Onset Of Mild Cognitive Impairment Research Articles

PET evidence of preclinical cerebellar amyloid plaque deposition in autosomal dominant Alzheimer’s disease-causing Presenilin-1 E280A mutation carriers

BackgroundIn contrast to sporadic Alzheimer’s disease, autosomal dominant Alzheimer’s disease (ADAD) is associated with greater neuropathological evidence of cerebellar amyloid plaque (Aβ) deposition. In this study, we used positron emission tomography (PET) measurements of fibrillar Aβ burden to characterize the presence and age at onset of cerebellar Aβ deposition in cognitively unimpaired (CU) Presenilin-1 (PSEN1) E280A mutation carriers from the world’s largest extended family with ADAD. Methods18F florbetapir and 11C Pittsburgh compound B (PiB) PET data from two independent studies – API ADAD Colombia Trial (NCT01998841) and Colombia-Boston (COLBOS) longitudinal biomarker study were included. The tracers were selected independently by the respective sponsors prior to the start of each study and used exclusively throughout. Template-based cerebellar Aβ-SUVR (standard-uptake value ratios) using a known-to-be-spared pons reference region (cerebellar SUVR_pons), to a) compare 28–56-year-old CU carriers and non-carriers; b) estimate the age at which cerebellar SUVR_pons began to differ significantly in carrier and non-carrier groups; and c) characterize in carriers associations with age, cortical SUVR_pons, delayed recall memory, and API ADAD composite score. ResultsFlorbetapir and PiB cerebellar SUVR_pons were significantly higher in carriers than non-carriers (p < 0.0001). Cerebellar SUVR_pons began to distinguish carriers from non-carriers at age 34, 10 years before the carriers’ estimated age at mild cognitive impairment onset. Florbetapir and PiB cerebellar SUVR_pons in carriers were positively correlated with age (r = 0.44 & 0.69, p < 0.001), cortical SUVR_pons (r = 0.55 & 0.69, p < 0.001), and negatively correlated with delayed recall memory (r = −0.21 & −0.50, p < 0.05, unadjusted for cortical SUVR_pons) and API ADAD composite (r = −0.25, p < 0.01, unadjusted for cortical SUVR_pons in florbetapir API ADAD cohort). ConclusionThis PET study provides evidence of cerebellar Aβ plaque deposition in CU carriers starting about a decade before the clinical onset of ADAD. Additional studies are needed to clarify the impact of using a cerebellar versus pons reference region on the power to detect and track ADAD changes, even in preclinical stages of this disorder.

Trajectory of Unawareness of Memory Decline in Individuals With Autosomal Dominant Alzheimer Disease

Recent studies have suggested that unawareness, or anosognosia, of memory decline is present in predementia stages of Alzheimer disease (AD) and may serve as an early symptomatic indicator of AD. To investigate the evolution of anosognosia of memory decline in individuals who carry the PSEN1 E280A variant for autosomal dominant AD compared with family members who do not carry the variant. This cohort study investigated a total of 2379 members of a Colombian kindred with autosomal dominant AD who were part of the Alzheimer's Prevention Initiative Registry. Assessments were completed at the University of Antioquia, Colombia, with data collected between January 1, 2000, and July 31, 2019. Awareness of memory function was operationalized using the discrepancy between self-report and study partner report on a memory complaint scale. Linear mixed effects models were used to assess memory self-awareness over age separately in variant carriers and noncarriers. This study included 396 variant carriers (mean [SD] age, 32.7 [11.9] years; 200 [50.5%] female), of whom 59 (14.9%) were cognitively impaired, and 1983 cognitively unimpaired noncarriers (mean [SD] age, 33.5 [12.5] years; 1129 [56.9%] female). The variant carriers demonstrated increased awareness until the mean (SD) age of 35.0 (2.0) years and had anosognosia at approximately 43 years of age, approximately 6 years before their estimated median age of dementia onset (49 years; 95% CI, 49-51 years). Cognitively unimpaired noncarriers reported more complaints than their study partners aged 20 and 60 years (10.1 points, P < .001). On the awareness index, a decrease with age (mean [SE] estimate, -0.04 [0.02] discrepant-points per years; t = -2.2; P = .03) in the noncarriers and in the variant carriers (mean [SE] estimate, -0.21 [0.04] discrepant-points per years; t = -5.1; P < .001) was observed. In this cohort study, increased participant complaints were observed in both groups, suggesting that increased awareness of memory function was common and nonspecific to AD in this cohort. In variant carriers, awareness of memory function decreased in the predementia stages, reaching anosognosia close to the age of mild cognitive impairment onset, providing support for the usefulness of awareness of memory decline.

