The Association Between Plasma Amyloid-ß 42/40 and Percentage of Semantic Intrusion Errors in Mild Cognitive Impairment.

Background: Semantic intrusion errors (SIEs) are both sensitive and specific to PET amyloid-ß (Aß) burden in older adults with amnestic mild cognitive impairment (aMCI). Objective: Plasma Aß biomarkers including the Aß42/40 ratio using mass spectrometry are expected to become increasingly valuable in clinical settings. Plasma biomarkers are more clinically informative if linked to cognitive deficits that are salient to Alzheimer's disease (AD). Methods: This study included 119 older adults enrolled in the 1Florida Alzheimer's Disease Research Center (ADRC), 45 aMCI participants scored below the established Aß42/40 ratio cut-off of 0.160 using the Quest AD-Detect™ assay indicating Aß positivity (Aß+), while 50 aMCI participants scored above this cut-off indicating Aß negative status (Aß-). Additionally, 24 cognitively unimpaired (CU) persons scored above the cut-off of 0.160 (Aß-). Results: The aMCI plasma Aß+ group evidenced the greatest percentage of SIEs, followed by the aMCI Aß-. The CU Aß- group exhibited the lowest percentage of SIEs. After adjustment for global cognitive impairment, aMCI plasma Aß+ continued to demonstrate greater SIEs on tests tapping the failure to recover from proactive semantic interference (frPSI) as compared to the aMCI Aß-group. Using pre-established cut-offs for frPSI impairment, 8.3% of CU Aß- participants evidenced deficits, compared to 37.8% of aMCI Aß-, and 74.0% of aMCI Aß+. Conclusions: SIEs reflecting frPSI were associated with aMCI Aß+ status based on the Aß42/40 ratio. Results suggest the importance of SIEs as salient cognitive markers that map onto underlying AD pathology in the blood.

Functional and free-water imaging in rapid eye movement behaviour disorder and Parkinson's disease.

It is established that one of the best predictors of a future diagnosis of Parkinson's disease is a current diagnosis of rapid eye movement behaviour disorder (RBD). In such patients, this provides a unique opportunity to study brain physiology and behavioural motor features of RBD that may precede early-stage Parkinson's disease. Based on prior work in early-stage Parkinson's disease, we aim to determine if the function of corticostriatal and cerebellar regions are impaired in RBD using task-based functional MRI and if structural changes can be detected within the caudate, putamen and substantia nigra in RBD using free-water imaging. To assess motor function, we measured performance on the Purdue Pegboard Test, which is affected in patients with RBD and Parkinson's disease. A cohort of 24 RBD, 39 early-stage Parkinson's disease and 25 controls were investigated. All participants were imaged at 3 Telsa. Individuals performed a unimanual grip force task during functional imaging. Participants also completed scales to assess cognition, sleep and motor symptoms. We found decreased functional activity in both RBD and Parkinson's disease within the motor cortex, caudate, putamen and thalamus compared with controls. There was elevated free-water-corrected fractional anisotropy in the putamen in RBD and Parkinson's disease and elevated free-water in the putamen and posterior substantia nigra in Parkinson's disease compared with controls. Participants with RBD and Parkinson's disease performed significantly worse on all tasks of the Purdue Pegboard Test compared with controls. The both hands task of the Purdue Pegboard Test was most sensitive in distinguishing between groups. A subgroup analysis of early-stage RBD (<2 years diagnosis) confirmed similar findings as those in the larger RBD group. These findings provide new evidence that the putamen is affected in early-stage RBD using both functional and free-water imaging. We also found evidence that the striatum, thalamus and motor cortex have reduced functional activity in early-stage RBD and Parkinson's disease. While the substantia nigra shows elevated free-water in Parkinson's disease, we did not observe this effect in early-stage RBD. These findings point to the corticostriatal and thalamocortical circuits being impaired in RBD patients.

Neuroimaging and biofluid biomarkers across race and ethnicity in older adults across the spectrum of cognition.

