Clinical Diagnosis Of Mild Cognitive Impairment Research Articles

25 Biases in Informant Ratings of Functional Abilities in Mild Cognitive Impairment: Predictors of Caregiver-Rated Functional Abilities While Controlling for Patient Objective Cognitive Status

Objective:An understanding of factors that contribute to informant ratings of patients’ functional abilities is crucial, not only because these ratings are used to diagnose individuals with mild cognitive impairment (MCI) versus dementia, but also because these ratings are commonly used as outcome measures in clinical trials. While these ratings are assumed to be largely accurate, research shows they are subject to biases. Caregiver distress, higher caregiver educational attainment, and higher patient age are associated with a higher discrepancy between informant and patient reports of functional abilities. Studies on informant ratings of functional abilities that simultaneously control for patient objective cognitive abilities remain sparse. The current study aims to evaluate caregiver characteristics as predictors of informant-rated functional status while controlling for patient objective cognitive abilities in MCI.Participants and Methods:Individuals with a clinical diagnosis of MCI (Albert, 2011 criteria) were referred to the Cognitive Empowerment Program (CEP), a comprehensive lifestyle program addressing modifiable risk factors associated with progression. This study included cross-sectional data from 118 newly enrolled individuals and their caregivers who served as informants. Patient cognitive functioning was assessed with the Montreal Cognitive Assessment (MoCA). Predictors of interest included caregiver-rated functional abilities (Functional Activities Questionnaire; FAQ), caregiver burden (Zarit Burden Interview; ZBD), caregiver depressive symptoms (Center for Epidemiological Studies Depression scale; CES-D), caregiver stress (Perceived Stress Scale; PSS), and caregivers’ self-rated communicative effectiveness (Communicative Effectiveness Index; CETI). Hierarchical linear regression models were run to predict FAQ while controlling for patient MoCA scores. Separate models were run for the caregiver variables of interest including caregiver age, ZBD, CES-D, PSS, and CETI.Results:Caregivers were 75.6% spouses, 17.1% adult children, 3.3% unmarried partners/cohabitating partners, and 4.1% friends. The mean age of individuals with MCI was 74.7 years (SD: 6.96, mean education = 16.2±2.60 years; 47% female) and the mean age of caregivers was 66.4 (SD: 12.88, mean education = 16.3±2.34; 66% female). Worse ratings of functional abilities on the informant-rated FAQ were found for patients with lower MoCA scores (ß = .242, p = .008). Importantly, while controlling for MoCA scores, worse ratings of functional abilities on the FAQ were found for informants with lower age (ß = -0.269, p = .003), higher perceived stress (ß = 0.267, p = .003), higher caregiver burden (ß = 0.289, p < 0.001), and lower self-rated communication effectiveness (ß = -0.324, p < .001). Caregiver depression (ß = 0.089, p = .084) and education (ß = -0.137, p = .147) were not significant predictors of functional ability ratings while controlling for MoCA scores.Conclusions:Results of the current study highlight the potential for biases in informant ratings regarding functional abilities in MCI. Informant ratings were found to be significantly influenced by caregiver age, stress, burden, and communicative effectiveness. A key finding is that younger caregivers, such as adult children, may report greater functional impairment in individuals with MCI. The current findings have implications for the use of perceived functional ratings, both for diagnostic purposes and as outcome measures in clinical trials.

Subjective Cognitive Decline as a predictor of Frailty in older adults: Hellenic Longitudinal Investigation of Aging and Diet study (HELIAD)

