ATN cerebrospinal fluid biomarkers in dementia with Lewy bodies: Initial results from the United States Dementia with Lewy Bodies Consortium.

INTRODUCTION: The National Institute on Aging - Alzheimer's Association (NIA-AA) ATN research framework proposes to use biomarkers for amyloid (A), tau (T), and neurodegeneration (N) to stage individuals with AD pathological features and track changes longitudinally. The overall aim was to utilize this framework to characterize pre-mortem ATN status longitudinally in a clinically diagnosed cohort of dementia with Lewy bodies (DLB) and to correlate it with the post mortem diagnosis. METHODS: The cohort was subtyped by cerebrospinal fluid (CSF) ATN category. A subcohort had longitudinal data, and a subgroup was neuropathologically evaluated. RESULTS: We observed a significant difference in Aß42/40 after 12 months in the A+T- group. Post mortem neuropathologic analyses indicated that most of the p-Tau 181 positive (T+) cases also had a high Braak stage. DISCUSSION: This suggests that DLB patients who are A+ but T- may need to be monitored to determine whether they remain A+ or ever progress to T positivity. HIGHLIGHTS: Some A+T- DLB subjects transition from A+ to negative after 12-months. Clinically diagnosed DLB with LBP-AD (A+T+) maintain their positivity. Clinically diagnosed DLB with LBP-AD (A+T+) maintain their positivity. Monitoring of the A+T- sub-type of DLB may be necessary.

Plasma inflammation for predicting phenotypic conversion and clinical progression of autosomal dominant frontotemporal lobar degeneration.

BACKGROUND: Measuring systemic inflammatory markers may improve clinical prognosis and help identify targetable pathways for treatment in patients with autosomal dominant forms of frontotemporal lobar degeneration (FTLD). METHODS: We measured plasma concentrations of IL-6, TNFα and YKL-40 in pathogenic variant carriers (MAPT, C9orf72, GRN) and non-carrier family members enrolled in the ARTFL-LEFFTDS Longitudinal Frontotemporal Lobar Degeneration consortium. We evaluated associations between baseline plasma inflammation and rate of clinical and neuroimaging changes (linear mixed effects models with standardised (z) outcomes). We compared inflammation between asymptomatic carriers who remained clinically normal ('asymptomatic non-converters') and those who became symptomatic ('asymptomatic converters') using area under the curve analyses. Discrimination accuracy was compared with that of plasma neurofilament light chain (NfL). RESULTS: We studied 394 participants (non-carriers=143, C9orf72=117, GRN=62, MAPT=72). In MAPT, higher TNFα was associated with faster functional decline (B=0.12 (0.02, 0.22), p=0.02) and temporal lobe atrophy. In C9orf72, higher TNFα was associated with faster functional decline (B=0.09 (0.03, 0.16), p=0.006) and cognitive decline (B=-0.16 (-0.22, -0.10), p<0.001), while higher IL-6 was associated with faster functional decline (B=0.12 (0.03, 0.21), p=0.01). TNFα was higher in asymptomatic converters than non-converters (ß=0.29 (0.09, 0.48), p=0.004) and improved discriminability compared with plasma NfL alone (ΔR2=0.16, p=0.007; NfL: OR=1.4 (1.03, 1.9), p=0.03; TNFα: OR=7.7 (1.7, 31.7), p=0.007). CONCLUSIONS: Systemic proinflammatory protein measurement, particularly TNFα, may improve clinical prognosis in autosomal dominant FTLD pathogenic variant carriers who are not yet exhibiting severe impairment. Integrating TNFα with markers of neuronal dysfunction like NfL could optimise detection of impending symptom conversion in asymptomatic pathogenic variant carriers and may help personalise therapeutic approaches.

Comprehensive cross-sectional and longitudinal analyses of plasma neurofilament light across FTD spectrum disorders.

