White matter hyperintensity increases are a feature of familial AD and are associated with increased brain atrophy

Abstract

AbstractBackgroundRelatively little is known about how white matter hyperintensity (WMH) changes relate to well‐characterised markers of disease progression such as brain atrophy rates in autosomal dominant familial AD (ADAD). Such analyses may improve models of disease progression and indicate whether WMH accrual and brain atrophy are associated features over the disease course.MethodsWe investigated WMH accrual in the Dominantly Inherited Alzheimer Network (DIAN) cohort. Participants included 72 controls, 95 PSEN1, 7 PSEN2 and 27 APP mutation carriers, with longitudinal multi‐modal imaging. WMH were segmented using a semi‐automated protocol. Brain atrophy rate was calculated using the boundary shift integral (BSI). Three statistical models were used: Model 1 used mixed‐effect linear regression to assess WMH accrual by mutation presence or type, adjusting for evidence of cognitive impairment (symptomatic status as defined using CDR). Model 2 assessed the effect of estimated years to onset (EYO) on WMH accrual. Model 3 estimated correlations between residual rates of change after allowing mean rates of change in WMH and brain volume to depend on proximity to expected onset. All models (1‐3) were allowed to depend upon total intracranial volume.ResultsThe table shows summary statistics and rates of change including annualised rates of WMH accrual and brain atrophy. Results from Model 1 showed differences in WMH accrual between mutation groups after adjustment for symptom status (p<0.001), with APP having higher rates of accrual than all other groups. Model 2 demonstrated WMH increases were associated with EYO in PSEN1 and APP groups (p≤0.001, both tests), with an accelerating rate of accrual observed approaching and passing estimated onset in the PSEN1 and PSEN2 groups (p≤0.005, both tests). Model 3 demonstrated associations between residual rates of change in WMH and brain volume in the PSEN1 (r 0.76, p<0.001) and APP (r 0.55, p=0.03) groups (the figure shows crude rates).ConclusionMutation type has an impact on WMH accrual, with APP mutation carriers in this cohort gaining more WMH over time. WMH changes are an important biomarker in ADAD with burden increasing with EYO. WMH and brain atrophy changes track together across the AD disease course.