Comparison of brief olfactory and cognitive assessments to neuroimaging biomarkers in the prediction of cognitive decline and dementia in the MCSA cohort.

INTRODUCTION: We evaluated impaired odor identification and global cognition as simple, cost-effective alternatives to neuroimaging biomarkers to predict cognitive decline and dementia in the Mayo Clinic Study of Aging. METHODS: Six hundred forty-seven participants (mean 8.1, standard deviation 3.4 years' follow-up) had the following baseline procedures: modified Blessed Information Memory Concentration Test (BIMCT), 12-item Brief Smell Identification Test (BSIT), structural brain magnetic resonance imaging (MRI), and positron emission tomography (PET) imaging with 11C-Pittsburgh compound B (11C-PiB) and fluorodeoxyglucose (FDG; subset). RESULTS: Cognitive decline developed in 102 participants and dementia in 34 participants. In survival analyses, PiB PET showed robust prediction for cognitive decline. Impaired BSIT, impaired BIMCT, MRI, and FDG measures were also significant predictors. The combination of demographics + BSIT + BIMCT showed strong predictive utility (C-index 0.81), similar to demographics + PiB PET (C-index 0.80). Similar but stronger results were obtained for prediction of dementia. DISCUSSION: Impairment in both odor identification test and global cognition was comparable to PiB PET for predicting cognitive decline and dementia. HIGHLIGHTS: In 647 participants in the population-based Mayo Clinic Study of Aging, several clinical markers and biomarkers each predicted cognitive decline or dementia during an average 8 years of follow-up. The combination of the demographic variables of age, sex, and education with a brief odor identification test (BSIT) and a global cognitive test (Blessed Information Memory Concentration Test) showed strong predictive utility (C-index 0.81) for cognitive decline that was similar to the demographic variables combined with Pittsburgh Compound B amyloid imaging (C-index 0.80). Combining a brief odor identification test with a brief cognitive test needs consideration as a simple, cost-effective option in the clinical assessment of individuals at risk of cognitive decline and dementia, as well as a potential tool to identify individuals who may benefit from disease-modifying treatments and to screen participants for prevention trials.

Clinical and radiological characteristics of early versus late mild cognitive impairment in patients with comorbid depressive disorder.

OBJECTIVE: The classification of mild cognitive impairment (MCI) continues to be debated though it has recently been subtyped into late (LMCI) versus early (EMCI) stages. Older adults presenting with both a depressive disorder (DEP) and cognitive impairment (CI) represent a unique, understudied population. Our aim was to examine baseline characteristics of DEP-CI patients in the DOTCODE trial, a randomized controlled trial of open antidepressant treatment for 16 weeks followed by add-on donepezil or placebo for 62 weeks. METHODS/DESIGN: Key inclusion criteria were diagnosis of major depression or dysthymic disorder with Hamilton Depression Rating Scale (HAM-D) score >14, and cognitive impairment defined by MMSE score ≥21 and impaired performance on the WMS-R Logical Memory II test. Patients were classified as EMCI or LMCI based on the 1.5 SD cutoff on tests of verbal memory, and compared on baseline clinical, neuropsychological, and anatomical characteristics. RESULTS: Seventy-nine DEP-CI patients were recruited of whom 39 met criteria for EMCI and 40 for LMCI. The mean age was 68.9, and mean HAM-D was 23.0. Late mild cognitive impairment patients had significantly worse ADAS-Cog (P < .001), MMSE (P = .004), Block Design (P = .024), Visual Rep II (P = .006), CFL Animal (P = .006), UPSIT (P = .051), as well as smaller right hippocampal volume (P = .037) compared to EMCI patients. MRI indices of cerebrovascular disease did not differ between EMCI and LMCI patients. CONCLUSIONS: Cognitive and neuronal loss markers differed between EMCI and LMCI among patients with DEP-CI, with LMCI being more likely to have the clinical and neuronal loss markers known to be associated with Alzheimer's disease.