Cumulative effects of sleep quality on risk for incident mild cognitive impairment (MCI): Results from the Einstein Aging Study (EAS) cohort

AbstractBackgroundSleep deficiency and sleep disorders are common in older adults and have been linked to cognitive decline and dementia risk. Better understanding the association of sleep patterns over time with onset of early cognitive changes may facilitate interventions to prevent AD and dementia. Few studies have reported on the association of cumulative longitudinal measures of sleep quality with onset of mild cognitive impairment (MCI). The Einstein Aging Study (EAS) longitudinal cohort provided the opportunity to examine whether cumulative exposure to poor sleep quality predicts incident MCI in a community‐based cohort.MethodAnalyses include 639 EAS participants from Bronx, NY, age &gt; 70 years (mean 78.6± 5.3, 62% female, 65% White/28% African American), without MCI or dementia at initial assessment and with at least one annual follow‐up. Sleep was assessed annually using the Medical Outcomes Study of Sleep (MOS‐S) questionnaire. Factor analysis of the 12 MOS‐S items yielded three factor scores based on the sum of items with loading ≥ 0.5, such that higher scores indicate better sleep quality. Factors included were: Daytime somnolence, Disturbed sleep and Perceived sleep adequacy. Trajectories of these indices over annual follow‐up were examined using linear mixed effects models. The associations of concurrent and cumulative sleep quality indices on MCI risk were estimated from Cox models with time dependent exposure, adjusting for age, sex, education and race/ethnicity.ResultOver a mean of 4.4 annual assessments, 162 cases of incident MCI occurred. During follow‐up, sleep adequacy increased (p &lt; 0.0001), daytime somnolence decreased (p = 0.025) and sleep disturbance showed no significant pattern of change (p &gt; 0.05. Cox models showed no association between concurrent indices of sleep quality and incident MCI (all p &gt; 0.05). However, cumulative effects of sleep quality on MCI risk were observed. Over time, less daytime somnolence, less frequent disturbed sleep and better sleep adequacy were associated with reduced risk of incident MCI (HR’s: Somnolence = 0.97, Disturbed = 0.98), Adequacy = 0.97; all p&lt; 0.0001).ConclusionAdverse effects of poor sleep quality on cognition may be cumulative suggesting that improving sleep in older adults may prevent or delay MCI onset.

Physical function parameters that predict the onset of mild cognitive impairment one year later in community-dwelling elderly women

Physical function parameters that predict the onset of mild cognitive impairment one year later in community-dwelling elderly women

Discriminative Accuracy of Plasma Phospho-tau217 for Alzheimer Disease vs Other Neurodegenerative Disorders

