Predicting progression and cognitive decline in amyloid-positive patients with Alzheimer’s disease

Abstract

Background In Alzheimer’s disease, amyloid- β (A β) peptides aggregate in the lowering CSF amyloid levels - a key pathological hallmark of the disease. However, lowered CSF amyloid levels may also be present in cognitively unimpaired elderly individuals. Therefore, it is of great value to explain the variance in disease progression among patients with A β pathology. Methods A cohort of n=2293 participants, of whom n=749 were A β positive, was selected from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database to study heterogeneity in disease progression for individuals with A β pathology. The analysis used baseline clinical variables including demographics, genetic markers, and neuropsychological data to predict how the cognitive ability and AD diagnosis of subjects progressed using statistical models and machine learning. Due to the relatively low prevalence of A β pathology, models fit only to A β-positive subjects were compared to models fit to an extended cohort including subjects without established A β pathology, adjusting for covariate differences between the cohorts. Results A β pathology status was determined based on the A β42/A β40 ratio. The best predictive model of change in cognitive test scores for A β-positive subjects at the 2-year follow-up achieved an R2 score of 0.388 while the best model predicting adverse changes in diagnosis achieved a weighted F1 score of 0.791. A β-positive subjects declined faster on average than those without A β pathology, but the specific level of CSF A β was not predictive of progression rate. When predicting cognitive score change 4 years after baseline, the best model achieved an R2 score of 0.325 and it was found that fitting models to the extended cohort improved performance. Moreover, using all clinical variables outperformed the best model based only on a suite of cognitive test scores which achieved an R2 score of 0.228. Conclusion Our analysis shows that CSF levels of A β are not strong predictors of the rate of cognitive decline in A β-positive subjects when adjusting for other variables. Baseline assessments of cognitive function accounts for the majority of variance explained in the prediction of 2-year decline but is insufficient for achieving optimal results in longer-term predictions. Predicting changes both in cognitive test scores and in diagnosis provides multiple perspectives of the progression of potential AD subjects.

Neuroimaging Methods to Map In Vivo Changes of OXPHOS and Oxidative Stress in Neurodegenerative Disorders

“…Studies in non-human primates additionally validated these findings in conscious, untreated, and MPTP-treated animals [69,70]. 18 F-BCPP-EF is currently under investigation for the assessment of patients with NDs. In PD patients, decreased binding levels of 18 F-BCPP-EF have been observed in several neuroanatomical key structures without reaching statistical significance [71].…”

“…In the same study, the longitudinal assessment of PD patients showed a trend without reaching the significance level [71]. In a multimodal PET imaging study in patients with AD, 18 F-BCPP-EF binding is closely associated with the in vivo tau deposition but not the overall amyloid load [72]. 18 F-BCPP-EF yields immense promises for evaluating mitochondrial dysfunction in patients with NDs.…”

“…Accompanying diagnostics could substantially enrich the frequency of disease-converters to ensure clinical trial success [17]. In NDs, the symptom severity and disease progression can be highly individual [18][19][20]. In addition, clinical trials in NDs evaluate disease-modifying properties of candidate drugs following long interventional periods [14].…”

“…Based on the prominent role of complex I disturbances in NDs, several PET radiotracers have been evaluated for quantitative imaging [67]. Out of these, the radiotracer 18 F-BCPP-EF has entered clinical evaluation. Rodent studies have shown that 18 F-BCPP-EF yields a high molecular specificity and undergoes dynamic changes following the administration of complex I inhibitors [68].…”

“…Out of these, the radiotracer 18 F-BCPP-EF has entered clinical evaluation. Rodent studies have shown that 18 F-BCPP-EF yields a high molecular specificity and undergoes dynamic changes following the administration of complex I inhibitors [68]. Studies in non-human primates additionally validated these findings in conscious, untreated, and MPTP-treated animals [69,70].…”