Association of Performance on Olfactory and Cognitive Screening Tests With Conversion to Dementia in a Biracial Cohort of Older Adults.

BACKGROUND AND OBJECTIVES: Odor identification deficits are associated with transition to dementia, whereas intact odor identification and global cognition test performance may identify lack of transition. The purpose of this study was to examine intact odor identification and global cognition as prognostic indicators of lack of transition to dementia in a biracial (Black and White) cohort. METHODS: In a community-dwelling sample of older adults from the Health, Aging, and Body Composition study, odor identification was measured using the Brief Smell Identification Test (BSIT), and global cognition was measured using the Teng Modified Mini-Mental State Examination (3MS). Survival analyses for dementia transition over 4 and 8 years of follow-up used Cox proportional hazards models. RESULTS: A total of 2,240 participants had an average age of 75.5 years (SD 2.8). Approximately 52.7% were female individuals. Approximately 36.7% were Black and 63.3% were White individuals. Impaired odor identification (hazard ratio [HR] 2.29, 95% CI 1.79-2.94, p < 0.001) and global cognition (HR 3.31, 95% CI 2.26-4.84, p < 0.001) were each independently associated with transition to dementia (n = 281). Odor identification remained robustly associated with transition to dementia for Black (HR 2.02, 95% CI 1.36-3.00, p < 0.001, n = 821) and White participants (HR 2.45, 95% CI 1.77-3.38, p < 0.001, n = 1,419), whereas global cognition was associated with transition among Black participants only (HR 5.06, 95% CI 3.18-8.07, p < 0.001). ApoE genotype was consistently associated with transition among White participants only (HR 1.75, 95% CI 1.20-2.54, p < 0.01). Among participants with intact performance on both odor identification (BSIT ≥9/12 correct) and global cognition (3MS ≥ 78/100 correct), 8.8% transitioned to dementia over 8 years. Intact performance on both measures had high positive predictive value for identifying individuals who did not transition to dementia over 4 years (0.98 for ages 70-75 years with only 2.3% transitioning, 0.94 for ages 76-82 years with only 5.8% transitioning). DISCUSSION: Odor identification testing paired with a global cognitive screening test identified individuals at low risk of transition to dementia in a biracial community cohort with a pronounced effect in the eighth decade of life. Identification of such individuals can reduce the need for extensive investigation to establish a diagnosis. Odor identification deficits showed utility in both Black and White participants, unlike the race-dependent utility of a global cognitive test and ApoE genotype.

Models of depressive pseudoamnestic disorder.

Objective: Little effort has been made in the past to validate depressive pseudodementia based on hypothesis-driven approaches. We extended this concept to individuals with amnestic Mild Cognitive Impairment and Major Depression, that is, pseudodepressive amnestic disorder. We tested two hypotheses consistent with the presentations and mechanisms associated with this potential syndrome: improvements in cognition would be significantly correlated with improvements in depression after treatment (Hypothesis 1), and if not confirmed, the presence of such an association could be identified once moderator variables were taken into account (Hypothesis 2). Methods: Within a clinical trial, 61 individuals received open label serotonin reuptake inhibitor (citalopram or venlafaxine) treatment over a 16-week period. Selective Reminding Test and Hamilton Depression scale were conducted serially to measure change in memory and depression, respectively. Magnetic resonance imaging, other cognitive measures (Alzheimer's Disease Assessment Scale-Cognitive and speed of processing tests), and additional depression measure (Beck Depression Inventory [BDI]) were also administered. Results: No significant associations between improvement in depression and improvement in cognition were observed. Sensitivity analyses with other cognitive measures, the BDI, and exclusion of possible "placebo" responders were negative as well. There were no significant moderation effects for baseline Hamilton Rating Scale for Depression as a measure of symptom severity or age. APOE ε4 genotype and white matter hyperintensity burden yielded counter-intuitive, albeit marginally significant results. Conclusions: Negative findings cast doubt on the frequency of depressive pseudoamnestic disorder in older populations with documented depression and memory impairments.