BackgroundSubjective cognitive decline (SCD) is a self-evaluation of cognitive impairment, in the absence of observed objective cognitive deficits on a neuropsychological assessment. Frailty refers to a multidimensional syndrome where the individual has poor health including falls, disabilities, hospitalization, and vulnerability. Both terms are associated with cognitive decline and increased incidence of dementia. The present longitudinal study explored whether the detection of SCD can predict the development of frailty over time.MethodsThe Hellenic Longitudinal Investigation of Aging and Diet (HELIAD) is an epidemiological, population-based study. From the original testing sample of 1,984 older Greek individuals (≥65 years old), 1,121 remained in the longitudinal analysis. Participants diagnosed with frailty, Mild Cognitive Impairment (MCI), dementia, severe depression, and anxiety, in the baseline assessment were excluded from the analysis (n=146), resulting in a total sample of 975 participants. The average follow-up interval was 3.1 years (SD=0.84 years). SCD was assessed in the baseline assessment with a series of eighteen questions. The questions regarding SCD were categorized according to cognitive domains. Frailty was assessed according to a phenotypic-physiologic (Fried’s definition) and a multidomain approach (Frailty Index). Univariate and multivariate Cox regression analyses were used for exploring the role of SCD in developing frailty.ResultsThe proportion of individuals with frailty according to Fried’s definition was greater compared to the Frailty Index. At follow-up according to Fried’s definition, a greater proportion of cases with frailty was found in those who reported SCD complaints regarding orientation (OD) (HR=3.12 95% CI:1.45–6.73 p<0.004) or in those who reported at least three SCD complaints regarding their memory performance (SMC3) (HR=1.92 95% CI:1.05–3.52 p<0.035) at the baseline assessment. Subjective complaints regarding orientation were predictive of a greater hazard of frailty as defined by the Fried scale (HR=3.12 95% CI:1.45–6.73 p<0.004) and the Frailty Index (HR=3.59 95% CI:1.77–7.25 p<0.001).ConclusionOur findings demonstrate that healthy older adults who report SCD complaints regarding orientation or state that they have at least three memory complaints have a higher risk of developing frailty. Additionally, the number of participants with a clinical diagnosis of MCI or dementia, compared to individuals with normal aging, at follow-up was found to be significantly greater in cases with frailty according to both frailty definitions applied (p<0.001). Consequently, it is advisable to use screening questionnaires for SCD covering multiple cognitive domains in clinical practice for identifying and managing frailty, thus, implementing effective interventions to promote healthy aging.

Baseline Predictors of Longitudinal Cognitive Outcomes in Persons with Mild Cognitive Impairment

Introduction: The study aimed to explore longitudinal cognitive outcomes and to ascertain predictors of conversion to dementia in a hospital-based mild cognitive impairment (MCI) cohort classified according to the neuropsychological phenotype at baseline. Materials and Methods: Subjects aged >55 years who had a clinical diagnosis of MCI at initial visit between 2010 and 2018, with at least one formal neuropsychological assessment at baseline and follow-up of a minimum of 2 years were included. The prospective study was completed based on evaluation at last follow-up to gauge conversion to dementia, quantification of performance on activities of daily living and when available, longitudinal neuropsychological test scores. Results: Ninety-five patients with MCI met the inclusion criteria with a mean age of 68.4 ± 6.4 years at baseline and a mean duration of follow-up for 6.4 ± 3.2 years. The cumulative conversion rate to dementia was 22.2% (21/95) and the annualized conversion rate was 3.3% per year of follow-up. The majority of subjects who had converted had multidomain MCI (66%). Only white matter changes on MRI brain revealed correlation with baseline neuropsychology tests. The multivariate logistic regression analysis revealed the utility of lower baseline list recognition (adjusted odds ratio: 0.735 [95% confidence interval: 0.589–0.916]; p 0.006), lower immediate logical memory (0.885 [0.790–0.990]; p 0.03), and high perseverative error scores on set shifting (3.116 [1.425–6.817]; p 0.004) as predictors of conversion. A model score of +2.615 could predict conversion with sensitivity of 72% and specificity of 98% over 6.4 years follow-up. Conclusion: There was a higher risk of conversion associated with multidomain MCI. Logistic regression-based estimations of dementia risk utilizing domain-based neuropsychology test scores in MCI have high specificity for diagnosis at baseline.

Associations Between the Digital Clock Drawing Test and Brain Volume: Large Community-Based Prospective Cohort (Framingham Heart Study).