There are limitations in current diagnostic testing approaches for Alzheimer disease (AD). To examine plasma tau phosphorylated at threonine 217 (P-tau217) as a diagnostic biomarker for AD. Three cross-sectional cohorts: an Arizona-based neuropathology cohort (cohort 1), including 34 participants with AD and 47 without AD (dates of enrollment, May 2007-January 2019); the Swedish BioFINDER-2 cohort (cohort 2), including cognitively unimpaired participants (n = 301) and clinically diagnosed patients with mild cognitive impairment (MCI) (n = 178), AD dementia (n = 121), and other neurodegenerative diseases (n = 99) (April 2017-September 2019); and a Colombian autosomal-dominant AD kindred (cohort 3), including 365 PSEN1 E280A mutation carriers and 257 mutation noncarriers (December 2013-February 2017). Plasma P-tau217. Primary outcome was the discriminative accuracy of plasma P-tau217 for AD (clinical or neuropathological diagnosis). Secondary outcome was the association with tau pathology (determined using neuropathology or positron emission tomography [PET]). Mean age was 83.5 (SD, 8.5) years in cohort 1, 69.1 (SD, 10.3) years in cohort 2, and 35.8 (SD, 10.7) years in cohort 3; 38% were women in cohort 1, 51% in cohort 2, and 57% in cohort 3. In cohort 1, antemortem plasma P-tau217 differentiated neuropathologically defined AD from non-AD (area under the curve [AUC], 0.89 [95% CI, 0.81-0.97]) with significantly higher accuracy than plasma P-tau181 and neurofilament light chain (NfL) (AUC range, 0.50-0.72; P < .05). The discriminative accuracy of plasma P-tau217 in cohort 2 for clinical AD dementia vs other neurodegenerative diseases (AUC, 0.96 [95% CI, 0.93-0.98]) was significantly higher than plasma P-tau181, plasma NfL, and MRI measures (AUC range, 0.50-0.81; P < .001) but not significantly different compared with cerebrospinal fluid (CSF) P-tau217, CSF P-tau181, and tau-PET (AUC range, 0.90-0.99; P > .15). In cohort 3, plasma P-tau217 levels were significantly greater among PSEN1 mutation carriers, compared with noncarriers, from approximately 25 years and older, which is 20 years prior to estimated onset of MCI among mutation carriers. Plasma P-tau217 levels correlated with tau tangles in participants with (Spearman ρ = 0.64; P < .001), but not without (Spearman ρ = 0.15; P = .33), β-amyloid plaques in cohort 1. In cohort 2, plasma P-tau217 discriminated abnormal vs normal tau-PET scans (AUC, 0.93 [95% CI, 0.91-0.96]) with significantly higher accuracy than plasma P-tau181, plasma NfL, CSF P-tau181, CSF Aβ42:Aβ40 ratio, and MRI measures (AUC range, 0.67-0.90; P < .05), but its performance was not significantly different compared with CSF P-tau217 (AUC, 0.96; P = .22). Among 1402 participants from 3 selected cohorts, plasma P-tau217 discriminated AD from other neurodegenerative diseases, with significantly higher accuracy than established plasma- and MRI-based biomarkers, and its performance was not significantly different from key CSF- or PET-based measures. Further research is needed to optimize the assay, validate the findings in unselected and diverse populations, and determine its potential role in clinical care.

Active bilingualism delays the onset of mild cognitive impairment

Lifelong bilingualism may contribute to cognitive reserve (CR) in neurodegenerative diseases as shown by a delay of the age at symptom onset in bilinguals with Alzheimer’s disease (AD) and Mild Cognitive Impairment (MCI). However, some studies have failed to show this bilingual advantage, suggesting that it might depend on the type and degree of bilingualism. In the present study, we tested the hypothesis that active bilingualism, defined as the continuous use of the two languages as opposed to second language exposition only, may protect against cognitive decline. Moreover, we investigated whether bilingualism as a CR factor may be explained by an advantage within the executive control (EC) system. To do so, we collected clinical measures (age at onset of cognitive symptoms, age at the first medical visit for cognitive impairments, and age at diagnosis) in patients with MCI and patients with AD with different degrees of language experience and usage of Catalan and Spanish. Additionally, all participants were tested on four EC tasks and one long-term memory recognition task. First, results from multiple regression analyses showed that active bilingualism was a significant predictor of delay in the age at onset for all the clinical measures in MCI, but not AD patients. Second, the effect of active bilingualism was independent of occupation, educational level and job attainment across the individuals’ lifespan. Finally, although we did not find an effect of active bilingualism across all EC tasks, we did find an effect for conflict resolution. These results are discussed in the context of CR hypotheses, suggesting that compensatory mechanisms may play a role in protecting against cognitive decline.

Plasma neurofilament light chain in the presenilin 1 E280A autosomal dominant Alzheimer's disease kindred: a cross-sectional and longitudinal cohort study.

