Utility of Plasma Neurofilament Light in the 1Florida Alzheimer's Disease Research Center (ADRC).

BACKGROUND: Plasma NfL (pNfL) levels are elevated in many neurological disorders. However, the utility of pNfL in a clinical setting has not been established. OBJECTIVE: In a cohort of diverse older participants, we examined: 1) the association of pNfL to age, sex, Hispanic ethnicity, diagnosis, and structural and amyloid imaging biomarkers; and 2) its association to baseline and longitudinal cognitive and functional performance. METHODS: 309 subjects were classified at baseline as cognitively normal (CN) or with cognitive impairment. Most subjects had structural MRI and amyloid PET scans. The most frequent etiological diagnosis was Alzheimer's disease (AD), but other neurological and neuropsychiatric disorders were also represented. We assessed the relationship of pNfL to cognitive and functional status, primary etiology, imaging biomarkers, and to cognitive and functional decline. RESULTS: pNfL increased with age, degree of hippocampal atrophy, and amyloid load, and was higher in females among CN subjects, but was not associated with Hispanic ethnicity. Compared to CN subjects, pNfL was elevated among those with AD or FTLD, but not those with neuropsychiatric or other disorders. Hippocampal atrophy, amyloid positivity and higher pNfL levels each added unique variance in predicting greater functional impairment on the CDR-SB at baseline. Higher baseline pNfL levels also predicted greater cognitive and functional decline after accounting for hippocampal atrophy and memory scores at baseline. CONCLUSION: pNfL may have a complementary and supportive role to brain imaging and cognitive testing in a memory disorder evaluation, although its diagnostic sensitivity and specificity as a stand-alone measure is modest. In the absence of expensive neuroimaging tests, pNfL could be used for differentiating neurodegenerative disease from neuropsychiatric disorders.

Depression and the Diagnosis of MCI in a Culturally Diverse Sample in the United States.

OBJECTIVE: To analyze (1) whether there are ethnic differences in the severity of depressive symptoms between groups of elders classified as cognitively normal (CN) or amnestic mild cognitive impairment (aMCI) and (2) the influence of depressive symptoms on specific cognitive performance by ethnicity across diagnoses, controlling for covariates. METHODS: 164 Hispanics residing in the United States (HAs) and European Americans (EAs) (100 women; Mage = 72.1, SD = 8.0) were diagnosed as either CN or aMCI. Depressive symptoms were measured with the Geriatric Depression Scale (GDS-15). Cognition was assessed using the Loewenstein-Acevedo Scales for Semantic Interference and Learning (semantic memory), Multilingual Naming Test (confrontation naming), and the Stroop Test (Color-Word condition; executive function). A 2 × 2 univariate ANCOVA as well as linear and logistic regressions explored differences in depressive symptoms among diagnostic and ethnic groups. RESULTS: Higher depression was seen in aMCI compared to the CN group for both ethnicities, after controlling for age, education, gender, and Mini-Mental State Examination score. Greater levels of depression also predicted lower scores in confrontation naming and semantic memory for only the EA group and marginally in scores of executive function for HA participants. GDS-15 scores of ≤ 4 also predicted less likelihood of aMCI diagnosis. CONCLUSIONS: Severity of depressive symptoms was associated with greater cognitive impairment, independent of ethnicity. Significant results suggest detrimental effects of depression on clinical diagnoses most evidently for subjects from the EA group.

The Association Between Functional Assessment and Structural Brain Biomarkers in an Ethnically Diverse Sample With Normal Cognition, Mild Cognitive Impairment, or Dementia.