Neuroimaging and biofluid biomarkers provide a proxy of pathological changes for Alzheimer's disease (AD) and are useful in improving diagnosis and assessing disease progression. However, it is not clear how race/ethnicity and different prevalence of AD risks impact biomarker levels. In this narrative review, we survey studies focusing on comparing biomarker differences between non-Hispanic White American(s) (NHW), African American(s) (AA), Hispanic/Latino American(s) (HLA), and Asian American(s) with normal cognition, mild cognitive impairment, and dementia. We found no strong evidence of racial and ethnic differences in imaging biomarkers after controlling for cognitive status and cardiovascular risks. For biofluid biomarkers, in AA, higher levels of plasma Aß42/Aß40, and lower levels of CSF total tau and p-tau 181, were observed after controlling for APOE status and comorbidities compared to NHW. Examining the impact of AD risks and comorbidities on biomarkers and their contributions to racial/ethnic differences in cognitive impairment are critical to interpreting biomarkers, understanding their generalizability, and eliminating racial/ethnic health disparities.

Houston, We Have AI Problem! Quality Issues with Neuroimaging-Based Artificial Intelligence in Parkinson's Disease: A Systematic Review.

In recent years, many neuroimaging studies have applied artificial intelligence (AI) to facilitate existing challenges in Parkinson's disease (PD) diagnosis, prognosis, and intervention. The aim of this systematic review was to provide an overview of neuroimaging-based AI studies and to assess their methodological quality. A PubMed search yielded 810 studies, of which 244 that investigated the utility of neuroimaging-based AI for PD diagnosis, prognosis, or intervention were included. We systematically categorized studies by outcomes and rated them with respect to five minimal quality criteria (MQC) pertaining to data splitting, data leakage, model complexity, performance reporting, and indication of biological plausibility. We found that the majority of studies aimed to distinguish PD patients from healthy controls (54%) or atypical parkinsonian syndromes (25%), whereas prognostic or interventional studies were sparse. Only 20% of evaluated studies passed all five MQC, with data leakage, non-minimal model complexity, and reporting of biological plausibility as the primary factors for quality loss. Data leakage was associated with a significant inflation of accuracies. Very few studies employed external test sets (8%), where accuracy was significantly lower, and 19% of studies did not account for data imbalance. Adherence to MQC was low across all observed years and journal impact factors. This review outlines that AI has been applied to a wide variety of research questions pertaining to PD; however, the number of studies failing to pass the MQC is alarming. Therefore, we provide recommendations to enhance the interpretability, generalizability, and clinical utility of future AI applications using neuroimaging in PD. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

What the trained eye cannot see: Quantitative kinematics and machine learning detect movement deficits in early-stage Parkinson's disease from videos.

BACKGROUND: Evaluation of disease severity in Parkinson's disease (PD) relies on motor symptoms quantification. However, during early-stage PD, these symptoms are subtle and difficult to quantify by experts, which might result in delayed diagnosis and suboptimal disease management. OBJECTIVE: To evaluate the use of videos and machine learning (ML) for automatic quantification of motor symptoms in early-stage PD. METHODS: We analyzed videos of three movement tasks-Finger Tapping, Hand Movement, and Leg Agility- from 26 aged-matched healthy controls and 31 early-stage PD patients. Utilizing ML algorithms for pose estimation we extracted kinematic features from these videos and trained three classification models based on left and right-side movements, and right/left symmetry. The models were trained to differentiate healthy controls from early-stage PD from videos. RESULTS: Combining left side, right side, and symmetry features resulted in a PD detection accuracy of 79 % from Finger Tap videos, 75 % from Hand Movement videos, 79 % from Leg Agility videos, and 86 % when combining the three tasks using a soft voting approach. In contrast, the classification accuracy varied between 40 % and 72 % when the movement side or symmetry were not considered. CONCLUSIONS: Our methodology effectively differentiated between early-stage PD and healthy controls using videos of standardized motor tasks by integrating kinematic analyses of left-side, right-side, and bilateral symmetry movements. These results demonstrate that ML can detect movement deficits in early-stage PD from videos. This technology is easy-to-use, highly scalable, and has the potential to improve the management and quantification of motor symptoms in early-stage PD.