Frontotemporal dementia (FTD) therapy development is hamstrung by a lack of susceptibility, diagnostic, and prognostic biomarkers. Blood neurofilament light (NfL) shows promise as a biomarker, but studies have largely focused only on core FTD syndromes, often grouping patients with different diagnoses. To expedite the clinical translation of NfL, we avail ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study resources and conduct a comprehensive investigation of plasma NfL across FTD syndromes and in presymptomatic FTD mutation carriers. We find plasma NfL is elevated in all studied syndromes, including mild cases; increases in presymptomatic mutation carriers prior to phenoconversion; and associates with indicators of disease severity. By facilitating the identification of individuals at risk of phenoconversion, and the early diagnosis of FTD, plasma NfL can aid in participant selection for prevention or early treatment trials. Moreover, its prognostic utility would improve patient care, clinical trial efficiency, and treatment outcome estimations.

Fluid and Tissue Biomarkers of Lewy Body Dementia: Report of an LBDA Symposium.

The Lewy Body Dementia Association (LBDA) held a virtual event, the LBDA Biofluid/Tissue Biomarker Symposium, on January 25, 2021, to present advances in biomarkers for Lewy body dementia (LBD), which includes dementia with Lewy bodies (DLBs) and Parkinson's disease dementia (PDD). The meeting featured eight internationally known scientists from Europe and the United States and attracted over 200 scientists and physicians from academic centers, the National Institutes of Health, and the pharmaceutical industry. Methods for confirming and quantifying the presence of Lewy body and Alzheimer's pathology and novel biomarkers were discussed.

Classification of Alzheimer's Disease, Mild Cognitive Impairment and Normal Control Subjects Using Resting-State fMRI Based Network Connectivity Analysis.

This paper proposes a robust method for the Alzheimer's disease (AD), mild cognitive impairment (MCI), and normal control subject classification under size limited fMRI data samples by exploiting the brain network connectivity pattern analysis. First, we select the regions of interest (ROIs) within the default mode network and calculate the correlation coefficients between all possible ROI pairs to form a feature vector for each subject. Second, we propose a regularized linear discriminant analysis (LDA) approach to reduce the noise effect due to the limited sample size. The feature vectors are then projected onto a one-dimensional axis using the proposed regularized LDA. Finally, an AdaBoost classifier is applied to carry out the classification task. The numerical analysis demonstrates that the purposed approach can increase the classification accuracy significantly. Our analysis confirms the previous findings that the hippocampus and the isthmus of the cingulate cortex are closely involved in the development of AD and MCI.

Corrigendum: Obesity and Co-morbid Conditions Are Associated with Specific Neuropsychiatric Symptoms in Mild Cognitive Impairment.

[This corrects the article on p. 164 in vol. 9, PMID: 28611655.].

Altered Behavioral and Autonomic Pain Responses in Alzheimer's Disease Are Associated with Dysfunctional Affective, Self-Reflective and Salience Network Resting-State Connectivity.

While pain behaviors are increased in Alzheimer's disease (AD) patients compared to healthy seniors (HS) across multiple disease stages, autonomic responses are reduced with advancing AD. To better understand the neural mechanisms underlying these phenomena, we undertook a controlled cross-sectional study examining behavioral (Pain Assessment in Advanced Dementia, PAINAD scores) and autonomic (heart rate, HR) pain responses in 24 HS and 20 AD subjects using acute pressure stimuli. Resting-state fMRI was utilized to investigate how group connectivity differences were related to altered pain responses. Pain behaviors (slope of PAINAD score change and mean PAINAD score) were increased in patients vs. CONTROLS: Autonomic measures (HR change intercept and mean HR change) were reduced in severe vs. mildly affected AD patients. Group functional connectivity differences associated with greater pain behavior reactivity in patients included: connectivity within a temporal limbic network (TLN) and between the TLN and ventromedial prefrontal cortex (vmPFC); between default mode network (DMN) subcomponents; between the DMN and ventral salience network (vSN). Reduced HR responses within the AD group were associated with connectivity changes within the DMN and vSN-specifically the precuneus and vmPFC. Discriminant classification indicated HR-related connectivity within the vSN to the vmPFC best distinguished AD severity. Thus, altered behavioral and autonomic pain responses in AD reflects dysfunction of networks and structures subserving affective, self-reflective, salience and autonomic regulation.