OBJECTIVE: To investigate the association between the functional activities questionnaire (FAQ) and brain biomarkers (bilateral hippocampal volume [HV], bilateral entorhinal volume [ERV], and entorhinal cortical thickness [ERT]) in cognitively normal (CN) individuals, mild cognitive impairment (MCI), or dementia. METHOD: In total, 226 participants (137 females; mean age = 71.76, SD = 7.93; Hispanic Americans = 137; European Americans = 89) were assessed with a comprehensive clinical examination, a neuropsychological battery, a structural magnetic resonance imaging, and were classified as CN or diagnosed with MCI or dementia. Linear regression analyses examined the association between functional activities as measured by the FAQ on brain biomarkers, including HV, ERV, and ERT, controlling for age, education, global cognition, gender, and ethnicity. RESULTS: The FAQ significantly predicted HV, ERV, and ERT for the entire sample. However, this association was not significant for ERV and ERT when excluding the dementia group. The FAQ score remained a significant predictor of HV for the non-dementia group. Age, education, gender, ethnicity, Montreal Cognitive Assessment score, and FAQ were also significant predictors of HV for the overall sample, suggesting that younger Hispanic females with fewer years of education, higher global mental status, and better functioning, were more likely to have larger HV. CONCLUSION: FAQ scores were related to HV in older adults across clinical groups (CN, MCI, and dementia), but its association with the entorhinal cortex was driven by individuals with dementia. Demographic variables, including ethnicity, additionally influenced these associations.

Types of errors on a semantic interference task in mild cognitive impairment and dementia.

OBJECTIVE: This research aimed to determine whether qualitative analysis of different types of intrusion errors on a verbal cognitive task was useful in detecting subtle cognitive impairment in preclinical stages prior to the progression to dementia. METHOD: Different types of semantic intrusions on the Loewenstein-Acevedo Scales of Semantic Interference and Learning (LASSI-L) were compared across 160 individuals diagnosed as cognitively normal (CN), amnestic Mild Cognitive Impairment (aMCI), and dementia. The sample included Hispanics and non-Hispanic European Americans. RESULTS: Across diagnostic groups, the most common type of intrusion error was actual targets presented from a competing word list under conditions eliciting proactive semantic interference (PSI), and retroactive semantic interference (RSI), followed by intrusions that represented one of three overlapping semantic categories but none of the targets from List A or B. Nonsemantic intrusions rarely occurred. These competing list intrusions (CLI) and semantically related intrusions (SRI) differentiated between aMCI and CN participants. Further, these intrusion error were related to brain amyloid load, indicating their importance as potential primary markers of AD-related neurodegeneration. Ethnicity effects were not seen across the types of intrusion errors. CONCLUSIONS: Two types of intrusion errors (CLI and SRI) showed differences between the CN and aMCI group, with the aMCI group evidencing a higher rate of these intrusion errors compared with the CN group. These results support previous literature about the LASSI-L's sensitivity at the earliest stages of abnormal aging. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Effects of Bilingualism on Verbal and Nonverbal Memory Measures in Mild Cognitive Impairment.

OBJECTIVES: Maintaining two active languages may increase cognitive and brain reserve among bilingual individuals. We explored whether such a neuroprotective effect was manifested in the performance of memory tests for participants with amnestic mild cognitive impairment (aMCI). METHODS: We compared 42 bilinguals to 25 monolinguals on verbal and nonverbal memory tests. We used: (a) the Loewenstein-Acevedo Scales for Semantic Interference and Learning (LASSI-L), a sensitive test that taps into proactive, retroactive, and recovery from proactive semantic interference (verbal memory), and (b) the Benson Figure delayed recall (nonverbal memory). A subsample had volumetric MRI scans. RESULTS: The bilingual group significantly outperformed the monolingual group on two LASSI-L cued recall measures (Cued A2 and Cued B2). A measure of maximum learning (Cued A2) showed a correlation with the volume of the left hippocampus in the bilingual group only. Cued B2 recall (sensitive to recovery from proactive semantic interference) was correlated with the volume of the hippocampus and the entorhinal cortex of both cerebral hemispheres in the bilingual group, as well as with the left and right hippocampus in the monolingual group. The memory advantage in bilinguals on these measures was associated with higher inhibitory control as measured by the Stroop Color-Word test. CONCLUSIONS: Our results demonstrated a superior performance of aMCI bilinguals over aMCI monolinguals on selected verbal memory tasks. This advantage was not observed in nonverbal memory. Superior memory performance of bilinguals over monolinguals suggests that bilinguals develop a different and perhaps more efficient semantic association system that influences verbal recall. (JINS, 2019, 25, 15-28).

A Brief Computerized Paired Associate Test for the Detection of Mild Cognitive Impairment in Community-Dwelling Older Adults.

