Relationship between the Montreal Cognitive Assessment and Mini-mental State Examination for assessment of mild cognitive impairment in older adults

BACKGROUND: The Montreal Cognitive Assessment (MoCA) was developed to enable earlier detection of mild cognitive impairment (MCI) relative to familiar multi-domain tests like the Mini-Mental State Exam (MMSE). Clinicians need to better understand the relationship between MoCA and MMSE scores. METHODS: For this cross-sectional study, we analyzed 219 healthy control (HC), 299 MCI, and 100 Alzheimer's disease (AD) dementia cases from the Alzheimer's Disease Neuroimaging Initiative (ADNI)-GO/2 database to evaluate MMSE and MoCA score distributions and select MoCA values to capture early and late MCI cases. Stepwise variable selection in logistic regression evaluated relative value of four test domains for separating MCI from HC. Functional Activities Questionnaire (FAQ) was evaluated as a strategy to separate dementia from MCI. Equi-percentile equating produced a translation grid for MoCA against MMSE scores. Receiver Operating Characteristic (ROC) analyses evaluated lower cutoff scores for capturing the most MCI cases. RESULTS: Most dementia cases scored abnormally, while MCI and HC score distributions overlapped on each test. Most MCI cases scored ≥ 17 on MoCA (96.3%) and ≥ 24 on MMSE (98.3%). The ceiling effect (28-30 points) for MCI and HC was less using MoCA (18.1%) versus MMSE (71.4%). MoCA and MMSE scores correlated most for dementia (r = 0.86; versus MCI r = 0.60; HC r = 0.43). Equi-percentile equating showed a MoCA score of 18 was equivalent to MMSE of 24. ROC analysis found MoCA ≥ 17 as the cutoff between MCI and dementia that emphasized high sensitivity (92.3%) to capture MCI cases. The core and orientation domains in both tests best distinguished HC from MCI groups, whereas comprehension/executive function and attention/calculation were not helpful. Mean FAQ scores were significantly higher and a greater proportion had abnormal FAQ scores in dementia than MCI and HC. CONCLUSIONS: MoCA and MMSE were more similar for dementia cases, but MoCA distributes MCI cases across a broader score range with less ceiling effect. A cutoff of ≥ 17 on the MoCA may help capture early and late MCI cases; depending on the level of sensitivity desired, ≥ 18 or 19 could be used. Functional assessment can help exclude dementia cases. MoCA scores are translatable to the MMSE to facilitate comparison

Empirically Defining Trajectories of Late-Life Cognitive and Functional Decline

Background: Alzheimer’s disease (AD) is associated with variable cognitive and functional decline, and it is difficult to predict who will develop the disease and how they will progress. Objective: This exploratory study aimed to define latent classes from participants in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database who had similar growth patterns of both cognitive and functional change using Growth Mixture Modeling (GMM), identify characteristics associated with those trajectories, and develop a decision tree using clinical predictors to determine which trajectory, as determined by GMM, individuals will most likely follow. Methods: We used ADNI early mild cognitive impairment (EMCI), late MCI (LMCI), AD dementia, and healthy control (HC) participants with known amyloid-β status and follow-up assessments on the Alzheimer’s Disease Assessment Scale - Cognitive Subscale or the Functional Activities Questionnaire (FAQ) up to 24 months postbaseline. GMM defined trajectories. Classification and Regression Tree (CART) used certain baseline variables to predict likely trajectory path. Results: GMM identified three trajectory classes (C): C1 (n = 162, 13.6%) highest baseline impairment and steepest pattern of cognitive/functional decline; C3 (n = 819, 68.7%) lowest baseline impairment and minimal change on both; C2 (n = 211, 17.7%) intermediate pattern, worsening on both, but less steep than C1. C3 had fewer amyloid- or apolipoprotein-E ɛ4 (APOE4) positive and more healthy controls (HC) or EMCI cases. CART analysis identified two decision nodes using the FAQ to predict likely class with 82.3% estimated accuracy. Conclusions: Cognitive/functional change followed three trajectories with greater baseline impairment and amyloid and APOE4 positivity associated with greater progression. FAQ may predict trajectory class

