6 years, 65.2%female). Cognitive evaluation and neuroimaging were performed and clinical and sociodemographic data were collected using questionnaires. A socioeconomic index was created using …education, income, occupation (manual or non-manual work), and race. The associations of the socioeconomic index with cognitive performance and brain volume were investigated using linear regression models adjusted for age, sex, time of hypertension since diagnosis, and comorbidities. A causal mediation analysis was also conducted. Results: Better socioeconomic status was associated with better visuospatial ability, executive function, and global cognition. We found associations between a better socioeconomic index and a higher parietal lobe volume. White matter hyperintensities were also not mediators in the relationship between the socioeconomic index and cognitive performance. Conclusion: Socioeconomic disadvantages are associated with worse cognitive performance and brain volume in individuals with hypertension. Show more

Keywords: Brain volume, cognitive dysfunction, executive function, hypertension, neuroimaging, social determinants of health, white matter hyperintensities

DOI: 10.3233/JAD-210143

Citation: Journal of Alzheimer's Disease, vol. 82, no. 2, pp. 815-826, 2021

Authors: Melo van Lent, Debora | O’Donnell, Adrienne | Beiser, Alexa S. | Vasan, Ramachandran S. | DeCarli, Charles S. | Scarmeas, Nikolaos | Wagner, Michael | Jacques, Paul F. | Seshadri, Sudha | Himali, Jayandra J. | Pase, Matthew P.

Article Type: Research Article

Abstract: Background: Adherence to the Mediterranean-DASH for Neurodegenerative Delay (MIND) diet has previously been associated with cognitive decline and dementia. To our knowledge, no prior study has investigated the association between the MIND diet and measures of brain volume, silent brain infarcts (SBIs), or brain atrophy. Objective: We evaluated whether adherence to the MIND diet associated with superior cognitive function, larger brain volumes, fewer SBIs, and less cognitive decline in the community-based Framingham Heart Study. Methods: 2,092 participants (mean±SD, age 61±9) completed Food Frequency Questionnaires, averaged across a maximum of 3-time points (examination cycles 5, 6, and …7), cognitive testing at examination cycle 7 (present study baseline: 1998–2001) and after a mean±SD of 6.6±1.1 years from baseline (n  = 1,584). A subset of participants also completed brain magnetic resonance imaging (MRI) at examination cycle 7 (n  = 1,904). In addition, participants with dementia, stroke, and other relevant neurological diseases such as significant head trauma, subdural hematoma, or multiple sclerosis were excluded from the analyses. Results: Higher MIND diet scores were associated with better global cognitive function (β±SE,+0.03SD±0.01; p  = 0.004), verbal memory, visual memory, processing speed, verbal comprehension/reasoning, and with larger total brain volume (TBV) following adjustments for clinical, lifestyle and demographic covariates, but not with other brain MRI measures (i.e., hippocampal volume, lateral ventricular volume, white matter hyperintensity volume, and SBIs) or cognitive decline. Conclusion: Higher MIND diet scores associated with better cognitive performance and larger TBV at baseline, but not with cognitive decline. Clinical trials are needed to ascertain whether adopting the MIND diet affects trajectories of cognitive decline. Show more

Keywords: Apolipoprotein ɛ4, brain volume, cognition, dietary pattern, framingham heart study, MIND diet, silent brain infarcts

DOI: 10.3233/JAD-201238

Citation: Journal of Alzheimer's Disease, vol. 82, no. 2, pp. 827-839, 2021

Authors: Schoemaker, Dorothee | Velilla-Jimenez, Lina | Zuluaga, Yesica | Baena, Ana | Ospina, Carolina | Bocanegra, Yamile | Alvarez, Sergio | Ochoa-Escudero, Martin | Guzmán-Vélez, Edmarie | Martinez, Jairo | Lopera, Francisco | Arboleda-Velasquez, Joseph F. | Quiroz, Yakeel T.

Article Type: Research Article

Abstract: Background: Cardiovascular risk factors increase the risk of developing dementia, including Alzheimer’s disease and vascular dementia. Objective: Studying individuals with autosomal dominant mutations leading to the early onset of dementia, this study examines the effect of the global cardiovascular risk profile on early cognitive and neuroimaging features of Alzheimer’s disease and vascular dementia. Methods: We studied 85 non-demented and stroke-free individuals, including 20 subjects with Presenilin1 (PSEN1) E280A mutation leading to the early onset of autosomal dominant Alzheimer’s disease (ADAD), 20 subjects with NOTCH3 mutations leading to cerebral autosomal dominant arteriopathy with subcortical infarcts …and leukoencephalopathy (CADASIL) and to the early onset of vascular dementia, and 45 non-affected family members (non-carriers). All subjects underwent clinical and neuropsychological evaluations and an MRI. The global cardiovascular risk profile was estimated using the office-based Framingham Cardiovascular Risk Profile (FCRP) score. Results: In individuals with CADASIL, a higher FCRP score was associated with a reduced hippocampal volume (B = –0.06, p  < 0.05) and an increased severity of cerebral microbleeds (B = 0.13, p  < 0.001), lacunes (B = 0.30, p  < 0.001), and perivascular space enlargement in the basal ganglia (B = 0.50, p  < 0.05). There was no significant association between the FCRP score and neuroimaging measures in ADAD or non-carrier subjects. While the FCRP score was related to performance in executive function in non-carrier subjects (B = 0.06, p  < 0.05), it was not significantly associated with cognitive performance in individuals with CADASIL or ADAD. Conclusion: Our results suggest that individuals with CADASIL and other forms of vascular cognitive impairment might particularly benefit from early interventions aimed at controlling cardiovascular risks. Show more

