ADCOMS sensitivity versus baseline diagnosis and progression phenotypes.

BACKGROUND: The Alzheimer's Disease COMposite Score (ADCOMS) is more sensitive in clinical trials than conventional measures when assessing pre-dementia. This study compares ADCOMS trajectories using clustered progression characteristics to better understand different patterns of decline. METHODS: Post-baseline ADCOMS values were analyzed for sensitivity using mean-to-standard deviation ratio (MSDR), partitioned by baseline diagnosis, comparing with the original scales upon which ADCOMS is based. Because baseline diagnosis was not a particularly reliable predictor of progression, individuals were also grouped into similar ADCOMS progression trajectories using clustering methods and the MSDR compared for each progression group. RESULTS: ADCOMS demonstrated increased sensitivity for clinically important progression groups. ADCOMS did not show statistically significant sensitivity or clinical relevance for the less-severe baseline diagnoses and marginal progression groups. CONCLUSIONS: This analysis complements and extends previous work validating the sensitivity of ADCOMS. The large data set permitted evaluation-in a novel approach-by the clustered progression group.

Perfusion Imaging and Inflammation Biomarkers Provide Complementary Information in Alzheimer's Disease.

BACKGROUND: Single photon emission tomography (SPECT) can detect early changes in brain perfusion to support the diagnosis of dementia. Inflammation is a driver for dementia progression and measures of inflammation may further support dementia diagnosis. OBJECTIVE: In this study, we assessed whether combining imaging with markers of inflammation improves prediction of the likelihood of Alzheimer's disease (AD). METHODS: We analyzed 91 participants datasets (Institutional Ethics Approval 20/NW/0222). AD biomarkers and markers of inflammation were measured in cerebrospinal fluid. Statistical parametric mapping was used to quantify brain perfusion differences in perfusion SPECT images. Logistic regression models were trained to evaluate the ability of imaging and inflammation markers, both individually and combined, to predict AD. RESULTS: Regional perfusion reduction in the precuneus and medial temporal regions predicted Aß42 status. Increase in inflammation markers predicted tau and neurodegeneration. Matrix metalloproteneinase-10, a marker of blood-brain barrier regulation, was associated with perfusion reduction in the right temporal lobe. Adenosine deaminase, an enzyme involved in sleep homeostasis and inflammation, was the strongest predictor of neurodegeneration with an odds ratio of 10.3. The area under the receiver operator characteristic curve for the logistic regression model was 0.76 for imaging and 0.76 for inflammation. Combining inflammation and imaging markers yielded an area under the curve of 0.85. CONCLUSIONS: Study results showed that markers of brain perfusion imaging and markers of inflammation provide complementary information in AD evaluation. Inflammation markers better predict tau status while perfusion imaging measures represent amyloid status. Combining imaging and inflammation improves AD prediction.

Brain PET and SPECT imaging and quantification: a survey of the current status in the UK.

OBJECTIVES: With disease-modifying therapies in development for neurological disorders, quantitative brain imaging techniques become increasingly relevant for objective early diagnosis and assessment of response to treatment. The aim of this study was to evaluate the use of Brain SPECT and PET scans in the UK and explore drivers and barriers to using quantitative analysis through an online survey. METHODS: A web-based survey with 27 questions was used to capture a snapshot of brain imaging in the UK. The survey included multiple-choice questions assessing the availability and use of quantification for DaTscan, Perfusion SPECT, FDG PET and Amyloid PET. The survey results were reviewed and interpreted by a panel of imaging experts. RESULTS: Forty-six unique responses were collected and analysed, with 84% of responses from brain imaging sites. Within these sites, 88% perform DaTscan, 50% Perfusion SPECT, 48% FDG PET, and 33% Amyloid PET, while a few sites use other PET tracers. Quantitative Brain analysis is used in 86% of sites performing DaTscans, 40% for Perfusion SPECT, 63% for FDG PET and 42% for Amyloid PET. Commercial tools are used more frequently than in-house software. CONCLUSION: The survey showed variations across the UK, with high availability of DaTscan imaging and quantification and lower availability of other SPECT and PET scans. The main drivers for quantification were improved reporting confidence and diagnostic accuracy, while the main barriers were a perception of a need for an appropriate database of healthy controls and a lack of training, time, and software availability.

Biomarkers of Inflammation Increase with Tau and Neurodegeneration but not with Amyloid-ß in a Heterogenous Clinical Cohort.

