Diagnostic Precision in the Detection of Mild Cognitive Impairment: A Comparison of Two Approaches.

OBJECTIVE: This study compared diagnostic rates and clinical predictors of discrepancies between diagnoses conferred via: 1) a comprehensive neuropsychological evaluation and National Institute on Aging-Alzheimer's Association (NIA-AA) criteria versus 2) a cognitive screener and Diagnostic Statistical Manual of Mental Disorders (DSM-5) criteria. DESIGN: Cross-sectional examination of baseline data from the Prevention of Alzheimer's dementia (AD) using Cognitive remediation and transcranial direct current stimulation in Mild Cognitive Impairment (MCI) and Depression (PACt-MD; ClinicalTrials.gov Identifier: NCT02386670) trial. SETTING: Five geriatric psychiatry and memory clinics located at academic hospitals affiliated with the Department of Psychiatry, University of Toronto. PARTICIPANTS: Older adults (N = 431) with a history of major depressive disorder (MDD) in remission, MCI, or both. MEASUREMENTS: Main outcome was a comparison of NIA-AA diagnostic rates of MCI or dementia versus DSM-5 rates of mild or major neurocognitive disorder. Secondary analyses examined demographic, race, gender, premorbid intellectual ability, psychosocial, health-related, and genetic predictors of discrepancy between DSM-5 and NIA-AA diagnoses. RESULTS: There were 103 (23.8%) discrepant cases, with most (91; 88.3%) of these discrepant cases reflecting more impairment with the detailed neuropsychological testing and NIA-AA criteria. Discrepancies were more likely in individuals with a history of MDD or who had at least one ApoE4 allele. CONCLUSION: The NIA-AA criteria, in conjunction with comprehensive neuropsychological testing, identified a greater prevalence of cognitive impairment than DSM-5 criteria, in conjunction with the Montreal Cognitive Assessment. Detailed neuropsychological evaluations are recommended for older adults who have a history of MDD or a genetic vulnerability to dementia.

Saccades during object viewing modulate oscillatory phase in the superior temporal sulcus.

Saccadic eye movements (SEMs) are the primary means of gating visual information in primates and strongly influence visual perception. The active exploration of the visual environment ("active vision") via SEMs produces suppression during saccades and enhancement afterward (i.e., during fixation) in occipital visual areas. In lateral temporal lobe visual areas, the influence, if any, of eye movements is less well understood, despite the necessity of these areas for forming coherent percepts of objects. The upper bank of the superior temporal sulcus (uSTS) is one such area whose sensitivity to SEMs is unknown. We therefore examined how saccades modulate local field potentials (LFPs) in the uSTS of macaque monkeys while they viewed face and nonface object stimuli. LFP phase concentration increased following fixation onset in the alpha (8-14 Hz), beta (14-30 Hz), and gamma (30-60 Hz) bands and was distinct from the image-evoked response. Furthermore, near-coincident onsets of fixation and image presentation--like those occurring in active vision--led to enhanced responses through greater phase concentration in the same frequency bands. Finally, single-unit activity was modulated by the phase of alpha, beta, and gamma oscillations, suggesting that the observed phase-locking influences spike timing in uSTS. Previous research implicates phase concentration in these frequency bands as a correlate of perceptual performance (Womelsdorf et al., 2006; Bosman et al., 2009). Together, these results demonstrate sensitivity to eye movements in an object-processing region of the brain and represent a plausible neural basis for the enhancement of object processing during active vision.

Time setting errors in the Clock Drawing Test are associated with both semantic and executive deficits.

The common requirement to set the time to "10 past 11" on the Clock Drawing Test is intended to elicit a stimulus bound response (SBR), in which the responder is "pulled" to the salient stimulus "10," resulting in hands set at "10 before 11." SBRs are considered markers of executive dysfunction, although this assumption has not yet been validated. We compared SBR and other time-setting errors on inhibitory control tests, hypothesizing that they represent related constructs. The role of semantic dysfunction in the formation of those errors was also investigated. We examined baseline test performance of participants with Mild Cognitive Impairment or a history of depression, and control participants, enrolled in a dementia prevention study. Among 258 participants, we identified clocks with SBRs (n = 16), other time errors (n = 22), or no errors at all (n = 42). Performance between the groups with SBRs and other time-setting errors did not differ on any of the executive tests, and both error groups performed significantly worse than the No Error group on the semantic tests. Control for covariates further supported semantic and executive components in time-setting errors. Both semantic and inhibitory control deficits may underlie time representation errors in general.

Design and Rationale of the PACt-MD Randomized Clinical Trial: Prevention of Alzheimer's dementia with Cognitive remediation plus transcranial direct current stimulation in Mild cognitive impairment and Depression.