Obesity and Co-morbid Conditions Are Associated with Specific Neuropsychiatric Symptoms in Mild Cognitive Impairment.

Background: Neuropsychiatric symptoms (NPSs) in MCI, and midlife obesity increase the likelihood of developing Alzheimer's disease. It is unknown whether obesity or related health conditions modify the risk of NPS or severity of cognitive impairment in MCI. Methods: One hundred and thirteen subjects with MCI were assessed near the time of MCI diagnosis. The sample was divided by BMI and related disorders, type-2 diabetes (T2D) and obstructive sleep apnea (OSA) to measure the relationship of these groups with NPS and severity of MCI. NPSs scores were evaluated based on the Neuropsychiatric Inventory-Questionnaire (NPI-Q) and Geriatric Depression Scale, along with NPI-Q clusters. MCI-severity was estimated based on a composite z-score of neuropsychological tests. Results: Obese and overweight subjects represented 65% of the sample and were on average 7 years younger than normal weight subjects. The presence of obesity, T2D and OSA status modified the prevalence and severity of specific NPI-Q symptom clusters, specifically affective symptoms were more frequent across groups and severe in OB and T2D. Total NPS scores were higher for subjects with T2D and OSA although MCI-severity did not differ across groups. Conclusion: MCI subjects with obesity, T2D and OSA demonstrated a higher susceptibility to psychopathologic changes.

The effect of ß-amyloid positivity on cerebral metabolism in cognitively normal seniors.

INTRODUCTION: We evaluated the effect of cerebral amyloid-ß (Aß) deposition in cognitively normal (CN) seniors on regional metabolism of specific brain regions known to be affected by p-tau deposition. METHODS: Fluorodeoxyglucose positron emission tomography (FDG-PET), volumetric magnetic resonance imaging scans, and global amyloid standardized uptake value ratios (SUVr) were obtained for 210 CNs from the Alzheimer's Disease Neuroimaging Initiative-2 (ADNI2). Region of interest (ROI) extraction was used to obtain functional SUVr from six bilateral ROIs: amygdala (AM), entorhinal cortex (EC), hippocampus, lateral orbitofrontal, posterior cingulate (PC), and middle temporal gyrus. Every metabolic SUVr set was averaged and analyzed against the corresponding subject's amyloid SUVr. Correlation analyses were conducted on the full group and between APOE ε4-positive and APOE ε4-negative subgroups. RESULTS: The APOE ε4+ group exhibited significantly higher metabolism in the EC (r = 0.270, P = .038) and AM (r = 0.267, P = .041). When a significance of the difference test was conducted between the APOE ε4+ and APOE ε4-groups, these same regions remained significant: P = .012 and P = .016, respectively. By contrast, the APOE ε4 group displayed only the conventionally expected result of reduced regional metabolism in the PC (r = -0.161, P = .048), with higher Aß load. CONCLUSIONS: The effect of amyloid positivity on brain metabolism is regionally specific, and APOE ε4 status substantially modulates regional glucose uptake in these regions. The APOE ε4 allele may cause earlier emergence of clinical symptoms in AD via a mechanism that influences regional metabolic demand in specifically those regions where p-tau deposition is known to occur earliest.

Predicting Progression from Mild Cognitive Impairment to Alzheimer's Dementia Using Clinical, MRI, and Plasma Biomarkers via Probabilistic Pattern Classification.