BACKGROUND: Semantic memory interference has been found to be a predictive cognitive marker of incipient AD. This is relevant given that developing assessment paradigms to identify subtle cognitive and functional deficits is a priority in preclinical Alzheimer's disease research. OBJECTIVE: To examine the utility of a novel computerized paired associate test in distinguishing between mild cognitive impairment (MCI) and cognitively normal (CN) groups of older adults residing in the community. METHODS: Participants that were CN (n = 64) or MCI (n = 34) were administered the Miami Test of Semantic Interference and Learning (MITSI-L). This novel instrument is a brief, computerized paired associate test that measured the strength of memory binding of semantically related word pairs and introduced a proactive semantic interference condition which required participants to make different associations between semantically similar targets. A series of ANOVAs explored differences on MITSI-L performance. Logistic regression and receiver operator curves (ROC) analyses were employed to further determine discriminative validity. RESULTS: MCI participants had lower scores on all indices relative to CN elders. A composite of two subscores correctly classified 85.3% of MCI and 84.4% of CN participants. Area under the ROC was higher relative to the MMSE, immediate memory for passages, and several subtests of a sensitive memory measure, the LASSI-L. CONCLUSIONS: The MITSI-L is a computerized test that can successfully differentiate MCI from CN participants. Area under the ROC curve exceeded that of global mental status and other memory measures. The effectiveness of the MITSI-L in detecting MCI, and its brief administration and portability render it worthy of further research.

A Novel Cognitive Stress Test for the Detection of Preclinical Alzheimer Disease: Discriminative Properties and Relation to Amyloid Load.

OBJECTIVE: To examine the utility of a novel "cognitive stress test" to detect subtle cognitive impairments and amyloid load within the brains of neuropsychologically normal community-dwelling elders. METHODS: Participants diagnosed as cognitively normal (CN), subjective memory impairment (SMI), mild cognitive impairment (MCI), and preclinical mild cognitive impairment (PreMCI) were administered the Loewenstein-Acevedo Scale for Semantic Interference and Learning (LASSI-L), a sensitive test of proactive semantic interference (PSI), retroactive semantic interference, and, uniquely, the ability to recover from the effects of PSI. Ninety-three subjects (31 men and 62 women) were recruited from three academic institutions in a research consortium. A subset of these individuals underwent 18F florbetapir positron emission tomography scanning. Relative percentages of impairment for each diagnostic group on the LASSI-L were calculated by χ(2) and Fisher's exact tests. Spearman's rho was used to examine associations between amyloid load and different cognitive measures. RESULTS: LASSI-L deficits were identified among 89% of those with MCI, 47% with PreMCI, 33% with SMI, and 13% classified as CN. CN subjects had no difficulties with recovery from PSI, whereas SMI, preMCI, and MCI participants evidenced deficits in recovery from PSI effects. Among a subgroup of participants with normal scores on traditional neuropsychological tests, the strong associations were between the failure to recover from the effects of PSI and amyloid load in the brain. CONCLUSION: Failure to recover or compensate for the effects of PSI on the LASSI-L distinguishes the LASSI-L from other widely used neuropsychological tests and appears to be sensitive to subtle cognitive impairments and increasing amyloid load.

Proactive Semantic Interference is Associated with Total and Regional Abnormal Amyloid Load in Non-Demented Community-Dwelling Elders: A Preliminary Study.

OBJECTIVE: To evaluate the relationship between susceptibility to proactive semantic interference (PSI) and retroactive semantic interference (RSI) and brain amyloid load in non-demented elders. METHODS: 27 participants (11 cognitively normal [CN] with subjective memory complaints, 8 CN without memory complaints, and 8 with mild cognitive impairment [MCI]) underwent complete neurological and neuropsychological evaluations. Participants also received the Semantic Interference Test (SIT) and AV-45 amyloid PET imaging. RESULTS: High levels of association were present between total amyloid load, regional amyloid levels, and the PSI measure (in the entire sample and a subsample excluding MCI subjects). RSI and other memory measures showed much weaker associations or no associations with total and regional amyloid load. No associations between amyloid levels and non-memory performance were observed. CONCLUSIONS: In non-demented individuals, vulnerability to PSI was highly associated with total and regional beta-amyloid load and may be an early cognitive marker of brain pathology.

The utility of age-specific cut-offs for visual rating of medial temporal atrophy in classifying Alzheimer's disease, MCI and cognitively normal elderly subjects.