BACKGROUND: By the time Alzheimer's disease and related disorders (ADRD) are diagnosed, efficacy of treatments is limited. Preventive interventions are urgently needed. OBJECTIVE: To design a randomized controlled trial to assess a novel intervention that aims to prevent ADRD in high-risk groups. METHODS: We report on the rationale and describe the design of a multisite randomized controlled trial that aims to prevent ADRD in older persons with: (1) mild cognitive impairment (MCI); (2) remitted major depressive disorder (MDD) without MCI; or (3) remitted MDD with MCI. RESULTS: PACt-MD (Prevention of Alzheimer's dementia with Cognitive remediation plus transcranial direct current stimulation in Mild cognitive impairment and Depression) is a trial that randomized 375 older participants with MCI, MDD, or MCI + MDD to cognitive remediation (CR) plus transcranial direct current stimulation (tDCS) or sham-CR + sham-tDCS for 5 days/week for 8 weeks followed by boosters for 5 days/week once every 6 months until participants progress to MCI or ADRD, or the end of the study. Between boosters, participants are asked to train on CR daily. At baseline, end of 8 weeks, and yearly from baseline, participants undergo clinical, cognitive, and functional assessments. The primary aims are to compare the efficacy of CR + tDCS versus sham + sham in preventing: 1) long-term cognitive decline; and 2) incidence of ADRD or MCI. The secondary aim is to assess for cognitive improvement after the 8-week course. We will also explore the moderating and mediating effects of several biomarkers collected from the participants. CONCLUSION: PACt-MD is unique in combining brain stimulation and a psychosocial intervention to prevent ADRD. PACt-MD is also a platform for studying multi-domain biomarkers that will advance our understanding of the relationships among MCI, MDD, and ADRD.

Correlating behavioral responses to FMRI signals from human prefrontal cortex: examining cognitive processes using task analysis.

The aim of this methods paper is to describe how to implement a neuroimaging technique to examine complementary brain processes engaged by two similar tasks. Participants' behavior during task performance in an fMRI scanner can then be correlated to the brain activity using the blood-oxygen-level-dependent signal. We measure behavior to be able to sort correct trials, where the subject performed the task correctly and then be able to examine the brain signals related to correct performance. Conversely, if subjects do not perform the task correctly, and these trials are included in the same analysis with the correct trials we would introduce trials that were not only for correct performance. Thus, in many cases these errors can be used themselves to then correlate brain activity to them. We describe two complementary tasks that are used in our lab to examine the brain during suppression of an automatic responses: the stroop(1) and anti-saccade tasks. The emotional stroop paradigm instructs participants to either report the superimposed emotional 'word' across the affective faces or the facial 'expressions' of the face stimuli(1,2). When the word and the facial expression refer to different emotions, a conflict between what must be said and what is automatically read occurs. The participant has to resolve the conflict between two simultaneously competing processes of word reading and facial expression. Our urge to read out a word leads to strong 'stimulus-response (SR)' associations; hence inhibiting these strong SR's is difficult and participants are prone to making errors. Overcoming this conflict and directing attention away from the face or the word requires the subject to inhibit bottom up processes which typically directs attention to the more salient stimulus. Similarly, in the anti-saccade task(3,4,5,6), where an instruction cue is used to direct only attention to a peripheral stimulus location but then the eye movement is made to the mirror opposite position. Yet again we measure behavior by recording the eye movements of participants which allows for the sorting of the behavioral responses into correct and error trials(7) which then can be correlated to brain activity. Neuroimaging now allows researchers to measure different behaviors of correct and error trials that are indicative of different cognitive processes and pinpoint the different neural networks involved.

Word wins over face: emotional Stroop effect activates the frontal cortical network.

The prefrontal cortex (PFC) has been implicated in higher order cognitive control of behavior. Sometimes such control is executed through suppression of an unwanted response in order to avoid conflict. Conflict occurs when two simultaneously competing processes lead to different behavioral outcomes, as seen in tasks such as the anti-saccade, go/no-go, and the Stroop task. We set out to examine whether different types of stimuli in a modified emotional Stroop task would cause similar interference effects as the original Stroop-color/word, and whether the required suppression mechanism(s) would recruit similar regions of the medial PFC (mPFC). By using emotional words and emotional faces in this Stroop experiment, we examined the two well-learned automatic behaviors of word reading and recognition of face expressions. In our emotional Stroop paradigm, words were processed faster than face expressions with incongruent trials yielding longer reaction times and larger number of errors compared to the congruent trials. This novel Stroop effect activated the anterior and inferior regions of the mPFC, namely the anterior cingulate cortex, inferior frontal gyrus as well as the superior frontal gyrus. Our results suggest that prepotent behaviors such as reading and recognition of face expressions are stimulus-dependent and perhaps hierarchical, hence recruiting distinct regions of the mPFC. Moreover, the faster processing of word reading compared to reporting face expressions is indicative of the formation of stronger stimulus-response associations of an over-learned behavior compared to an instinctive one, which could alternatively be explained through the distinction between awareness and selective attention.