Neurofilament light chain (NfL) is a promising biomarker of active axonal injury and neuronal degeneration. We aimed to characterise cross-sectional and longitudinal plasma NfL measurements and determine the age at which NfL concentrations begin to differentiate between carriers of the presenilin 1 (PSEN1) E280A (Glu280Ala) mutation and age-matched non-carriers from the Colombian autosomal dominant Alzheimer's disease kindred. In this cross-sectional and longitudinal cohort study, members of the familial Alzheimer's disease Colombian kindred aged 8-75 years with no other neurological or health conditions were recruited from the Alzheimer's Prevention Initiative Registry at the University of Antioquia (Medellín, Colombia) between Aug 1, 1995, and Dec 15, 2018. We used a single molecule array immunoassay and log-transformed data to examine the relationship between plasma NfL concentrations and age, and establish the earliest age at which NfL concentrations begin to diverge between mutation carriers and non-carriers. We enrolled a cohort of 1070 PSEN1 E280A mutation carriers and 1074 non-carriers with baseline assessments; of these participants, longitudinal measures (with a mean follow-up of 6 years) were available for 242 mutation carriers and 262 non-carriers. Plasma NfL measurements increased with age in both groups (p<0·0001), and began to differentiate carriers from non-carriers when aged 22 years (22 years before the estimated median age at mild cognitive impairment onset of 44 years), although the ability of plasma NfL to discriminate between carriers and non-carriers only reached high sensitivity close to the age of clinical onset. Our findings further support the promise of plasma NfL as a biomarker of active neurodegeneration in the detection and tracking of Alzheimer's disease and the evaluation of disease-modifying therapies. National Institute on Aging, National Institute of Neurological Disorders and Stroke, Banner Alzheimer's Foundation, COLCIENCIAS, the Torsten Söderberg Foundation, the Swedish Research Council, the Swedish Alzheimer Foundation, the Swedish Brain Foundation, and the Swedish state under the ALF-agreement.

Depressive symptoms and CSF Alzheimer's disease biomarkers in relation to clinical symptom onset of mild cognitive impairment.

IntroductionWe sought to examine whether depressive symptoms and level of Alzheimer's disease (AD) pathology are independently or interactively associated with the risk of progression to mild cognitive impairment (MCI).MethodsThe study included a total of 216 participants from the Biomarkers for Older Controls at Risk for Alzheimer's Disease study, a cohort of individuals who were cognitively normal at baseline (mean age = 57) and followed for more than 20 years (mean = 12.7 years), who had baseline Hamilton Depression Scale (HAM‐D) scores and cerebrospinal fluid (CSF) amyloid beta (Aβ)1‐42 , t‐tau, and p‐tau measures available.ResultsCox regression demonstrated that baseline HAM‐D and CSF AD biomarkers were both associated with time to onset of MCI. There was an interaction between HAM‐D scores and markers of AD pathology, in which depression was associated with time of onset in participants with low levels of AD pathology (hazard ratio = 0.64; 95% confidence interval = 0.43–0.95; P= .026).DiscussionThe effect of depressive symptoms on progression to clinical symptoms of MCI may be most evident among individuals with low levels of AD pathology.

White matter hyperintensities and CSF Alzheimer disease biomarkers in preclinical Alzheimer disease.

Recent studies suggest that white matter hyperintensities (WMH) on MRI, which primarily reflect small vessel cerebrovascular disease, may play a role in the evolution of Alzheimer disease (AD). In a longitudinal study, we investigated whether WMH promote the progression of AD pathology, or alter the association between AD pathology and risk of progression from normal cognition to mild cognitive impairment (MCI). Two sets of analyses were conducted. The relationship between whole brain WMH load, based on fluid-attenuated inversion recovery MRI, obtained in initially cognitively normal participants (n = 274) and time to onset of symptoms of MCI (n = 60) was examined using Cox regression models. In a subset of the participants with both MRI and CSF data (n = 204), the interaction of WMH load and CSF AD biomarkers was also evaluated. Baseline WMH load interacted with CSF total tau (t-tau) with respect to symptom onset, but not with CSF β-amyloid 1-42 or phosphorylated tau (p-tau) 181. WMH volume was associated with time to symptom onset of MCI among individuals with low t-tau (hazard ratio [HR] 1.35, confidence interval [CI] 1.06-1.73, p = 0.013), but not those with high t-tau (HR 0.86, CI 0.56-1.32, p = 0.47). The rate of change in the CSF biomarkers over time was not associated with the rate of change in WMH volumes. These results suggest that WMH primarily affect the risk of progression when CSF measures of neurodegeneration or neuronal injury (as reflected by t-tau) are low. However, CSF biomarkers of amyloid and p-tau and WMH appear to have largely independent and nonsynergistic effects on the risk of progression to MCI.

Characteristics of Mild Cognitive Impairment in Northern Japanese Community-Dwellers from the ORANGE Registry.