BackgroundThe digital Clock Drawing Test (dCDT) has been recently used as a more objective tool to assess cognition. However, the association between digitally obtained clock drawing features and structural neuroimaging measures has not been assessed in large population-based studies.ObjectiveWe aimed to investigate the association between dCDT features and brain volume.MethodsThis study included participants from the Framingham Heart Study who had both a dCDT and magnetic resonance imaging (MRI) scan, and were free of dementia or stroke. Linear regression models were used to assess the association between 18 dCDT composite scores (derived from 105 dCDT raw features) and brain MRI measures, including total cerebral brain volume (TCBV), cerebral white matter volume, cerebral gray matter volume, hippocampal volume, and white matter hyperintensity (WMH) volume. Classification models were also built from clinical risk factors, dCDT composite scores, and MRI measures to distinguish people with mild cognitive impairment (MCI) from those whose cognition was intact.ResultsA total of 1656 participants were included in this study (mean age 61 years, SD 13 years; 50.9% women), with 23 participants diagnosed with MCI. All dCDT composite scores were associated with TCBV after adjusting for multiple testing (P value <.05/18). Eleven dCDT composite scores were associated with cerebral white matter volume, but only 1 dCDT composite score was associated with cerebral gray matter volume. None of the dCDT composite scores was associated with hippocampal volume or WMH volume. The classification model for differentiating MCI and normal cognition participants, which incorporated age, sex, education, MRI measures, and dCDT composite scores, showed an area under the curve of 0.897.ConclusionsdCDT composite scores were significantly associated with multiple brain MRI measures in a large community-based cohort. The dCDT has the potential to be used as a cognitive assessment tool in the clinical diagnosis of MCI.

Do fine motor impairments constitute a key feature of mild cognitive impairment? A systematic review and meta‐analysis

AbstractBackgroundTypical symptoms of mild cognitive impairment (MCI) include impairments in memory, executive function, and visuospatial skills. While impairments in these cognitive domains are highly apparent after MCI, impairments in motor domain are not so conspicuous. Converging evidence suggests that individuals with MCI demonstrate motor impairments in lower extremity such as reduced balance and impaired gait performance. However, the impact of MCI on upper extremity motor impairments is not well understood. In the current meta‐analysis, we examine whether fine motor impairments are a key feature of mild cognitive impairment.MethodWe performed a systematic search of electronic databases for articles published between 1990 and 2019. The meta‐analysis included studies that compared healthy older adults and adults with a clinical diagnosis of MCI on fine motor tasks such as handwriting, finger tapping, and hand dexterity.ResultTen studies with over 800 participants qualified for inclusion. Rigorous meta‐analytic techniques using random effects model, forest and funnels plots revealed a standardized mean difference effect of 0.48 (95% CI = 0.77 to 0.19, p=0.001). This moderate effect indicated deficits in fine motor control are a likely feature of MCI.ConclusionThe cumulative evidence suggests that fine motor impairments are pervasive in MCI across a range of upper extremity motor tasks. Quantitative assessment of the decline in fine motor function in MCI may be promising approach to understand the changes in motor function that occur with the onset of Alzheimer’s disease and are clearly differentiated from normal aging‐related decline.

Influence of Social and Demographic Factors on the Montreal Cognitive Assessment (MoCA) Test in Rural Population of North-Eastern Greece.

The current study aims to investigate the influence of socio-demographic factors on the Montreal Cognitive Assessment (MoCA) test results in a Greek-speaking population consisting of a sample of healthy older adults, individuals with mild cognitive impairment (MCI), and dementia patients in rural areas. In addition, the current research focuses on determining optimal cut-off scores for the clinical diagnoses of MCI and dementia. The data originated from 283 participants in an ongoing registry of the Neurology Department of Alexandroupolis University Hospital, recruited in different rural districts of north-eastern Greece, across a broad range of educational and occupational categories. Total and sub-domain scores for the MoCA varied significantly, according to sex, age, and education, among the three study groups. The optimal cut-off points of 25/26 for the MoCA total score was determined to classify healthy subjects from individuals with MCI, 24 to discriminate healthy participants from demented, and 21/22 to discriminate subjects with MCI from dementia. Overall, the clinical use of the MoCA test can be supported by demographically adjusted standard scores in a Greek-speaking rural population. These findings serve to improve the diagnostic accuracy and utility of the MoCA test.

Measuring Cognitive Health in Ethnically Diverse Older Adults.