Florbetapir positron emission tomography and cerebrospinal fluid biomarkers

BACKGROUND: We evaluated the relationship between florbetapir-F18 positron emission tomography (FBP PET) and cerebrospinal fluid (CSF) biomarkers. METHODS: Alzheimer's Disease Neuroimaging Initiative-Grand Opportunity and Alzheimer's Disease Neuroimaging Initiative 2 (GO/2) healthy control (HC), mild cognitive impairment (MCI), and Alzheimer's disease (AD) dementia subjects with clinical measures and CSF collected ±90 days of FBP PET data were analyzed using correlation and logistic regression. RESULTS: In HC and MCI subjects, FBP PET anterior and posterior cingulate and composite standard uptake value ratios correlated with CSF amyloid beta (Aβ1-42) and tau/Aβ1-42 ratios. Using logistic regression, Aβ1-42, total tau (t-tau), phosphorylated tau181P (p-tau), and FBP PET composite each differentiated HC versus AD. Aβ1-42 and t-tau distinguished MCI versus AD, without additional contribution by FBP PET. Total tau and p-tau added discriminative power to FBP PET when classifying HC versus AD. CONCLUSION: Based on cross-sectional diagnostic groups, both amyloid and tau measures distinguish healthy from demented subjects. Longitudinal analyses are needed

Florbetapir F18 PET Amyloid Neuroimaging and Characteristics in Patients With Mild and Moderate Alzheimer Dementia

Background Clinical diagnosis of Alzheimer disease (AD) is challenging, with a 70.9%–87.3% sensitivity and 44.3%–70.8% specificity, compared with autopsy diagnosis. Florbetapir F18 positron emission tomography (FBP-PET) estimates beta-amyloid plaque density antemortem. Methods Of 2052 patients (≥55 years old) clinically diagnosed with mild or moderate AD dementia from 2 solanezumab clinical trials, 390 opted to participate in a FBP-PET study addendum. We analyzed baseline prerandomization characteristics. Results A total of 22.4% had negative FBP-PET scans, whereas 72.5% of mild and 86.9% of moderate AD patients had positive results. No baseline clinical variable reliably differentiated negative from positive FBP-PET scan groups. Conclusions These data confirm the challenges of correctly diagnosing AD without using biomarkers. FBP-PET can aid AD dementia differential diagnosis by detecting amyloid pathology antemortem, even when the diagnosis of AD is made by expert clinicians

Lasmiditan mechanism of action – review of a selective 5-HT1F agonist

Migraine is a leading cause of disability worldwide, but it is still underdiagnosed and undertreated. Research on the pathophysiology of this neurological disease led to the discovery that calcitonin gene-related peptide (CGRP) is a key neuropeptide involved in pain signaling during a migraine attack. CGRP-mediated neuronal sensitization and glutamate-based second- and third-order neuronal signaling may be an important component involved in migraine pain. The activation of several serotonergic receptor subtypes can block the release of CGRP, other neuropeptides, and neurotransmitters, and can relieve the symptoms of migraine. Triptans were the first therapeutics developed for the treatment of migraine, working through serotonin 5-HT1B/1D receptors. The discovery that the serotonin 1F (5-HT1F) receptor was expressed in the human trigeminal ganglion suggested that this receptor subtype may have a role in the treatment of migraine. The 5-HT1F receptor is found on terminals and cell bodies of trigeminal ganglion neurons and can modulate the release of CGRP from these nerves. Unlike 5-HT1B receptors, the activation of 5-HT1F receptors does not cause vasoconstriction. The potency of different serotonergic agonists towards 5-HT1F was correlated in an animal model of migraine (dural plasma protein extravasation model) leading to the development of lasmiditan. Lasmiditan is a newly approved acute treatment for migraine in the United States and is a lipophilic, highly selective 5-HT1F agonist that can cross the blood-brain barrier and act at peripheral nervous system (PNS) and central nervous system (CNS) sites. Lasmiditan activation of CNS-located 5-HT1F receptors (e.g., in the trigeminal nucleus caudalis) could potentially block the release of CGRP and the neurotransmitter glutamate, thus preventing and possibly reversing the development of central sensitization. Activation of 5-HT1F receptors in the thalamus can block secondary central sensitization of this region, which is associated with progression of migraine and extracephalic cutaneous allodynia. The 5-HT1F receptors are also elements of descending pain modulation, presenting another site where lasmiditan may alleviate migraine. There is emerging evidence that mitochondrial dysfunction might be implicated in the pathophysiology of migraine, and that 5-HT1F receptors can promote mitochondrial biogenesis. While the exact mechanism is unknown, evidence suggests that lasmiditan can alleviate migraine through 5-HT1F agonist activity that leads to inhibition of neuropeptide and neurotransmitter release and inhibition of PNS trigeminovascular and CNS pain signaling pathways

Clinical use of amyloid-positron emission tomography neuroimaging: Practical and bioethical considerations