Odorant-induced brain activation as a function of normal aging and Alzheimer's disease: A preliminary study.

Olfactory dysfunction consistently occurs in patients with Alzheimer's disease (AD), beyond the mild and gradual decline in olfactory ability found in normal aging. This dysfunction begins early in the disease course, typically before clinical diagnosis, and progresses with disease severity. While odor identification and detection deficits clearly differentiate AD from controls, there remains uncertainty as to whether these are determined by olfactory threshold. The purpose of the current preliminary fMRI study was to examine the neural correlates of olfactory processing in healthy young and old adults and compare them with AD patients. We also explored the interplay between age and disease-related psychophysical olfactory declines and odorant-induced brain activation. Results indicated AD patients had decreased odor detection task-related signal in all regions of the primary olfactory cortex, with activity in the entorhinal cortex best differentiating the groups. Moderated-mediation analyses on neuro-psychophysical relationships found that increased brain activation in the entorhinal cortex moderated the negative effect of disease-related threshold changes on olfactory detection. Therefore, even in the face of higher (worse) olfactory thresholds, older adults and AD patients compensated for this effect with increased brain activation in a primary olfactory brain region. This was the case for odor detection but not odor identification. fMRI activation induced by an olfactory detection task may eventually be useful in improving early discovery of AD and may, eventually, facilitate early treatment interventions in subjects at risk for AD.

Odor identification impairment and cholinesterase inhibitor treatment in Alzheimer's disease.

INTRODUCTION: This study evaluated acute change in odor identification following atropine nasal spray challenge, and 8-week change in odor identification ability, as a predictor of long-term improvement in patients with mild to moderate Alzheimer's disease (AD) who received open-label cholinesterase inhibitor treatment. METHODS: In patients with clinical AD, the University of Pennsylvania Smell identification Test (UPSIT) was administered before and after an anticholinergic atropine nasal spray challenge. Patients were then treated with donepezil for 52 weeks. RESULTS: In 21 study participants, acute atropine-induced decrease in UPSIT was not associated with change in the Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog) or Selective Reminding Test (SRT). Decline in odor identification performance from baseline to week 8 was indicative of a future decline in cognitive performance over 52 weeks. DISCUSSION: Change in odor identification with atropine challenge is not a useful predictor of treatment response to cholinesterase inhibitors. Short-term change in odor identification performance needs further investigation as a potential predictor of cognitive improvement with cholinesterase inhibitor treatment.

Cortical Thickness and Hippocampal Volume in Vascular and Non-vascular Depressed Patients.

Background: Reduced cortical thickness and hippocampal volume are prevalent markers of late life depression as well as mild cognitive impairment (MCI) but are conspicuously absent in the vascular depression (VD) literature. The present study aimed to determine differences in cortical thickness and hippocampal volume between VD and non-VD patients. Methods: Participants were enrolled in an 8-week open treatment antidepressant trial. Forty-one depressed individuals aged 50 and older underwent brain magnetic resonance imaging at baseline and were classified as VD or non-VD. Cortical thickness values for the left and right entorhinal, parahippocampal, and precuneal cortices, as well as left and right hippocampal volume, were linearly regressed on VD status to determine mean differences between VD and non-VD. Covariates included site, age, sex, and mean thickness or intracranial volume. Results: No statistical differences were found between VD and non-VD patients in cortical thickness of the bilateral precuneal, entorhinal, or parahippocampal cortices, or hippocampal volume (p > 0.001). Conclusions: The absence of statistical differences in gray matter between VD and non-VD patients raises several diagnostic, etiological, and developmental possibilities, namely that VD may not be connected with other late-life psychiatric illnesses such as MCI or dementia and that vascular disease may not be a common etiological risk factor for depression and dementia. Larger datasets, prospective longitudinal studies, and cognitively intact controls are needed to further address these types of questions.

Cortical thickness predicts remission of depression with antidepressants in patients with late-life depression and cognitive impairment.