BACKGROUND: Individuals with mild cognitive impairment (MCI) have a substantially increased risk of developing dementia due to Alzheimer's disease (AD). In this study, we developed a multivariate prognostic model for predicting MCI-to-dementia progression at the individual patient level. METHODS: Using baseline data from 259 MCI patients and a probabilistic, kernel-based pattern classification approach, we trained a classifier to distinguish between patients who progressed to AD-type dementia (n = 139) and those who did not (n = 120) during a three-year follow-up period. More than 750 variables across four data sources were considered as potential predictors of progression. These data sources included risk factors, cognitive and functional assessments, structural magnetic resonance imaging (MRI) data, and plasma proteomic data. Predictive utility was assessed using a rigorous cross-validation framework. RESULTS: Cognitive and functional markers were most predictive of progression, while plasma proteomic markers had limited predictive utility. The best performing model incorporated a combination of cognitive/functional markers and morphometric MRI measures and predicted progression with 80% accuracy (83% sensitivity, 76% specificity, AUC = 0.87). Predictors of progression included scores on the Alzheimer's Disease Assessment Scale, Rey Auditory Verbal Learning Test, and Functional Activities Questionnaire, as well as volume/cortical thickness of three brain regions (left hippocampus, middle temporal gyrus, and inferior parietal cortex). Calibration analysis revealed that the model is capable of generating probabilistic predictions that reliably reflect the actual risk of progression. Finally, we found that the predictive accuracy of the model varied with patient demographic, genetic, and clinical characteristics and could be further improved by taking into account the confidence of the predictions. CONCLUSIONS: We developed an accurate prognostic model for predicting MCI-to-dementia progression over a three-year period. The model utilizes widely available, cost-effective, non-invasive markers and can be used to improve patient selection in clinical trials and identify high-risk MCI patients for early treatment.

Effects of Alzheimer Disease on the Facial Expression of Pain.

OBJECTIVES: Facial expression may be a surrogate marker of pain in Alzheimer disease (AD) when self-report of pain is compromised. Recent studies have demonstrated increased pain sensitivity in AD; however, experimental pain studies analyzing facial expressions in AD are limited and report inconsistent results. The aims of this study were to examine facial expression of pain in AD patients and its relationship to sum-scored measures of multiple pain behavioral domains and subjective pain ratings. MATERIALS AND METHODS: The Facial Action Coding System (FACS) was used to characterize facial expressions in 35 AD patients and 33 healthy seniors during pressure algometry. To improve pain specificity, facial responses were categorized as pain-relevant or pain-irrelevant before group analyses. We also assessed the relationship of AD severity to differential facial responsiveness by correlating FACS-based results with clinical pain scales (portions of the Pain Assessment in Advanced Dementia scale and the Faces Pain Scale-Revised [FPS-R]). RESULTS: No significant relationship was found between AD severity and FACS scores. Pain-relevant, but not irrelevant, FACS scores were increased in AD patients compared with seniors without AD. Pain Assessment in Advanced Dementia scale stimulus-response slopes were correlated with those of pain-relevant FACS and FPS-R in both the groups. Pain-relevant FACS slopes showed no relationship with those of the FPS-R in either group. DISCUSSION: Pain sensitivity is increased across all severities of AD when measured using the FACS. Clinical observational pain scales support the relevance of facial expression as a partial compensatory pain communication modality for AD. However, measures of pain behavior that sum across objective coding of several domains provide a better indicator of subjective pain than measures of facial expression alone.

Autonomic, Behavioral, and Subjective Pain Responses in Alzheimer's Disease.

OBJECTIVE: To compare autonomic, behavioral, and subjective pain responses of patients with Alzheimer's disease (AD) to those of healthy seniors (HS). As few studies have examined patients with severe Alzheimer's disease (sAD), we emphasized inclusion of these patients together with mild/moderate Alzheimer's disease (mAD) patients to characterize pain responses potentially affected by disease severity. DESIGN: A controlled cross-sectional study involving repeated measures behavioral pain testing. SETTING: An outpatient clinical setting and local nursing facilities. SUBJECTS: Community dwelling HS controls (N = 33) and individuals with chart-confirmed diagnoses of AD (N = 38, Diagnostic and Statistical Manual-IV criteria). METHODS: HS and AD groups were compared in their responses to repeated applications of five pressure intensities (1-5 kg) on the distal forearm. Autonomic responses (heart rate [HR]), pain behaviors (vocal, facial, and bodily as scored by the Pain Assessment in Advanced Dementia [PAINAD] scale), and subjective pain ratings (Faces Pain Scale-Revised) were measured. RESULTS: HR responses to pressure stimuli were differentially affected based on AD severity: sAD patients had generally decreased HR reactivity compared with other groups (P < 0.01). In contrast, pain behaviors were increased in AD regardless of severity (P < 0.001), compared with HS, for all but the lowest pressure intensity. Increased behaviors occurred in all measured domains of the PAINAD (P < 0.005). While sAD were unreliable subjective reporters, mAD patients (N = 17) rated low level pressures as more painful than HS (P < 0.01). CONCLUSION: These findings provide behavioral and subjective-report evidence of increased acute pain sensitivity in AD, which should be taken into consideration with respect to pain management across the spectrum of AD severity.