Transcallosal white matter and cortical gray matter variations in autistic adults ages 30-73 years: A bi-tensor free water imaging approach.

Background: Autism spectrum disorder (ASD) has long been recognized as a lifelong condition, but brain aging studies in autistic adults aged >30 years are limited. Free water, a novel brain imaging marker derived from diffusion MRI (dMRI), has shown promise in differentiating typical and pathological aging and monitoring brain degeneration. We aimed to examine free water and free water corrected dMRI measures to assess white and gray matter microstructure and their associations with age in autistic adults. Methods: Forty-three autistic adults ages 30-73 years and 43 age, sex, and IQ matched neurotypical controls participated in this cross-sectional study. We quantified fractional anisotropy (FA), free water, and free water-corrected FA (fwcFA) across 32 transcallosal white matter tracts and 94 gray matter areas in autistic adults and neurotypical controls. Follow-up analyses assessed age effect on dMRI metrics of the whole brain for both groups and the relationship between dMRI metrics and clinical measures of ASD in regions that significantly differentiated autistic adults from controls. Results: We found globally elevated free water in 24 transcallosal tracts in autistic adults. We identified negligible differences in dMRI metrics in gray matter between the two groups. Age-associated FA reductions and free water increases were featured in neurotypical controls; however, this brain aging profile was largely absent in autistic adults. Additionally, greater autism quotient (AQ) total raw score was associated with increased free water in the inferior frontal gyrus pars orbitalis and lateral orbital gyrus in autistic adults. Limitations: All autistic adults were cognitively capable individuals, minimizing the generalizability of the research findings across the spectrum. This study also involved a cross-sectional design, which limited inferences about the longitudinal microstructural changes of white and gray matter in ASD. Conclusions: We identified differential microstructural configurations between white and gray matter in autistic adults and that autistic individuals present more heterogeneous brain aging profiles compared to controls. Our clinical correlation analysis offered new evidence that elevated free water in some localized white matter tracts may critically contribute to autistic traits in ASD. Our findings underscored the importance of quantifying free water in dMRI studies of ASD.

Plasma p-tau217 concordance with amyloid PET among ethnically diverse older adults.

INTRODUCTION: Commercially available plasma p-tau217 biomarker tests are not well studied in ethnically diverse samples. METHODS: We evaluated associations between ALZPath plasma p-tau217 and amyloid-beta positron emission tomography (Aß-PET) in Hispanic/Latino (88% of Cuban or South American ancestry) and non-Hispanic/Latino older adults. One- and two-cutoff ranges were derived and evaluated to assess agreement with Aß-PET. RESULTS: A total of 239 participants underwent blood draw and Aß-PET (age 70.8 ± 7.8, 55.2% female, education 15.6 ± 3.4 years, 48.9% Hispanic/Latino, 94.9% white). Plasma p-tau217 showed excellent discrimination of Aß-PET positive and negative participants (visual read: AUC = 0.91 [0.87-0.95], p < 0.001; Centiloids quantification: AUC = 0.90 [0.86-0.94]). There was a greater percent agreement between low p-tau217 and negative Aß-PET (95.8%) than high p-tau217 and positive Aß-PET (86.3%). Analyses within ethnicity-specific subgroups suggested similar p-tau217 performance. DISCUSSION: Plasma p-tau217 (ALZPath) relates to brain Aß in Hispanic/Latino and non-Hispanic/Latino older adults. Independent validation and replication are necessary to establish reference ranges and inform appropriate contexts of use across ethno-racially diverse populations. HIGHLIGHTS: Plasma p-tau217 (ALZPath) and Aß-PET were measured in Hispanic/Latino and non-Hispanic/Latino older adults.Plasma p-tau217 accurately discriminated Aß-PET positive and negative participants.Applying a two-cutoff "intermediate" plasma p-tau217 approach could reduce need for more invasive and costly testing.Plasma p-tau217 associations with Aß-PET were strong within both Hispanic/Latino and non-Hispanic/Latino groups.