BACKGROUND: Depression (DEP) and cognitive impairment (CI) share etiological risk factors, anatomical underpinnings, and interact to produce deleterious treatment outcomes. Both DEP and CI exhibit altered patterns of cortical thickness which may impact the course of antidepressant treatment, though inconsistencies in directionality and affected brain regions have been reported. In this study, we examined the relationship between cortical thickness and treatment outcome in older adults with comorbid DEP-CI. METHODS: 55 patients with DEP-CI received baseline MRI scans as part of a larger clinical trial at NYSPI/Columbia University Medical Center and Duke University Medical Center. Mood was assessed using the Hamilton Depression Rating Scale. Patients received open antidepressant treatment for 8 weeks followed by another 8 weeks of the same medication or switch to another antidepressant for a total of 16 weeks. Cortical thickness was extracted using an automated brain segmentation program (FreeSurfer). Vertex-wise analyses evaluated the relationship between cortical thickness and treatment outcome. RESULTS: Remitters exhibited diffuse clusters of greater cortical thickness and reduced cortical thickness compared to non-remitters. Thicker baseline middle frontal gyrus most consistently predicted greater likelihood and faster rate of remission. White matter hyperintensities and hippocampal volume were not associated with antidepressant treatment outcome. LIMITATIONS: MRI was conducted at baseline only and sample size was small. DISCUSSION: Cortical thickness predicts treatment remission and magnitude of early improvement. Results indicate that individuals with DEP-CI exhibit unique patterns of structural abnormalities compared to their depressed peers without CI that have consequences for their recovery with antidepressant treatment.

Vascular depression for radiology: A review of the construct, methodology, and diagnosis.

Vascular depression (VD) as defined by magnetic resonance imaging (MRI) has been proposed as a unique subtype of late-life depression. The VD hypothesis posits that cerebrovascular disease, as characterized by the presence of MRI-defined white matter hyperintensities, contributes to and increases the risk for depression in older adults. VD is also accompanied by cognitive impairment and poor antidepressant treatment response. The VD diagnosis relies on MRI findings and yet this clinical entity is largely unfamiliar to neuroradiologists and is rarely, if ever, discussed in radiology journals. The primary purpose of this review is to introduce the MRI-defined VD construct to the neuroradiology community. Case reports are highlighted in order to illustrate the profile of VD in terms of radiological, clinical, and neuropsychological findings. A secondary purpose is to elucidate and elaborate on the measurement of cerebrovascular disease through visual rating scales and semi- and fully-automated volumetric methods. These methods are crucial for determining whether lesion burden or lesion severity is the dominant pathological contributor to VD. Additionally, these rating methods have implications for the growing field of computer assisted diagnosis. Since VD has been found to have a profile that is distinct from other types of late-life depression, neuroradiologists, in conjunction with psychiatrists and psychologists, should consider VD in diagnosis and treatment planning.

Testing the Mechanism of Action of Computerized Cognitive Training in Young Adults with Depression: Protocol for a Blinded, Randomized, Controlled Treatment Trial.

BACKGROUND: Depression is associated with a broad range of cognitive deficits, including processing speed (PS) and executive functioning (EF). Cognitive symptoms commonly persist with the resolution of affective symptoms and increase risk of relapse and recurrence. The cognitive control network is comprised of brain areas implicated in EF and mood regulatory functions. Prior research has demonstrated the effectiveness of computerized cognitive training (CCT) focused on PS and EF in mitigating both cognitive and affective symptoms of depression. METHODS: Ninety participants aged 18-29 with a current diagnosis of major depressive disorder or persistent depressive disorder, or a Hamilton Depression Rating Scale score ≥12, will be randomized to either PS/EF CCT, verbal CCT, or waitlist control. Participants in the active groups will complete 15 min of training 5 days/week for 8 weeks. Clinical and neuropsychological assessments will be completed at baseline, week 4, week 8, and 3-month follow-up. Structural and functional magnetic resonance imaging (fMRI) will be completed at baseline and week 8. We will compare changes in mood, cognition, daily functioning, and fMRI data. We will explore cognitive control network functioning using resting-state and task-based fMRI. RESULTS: Recruitment began in October 2019; we expect to finish recruitment by April 2022 and subsequently begin data analysis. CONCLUSIONS: This study is innovative in that it will include both active and waitlist control conditions and will explore changes in neural activation. Identifying the neural networks associated with improvements following CCT will allow for the development of more precise and effective interventions. TRIAL REGISTRATION: ClinicalTrials.gov NCT03869463; https://clinicaltrials.gov/ct2/show/NCT03869463.