BACKGROUND: Neuroinflammation is an integral part of Alzheimer's disease (AD) pathology. Inflammatory mediators can exacerbate the production of amyloid-ß (Aß), the propagation of tau pathology and neuronal loss. OBJECTIVE: To evaluate the relationship between inflammation markers and established markers of AD in a mixed memory clinic cohort. METHODS: 105 cerebrospinal fluid (CSF) samples from a clinical cohort under investigation for cognitive complaints were analyzed. Levels of Aß42, total tau, and phosphorylated tau were measured as part of the clinical pathway. Analysis of inflammation markers in CSF samples was performed using multiplex immune assays. Participants were grouped according to their Aß, tau, and neurodegeneration status and the Paris-Lille-Montpellier (PLM) scale was used to assess the likelihood of AD. RESULTS: From 102 inflammatory markers analyzed, 19 and 23 markers were significantly associated with CSF total tau and phosphorylated tau levels respectively (p < 0.001), while none were associated with Aß42. The CSF concentrations of 4 inflammation markers were markedly elevated with increasing PLM class indicating increased likelihood of AD (p < 0.001). Adenosine deaminase, an enzyme involved in sleep homeostasis, was the single best predictor of high likelihood of AD (AUROC 0.788). Functional pathway analysis demonstrated a widespread role for inflammation in neurodegeneration, with certain pathways explaining over 30% of the variability in tau values. CONCLUSION: CSF inflammation markers increase significantly with tau and neurodegeneration, but not with Aß in this mixed memory clinic cohort. Thus, such markers could become useful for the clinical diagnosis of neurodegenerative disorders alongside the established Aß and tau measures.

Imaging Care Requirements: Use of Functional Neuroimaging to Predict Dementia Caregiver Burden.

BACKGROUND: Dementia caregivers frequently report high stress, with increased burden associated with worse outcomes for both patients and caregivers. Although many studies relate clinical phenotypes to burden, the relationship between imaging pathology and burden, irrespective of diagnosis, is unknown. This study investigated the relationship between caregiver burden and patient regional cerebral blood flow in dementia. METHODS: Seventy-sev en patients with cognitive impairment undergoing brain perfusion single-photon emission computed tomography imaging in normal clinical care and their caregivers were recruited. Caregiver burden was ranked from "little" to "severe" using the Zarit Burden Interview and perfusion values extracted from the patient images for predefined regions of interest. The associations between burden score and regional function on imaging were tested. RESULTS: Burden score was significantly higher for caregivers of patients with abnormal perfusion compared to those with normal perfusion in the left and right frontal, right parietal, and right temporal lobes. No difference in burden was found in the left parietal or temporal groups. Correlations showed that a higher caregiver burden was associated with lower patient perfusion scores in the same regions. CONCLUSION: Caregiver burden is strongly related to the extent of frontal or right-predominant parietal or temporal lobe dysfunction. Regional abnormality on perfusion imaging can be used to facilitate identification of individuals who are likely to create a high burden on caregivers.

Occipital lobe and posterior cingulate perfusion in the prediction of dementia with Lewy body pathology in a clinical sample.

OBJECTIVE: The aim of this study was to investigate the diagnostic value of occipital lobe and posterior cingulate perfusion in predicting dopamine transporter imaging outcome using a quantitative measure of analysis. PATIENTS AND METHODS: In total, 99 patients with cognitive complaints who had undergone both technetium-99m-hexamethylpropyleneamine oxime single-photon emission computed tomography (Tc-HMPAO SPECT) and I ioflupane (I-FP-CIT also called DaTSCAN) imaging in a dementia diagnostic center were analyzed. Measures of perfusion were calculated from HMPAO SPECT images for the medial and lateral occipital lobe, the posterior cingulate cortex, precuneus and cuneus regions of interest using statistical parametric mapping 8. DaTSCAN images were quantified and specific binding ratios were calculated independent from HMPAO SPECT results. Statistical parametric mapping and tests of associations between perfusion and I-FP-CIT imaging were completed. RESULTS: Regions of interest on HMPAO yielded poor predictive values when used independently to predict I-FP-CIT status; however, the combination of normal posterior cingulate perfusion with medial and lateral occipital hypoperfusion was associated significantly with I-FP-CIT status, χ (1, N=99)=9.72, P=0.002. This combination also yielded a high positive likelihood ratio and specificity (11.1, 98%). Sensitivity was, however, low (22%). No significant perfusion differences were found when abnormal and normal I-FP-CIT groups were compared directly using voxel-based morphometry (P<0.05, family-wise error). CONCLUSION: The combination of medial and lateral occipital hypoperfusion with preserved posterior cingulate gyrus perfusion is highly specific for individuals with a positive I-FP-CIT scan in a clinical sample where diagnostic doubt exists. This regional combination, however, lacks sensitivity; therefore, absence of the sign cannot be used to rule out dementia with Lewy bodies. A positive finding provides strong evidence to rule in dementia with Lewy bodies.