Clinical utility of plasma Aß42/40 ratio by LC-MS/MS in Alzheimer's disease assessment.

Introduction: Plasma Aß42/40 ratio can help predict amyloid PET status, but its clinical utility in Alzheimer's disease (AD) assessment is unclear. Methods: Aß42/40 ratio was measured by LC-MS/MS for 250 specimens with associated amyloid PET imaging, diagnosis, and demographic data, and for 6,192 consecutive clinical specimens submitted for Aß42/40 testing. Results: High diagnostic sensitivity and negative predictive value (NPV) for Aß-PET positivity were observed, consistent with the clinical performance of other plasma LC-MS/MS assays, but with greater separation between Aß42/40 values for individuals with positive vs. negative Aß-PET results. Assuming a moderate prevalence of Aß-PET positivity, a cutpoint was identified with 99% NPV, which could help predict that AD is likely not the cause of patients' cognitive impairment and help reduce PET evaluation by about 40%. Conclusion: High-throughput plasma Aß42/40 LC-MS/MS assays can help identify patients with low likelihood of AD pathology, which can reduce PET evaluations, allowing for cost savings.

Longitudinal Free-Water Changes in Dementia with Lewy Bodies.

BACKGROUND: Diffusion-weighted magnetic resonance imaging (dMRI) examines tissue microstructure integrity in vivo. Prior dementia with Lewy bodies (DLB) diffusion tensor imaging studies yielded mixed results. OBJECTIVE: We employed free-water (FW) imaging to assess DLB progression and correlate with clinical decline in DLB. METHODS: Baseline and follow-up MRIs were obtained at 12 and/or 24 months for 27 individuals with DLB or mild cognitive impairment with Lewy bodies (MCI-LB). FW was analyzed using the Mayo Clinic Adult Lifespan Template. Primary outcomes were FW differences between baseline and 12 or 24 months. To compare FW change longitudinally, we included 20 cognitively unimpaired individuals from the Alzheimer's Disease Neuroimaging Initiative. RESULTS: We followed 23 participants to 12 months and 16 participants to 24 months. Both groups had worsening in Montreal Cognitive Assessment (MoCA) and Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) scores. We found significant FW increases at both time points compared to baseline in the insula, amygdala, posterior cingulum, parahippocampal, entorhinal, supramarginal, fusiform, retrosplenial, and Rolandic operculum regions. At 24 months, we found more widespread microstructural changes in regions implicated in visuospatial processing, motor, and cholinergic functions. Between-group analyses (DLB vs. controls) confirmed significant FW changes over 24 months in most of these regions. FW changes were associated with longitudinal worsening of MDS-UPDRS and MoCA scores. CONCLUSIONS: FW increased in gray and white matter regions in DLB, likely due to neurodegenerative pathology associated with disease progression. FW change was associated with clinical decline. The findings support dMRI as a promising tool to track disease progression in DLB. © 2024 International Parkinson and Movement Disorder Society.

Diffusion MRI relates to plasma Aß42/40 in PET negative participants without dementia.

INTRODUCTION: Magnetic resonance imaging (MRI) biomarkers are needed for indexing early biological stages of Alzheimer's disease (AD), such as plasma amyloid-ß (Aß42/40) positivity in Aß positron emission tomography (PET) negative individuals. METHODS: Diffusion free-water (FW) MRI was acquired in individuals with normal cognition (NC) and mild cognitive impairment (MCI) with Aß plasma-/PET- (NC = 22, MCI = 60), plasma+/PET- (NC = 5, MCI = 20), and plasma+/PET+ (AD dementia = 21) biomarker status. Gray and white matter FW and fractional anisotropy (FAt) were compared cross-sectionally and the relationships between imaging, plasma and PET biomarkers were assessed. RESULTS: Plasma+/PET- demonstrated increased FW (24 regions) and decreased FAt (66 regions) compared to plasma-/PET-. FW (16 regions) and FAt (51 regions) were increased in plasma+/PET+ compared to plasma+/PET-. Composite brain FW correlated with plasma Aß42/40 and p-tau181. DISCUSSION: FW imaging changes distinguish plasma Aß42/40 positive and negative groups, independent of group differences in cognitive status, Aß PET status, and other plasma biomarkers (i.e., t-tau, p-tau181, glial fibrillary acidic protein, neurofilament light). HIGHLIGHTS: Plasma Aß42/40 positivity is associated with brain microstructure decline. Plasma+/PET- demonstrated increased FW in 24 total GM and WM regions. Plasma+/PET- demonstrated decreased FAt in 66 total GM and WM regions. Whole-brain FW correlated with plasma Aß42/40 and p-tau181 measures. Plasma+/PET- demonstrated decreased cortical volume and thickness.