A gradually increasing prevalence of mild cognitive impairment (MCI) is recognized in the super-aging society that Japan faces, and early detection and intervention in community-dwellers with MCI are critical issues to prevent dementia. Although many previous studies have revealed MCI/non-MCI differences in older individuals, information on the prevalence and characteristics of MCI in rural older adults is limited. The aim of this study was to investigate differential characteristics between older adults with and without MCI. The investigation was conducted over one year from 2018 to 2019. Participants were recruited from Akita in northern Japan. Neuropsychological assessments were applied to classify MCI, including the National Center for Geriatrics and Gerontology Functional Assessment Tool (NCGG-FAT) and the Touch panel-type Dementia Assessment Scale (TDAS) based on the Alzheimer’s disease assessment scale. Our samples consisted of 103 older adults divided into 54 non-MCI and 49 MCI. The MCI group had lower scores of all cognitive items. Our results showed that individuals with MCI had significantly slower walking speed (WS) and worse geriatric depression scale (GDS) compared to non-MCI. In addition, WS was significantly associated with some cognitive items in non-MCI, but not in MCI. Finally, we showed that predictive variables of MCI were WS and GDS. Our study provides important information about MCI in rural community-dwellers. We suggest that older adults living in a super-aging society should receive lower limb training, and avoiding depression in older adults through interaction of community-dwellers may contribute to preventing the onset of MCI.

THE IMPORTANCE OF MAINTAINING PHYSICAL ACTIVITY FOR TRANSITIONS BETWEEN COGNITIVE STATES: A COORDINATED ANALYSIS

Although existing research shows that physical activity (PA) protects against cognitive decline, it is unclear if maintenance of PA throughout older adulthood influences the timing of onset or transitions through cognitive states. Further understanding of modifiable lifestyle factors that protect against cognitive changes characteristic of both normal aging and pathological aging, such as Alzheimer’s disease and other dementias, is imperative. Data were drawn from fourteen longitudinal studies of aging from Europe and America (total N=53,069). Controlling for demographics and chronic conditions, multi-state models were independently fit between datasets to investigate the impact of PA (computed based on Metabolic Equivalent of Task Method) on the likelihood of transitioning through three cognitive states, while also accounting for death as a competing risk factor. Random effects meta-analysis of transition probabilities indicated that more PA was associated with a reduced risk of transitioning from normal cognition to mildly impaired cognition (HR=0.90, CI’s=0.84, 0.97, p=0.007) and death (HR=0.24, CI’s=0.06, 0.92, p=0.04), as well as an increased likelihood of transitioning from severe impairment back to mild impairment (HR=1.09, CI’s=1.01, 1.17, p=0.03). Engagement in national minimum recommendations for PA (~150 minutes/week) increased total life expectancy for 70 year old males and females by 4.08 and 5.47 years, respectively. These results suggest that engaging in at least 150 minutes of physical activity per week in older adulthood contributes to delays in onset of mild cognitive impairment, substantially increases life expectancy, and may also diminish the symptoms that contribute to poor cognitive performance at the severely impaired stage.

TDP-43 inhibitory peptide alleviates neurodegeneration and memory loss in an APP transgenic mouse model for Alzheimer's disease

Alzheimer's disease (AD) is the leading cause of dementia in the elderly, characterized clinically by progressive decline in cognitive function and neuropathologically by the presence of senile plaques and neuronal loss in the brain. While current drugs for AD are always employed as symptomatic therapies with variable benefits, there is no treatment to delay its progression or halt neurodegeneration. TAR DNA-binding protein 43 (TDP-43) proteinopathy has increasingly been implicated as a prominent histopathological feature of AD and related dementias. Our recent studies have implicated mitochondria as critical targets of TDP-43 neurotoxicity. Here, we demonstrate that the suppression of mitochondrial-associated TDP-43 protects against neuronal loss and behavioral deficits in 5XFAD transgenic mice recapitulating AD-related phenotypes. In AD patients and 5XFAD mice, the level of TDP-43 is increased in mitochondria, and TDP-43 highly co-localizes with mitochondria in brain neurons exhibiting TDP-43 proteinopathy. Chronic administration of a TDP-43 mitochondrial localization inhibitory peptide, PM1, significantly alleviates TDP-43 proteinopathy, mitochondrial abnormalities, microgliosis and even neuronal loss without effect on amyloid plaque load in 12-month-old 5XFAD mice well after the onset of symptoms. Additionally, PM1 also improves the cognitive and motor function in 12-month-old 5XFAD mice and completely prevents the onset of mild cognitive impairment in 6-month-old 5XFAD mice. These data indicate that mitochondria-associated TDP-43 is likely involved in AD pathogenesis and that the inhibitor of mitochondria-associated TDP-43 may be a valuable drug to treat underlying AD.