BACKGROUND: New research criteria for diagnosing Alzheimer's disease (AD) in the mild cognitive impairment stage (MCI-AD) incorporate biomarkers to assign a level of certainty to the diagnosis. Structural MRI is widely available but greatly under-utilized for assessing atrophy of structures affected in early AD, such as the hippocampus (HP), because the quantification of HP volumes (HP-v) requires special expertise, and normative values have not been established. METHODS: Elderly subjects (n =273) from the Florida ADRC were classified as having no cognitive impairment (cognitively normal, CN), amnestic mild cognitive impairment (aMCI) or AD. Volumes for the hippocampus (HP-v) were measured on structural MRI scans. A validated visual rating system for measuring medial temporal atrophy (VRS-MTA), including hippocampal, entorhinal cortex and perirhinal cortex atrophy was employed. The participants were subdivided into younger (less than or equal to 75 years of age) and older (greater than 75 years of age) subgroups. RESULTS: Volumetric and VRS-MTA measures were equivalent in predicting classification of CN vs. aMCI for older (area under the receiver operator curves [aROC]: 0.652 vs. 0.723) and younger subjects (aROC: 0.764 vs. 0.736). However, for younger AD subjects, aROC values were significantly higher for VRS-MTA measures (0.920) than for volumetric measures (0.847). Relative to HP-v, VRS-MTA score was significantly more correlated to impairment on a range of memory tests and was more associated with progression of aMCI to AD than HP-v. CONCLUSION: Structural MRI with VRS-MTA assessment can serve as a biomarker for supporting the diagnosis of MCI-AD. Age-adjusted VRS-MTA scores are at least as effective as HP-v for distinguishing aMCI and AD from CN and for predicting progression from aMCI to AD. VRS-MTA is convenient for use in the clinic as well as for clinical trials and can readily be incorporated into a standardized radiological report.

Comparing new templates and atlas-based segmentations in the volumetric analysis of brain magnetic resonance images for diagnosing Alzheimer's disease.

BACKGROUND: The segmentation of brain structures on magnetic resonance imaging scans for calculating regional brain volumes, using automated anatomic labeling, requires the use of both brain atlases and templates (template sets). This study aims to improve the accuracy of volumetric analysis of hippocampus (HP) and amygdala (AMG) in the assessment of early Alzheimer's disease (AD) by developing template sets that correspond more closely to the brains of elderly individuals. METHODS: Total intracranial volume and HP and AMG volumes were calculated for elderly subjects with no cognitive impairment (n = 103), with amnestic mild cognitive impairment (n = 68), or with probable AD (n = 46) using the following: (1) a template set consisting of a standard atlas (atlas S), drawn on a young adult male brain, and the widely used Montreal Neurological Institute template (MNI template set); (2) a template set (template S set) in which the template is based on smoothing the image from which atlas S is derived; and (3) a new template set (template E set) in which the template is based on an atlas (atlas E) created from the brain of an elderly individual. RESULTS: Correspondence to HP and AMG volumes derived from manual segmentation was highest with automated segmentation by template E set, intermediate with template S set, and lowest with the MNI template set. The areas under the receiver operating curve for distinguishing elderly subjects with no cognitive impairment from elderly subjects with amnestic mild cognitive impairment or probable AD and the correlations between HP and AMG volumes and cognitive and functional scores were highest for template E set, intermediate for template S set, and lowest for the MNI template set. CONCLUSIONS: The accuracy of automated anatomic labeling and the diagnostic value of the derived volumes are improved with template sets based on brain atlases closely resembling the anatomy of the to-be-segmented brain magnetic resonance imaging scans.

An investigation of PreMCI: subtypes and longitudinal outcomes.