Different aspects of failing to recover from proactive semantic interference predicts rate of progression from amnestic mild cognitive impairment to dementia.

Introduction: This study investigated the role of proactive semantic interference (frPSI) in predicting the progression of amnestic Mild Cognitive Impairment (aMCI) to dementia, taking into account various cognitive and biological factors. Methods: The research involved 89 older adults with aMCI who underwent baseline assessments, including amyloid PET and MRI scans, and were followed longitudinally over a period ranging from 12 to 55 months (average 26.05 months). Results: The findings revealed that more than 30% of the participants diagnosed with aMCI progressed to dementia during the observation period. Using Cox Proportional Hazards modeling and adjusting for demographic factors, global cognitive function, hippocampal volume, and amyloid positivity, two distinct aspects of frPSI were identified as significant predictors of a faster decline to dementia. These aspects were fewer correct responses on a frPSI trial and a higher number of semantic intrusion errors on the same trial, with 29.5% and 31.6 % increases in the likelihood of more rapid progression to dementia, respectively. Discussion: These findings after adjustment for demographic and biological markers of Alzheimer's Disease, suggest that assessing frPSI may offer valuable insights into the risk of dementia progression in individuals with aMCI.

Cortico-basal ganglia white matter microstructure is linked to restricted repetitive behavior in autism spectrum disorder.

BACKGROUND: Restricted repetitive behavior (RRB) is one of two behavioral domains required for the diagnosis of autism spectrum disorder (ASD). Neuroimaging is widely used to study brain alterations associated with ASD and the domain of social and communication deficits, but there has been less work regarding brain alterations linked to RRB. METHODS: We utilized neuroimaging data from the National Institute of Mental Health Data Archive to assess basal ganglia and cerebellum structure in a cohort of children and adolescents with ASD compared to typically developing (TD) controls. We evaluated regional gray matter volumes from T1-weighted anatomical scans and assessed diffusion-weighted scans to quantify white matter microstructure with free-water imaging. We also investigated the interaction of biological sex and ASD diagnosis on these measures, and their correlation with clinical scales of RRB. RESULTS: Individuals with ASD had significantly lower free-water corrected fractional anisotropy (FAT) and higher free-water (FW) in cortico-basal ganglia white matter tracts. These microstructural differences did not interact with biological sex. Moreover, both FAT and FW in basal ganglia white matter tracts significantly correlated with measures of RRB. In contrast, we found no significant difference in basal ganglia or cerebellar gray matter volumes. LIMITATIONS: The basal ganglia and cerebellar regions in this study were selected due to their hypothesized relevance to RRB. Differences between ASD and TD individuals that may occur outside the basal ganglia and cerebellum, and their potential relationship to RRB, were not evaluated. CONCLUSIONS: These new findings demonstrate that cortico-basal ganglia white matter microstructure is altered in ASD and linked to RRB. FW in cortico-basal ganglia and intra-basal ganglia white matter was more sensitive to group differences in ASD, whereas cortico-basal ganglia FAT was more closely linked to RRB. In contrast, basal ganglia and cerebellar volumes did not differ in ASD. There was no interaction between ASD diagnosis and sex-related differences in brain structure. Future diffusion imaging investigations in ASD may benefit from free-water estimation and correction in order to better understand how white matter is affected in ASD, and how such measures are linked to RRB.

Plasma Alzheimer's biomarkers and brain amyloid in Hispanic and non-Hispanic older adults.