Computerized cognitive training in young adults with depressive symptoms: Effects on mood, cognition, and everyday functioning.

BACKGROUND: Computerized cognitive training (CCT) has previously improved cognition and mood in people with depression. Existing research has not determined if the benefits following CCT are specific to the content of CCT or are a function of participation in an engaging activity. In this double-blind randomized controlled trial, we tested whether executive functioning and processing speed (EF/PS)-focused CCT could outperform verbal ability-focused CCT. METHODS: 46 young adults with at least mild depressive symptoms (HDRS ≥ 10) were recruited from the community and randomized to either EF/PS CCT or verbal ability CCT. Participants trained on their mobile device 5 days per week for 8 weeks. Depressive severity, everyday functioning, and cognition were evaluating pre and post-training. RESULTS: The EF/PS group had greater gains in executive functioning and processing speed than the verbal group. There were no differences between groups in mood or everyday functioning improvement, though the EF/PS obtained equivalent improvement with half the training time. Both groups saw significant improvements in self and clinician-rated depressive severity, everyday functioning, and cognition. LIMITATIONS: There was no waitlist control condition and the sample consisted of individuals with mild depressive symptoms and not diagnosed major depressive disorder. CONCLUSIONS: CCT is associated with improved mood, cognition, and everyday functioning, though the type of CCT content does not differentially impact depressive symptom change. EF/PS focused CCT has greater impact on processing speed and executive functioning and leads to equivalent mood/everyday functioning gains as verbal-focused CCT more efficiently. Common factors remain plausible drivers of CCT's therapeutic effects.

Computerized cognitive training and functional recovery in major depressive disorder: A meta-analysis.

OBJECTIVE: Depression is common, frequently resistant to antidepressant treatment, and associated with impairments in cognition and everyday functioning. Computerized cognitive training (CCT) paradigms offer potential to improve cognition, mood and everyday functioning, but their effectiveness is not well established. The goal of this article was to conduct a systematic review and meta-analysis to determine the efficacy of CCT in depressive disorders. METHOD: A search was conducted to identify high quality randomized controlled CCT trials per PRISMA guidelines using PsycINFO and MEDLINE with the keywords "Cognitive training" or "Cognitive remediation" or "Cognitive rehabilitation" and "Depression". 9 randomized trials for depressed adults met inclusion criteria. Effect sizes (Hedge's g) were calculated for key outcome measures of mood symptom severity, daily functioning, and cognition. A 3-level Bayesian hierarchical linear model was used to estimate effect sizes for each domain and study. Publication bias was assessed using Classic Fail Safe N's and homogeneity was evaluated using Q and I(2) indexes. RESULTS: Significant small-moderate effects for Symptom Severity (0.43) and Daily Functioning (0.72), and moderate-large effects for Attention (0.67), Working Memory (0.72), and Global Functioning (1.05) were found. No significant effects were found for Executive Functioning or Verbal Memory. Moderator variable analysis revealed decreased effect of CCT with age. Gender and concurrent medication treatment did not affect the results. LIMITATIONS: Small sample size, short duration, pseudo-specificity, and high heterogeneity for Verbal Memory measures. CONCLUSIONS: CCT is associated with improvement in depressive symptoms and everyday functioning, though produces inconsistent effects on cognition.