Longitudinal Association of Depression Symptoms With Cognition and Cortical Amyloid Among Community-Dwelling Older Adults

Depressive symptoms are prevalent among older adults and may be early manifestations of Alzheimer disease (AD) before onset of mild cognitive impairment. However, it remains unclear whether worsening depressive symptoms in the presence of AD pathology are associated with cognitive decline in older adults. To determine the longitudinal association between depressive symptoms, cognition, and cortical amyloid in community-dwelling older adults. Participants from the Harvard Aging Brain Study, a cohort study, underwent annual assessments of depression and cognition and baseline cortical amyloid measurement (mean, 4.42 years; range, 2-7 years). Data collection was from September 2010 to August 2017 in a convenience sample of community-dwelling adults (276 participants, all cognitively unimpaired) with at most mild depression at entry. Depression (Geriatric Depression Scale [GDS]), cognition (Preclinical Alzheimer Cognitive Composite [PACC]), and a continuous measure of cortical amyloid (Pittsburgh Compound-B positron emission tomography imaging). Change in GDS and baseline amyloid were examined as interactive predictors of PACC decline in a linear mixed model with backward elimination, adjusting for age, sex, and education. Participants were 164 women and 112 men (mean [SD] age, 73.5 [6.0] years). At baseline, the mean (SD) GDS score was 3.0 (2.8) (range, 0-12), the mean (SD) PACC score was -0.004 (0.67) (range, -2.32 to 1.88), and the mean (SD) amyloid positron emission tomography distribution volume ratio was 1.16 (0.20) (range, 0.92-1.94). At last follow-up, the mean (SD) GDS score was 3.9 (2.9) (range, 0-12), and the mean (SD) PACC score was -0.09 (1.27) (range, -5.66 to 1.67). The interaction between cortical amyloid and increasing GDS was associated with declining cognition (β = -0.19; 95% CI, -0.27 to -0.12; P < .001). In this study, cortical amyloid moderated the association between worsening depressive symptoms and declining cognition in older adults. While future work is needed to better understand causal associations, these findings may enhance early detection and prevention of AD clinical symptoms.

Neuropsychiatric Symptoms as Risk Factors for Cognitive Decline in Clinically Normal Older Adults: The Cache County Study

There has been considerable progress in identifying early cognitive and biomarker predictors of Alzheimer's disease (AD). Neuropsychiatric symptoms (NPS) are common in AD and appear to predict progression after the onset of mild cognitive impairment or dementia. The objective of the study is to examine the relationship between NPS in clinically normal older adults and subsequent cognitive decline in a population-based sample. The Cache County Study on Memory in Aging consists of a population-based sample of 5,092 older adults. We identified 470 clinically normal adults who were followed for an average period of 5.73 years. NPS were evaluated at the baseline clinical assessment using the Neuropsychiatric Inventory (NPI). NPI domain scores were quantified as the product of frequency X severity in individual NPI domains, and then summed for the NPI-Total. Neuropsychological measures were collected at baseline and at each subsequent follow-up wave. Linear mixed-effects models assessed the association of NPI-Total, NPI-Depression, and NPI-Anxiety scores (obtained at baseline) on longitudinal change in neuropsychological performance, controlling for age, sex, and education. Baseline NPI-Total score was associated with a more rapid rate of decline in word list memory, praxis recall, and animal fluency. Baseline NPI-Depression was not associated with later decline on any of the cognitive tests, while baseline NPI-Anxiety was associated with decline in Symbol Digit Modality. In conclusion, among clinically normal older adults derived from this population-based study, total burden of NPS was associated with longitudinal cognitive decline. These results add to the evidence that NPS are risk factors for or clinical indicators of preclinical dementia syndrome. Our study was an exploratory study and we did not control for multiple comparisons.

Influence of mild cognitive impairment on activities of daily living in patients with cardiovascular disease.