Until recently, estimation of β-amyloid plaque density as a key element for identifying Alzheimer's disease (AD) pathology as the cause of cognitive impairment was only possible at autopsy. Now with amyloid-positron emission tomography (amyloid-PET) neuroimaging, this AD hallmark can be detected antemortem. Practitioners and patients need to better understand potential diagnostic benefits and limitations of amyloid-PET and the complex practical, ethical, and social implications surrounding this new technology. To complement the practical considerations, Eli Lilly and Company sponsored a Bioethics Advisory Board to discuss ethical issues that might arise from clinical use of amyloid-PET neuroimaging with patients being evaluated for causes of cognitive decline. To best address the multifaceted issues associated with amyloid-PET neuroimaging, we recommend this technology be used only by experienced imaging and treating physicians in appropriately selected patients and only in the context of a comprehensive clinical evaluation with adequate explanations before and after the scan

Relationship of Hippocampal Volume to Amyloid Burden across Diagnostic Stages of Alzheimer’s Disease

Aims: To assess how hippocampal volume (HV) from volumetric magnetic resonance imaging (vMRI) is related to the amyloid status at different stages of Alzheimer's disease (AD) and its relevance to patient care. Methods: We evaluated the ability of HV to predict the florbetapir positron emission tomography (PET) amyloid positive/negative status by group in healthy controls (HC, n = 170) and early/late mild cognitive impairment (EMCI, n = 252; LMCI, n = 136), and AD dementia (n = 75) subjects from the Alzheimer's Disease Neuroimaging Initiative Grand Opportunity (ADNI-GO) and ADNI2. Logistic regression analyses, including elastic net classification modeling with 10-fold cross-validation, were used with age and education as covariates. Results: HV predicted amyloid status only in LMCI using either logistic regression [area under the curve (AUC) = 0.71, p < 0.001] or elastic net classification modeling [positive predictive value (PPV) = 72.7%]. In EMCI, age (AUC = 0.70, p < 0.0001) and age and/or education (PPV = 63.1%), but not HV, predicted amyloid status. Conclusion: Using clinical neuroimaging, HV predicted amyloid status only in LMCI, suggesting that HV is not a biomarker surrogate for amyloid PET in clinical applications across the full diagnostic spectrum

Relationship between the Montreal Cognitive Assessment and Mini-mental State Examination for assessment of mild cognitive impairment in older adults.

BackgroundThe Montreal Cognitive Assessment (MoCA) was developed to enable earlier detection of mild cognitive impairment (MCI) relative to familiar multi-domain tests like the Mini-Mental State Exam (MMSE). Clinicians need to better understand the relationship between MoCA and MMSE scores.MethodsFor this cross-sectional study, we analyzed 219 healthy control (HC), 299 MCI, and 100 Alzheimer's disease (AD) dementia cases from the Alzheimer's Disease Neuroimaging Initiative (ADNI)-GO/2 database to evaluate MMSE and MoCA score distributions and select MoCA values to capture early and late MCI cases. Stepwise variable selection in logistic regression evaluated relative value of four test domains for separating MCI from HC. Functional Activities Questionnaire (FAQ) was evaluated as a strategy to separate dementia from MCI. Equi-percentile equating produced a translation grid for MoCA against MMSE scores. Receiver Operating Characteristic (ROC) analyses evaluated lower cutoff scores for capturing the most MCI cases.ResultsMost dementia cases scored abnormally, while MCI and HC score distributions overlapped on each test. Most MCI cases scored ≥ 17 on MoCA (96.3%) and ≥ 24 on MMSE (98.3%). The ceiling effect (28-30 points) for MCI and HC was less using MoCA (18.1%) versus MMSE (71.4%). MoCA and MMSE scores correlated most for dementia (r = 0.86; versus MCI r = 0.60; HC r = 0.43). Equi-percentile equating showed a MoCA score of 18 was equivalent to MMSE of 24. ROC analysis found MoCA ≥ 17 as the cutoff between MCI and dementia that emphasized high sensitivity (92.3%) to capture MCI cases. The core and orientation domains in both tests best distinguished HC from MCI groups, whereas comprehension/executive function and attention/calculation were not helpful. Mean FAQ scores were significantly higher and a greater proportion had abnormal FAQ scores in dementia than MCI and HC.ConclusionsMoCA and MMSE were more similar for dementia cases, but MoCA distributes MCI cases across a broader score range with less ceiling effect. A cutoff of ≥ 17 on the MoCA may help capture early and late MCI cases; depending on the level of sensitivity desired, ≥ 18 or 19 could be used. Functional assessment can help exclude dementia cases. MoCA scores are translatable to the MMSE to facilitate comparison