Understanding racial/ethnic disparities in late-life cognitive health is a public health imperative. We used baseline data from the Kaiser Healthy Aging and Diverse Life Experiences (KHANDLE) study to examine how age, education, gender, and clinical diagnosis, a proxy for brain health, are associated with cross-sectional measures of cognition in diverse racial/ethnic groups. Comprehensive measures of cognition were obtained using the Spanish and English Neuropsychological Assessment Scales and the National Institutes of Health Toolbox Cognitive Health Battery in a sample of 1,695 KHANDLE participants (Asians 24%, Blacks 26%, Latinos 20%, Whites 29%). A 25% random subsample was clinically evaluated and diagnosed with normal cognition, mild cognitive impairment (MCI), or dementia. Cognitive test scores were regressed on core demographic variables and diagnosis in the combined sample and in multiple group analyses stratified by racial/ethnic group. Race/ethnicity and education were variably associated with test scores with strongest associations with tests of vocabulary and semantic memory. Older age was associated with poorer performance on all measures, and gender differences varied across cognitive tests. Clinical diagnosis of MCI or dementia was associated with average decrements in test scores that ranged from -0.41 to -0.84 SD, with largest differences on tests of executive function and episodic memory. With few exceptions, associations of demographic variables and clinical diagnosis did not differ across racial/ethnic groups. The robust associations of cognitive test results with clinical diagnosis independent of core demographic variables and race/ethnicity support the validity of cognitive tests as indicators for brain health in diverse older adults.

The Italian Version of the Test Your Memory (TYM-I): A Tool to Detect Mild Cognitive Impairment in the Clinical Setting.

The Test Your Memory (TYM) is a brief self-administered, cognitive screening test, currently used in several settings. It requires minimal administrator supervision and the computation of the final test score takes approximately 2 min. We assessed the discrimination ability of the Italian version of the TYM (TYM-I) in detecting Mild Cognitive Impairment (MCI) in clinical setting. TYM-I was administered to 94 MCI patients and 134 healthy controls. The clinical diagnosis of MCI was considered as the gold standard. An extended formal neuropsychological test battery was used to define MCI subtypes. Receiver Operating Characteristic (ROC) analyses were conducted to find the optimal cut-off and measure discrimination ability of TYM-I in detecting MCI. TYM-I had a similar area under the curve (AUC = 0.85) point estimate as Mini Mental State Examination (MMSE) (AUC = 0.83). A TYM-I score lower or equal to 36 was found to be optimal cut off to detect MCI. The TYM-I showed the highest discrimination ability among individuals aged more than 70 and high educational level (AUC = 0.89). The amnestic MCI subtype patients, compared to non-amnestic MCI patients, had worse performance in recall, orientation and visuospatial abilities TYM-I subscores. The TYM-I is a valid screening test in detecting cognitive dysfunction, easily carried out in clinical practice. The TYM-I subscores may allow to identify amnestic and non-amnestic MCI subtypes.

Identifying Mild Cognitive Impairment with Random Forest by Integrating Multiple MRI Morphological Metrics.

Mild cognitive impairment (MCI) exhibits a high risk of progression to Alzheimer's disease (AD), and it is commonly deemed as the precursor of AD. It is important to find effective and robust ways for the early diagnosis of MCI. In this paper, a random forest-based method combining multiple morphological metrics was proposed to identify MCI from normal controls (NC). Voxel-based morphometry, deformation-based morphometry, and surface-based morphometry were utilized to extract morphological metrics such as gray matter volume, Jacobian determinant value, cortical thickness, gyrification index, sulcus depth, and fractal dimension. An initial discovery dataset (56 MCI/55 NC) from the ADNI were used to construct classification models and the performances were testified with 10-fold cross validation. To test the generalization of the proposed method, two extra validation datasets including longitudinal ADNI data (30 MCI/16 NC) and collected data from Xuanwu Hospital (27 MCI/32 NC) were employed respectively to evaluate the performance. No matter whether testing was done on the discovery dataset or the extra validation datasets, the accuracies were about 80% with the combined morphological metrics, which were significantly superior to single metric (accuracy: 45% ∼76%) and also displayed good generalization across datasets. Additionally, gyrification index and cortical thickness derived from surface-based morphometry outperformed other features in MCI identification, suggesting they were some key morphological biomarkers for early MCI diagnosis. Combining the multiple morphological metrics together resulted in a significantly better and reliable identification model, which may be helpful to assist in the clinical diagnosis of MCI.