BACKGROUND/AIMS: To investigate the clinical features and rates of progression of conditions that are not considered to be normal, but do not fulfill criteria for mild cognitive impairment (MCI). METHODS: We longitudinally evaluated 269 elderly subjects who did not meet formal criteria for MCI at baseline but had: (1) a clinical history suggesting MCI without neuropsychological deficits (PreMCI-Clinical); or (2) neuropsychological deficits on one or more memory measures in conjunction with a negative clinical examination (amnestic PreMCI-NP) or were normal on both neuropsychological and clinical examination. RESULTS: The rate of progression to MCI or dementia over an average of 2- to 3 years was 3.7% for no cognitive impairment subjects, whereas it was significantly greater for all PreMCI subtypes (22.0% for PreMCI-Clinical, 38.9% for amnestic PreMCI-NP subjects with two or more memory impairments). Among PreMCI subjects as a whole, lower baseline scores on object memory and category fluency tests were the best predictors of progression to MCI or dementia. Cardiovascular risk factors, Parkinsonian symptoms, and hippocampal atrophy were not associated with progression. CONCLUSION: Distinct PreMCI subtypes defined on the basis of clinical and neuropsychological evaluations were found to have distinct characteristics, but both subtypes demonstrated elevated risk for progression to MCI or dementia. Despite the lack of evidence of clinical impairment, subjects with neuropsychological deficits in two memory domains were particularly at increased risk for progression of their deficits.

Volumetric and visual rating of magnetic resonance imaging scans in the diagnosis of amnestic mild cognitive impairment and Alzheimer's disease.

BACKGROUND: In the diagnosis of Alzheimer's disease (AD), structural magnetic resonance imaging (MRI) scans have been used primarily to exclude non-Alzheimer's causes of dementia. However, the pattern and the extent of medial temporal atrophy on structural MRI scans, which correlate strongly with the pathological severity of AD, can be used to support the diagnosis of a degenerative dementia, especially AD, even in its early predementia stage. METHODS: Elderly subjects (n = 224) were diagnosed with either no cognitive impairment (NCI), amnestic mild cognitive impairment (aMCI), or AD. Hippocampal and hemispheric gray matter volumes were measured on structural MRI scans, and a new visual rating system was used to score the severity of medial temporal atrophy (VRS-MTA) of the hippocampus (HPC), entorhinal cortex, and perirhinal cortex on a coronal image intersecting the mammillary bodies. RESULTS: Although both VRS-MTA scores and HPC volumes distinguished between subjects with NCI, aMCI, and AD, subjects with aMCI and NCI could be better distinguished using right VRS-MTA scores, in comparison with right HPC volumes. VRS-MTA scores were more highly correlated with episodic memory and Clinical Dementia Rating scores. A combination of left sided VRS-MTA scores and left sided hippocampal volume was the most predictive measure of diagnostic classification. CONCLUSION: VRS-MTA is a clinically convenient method or distinguishing aMCI or AD from NCI. As compared with volumetric measures, it provides better discriminatory power and correlates more strongly with memory and functional scores.

Minimal atrophy of the entorhinal cortex and hippocampus: progression of cognitive impairment.

BACKGROUND: In Alzheimer's disease, neurodegenerative atrophy progresses from the entorhinal cortex (ERC) to the hippocampus (HP), limbic system and neocortex. The significance of very mild atrophy of the ERC and HP on MRI scans among elderly subjects is unknown. METHODS: A validated visual rating system on coronal MRI scans was used to identify no atrophy of the HP or ERC (HP(0); ERC(0)), or minimal atrophy of the HP or ERC (HP(ma); ERC(ma)), among 414 participants. Subjects fell into the following groups: (1) ERC(0)/HP(0), (2) ERC(ma)/HP(0), (3) ERC(0)/HP(ma), and (4) ERC(ma)/HP(ma). HP volume was independently measured using volumetric methods. RESULTS: In comparison to ERC(0)/HP(0) subjects, those with ERC(0)/HP(ma) had impairment on 1 memory test, ERC(ma)/HP(0) subjects had impairment on 2 memory tests and the Mini Mental State Examination (MMSE), while ERC(ma)/HP(ma) subjects had impairment on 3 memory tests, the MMSE and Clinical Dementia Rating. Progression rates of cognitive and functional impairment were significantly greater among subjects with ERC(ma). CONCLUSION: Minimal atrophy of the ERC results in greater impairment than minimal atrophy of the HP, and the combination is additive when measured by cognitive and functional tests. Rates of progression to greater impairment were higher among ERC(ma) subjects.

Pre-MCI and MCI: neuropsychological, clinical, and imaging features and progression rates.