Alzheimer's disease and amnestic mild cognitive impairment weaken connections within the default-mode network: a multi-modal imaging study.

We applied a multi-modal imaging approach to examine structural and functional alterations in the default-mode network (DMN) that are associated with Alzheimer's disease (AD) and amnestic mild cognitive impairment (aMCI), a transitional phase between healthy cognitive aging and dementia. Subjects included 10 patients with probable AD, 11 patients with aMCI, and 12 age- and education-matched normal controls (NC). Whole-brain resting-state functional, diffusion-weighted, and volumetric magnetic resonance imaging (MRI) data as well as 18F-fluorodeoxyglucose-based positron emission tomography (FDG-PET) data were acquired. We carried out resting-state functional MRI-based functional connectivity and diffusion MRI-based structural connectivity analyses using isthmus of the cingulate cortex (ICC) and the subjacent white matter as the seeds. Whole-brain group and region of interest-based analyses demonstrated that AD weakens the structural and functional connections between ICC and other regions within the DMN, consistent with regional reduction of metabolic activity and atrophy within the DMN. A progressive weakening trend of these connections was also observed from NC to aMCI and then AD, although significant differences between aMCI and the other two groups were not found. Overall, based on both FDG-PET and MRI results, the DMN appears to serve as a window to understanding structural and functional brain changes associated with AD and aMCI.

Disruption of limbic white matter pathways in mild cognitive impairment and Alzheimer's disease: a DTI/FDG-PET study.

BACKGROUND: Alzheimer's disease (AD) and mild cognitive impairment (MCI) affect the limbic system, causing medial temporal lobe (MTL) atrophy and posterior cingulate cortex (PCC) hypometabolism. Additionally, diffusion tensor imaging (DTI) studies have demonstrated that MCI and AD involve alterations in cerebral white matter (WM) integrity. OBJECTIVES: To test if (1) patients with MCI and AD exhibit decreases in the integrity of limbic WM pathways; (2) disconnection between PCC and MTL, manifested as disruption of the cingulum bundle, contributes to PCC hypometabolism during incipient AD. METHODS: We measured fractional anisotropy (FA) and volume of the fornix and cingulum using DTI in 23 individuals with MCI, 21 with mild-to-moderate AD, and 16 normal control (NC) subjects. We also measured PCC metabolism using (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) in AD and MCI patients. RESULTS: Fornix FA and volume were reduced in MCI and AD to a similar extent. Descending cingulum FA was reduced in AD while volume was reduced in MCI and even more so in AD. Both FA and volume of the fornix and descending cingulum reliably discriminated between NC and AD. Fornix FA and descending cingulum volume also reliably discriminated between NC and MCI. Only descending cingulum volume reliably discriminated between MCI and AD. In the combined MCI-AD cohort, PCC metabolism directly correlated with both FA and volume of the descending cingulum. CONCLUSIONS: Disruption of limbic WM pathways is evident during both MCI and AD. Disconnection of the PCC from MTL at the cingulum bundle contributes to PCC hypometabolism during incipient AD.

Preservation of the capacity to appoint a proxy decision maker: implications for dementia research.