Time Preferences of Older People With Mild Cognitive Impairment

Aging is frequently accompanied by a decline in cognitive abilities that may impair problem-solving abilities and influence decision-making capabilities. Executive functions play a central role in the ability to plan and solve problems. We examined the association between financial time preferences and executive function in older adults with mild cognitive impairment (MCI). Subjects aged 60 years and older with a clinical diagnosis of MCI and a group of individuals whose cognitive function was within normal limits, underwent cognitive evaluation using a computerized cognitive assessment battery (Neurotrax). In addition, participants completed a questionnaire to determine the subjective discount rate (SDR) based on preferences for various sums of money and time periods. Univariate and multivariate models were constructed to determine the influence of cognitive scores on SDR.

The effects of an extensive exercise programme on the progression of Mild Cognitive Impairment (MCI): study protocol for a randomised controlled trial

BackgroundExercise interventions to prevent dementia and delay cognitive decline have gained considerable attention in recent years. Human and animal studies have demonstrated that regular physical activity targets brain function by increasing cognitive reserve. There is also evidence of structural changes caused by exercise in preventing or delaying the genesis of neurodegeneration. Although initial studies indicate enhanced cognitive performance in patients with mild cognitive impairment (MCI) following an exercise intervention, little is known about the effect of an extensive, controlled and regular exercise regimen on the neuropathology of patients with MCI. This study aims to determine the effects of an extensive exercise programme on the progression of MCI.Methods/designThis randomised controlled clinical intervention study will take place across three European sites. Seventy-five previously sedentary patients with a clinical diagnosis of MCI will be recruited at each site. Participants will be randomised to one of three groups. One group will receive a standardised 1-year extensive aerobic exercise intervention (3 units of 45 min/week). The second group will complete stretching and toning (non-aerobic) exercise (3 units of 45 min/week) and the third group will act as the control group. Change in all outcomes will be measured at baseline (T0), after six months (T1) and after 12 months (T2). The primary outcome, cognitive performance, will be determined by a neuropsychological test battery (CogState battery, Trail Making Test and Verbal fluency). Secondary outcomes include Montreal Cognitive Assessment (MoCA), cardiovascular fitness, physical activity, structural changes of the brain, quality of life measures and measures of frailty. Furthermore, outcome variables will be related to genetic variations on genes related to neurogenesis and epigenetic changes in these genes caused by the exercise intervention programme.DiscussionThe results will add new insights into the prevailing notion that exercise may slow the rate of cognitive decline in MCI.Trial registrationClinicalTrials.gov NCT02913053

A Mutual Self- and Informant-Report of Cognitive Complaint Correlates with Neuropathological Outcomes in Mild Cognitive Impairment.

BackgroundThis study examines whether different sources of cognitive complaint (i.e., self and informant) predict Alzheimer’s disease (AD) neuropathology in elders with mild cognitive impairment (MCI).MethodsData were drawn from the National Alzheimer’s Coordinating Center Uniform and Neuropathology Datasets (observational studies) for participants with a clinical diagnosis of MCI and postmortem examination (n = 1843, 74±8 years, 52% female). Cognitive complaint (0.9±0.5 years prior to autopsy) was classified into four mutually exclusive groups: no complaint, self-only, informant-only, or mutual (both self and informant) complaint. Postmortem neuropathological outcomes included amyloid plaques and neurofibrillary tangles. Proportional odds regression related complaint to neuropathology, adjusting for age, sex, race, education, depressed mood, cognition, APOE4 status, and last clinical visit to death interval.ResultsMutual complaint related to increased likelihood of meeting NIA/Reagan Institute (OR = 6.58, p = 0.004) and Consortium to Establish a Registry for Alzheimer’s Disease criteria (OR = 5.82, p = 0.03), and increased neurofibrillary tangles (OR = 3.70, p = 0.03), neuritic plaques (OR = 3.52, p = 0.03), and diffuse plaques (OR = 4.35, p = 0.02). Informant-only and self-only complaint was not associated with any neuropathological outcome (all p-values>0.12).ConclusionsIn MCI, mutual cognitive complaint relates to AD pathology whereas self-only or informant-only complaint shows no relation to pathology. Findings support cognitive complaint as a marker of unhealthy brain aging and highlight the importance of obtaining informant corroboration to increase confidence of underlying pathological processes.