INTRODUCTION: Alzheimer's disease studies often lack ethnic diversity. METHODS: We evaluated associations between plasma biomarkers commonly studied in Alzheimer's (p-tau181, GFAP, and NfL), clinical diagnosis (clinically normal, amnestic MCI, amnestic dementia, or non-amnestic MCI/dementia), and Aß-PET in Hispanic and non-Hispanic older adults. Hispanics were predominantly of Cuban or South American ancestry. RESULTS: Three-hundred seventy nine participants underwent blood draw (71.9 ± 7.8 years old, 60.2% female, 57% Hispanic of which 88% were Cuban or South American) and 240 completed Aß-PET. P-tau181 was higher in amnestic MCI (p = 0.004, d = 0.53) and dementia (p < 0.001, d = 0.97) than in clinically normal participants and discriminated Aß-PET[+] and Aß-PET[-] (AUC = 0.86). P-tau181 outperformed GFAP and NfL. There were no significant interactions with ethnicity. Among amnestic MCI, Hispanics had lower odds of elevated p-tau181 than non-Hispanic (OR = 0.41, p = 0.006). DISCUSSION: Plasma p-tau181 informs etiological diagnosis of cognitively impaired Hispanic and non-Hispanic older adults. Hispanic ethnicity may relate to greater likelihood of non-Alzheimer's contributions to memory loss. HIGHLIGHTS: Alzheimer's biomarkers were measured in Hispanic and non-Hispanic older adults. Plasma p-tau181 related to amnestic cognitive decline and brain amyloid burden. AD biomarker associations did not differ between Hispanic and non-Hispanic ethnicity. Hispanic individuals may be more likely to have non-Alzheimer causes of memory loss.

Free-water imaging reveals unique brain microstructural deficits in hispanic individuals with Dementia.

Prior evidence suggests that Hispanic and non-Hispanic individuals differ in potential risk factors for the development of dementia. Here we determine whether specific brain regions are associated with cognitive performance for either ethnicity along various stages of Alzheimer's disease. For this cross-sectional study, we examined 108 participants (61 Hispanic vs. 47 Non-Hispanic individuals) from the 1Florida Alzheimer's Disease Research Center (1Florida ADRC), who were evaluated at baseline with diffusion-weighted and T1-weighted imaging, and positron emission tomography (PET) amyloid imaging. We used FreeSurfer to segment 34 cortical regions of interest. Baseline Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) were used as measures of cognitive performance. Group analyses assessed free-water measures (FW) and volume. Statistically significant FW regions based on ethnicity x group interactions were used in a stepwise regression function to predict total MMSE and MoCA scores. Random forest models were used to identify the most predictive brain-based measures of a dementia diagnosis separately for Hispanic and non-Hispanic groups. Results indicated elevated FW values for the left inferior temporal gyrus, left middle temporal gyrus, left banks of the superior temporal sulcus, left supramarginal gyrus, right amygdala, and right entorhinal cortex in Hispanic AD subjects compared to non-Hispanic AD subjects. These alterations occurred in the absence of different volumes of these regions in the two AD groups. FW may be useful in detecting individual differences potentially reflective of varying etiology that can influence cognitive decline and identify MRI predictors of cognitive performance, particularly among Hispanics.

Magnetic Resonance Imaging and Nuclear Imaging of Parkinsonian Disorders: Where do we go from here?

Parkinsonian disorders are a heterogeneous group of incurable neurodegenerative diseases that significantly reduce quality of life and constitute a substantial economic burden. Nuclear imaging (NI) and magnetic resonance imaging (MRI) have played and continue to play a key role in research aimed at understanding and monitoring these disorders. MRI is cheaper, more accessible, nonirradiating, and better at measuring biological structures and hemodynamics than NI. NI, on the other hand, can track molecular processes, which may be crucial for the development of efficient diseasemodifying therapies. Given the strengths and weaknesses of NI and MRI, how can they best be applied to Parkinsonism research going forward? This review aims to examine the effectiveness of NI and MRI in three areas of Parkinsonism research (differential diagnosis, prodromal disease identification, and disease monitoring) to highlight where they can be most impactful. Based on the available literature, MRI can assist with differential diagnosis, prodromal disease identification, and disease monitoring as well as NI. However, more work is needed, to confirm the value of MRI for monitoring prodromal disease and predicting phenoconversion. Although NI can complement or be a substitute for MRI in all the areas covered in this review, we believe that its most meaningful impact will emerge once reliable Parkinsonian proteinopathy tracers become available. Future work in tracer development and high-field imaging will continue to influence the landscape for NI and MRI.