Activities of daily living (ADL) are maintained in patients with mild cognitive impairment (MCI), but, in patients with cardiovascular disease, ADL may have already declined. MCI combined with cardiac disease may accentuate the decline of ADL in these patients. Because the relationship between MCI and ADL in patients with cardiovascular disease is unclear, we examined the associations between MCI and ADL in these patients. We conducted a cross-sectional study of 114 patients with cardiovascular disease but without probable dementia. MCI was estimated with the Japanese version of the Montreal Cognitive Assessment (MoCA-J). We classified patients into the normal cognitive group and MCI group, and compared their clinical characteristics, physical function [Short Physical Performance Battery (SPPB), gait speed, handgrip strength, and knee extensor muscle strength], and ADL [via the Functional Independence Measure (FIM)]. We used logistic regression analysis to evaluate the specific association between MCI and ADL. The incidence of MCI was 36.0%. Significant differences between the two groups were identified for age, body mass index, estimated glomerular filtration rate, albumin, dyslipidemia, educational background, SPPB, gait speed, handgrip strength, and FIM. However, after adjustment for covariates, only FIM was significantly associated with MCI (odds ratio 0.74, 95% confidence interval 0.65-0.84, p < 0.001). ADL was the only independent factor significantly associated with MCI in patients with cardiovascular disease. ADL may be hindered in these patients, even at an early stage of MCI. Therefore, early intervention is necessary to prevent ADL decline from the time of MCI onset or before.

A divergent breakdown of neurocognitive networks in Parkinson's Disease mild cognitive impairment.

Cognitive decline is a major disabling feature in Parkinson's disease (PD). Multimodal imaging studies have shown functional disruption in neurocognitive networks related to cognitive impairment. However, it remains unknown whether these changes are related to gray matter loss, or whether they outline network vulnerability in the early stages of cognitive impairment. In this work, we intended to assess functional connectivity and graph theoretical measures and their relation to gray matter loss in Parkinson's disease with mild cognitive impairment (PD-MCI). We recruited 53 Parkinson's disease patients and classified them for cognitive impairment using Level-1 Movement Disorders Society-Task Force Criteria. Voxel-based morphometry, functional connectivity and graph theoretical measures were obtained on a 3-Tesla MRI scanner. Loss of gray matter was observed in the default mode network (bilateral precuneus), without a corresponding disruption of functional or graph theoretical properties. However, functional and graph theoretical changes appeared in salience network nodes, without evidence of gray matter loss. Global cognition and executive scores showed a correlation with node degree in the right anterior insula. We also found a correlation between visuospatial scores and right supramarginal gyrus node degree. Our findings highlight the loss of functional connectivity and topological features without structural damage in salience network regions in PD-MCI. They also underline the importance of multimodal hubs in the transition to mild cognitive impairment. This functional disruption in the absence of gray matter atrophy suggests that the salience network is a key vulnerable system at the onset of mild cognitive impairment in PD.

The TOMMORROW study: Design of an Alzheimer's disease delay-of-onset clinical trial

IntroductionAlzheimer's disease (AD) is a continuum with neuropathologies manifesting years before clinical symptoms; thus, AD research is attempting to identify more disease-modifying approaches to test treatments administered before full disease expression. Designing such trials in cognitively normal elderly individuals poses unique challenges. MethodsThe TOMMORROW study was a phase 3 double-blind, parallel-group study designed to support qualification of a novel genetic biomarker risk assignment algorithm (BRAA) and to assess efficacy and safety of low-dose pioglitazone to delay onset of mild cognitive impairment due to AD. Eligible participants were stratified based on the BRAA (using TOMM40 rs 10524523 genotype, Apolipoprotein E genotype, and age), with high-risk individuals receiving low-dose pioglitazone or placebo and low-risk individuals receiving placebo. The primary endpoint was time to the event of mild cognitive impairment due to AD. The primary objectives were to compare the primary endpoint between high- and low-risk placebo groups (for BRAA qualification) and between high-risk pioglitazone and high-risk placebo groups (for pioglitazone efficacy). Approximately 300 individuals were also asked to participate in a volumetric magnetic resonance imaging substudy at selected sites. ResultsThe focus of this paper is on the design of the study; study results will be presented in a separate paper. DiscussionThe design of the TOMMORROW study addressed many key challenges to conducting a dual-objective phase 3 pivotal AD clinical trial in presymptomatic individuals. Experiences from planning and executing the TOMMORROW study may benefit future AD prevention/delay-of-onset trials.