OBJECTIVE: To compare clinical, imaging, and neuropsychological characteristics and longitudinal course of subjects with pre-mild cognitive impairment (pre-MCI), who exhibit features of MCI on clinical examination but lack impairment on neuropsychological examination, to subjects with no cognitive impairment (NCI), nonamnestic MCI (naMCI), amnestic MCI (aMCI), and mild dementia. METHODS: For 369 subjects, clinical dementia rating sum of boxes (CDR-SB), ApoE genotyping, cardiovascular risk factors, parkinsonism (UPDRS) scores, structural brain MRIs, and neuropsychological testing were obtained at baseline, whereas 275 of these subjects received an annual follow-up for 2-3 years. RESULTS: At baseline, pre-MCI subjects showed impairment on tests of executive function and language, higher apathy scores, and lower left hippocampal volumes (HPCV) in comparison to NCI subjects. Pre-MCI subjects showed less impairment on at least one memory measure, CDR-SB and UPDRS scores, in comparison to naMCI, aMCI and mild dementia subjects. Follow-up over 2-3 years showed 28.6% of pre-MCI subjects, but less than 5% of NCI subjects progressed to MCI or dementia. Progression rates to dementia were equivalent between naMCI (22.2%) and aMCI (34.5%) groups, but greater than for the pre-MCI group (2.4%). Progression to dementia was best predicted by the CDR-SB, a list learning and executive function test. CONCLUSION: This study demonstrates that clinically defined pre-MCI has cognitive, functional, motor, behavioral and imaging features that are intermediate between NCI and MCI states at baseline. Pre-MCI subjects showed accelerated rates of progression to MCI as compared to NCI subjects, but slower rates of progression to dementia than MCI subjects.

A comparative analysis of structural brain MRI in the diagnosis of Alzheimer's disease.

Dementia is a debilitating and life-altering disease which leads to both memory impairment and decline of normal executive functioning. While causes of dementia are numerous and varied, the leading cause among patients 60 years and older is Alzheimer's disease. The gold standard for Alzheimer's diagnosis remains histological identification of amyloid plaques and neurofibrillary tangles within the medial temporal lobe, more specifically the entorhinal cortex and hippocampus. Although no definitive cure for Alzheimer's disease currently exists, there are treatments targeted at preserving cognition and memory while delaying continued loss of function. Alzheimer's disease exists along a spectrum of cognitive decline and is often preceded by Mild Cognitive Impairment (MCI). Patients with MCI demonstrate memory loss and cognitive impairment while still continuing normal activities of daily living, and are considered to be at increased risk for developing Alzheimer's Dementia. Identifying patients with prodromal states of Alzheimer's dementia such as MCI may allow initiation of appropriate treatment planning and delay of cognitive decline. Therefore, the need for a non-invasive early biomarker for the detection of Alzheimer's disease has never been greater. Multiple neuroimaging methods utilizing visual rating scales, volumetric measurements, and automated methods have been developed to identify, quantify, and track anatomic sequelae of Alzheimer's Disease.

Severity of medial temporal atrophy and amnestic mild cognitive impairment: selecting type and number of memory tests.

OBJECTIVE: Medial temporal lobe atrophy (MTA) can be used as a biomarker of pathology that affects mechanisms of episodic memory. The authors compared the strength of this biomarker with performance on four memory measures and examined the influence of demographic factors including age, level of education, and primary language (English or Spanish). METHODS: The Hopkins Verbal Learning Test-revised, Fuld Object Memory Evaluation (FOME), delayed memory for a story passage, and delayed visual reproduction of the Wechsler Memory Scale-revised tests were administered to 281 subjects who were diagnosed as having no cognitive impairment, mild cognitive impairment (MCI), impaired non-MCI, or dementia. MTA scores were obtained from visual ratings of the hippocampus, entorhinal cortex, and perirhinal cortex on coronal magnetic resonance imaging scans using a magnetization-prepared rapid gradient echo protocol. RESULTS: Age was associated with scores on all memory measures and MTA. Level of educational attainment had no influence on FOME performance but had greater associations with scores on other memory measures. In regression models, FOME scores had the strongest relationship with MTA scores, accounting for 31% of the explained variability. Among subjects with MCI, an index representing the total number of memory tests that were impaired was also predictive of the severity of MTA scores. CONCLUSION: Among four common tests of memory, the FOME was highly associated with MTA, and it exhibited minimal influences of education. Impairment on more than one memory test was more predictive of MTA than impairment on a single memory test.