Semantic intrusion errors are associated with plasma Ptau-181 among persons with amnestic mild cognitive impairment who are amyloid positive.

Introduction: Semantic intrusion errors (SI) have distinguished between those with amnestic Mild Cognitive Impairment (aMCI) who are amyloid positive (A+) versus negative (A-) on positron emission tomography (PET). Method: This study examines the association between SI and plasma - based biomarkers. One hundred and twenty-eight participants received SiMoA derived measures of plasma pTau-181, ratio of two amyloid-ß peptide fragments (Aß42/Aß40), Neurofilament Light protein (NfL), Glial Fibrillary Acidic Protein (GFAP), ApoE genotyping, and amyloid PET imaging. Results: The aMCI A+ (n = 42) group had a higher percentage of ApoE ɛ4 carriers, and greater levels of pTau-181 and SI, than Cognitively Unimpaired (CU) A- participants (n = 25). CU controls did not differ from aMCI A- (n = 61) on plasma biomarkers or ApoE genotype. Logistic regression indicated that ApoE ɛ4 positivity, pTau-181, and SI were independent differentiating predictors (Correct classification = 82.0%; Sensitivity = 71.4%; Specificity = 90.2%) in identifying A+ from A- aMCI cases. Discussion: A combination of plasma biomarkers, ApoE positivity and SI had high specificity in identifying A+ from A- aMCI cases.

Distinct cortical and subcortical predictors of Purdue Pegboard decline in Parkinson's disease and atypical parkinsonism.

Objective measures of disease progression are critically needed in research on Parkinson's disease (PD) and atypical Parkinsonism but may be hindered by both practicality and cost. The Purdue Pegboard Test (PPT) is objective, has high test-retest reliability, and has a low cost. The goals of this study were to determine: (1) longitudinal changes in PPT in a multisite cohort of patients with PD, atypical Parkinsonism, and healthy controls; (2) whether PPT performance reflects brain pathology revealed by neuroimaging; (3) quantify kinematic deficits shown by PD patients during PPT. Parkinsonian patients showed a decline in PPT performance that correlated with motor symptom progression, which was not seen in controls. Neuroimaging measures from basal ganglia were significant predictors of PPT performance in PD, whereas cortical, basal ganglia, and cerebellar regions were predictors for atypical Parkinsonism. Accelerometry in a subset of PD patients showed a diminished range of acceleration and irregular patterns of acceleration, which correlated with PPT scores.

Imaging features of small vessel disease in cerebral amyloid angiopathy among patients with Alzheimer's disease.