Signs and Artifacts in Amyloid PET.

Establishing a diagnosis of Alzheimer dementia can be challenging, particularly early in the course of the disease. However, with disease-modifying therapies on the horizon, it is becoming increasingly important to achieve the correct diagnosis as soon as possible. In challenging presentations of dementia, such as patients with clinically atypical features or early-age onset of mild cognitive impairment, amyloid PET is a valuable tool in determining the diagnosis of Alzheimer dementia. Furthermore, preliminary data show that amyloid PET findings alter clinical management in patients who meet the appropriate use criteria. There are currently three U.S. Food and Drug Administration (FDA)-approved fluorine 18 (18F)-labeled radiopharmaceuticals that allow in vivo detection of cerebral amyloid deposition, which is a hallmark pathologic feature of Alzheimer dementia. Knowledge of the common imaging features among these three 18F-labeled radiopharmaceuticals in the normal and abnormal brain will enable the radiologist to more accurately interpret amyloid PET studies. As in other subspecialties of radiology, imaging signs in amyloid PET are helpful to distinguish if a region is normal or abnormal. This article reviews appropriate use criteria for amyloid PET, introduces the properties of the radiopharmaceuticals, explains the algorithmic approach to interpretation with examples of normal and abnormal amyloid PET scans with MRI correlation, and provides an atlas of regional amyloid PET signs and common artifacts. ©RSNA, 2018.

Traumatic Brain Injury and Age of Onset of Dementia with Lewy Bodies.

Traumatic brain injury (TBI) with loss of consciousness (LOC) has been associated with earlier onset of mild cognitive impairment, frontotemporal dementia, Parkinson's disease, and Alzheimer's disease (AD), but has not been examined as a risk factor for earlier onset of dementia with Lewy bodies (DLB). The purpose of this study was to assess the association between a history of TBI and the age of onset of DLB. Data from 576 subjects with a clinical diagnosis of DLB were obtained from the National Alzheimer's Coordinating Center (NACC). Analyses of Covariance examined whether self-reported history of remote TBI with LOC (i.e., >1 year prior to the first Alzheimer's Disease Center visit) was associated with earlier DLB symptom onset. Controlling for sex, those with a history of remote TBI had an approximately 1.5-year earlier clinician-estimated age of onset (F = 0.87, p = 0.35) and 0.75-years earlier age of diagnosis (F = 0.14, p = 0.71) of DLB compared to those without a history of TBI, though the differences did not reach statistical significance. Analysis of subjects with autopsy-confirmed diagnoses was underpowered due to the low number of TBI+ subjects. Remote TBI with LOC was not significantly associated with DLB onset, despite being a significant risk factor for cognitive decline and earlier age of onset in other neurodegenerative conditions. Replication of these results using a larger cohort of DLB subjects with and without a TBI history who have undergone autopsy is indicated, as our TBI+ subjects did show a slightly earlier onset of about 1.5 years. Further investigations into other potential DLB risk factors are also warranted.

Depressive symptoms in relation to clinical symptom onset of mild cognitive impairment.

These analyses included 300 participants from the BIOCARD study, a cohort of individuals who were cognitively normal at baseline (mean age = 57.4 years) and followed for up to 20 years (mean follow-up = 2.5 years). Depression symptom severity was measured using the Hamilton Depression Scale (HAM-D). The authors assessed the association between dichotomous and continuous HAM-D and time to onset of MCI within 7 years versus after 7 years from baseline (reflecting the mean time from baseline to onset of clinical symptoms in the cohort) using Cox regression models adjusted for gender, age, and education. At baseline, subjects had a mean HAM-D score of 2.2 (SD = 2.8). Higher baseline HAM-D scores were associated with an increased risk of progression from normal cognition to clinical symptom onset ≤ 7 years from baseline (p = 0.043), but not with progression &gt; 7 years from baseline (p = 0.194). These findings remained significant after adjustment for baseline cognition. These results suggest that low levels of depressive symptoms may be predictive of clinical symptom onset within approximately 7 years among cognitively normal individuals and may be useful in identifying persons at risk for MCI due to Alzheimer's disease.