The presence of cognitive fluctuations significantly worsened Clinical Dementia Ratings and was associated with diminished cognitive performance. After controlling for age, participants with cognitive fluctuations (3 or 4 individual symptoms) were at more than an eightfold risk of dementia compared with participants who did not fluctuate. When examined by individual symptoms, participants who presented with disorganized, illogical thinking had more than a sevenfold increased risk of being rated as cognitively impaired (CDR >0). We found that the risk of receiving a CDR 0.5 rating among those who presented with cognitive fluctuations was 13 times higher than among those individuals without fluctuations. The risk of being rated CDR 1 increased 34-fold among participants with fluctuations.
The presence of fluctuations was also associated with poorer performance on neuropsychological testing with the strongest relationship between disorganized or illogical thinking. Compared with participants who did not exhibit fluctuations, there were declines across composite measures of cognitive abilities. Because fluctuations may transiently affect attention, alertness, and concentration, we examined whether changes in daytime sleepiness (measured by the Mayo Sleep Questionnaire25
) affected dementia ratings. Increased alertness as reported by an informant was associated with a lower risk of being rated with dementia by the examiner. However, there was no relationship between the REM behavior question (acting out dreams) and cognitive fluctuations, supporting the contention that the samples were free of unrecognized DLB cases.
Although thought to be a core feature of DLB and frequently present in PD dementia,26–28
fluctuations may occur in older adults without dementia and are present in 12% of AD cases in our sample. When present, fluctuations were associated with poorer rating on the CDR staging of the participant, and poorer performance on cognitive testing.
The Mayo Fluctuation Questionnaire3
captures 4 unique aspects of fluctuations and may reliably discriminate DLB from AD; however, we demonstrate here that asking these questions in assessment of cognitive abilities regardless of whether other DLB core features are present has utility. The presence of fluctuations worsens both the clinical rating of dementia and neuropsychological performance.
Few studies have assessed fluctuations in AD. In a comparison of 13 patients with DLB with 12 patients with AD, informants described DLB fluctuations as spontaneous and transient and as impacting functional abilities. Fluctuations in patients with AD highlighted episodes of memory failure and the concept of “good” vs “bad” days.29
A larger prospective study5
compared attentional deficits and fluctuations in 85 patients with DLB and 80 patients with AD. Cognitive processing speed, attention, and fluctuations were all more impaired in DLB compared with AD, although patients with AD at the moderate stage also demonstrated fluctuations. Although these studies correlated fluctuations with cognitive performance, the inclusion of a DLB group may have masked the impact of fluctuations on the cognitive performance of AD because the goal in each of these studies was to compare DLB with AD.
The biologic bases of fluctuations are not well understood.30
Ascending cholinergic pathways from the pedunculopontine nucleus and laterodorsal tegmental nuclei are involved in arousal.31
The loss of these projections has been described in DLB, but neuronal counts did not correlate with sleep disturbances or fluctuations. DLB is associated with greater attentional deficits compared with AD32
; however, loss of attentional control is also an early finding in AD.33,34
EEG recordings of patients with AD and patients with DLB demonstrate differences in compressed spectral arrays favoring posterior alpha activity in patients with DLB with fluctuations.35
SPECT imaging of patients with DLB demonstrates significant correlation between fluctuations and increased thalamic and decreased occipital perfusion.36
Such studies have not been performed in patients with AD who experience cognitive fluctuations.
Our study has limitations. Although patients with clinically diagnosed DLB were excluded from this study, it is possible that patients with AD who fluctuate may go on to develop other core features of DLB. At the time of evaluation, however, no other core features (extrapyramidal signs, hallucinations, REM behavior disorder) were detected. It is difficult to accurately capture all aspects of cognitive fluctuation. Fluctuations may represent brief interruptions of consciousness, periods of increased confusion and cognitive impairment, episodes of diminished arousal, or what seem to be periods of prolonged sleep. Many issues regarding fluctuations are unresolved, including how important the assessment of fluctuations is to making a dementia diagnosis.37
We demonstrate here that fluctuations in AD worsen cognitive performance and lead to poorer CDR ratings. There are now several rating scales available to assess fluctuations, each of which assesses different aspects.3,38
The Mayo Fluctuation Questionnaire3
asks informants to indicate whether the symptom was present or absent; however, there is no consideration of the degree of change. The sample was not population-based; however, this sample is representative of our longstanding longitudinal study of over 3,000 individuals. As with any volunteer sample, there may be selection biases, thus limiting generalization of the results. Our convenience sample has demographic attributes and comorbid disorders that reflect those of the similarly aged population in the greater St. Louis metropolitan area, except they are slightly more educated.
Fluctuations are common in DLB1–5
; however, it was unknown what effect fluctuations play in AD. To address this, we compared patients with AD with older adults without dementia. Cognitive fluctuations do occur in AD and their presence significantly worsens CDR ratings by expert dementia clinicians and worsens cognitive performance across all domains. The inclusion of fluctuation scales such as the Mayo Fluctuations Questionnaire3
in the assessment of older adults for cognitive disorders may capture these clinically important events.