Keywords: Autosomal dominant Alzheimer’s disease, CADASIL, cardiovascular risk factors, cerebral small vessel disease, cognition, magnetic resonance imaging

DOI: 10.3233/JAD-210313

Citation: Journal of Alzheimer's Disease, vol. 82, no. 2, pp. 841-853, 2021

Authors: Niu, Jiahui | Iqbal, Khalid | Liu, Fei | Hu, Wen

Article Type: Research Article

Abstract: Background: Women have a two-fold higher risk than men to Alzheimer’s disease (AD) at midlife. Larger brain tau burden was consistently shown in older women than age-matched men. The biological basis for this gender disparity remains elusive. Objective: We sought to know whether tau expression and phosphorylation physiologically differ between males and females. Methods: We used western blots and immunohistochemistry to compare the levels of total tau and phosphorylated tau in the hippocampus and entorhinal cortex (EC) between sexes in Wistar rats at 40 days, and 8 and 20 months of age. Results: We …detected no statistically significant difference in total tau, 3R-tau, and 4R-tau between sexes. However, female rats exhibited lower levels of tau unphosphorylated at the Tau-1 site at 40 days of age. At 8 months of age, females showed higher levels of tau phosphorylated at Ser190 , Ser387 , and Ser395 (Ser199 , Ser396 , and Ser404 of human tau, respectively) than males in EC. At 20 months of age, both brain regions of female rats consistently showed higher levels than males of tau phosphorylated at Ser253 , Ser387 , PHF-1 (Ser387/395 ), and Ser413 sites, which correspond to Ser262 , Ser396 , Ser396/404 , and Ser422 of human tau, respectively. Conclusion: Rats of both sexes have comparable levels of total tau, 3R-tau, and 4R-tau, whereas females exhibit higher levels of tau phosphorylated at multiple sites that are implicated in AD tau pathology, indicating a sexual dimorphism of tau phosphorylation that may potentially underlie the disparity in brain tau burden and risk for AD between sexes. Show more

Keywords: Alzheimer’s disease, entorhinal cortex, gender, hippocampus, protein phosphorylation, tau expression, tau isoforms

DOI: 10.3233/JAD-210341

Citation: Journal of Alzheimer's Disease, vol. 82, no. 2, pp. 855-869, 2021

Authors: Vecchio, Fabrizio | Miraglia, Francesca | Alú, Francesca | Orticoni, Alessandro | Judica, Elda | Cotelli, Maria | Rossini, Paolo Maria

Article Type: Research Article

Abstract: Background: Most common progressive brain diseases in the elderly are Alzheimer’s disease (AD) and vascular dementia (VaD). They present with relatively similar clinical symptoms of cognitive decline, but the underlying pathophysiological mechanisms are different. Objective: The aim is to explore the brain connectivity differences between AD and VaD patients compared to mild cognitive impairment (MCI) and normal elderly (Nold) subjects applying graph theory, in particular the Small World (SW) analysis. Methods: 274 resting state EEGs were analyzed in 100 AD, 80 MCI, 40 VaD, and 54 Nold subjects. Graph theory analyses were applied to undirected and …weighted networks obtained by lagged linear coherence evaluated by eLORETA tool. Results: VaD and AD patients presented more ordered low frequency structure (lower value of SW) than Nold and MCI subjects, and more random organization (higher value of SW) in low and high frequency alpha rhythms. Differences between patients have been found in high frequency alpha rhythms in VaD (higher value of SW) with respect to AD, and in theta band with a trend which is more similar to MCI and Nold than to AD. MCI subjects presented a network organization which is intermediate, in low frequency bands, between Nold and patients. Conclusion: Graph theory applied to EEG data has proved very useful in identifying differences in brain network patterns in subjects with dementia, proving to be a valid tool for differential diagnosis. Future studies will aim to validate this method to diagnose especially in the early stages of the disease and at single subject level. Show more

Keywords: Brain networks, EEG, functional coupling, LORETA, Small World

DOI: 10.3233/JAD-210394

Citation: Journal of Alzheimer's Disease, vol. 82, no. 2, pp. 871-879, 2021