CONTEXT: Research involving persons with impaired decision-making capacity (such as persons with Alzheimer disease [AD]) remains ethically challenging, especially when the research involves significant risk. If individuals incapable of consenting to research studies were able to appoint a research proxy, it would allow for an appointed surrogate (rather than a de facto surrogate) to represent the subject. OBJECTIVE: To assess the extent to which persons with AD retain their capacity to appoint a research proxy. DESIGN: Interview study. SETTING: Academic research. PARTICIPANTS: One hundred eighty-eight persons with AD were interviewed for their capacity to appoint a proxy for research and to provide consent to 2 hypothetical research scenarios, a lower-risk randomized clinical trial testing a new drug (drug RCT) and a higher-risk randomized clinical trial testing neurosurgical cell implants using a sham control condition (neurosurgical RCT). Categorical capacity status for each subject was determined by independent videotaped reviews of capacity interviews by 5 experienced psychiatrists. MAIN OUTCOME MEASURES: Categorical capacity determinations for the capacity to appoint a research proxy, capacity to consent to a drug RCT, and capacity to consent to a neurosurgical RCT. RESULTS: Data showed that 37.7% (40 of 106) of those deemed incapable of consenting to the drug RCT and 54.8% (86 of 157) of those deemed incapable of consenting to the neurosurgical RCT were found capable of appointing a research proxy. Only 7 of 186 (3.8%) were deemed capable of consenting to the neurosurgical RCT by all 5 psychiatrists. CONCLUSIONS: A substantial proportion of persons with AD who were thought incapable of consenting to lower-risk or higher-risk studies have preserved capacity for appointing a research proxy. Because few persons are found to be unequivocally capable of providing independent consent to higher-risk AD research, providing for an appointed surrogate even after the onset of AD, which might best be done in the early stages of the illness, may help address key ethical challenges to AD research.

The existence of cognitive plateaus in Alzheimer's disease.

BACKGROUND: The objective of this study was to evaluate the existence of cognitive plateaus in some individuals during the course of Alzheimer's disease (AD). METHODS: Data came from the historical patient group collected via the Consortium to Establish a Registry for Alzheimer's Disease (CERAD, Duke University, 1988-1996). Data reduction was performed by using principal components analysis to derive a single cognitive measure (F1), followed by application of a novel plateau-searching algorithm to individual patient data, looking for stable periods of 3 years or longer. To evaluate the time dependence of F1, we fitted a linear mixed model to the group and to individual data points. RESULTS: Twenty-two percent of AD subjects (54/243) and 98% of healthy control subjects (253/258) exhibited a plateau. Within the AD plateau group, the most common pattern was a single plateau (mean, 3.6 years; range, 3 to 7 years) that extended for the entire measurement period (28/54 subjects). Briefer plateau durations were seen at the beginning or end of the measurement period. Initial cognitive function (F1) was slightly higher in the plateau group, which was also slightly older and less well-educated. Men and women were equally represented. CONCLUSIONS: In a patient sample predating the widespread use of cholinesterase inhibitors, we found that approximately one fifth of individuals with AD demonstrated periods of prolonged cognitive stability. This significant interindividual variability must be considered when providing prognostic information to families and when assessing individual patient responses to pharmacotherapy. We advise caution when assessing results of potentially disease-modifying agents at the individual patient level.

Frontotemporal lobar degeneration insights from neuropsychology and neuroimaging.

Frontotemporal lobar degeneration (FTLD) is a diagnostic term that encompasses three distinctly different syndromes, united by historic as well as pathologic commonalities. We briefly review the origins of the current classification scheme for diagnosing the three major subtypes--frontotemporal dementia, semantic dementia, and primary progressive aphasia, highlighting the differences between subtypes as well as from Alzheimer's disease (AD). We briefly examine current understanding regarding the histopathology and genetics of FTLD but note that there is a poor correspondence of these features with specific subtypes of FTLD. For clinicians and clinical researchers, this implicates the need for other diagnostic strategies. Neuropsychological and neurobehavioral testing currently offers the most sensitive and specific method for identifying subtypes, and discriminating FTLD from other forms of dementia. Multiple studies from the relevant literature are reviewed, highlighting those findings that are likely to be most valuable to physicians. Finally, we analyze some of the major findings from the large body of work on neuroimaging of FTLD, again focusing on those studies that potentially help discriminate FTLD subtypes or assist with the discrimination of FTLD from AD.