Stability of amnestic mild cognitive impairment: Cantab paired associate learning as a predictor of a consistent diagnosis

Background: The initial clinical diagnosis of mild cognitive impairment (MCI) can be unstable, with the degree of cognitive impairment rapidly worsening in some people, and apparently resolving in others. This study used a computerised measure of paired associate learning (Cantab PAL) to predict stable versus transient MCI from baseline cognitive scores. Methods: Participants were recruited from a longitudinal study of neuropsychological function in community-residing adults with suspected MCI. Inclusion criteria were: (i) presence of a subjective cognitive complaints (ii) preserved general cognition; (iii) independent daily functioning. From initial recruitment (n ¼ 286), 200 participants were classified as either amnestic MCI (aMCI: impairments including one or more visual or verbal memory tasks), non-amnestic MCI (na-MCI: impairments in one or more non-memory task) or unimpaired (no cognitive scores <10th percentile relative to normative sample). At 10 month follow-up (n¼122), a number of MCI cases had resolved. The final analysis includes 21 unimpaired controls, 43 with naMCI, 17 with a-MCI, 21 with resolved a-MCI and 43 with resolved na-MCI. Participants underwent Cantab PAL testing as part of their neuropsychological testing at baseline and 10 months. Results: At both baseline and follow-up, PAL performance was significantly worse in a-MCI patients compared to all other groups, which were not significantly different from each other. This included participants initially diagnosed with an initial diagnosis of a-MCI which then resolved. There was a significant interaction between group (a-MCI vs others) and time, indicating that the rate of decline in the a-MCI group was greater than other groups. Logistic regression showed that both PAL impairment at baseline and change in PAL scores predicted a-MCI group membership, even controlling for age, education and gender. Conclusions: The Cantab PAL task is a sensitive and specific indicator of amnestic MCI. Patients who perform badly on this test at baseline are a stable group with a clinically-relevant impairment that worsens steadily over time.

Prognostic value of 8F-Florbetapir scan: a 36-month follow up analysis using ADNI data

Background: The Alzheimer’s Disease Neuroimaging Initiative (ADNI) provides an opportunity to investigate the relationship between β-Amyloid neuropathology and patients’ long-term cognitive function change. We examined baseline 18F-florbetapir PET amyloid imaging status and 36-months’ change from baseline in cognitive performance in subjects with mild cognitive impairment (MCI). Method: The study included all ADNI subjects who underwent PET-imaging with 18F-florbetapir and had a clinical diagnosis of MCI at the visit closest to florbetapir imaging. β-Amyloid deposition was measured by florbetapir standard uptake value ratio (SUVR), and dichotomized as Aβ+(SUVR&gt;1.1) or Aβ–(SUVR≤1.1). Cognitive scores, including ADAS11, MMSE and CDR sum of boxes (CDR-SB), were evaluated for up to 36 months. Results: Of 478 MCI-subjects who had at least one florbetapir scan, 153 had a cognitive evaluation at 36-month follow-up. Of those, 79 were Aβ– and 74 Aβ+. At 36-months, the Aβ+ vs. Aβ– group scores changed from baseline (LS means 4.03 vs. 0.26 for ADAS11; -2.61 vs.-0.40 for MMSE; 1.53 vs. -0.11 for CDR-SB [p&lt; 0.0001 all comparisons]). Generalised estimating equation analysis on clinically significant cognitive change showed a marginal Odds Ratio=2.18 (95% CI: 1.47–3.21) for Aβ+ vs. Aβ– groups. Conclusion: MCI subjects with higher β-Amyloid deposition had greater deterioration in cognitive function over 36 months while subjects with no β-Amyloid accumulation tended to be stable.

Interaction of transactive response DNA binding protein 43 with nuclear factor κB in mild cognitive impairment with episodic memory deficits.