BACKGROUND AND PURPOSE: Cerebral small vessel disease biomarkers including white matter hyperintensities (WMH), lacunes, and enlarged perivascular spaces (ePVS) are under investigation to identify those specific to cerebral amyloid angiopathy (CAA). In subjects with Alzheimer's disease (AD), we assessed characteristic features and amounts of WMH, lacunes, and ePVS in four CAA categories (no, mild, moderate and severe CAA) and correlated these with Clinical Dementia Rating sum of boxes (CDRsb) score, ApoE genotype, and neuropathological changes at autopsy. METHODS: The study included patients with a clinical diagnosis of dementia due to AD and neuropathological confirmation of AD and CAA in the National Alzheimer's Coordinating Center (NACC) database. The WMH, lacunes, and ePVS were evaluated using semi-quantitative scales. Statistical analyses compared the WMH, lacunes, and ePVS values in the four CAA groups with vascular risk factors and AD severity treated as covariates, and to correlate the imaging features with CDRsb score, ApoE genotype, and neuropathological findings. RESULTS: The study consisted of 232 patients, of which 222 patients had FLAIR data available and 105 patients had T2-MRI. Occipital predominant WMH were significantly associated with the presence of CAA (p = 0.007). Among the CAA groups, occipital predominant WMH was associated with severe CAA (ß = 1.22, p = 0.0001) compared with no CAA. Occipital predominant WMH were not associated with the CDRsb score performed at baseline (p = 0.68) or at follow-up 2-4 years after the MRI (p = 0.92). There was no significant difference in high grade ePVS in the basal ganglia (p = 0.63) and centrum semiovale (p = 0.95) among the four CAA groups. The WMH and ePVS on imaging did not correlate with the number of ApoE ε4 alleles but the WMH (periventricular and deep) correlated with the presence of infarcts, lacunes and microinfarcts on neuropathology. CONCLUSION: Among patients with AD, occipital predominant WMH is more likely to be found in patients with severe CAA than in those without CAA. The high-grade ePVS in centrum semiovale were common in all AD patients regardless of CAA severity.

Behavioral Classification of Sequential Neural Activity Using Time Varying Recurrent Neural Networks.

Shifts in data distribution across time can strongly affect early classification of time-series data. When decoding behavior from neural activity, early detection of behavior may help in devising corrective neural stimulation before the onset of behavior. Recurrent Neural Networks (RNNs) are common models for sequence data. However, standard RNNs are not able to handle data with temporal distributional shifts to guarantee robust classification across time. To enable the network to utilize all temporal features of the neural input data, and to enhance the memory of an RNN, we propose a novel approach: RNNs with time-varying weights, here termed Time-Varying RNNs (TV-RNNs). These models are able to not only predict the class of the time-sequence correctly but also lead to accurate classification earlier in the sequence than standard RNNs. In this work, we focus on early sequential classification of brain-wide neural activity across time using TV-RNNs applied to a variety of neural data from mice and humans, as subjects perform motor tasks. Finally, we explore the contribution of different brain regions on behavior classification using SHapley Additive exPlanation (SHAP) value, and find that the somatosensory and premotor regions play a large role in behavioral classification.

Mediation of Reduced Hippocampal Volume by Cerebral Amyloid Angiopathy in Pathologically Confirmed Patients with Alzheimer's Disease.

BACKGROUND: Hippocampal atrophy in cerebral amyloid angiopathy (CAA) has been reported to be similar to that in Alzheimer's disease (AD). OBJECTIVE: To evaluate if CAA pathology partly mediates reduced hippocampal volume in patients with AD. METHODS: Patients with a clinical diagnosis of AD and neuropathological confirmation of AD+/-CAA in the National Alzheimer's Coordinating Center database were included in the study. The volumes of temporal lobe structures were calculated on T1-weighted imaging (T1-MRI) using automated FreeSurfer software, from images acquired on average 5 years prior to death. Multivariate regression analysis was performed to compare brain volumes in four CAA groups. The hippocampal volume on T1-MRI was correlated with Clinical Dementia Rating sum of boxes (CDRsb) score, apolipoprotein E (APOE) genotype, and hippocampal atrophy at autopsy. RESULTS: The study included 231 patients with no (n = 45), mild (n = 70), moderate (n = 67), and severe (n = 49) CAA. Among the four CAA groups, patients with severe CAA had a smaller mean left hippocampal volume (p = 0.023) but this was not significant when adjusted for APOE ɛ4 (p = 0.07). The left hippocampal volume on MRI correlated significantly with the hippocampal atrophy grading on neuropathology (p = 0.0003). Among patients with severe CAA, the left hippocampal volume on T1-MRI: (a) decreased with an increase in the number of APOE ɛ4 alleles (p = 0.04); but (b) had no evidence of correlation with CDRsb score (p = 0.57). CONCLUSION: Severe CAA was associated with smaller left hippocampal volume on T1-MRI up to five years prior to death among patients with neuropathologically confirmed AD. This relationship was dependent on APOE ɛ4 genotype.