White Matter Hyperintensities Relate to Clinical Progression in Subjective Cognitive Decline
Background and Purpose—In patients with subjective cognitive decline, we assessed whether small vessel disease was associated with clinical progression and cognitive decline.
Methods—We included 334 patients with subjective cognitive decline. Follow-up was 3±2 years.
Results—Fifty-three (16%) patients progressed clinically to mild cognitive impairment or dementia. White matter hyperintensities were associated with clinical progression and with annual decline on memory, attention, executive functioning, and global cognition. Microbleeds and lacunes were not associated with clinical progression or cognitive decline.
Conclusions—In patients with subjective cognitive decline, patients with white matter hyperintensities are at increased risk of clinical progression and cognitive decline.
- cognitive decline
- small vessel disease
- subjective complaints
- vascular cognitive impairment
- white matter lesions
A substantial part of patients who are admitted to a memory clinic have subjective complaints that cannot be objectified by cognitive testing. Increasing evidence indicates that the subjective experience of cognitive decline may reflect an early stage of actual cognitive decline.1 The term subjective cognitive decline (SCD) has been introduced to refer to these patients.2
Patients labeled with SCD may present with markers for small vessel disease (SVD), such as white matter hyperintensities (WMH), microbleeds, or lacunes.3 SVD is among the most important causes of cognitive decline and the term vascular cognitive impairment has been proposed to capture all forms of cognitive impairment that are attributable to any type of cerebrovascular disease.4
It is currently unknown whether SVD relates to clinical progression in SCD. We assessed whether SVD is associated with clinical progression and cognitive decline.
From the Amsterdam Dementia Cohort,5 we included all patients who came to our memory clinic because of their cognitive complaints and who were considered to have SCD,2 with a baseline visit between 2000 and 2013, an available baseline magnetic resonance imaging, and at least 1 year of follow-up (n=344). The local medical ethics committee approved the study. All patients provided written informed consent. WMH, microbleeds, and lacunes were rated on baseline magnetic resonance imaging.
Follow-up took place by clinical routine visits in which subject history, cognitive testing, and a general physical and neurological examination were repeated. Clinical progression was defined as progression to mild cognitive impairment or any cause of dementia. Cognitive decline was assessed using repeated neuropsychological evaluation.
Kaplan–Meier curves and Cox proportional-hazard models were used to assess the predictive value of WMH, microbleeds, and lacunes for clinical progression. Linear mixed models were used to estimate effects on cognitive performance over time.
Detailed methods are provided in the online-only Data Supplement.
Table I in the online-only Data Supplement summarized study population characteristics. Fifty-three patients (16%) showed clinical progression to mild cognitive impairment (n=38) or dementia (Alzheimer's disease, 9; vascular dementia, 3; Frontotemporal lobe degeneration, 3).
Mild, moderate, and severe WMH were associated with clinical progression in unadjusted models (Table 1; Figure). After adjustment, mild and severe WMH remained associated. In unadjusted models, the presence of ≥5 microbleeds conferred an increased risk for clinical progression (model 1; Figure). However, microbleeds and lacunes were not associated with clinical progression in adjusted models. A multivariate model yielded no independent associations. There was no significant interaction for WMH×medial temporal lobe atrophy.
Neuropsychological testing at follow-up was available for 262 (78%) patients (see Figure I in the online-only Data Supplement). Table II in the online-only Data Supplement gives cognitive performance at baseline. Moderate WMH was associated with a steeper rate of decline on memory and global cognition (Table 2). Severe WMH was associated with a steeper rate of decline on attention and executive functioning. In addition, severe WMH was borderline associated with a less rapid decline in language. There was a significant Ptrend for WMH severity with decline on memory, attention, executive functions, and global cognition. Microbleeds and lacunes were not associated with cognitive decline. Results remained comparable in a multivariate model.
Half of the patients with SCD had SVD to some extent, but severe SVD was rare. Although the majority of the patients with SVD remained stable over 3 years, patients with severe WMH had a 4-fold higher risk to show clinical progression to mild cognitive impairment or dementia, compared with patients without WMH. In addition, increasing WMH severity was associated with decline on memory, attention, executive functioning, and global cognition. These associations were independent of age and medial temporal lobe atrophy; 2 factors that previously have been pointed out as strong predictors for mild cognitive impairment and dementia.6–9 Our results seem in line with findings from the Leukoaraiosis and Disability study, in which a heterogeneous population of nondisabled elderly with WMH was included.10 We are, however, the first to show this in patients presenting with SCD to a memory clinic.
A major strength of this study is the longitudinal design with substantial follow-up in a well-characterized set of patients with SCD. A limitation is that groups with severe SVD and groups that converted to dementia were rather small. In addition, although SVD is generally assumed to represent vascular pathology, associations with degenerative processes have been reported as well.4
SVD may in itself drive clinical progression in a cascade of events that eventually leads to dementia11 or it may coexist with Alzheimer's disease pathology and by that lowering the threshold for clinical symptoms. Recently, Jack et al12 proposed an Alzheimer's disease biomarker model to better understand Alzheimer pathology in relation to clinical symptoms. Our finding of an independent association between WMH and clinical progression might argue for a role for vascular pathology as well.
Our findings may also have implications for the vascular cognitive impairment criteria4 that do not yet include SCD in the spectrum of cognitive impairment. Including patients with SCD into the concept of vascular cognitive impairment will not only allow anticipation on prognosis, but will also increase awareness for prevention and treatment.
Sources of Funding
The Alzheimer Center receives unrestricted funding from various sources through the VUmc Fonds. This research was supported by Stichting Diopraphte, Alzheimer Nederland, Stichting VUmc fonds, and the Gieskes-Strijbis fonds.
P. Scheltens has served on the advisory boards of Genentech, Novartis, Roche, Danone, Nutricia, Lilly, and Lundbeck. He has been a speaker at symposia organized by Lundbeck, Merz, Danone, Novartis, Roche, GE, and Genentech. He receives no personal compensation. F. Barkhof has served on the advisory boards of Bayer-Schering Pharma, Sanofi-Aventis, Biogen Idec, UCB, Merck-Serono, Novartis, and Roche. He received funding from the Dutch MS Society and has been a speaker at symposia organized by the Serono Symposia Foundation. W.M. van der Flier conducts research with Boehringer. All other authors report no diclosures.
The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.115.009475/-/DC1.
- Received March 25, 2015.
- Revision received May 26, 2015.
- Accepted June 8, 2015.
- © 2015 American Heart Association, Inc.
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