IntroductionTransactive response DNA binding protein 43 (TDP-43) is detected in pathological inclusions in many cases of Alzheimer’s disease (AD) and mild cognitive impairment (MCI), but its pathological role in AD and MCI remains unknown. Recently, TDP-43 was reported to contribute to pathogenesis in amyotrophic lateral sclerosis through its interaction with p65 nuclear factor κB (NF-κB) resulting in abnormal hyperactivation of this signaling pathway in motor neurons. Hence, we investigated the interaction of TDP-43 with p65 in the temporal cortex of subjects with a clinical diagnosis of MCI (n = 12) or AD (n = 12) as well as of age-matched controls with no cognitive impairment (NCI, n = 12).ResultsImmunoprecipitation and immunofluorescence approaches revealed a robust interaction of TDP-43 with p65 in the nucleus of temporal lobe neurons in four individuals with MCI (named MCI-p). These MCI-p cases exhibited high expression levels of soluble TDP-43, p65, phosphorylated p65 and low expression levels of β-amyloid 40 when compared to AD or NCI cases. The analysis of cognitive performance tests showed that MCI-p individuals presented intermediate deficits of global cognition and episodic memory between those of AD cases and of NCI cases and MCI cases with no interaction of TDP-43 with p65.ConclusionsFrom these results, we propose that enhanced NF-κB activation due to TDP-43 and p65 interaction may contribute to neuronal dysfunction in MCI individuals with episodic memory deficits. Accordingly, treatment with inhibitors of NF-κB activation may be considered for MCI individuals with episodic memory deficits.

Screening for cognitive and affective dysfunction in patients suspected of mild cognitive impairment

Disturbances of affect expression and perception, as well as accuracy of predicting memory difficulties, have been reported in various brain dysfunctional groups. Screening tests of higher cerebral functions seldom sample these dimensions. The goal of this study was to determine if patients with mild cognitive impairment (MCI) of the amnestic type would demonstrate impairments in these domains, as well as show expected memory deficits. Thirty-nine French-speaking patients with a clinical diagnosis of MCI were compared with 39 age- and education-matched normal functioning individuals on the French translation of the Barrow Neurological Institute Screen for Higher Cerebral Functions (BNIS). Patients and controls also made subjective ratings regarding their cognitive and affective functioning in everyday life. Patients with MCI performed significantly worse than controls on the BNIS subtests sampling memory, orientation, affect expression and perception, and accurate prediction of memory performance. They did not differ on other subtests of the BNIS, as predicted. Poor self-awareness (i.e., inaccurate prediction of the number of words one could recall after distraction) correlated with self-reported deficits in several areas of cognitive and affective functioning. This sample of MCI patients demonstrated disturbances not only in memory but also in self-awareness and affect expression and perception on the BNIS. These dimensions should be included in the neuropsychological assessment of patients suspected of MCI.

Endothelial dysfunction associated with mild cognitive impairment in elderly population

According to the original Petersen criteria, we investigated the association between endothelial dysfunction and mild cognitive impairment (MCI) by flow-mediated dilation (FMD). We aimed to verify if endothelial dysfunction occurs in MCI and whether vascular factors are implicated in the MCI pathogenesis. This is a cross-sectional study performed on 34 subjects with clinical diagnosis of MCI and 37 controls, older than 60years. Patients were enrolled from a geriatric outpatient clinic. All the recognized cardiovascular risk factors and an objective state of cognitive impairment were used as exclusion criteria. Cognitive function was evaluated using a scientific-validated neuropsychological battery, whereas MCI was recognized according to the Petersen criteria. Endothelial function was evaluated according to FMD from the brachial artery. The association between FMD and MCI was evaluated both by using a multivariate analysis and a correlation test. Finally, using the ANOVA analysis of variance, we tested the differences in flow-mediated dilation among MCI subgroups. Brachial FMD was significantly associated with MCI (p<0.01). The multivariate analysis showed that age, years of education and MMSE independently predicted the FMD variation (r (2) =0.73; p<0.0001). In addition, MCI patients with prevalent amnestic multiple domain impairment showed the worst brachial FMD. This finding suggests that vascular dysfunction may play a role in the pathogenesis of cognitive impairment and underlines the lack of therapeutic strategies targeted to such dysfunctions.

Searching for Predictive Blood Biomarkers: Misfolded p53 In Mild Cognitive Impairment

The identification and validation of biomarkers for preclinical patients with mild cognitive impairment (MCI) at-risk for Alzheimer's disease (AD) development is increasingly important. We used the cytofluorimetric analysis of unfolded p53 to determine the prognostic ability of the protein as predictive signature from MCI to AD in a longitudinal study of a population of presymptomatic patients with the clinical diagnosis of MCI. Venous blood samples from 24 healthy subjects, 28 MCI and 15 AD were analyzed with the cytofluorimetric method for unfolded p53 protein detection. Twenty-four MCI patients had clinical follow-up subsequent to the analysis for unfolded p53. Elevated levels of the conformationally altered protein were able to discriminate both MCI and AD patients comparing with healthy subjects. Longitudinal follow-up revealed that 7/24 MCI patients progressed to AD. All converters (100%) were predicted by elevated levels of unfolded p53, with a positive predictive value of 87.5%. These data support and extend our previous observation that the cytofluorimetric approach for unfolded p53 protein was able to discriminate AD patients from healthy subjects and to predict the progression from MCI to AD in presymptomatic patients before clinical diagnosis for AD was evident.

Neuronal LR11 Expression Does Not Differentiate between Clinically-Defined Alzheimer's Disease and Control Brains

Alzheimer's disease (AD) is the leading cause of dementia in the elderly. Because the pathological changes underlying this disease can begin decades prior to the onset of cognitive impairment, identifying the earliest events in the AD pathological cascade has critical implications for both the diagnosis and treatment of this disease. We previously reported that compared to autopsy confirmed healthy control brain, expression of LR11 (or SorLA) is markedly reduced in AD brain as well as in a subset of people with mild cognitive impairment (MCI), a prodromal clinical stage of AD. Recent studies of the LR11 gene SORL1 have suggested that the association between SORL1 single nucleotide polymorphisms (SNPs) and AD risk may not be universal. Therefore, we sought to confirm our earlier findings in a population chosen solely based on clinical criteria, as in most genetic studies. Quantitative immunohistochemistry was used to measure LR11 expression in 43 cases from the Religious Orders Study that were chosen based on a final pre-mortem clinical diagnosis of MCI, mild/moderate AD or no cognitive impairment (NCI). LR11 expression was highly variable in all three diagnostic groups, with no significant group differences. Low LR11 cases were identified using the lowest tertile of LR11 expression observed across all cases as a threshold. Contrary to previous reports, low LR11 expression was found in only 29% of AD cases. A similar proportion of both the MCI and NCI cases also displayed low LR11 expression. AD-associated lesions were present in the majority of cases regardless of diagnostic group, although we found no association between LR11 levels and pathological variables. These findings suggest that the relationship between LR11 expression and the development of AD may be more complicated than originally believed.

Differential Reports of Pain and Depression Differentiate Mild Cognitive Impairment From Cognitively Intact Elderly Participants

Positive associations between pain and depression in the general population have been well characterized; however, the interplay between pain, depression, and early cognitive decline, characterized as mild cognitive impairment (MCI), is poorly understood. The current study examined the association of self-reported pain complaints (measured by the 36-item Short Form Health Survey) and self-reported depressive symptoms (measured by the 30-item Geriatric Depression Scale) in cognitively intact participants (n = 492) and participants with a clinical diagnosis of MCI (n = 83). Depressive symptoms and subjective reports of pain were significantly associated in the entire sample (r = .29; P < .0001). Multiple logistic regression modeling (adjusted for age, education, and APOE4 status as covariates) demonstrated that while depressive symptoms were positively associated with the diagnosis of MCI (P < .001), subjective pain reports were negatively associated with MCI (P < .002). While the negative association of subjective pain complaints with MCI might arguably be explained by the development of anosognosia, self-reports of depressive symptoms were actually increased in these participants, suggesting preserved insight into cognitive decline-associated symptoms. It is possible that preferential involvement of limbic circuitry in MCI could explain these findings. Future studies are needed to elucidate the reasons for the dissociation of pain and depressive symptoms in MCI described in the present article.