Our results suggest that NPS are common among MCI patients. Approximately 75% of MCI patients referred to the California Alzheimer's Centers experienced at least one NPS. Patients with an elevated number of NPS had more medical co-morbidities and lower functional status, and were more likely to be of the amnestic MCI subtype. In addition, patients with amnestic MCI were twice as likely to have depressive symptoms, compared to patients with the other MCI subtypes. Of particular interest is our finding that patients with an elevated number of NPS at baseline were almost 2.5 times more likely to have dementia at follow-up.
Our results are consistent with those of other studies that have shown that NPS are common in MCI. Lyketsos et. al found that among patients with MCI in the community-based Cardiovascular Health Study (CHS), 43% had NPS, with 29% being rated as being clinically significant.9
The fact that our sample was clinically-based and not community-based may account for the higher prevalence observed among our participants. Anxiety, sleep changes, and depression were the most frequently reported NPS in our cohort and this is consistent with relative frequencies in previous studies. Depression, apathy, anxiety, and sleep changes were among the most frequently reported in the CHS.9
Similarly, other studies have found that frontally mediated behaviors (apathy and executive dysfunction) were reported most often.26
Most demographic variables did not differ among the NPS groups. For example, we did not find a relationship between race and NPS. Chan et al, found, however, that non-white MCI patients were at an increased risk for NPS, compared to whites.27
In the present study, participants with ≥ 4 NPS also experienced more co-morbid illness than those with 0-3 NPS. It is not surprising that burden of illness is related to NPS in MCI; patients with a greater number of medical illnesses might experience symptoms of depression or anxiety as a result of stress related to the symptoms of these comorbidities and their management. Similarly, those with greater functional impairment may be experiencing more NPS as a result of lower function, or vice versa
. A study by Feldman et al. found that MCI patients with NPS exhibit greater functional impairment,28
and NPS have been associated with functional impairment in dementia patients as well.29
We also observed a trend-level association between MMSE and NPS, and this is consistent with prior findings.28
Given that a higher number of NPS is associated with greater comorbidity, functional impairment, and cognitive impairment, it is possible that NPS could serve as a marker for overall disease severity and burden in the setting of MCI.
Consistent with our hypothesis that NPS would differ by MCI subtype, patients with elevated NPS were more likely to have the amnestic MCI subtype, and depressive symptoms were especially common among participants with the amnestic subtype. It may be that those with amnestic MCI are more likely to develop depressive symptoms, or it may be that depression is a risk factor for amnestic MCI. Previous research in amnestic MCI patients has shown high prevalence of depressive symptoms, as well as increased risk for Alzheimer disease (AD) for those with depressive symptoms.30
Indeed, depressive symptoms have been shown to be a risk factor for AD in multiple studies.31-33
We also hypothesized that those with a higher number of NPS would be more likely to progress to dementia. We found that an elevated number of NPS at baseline was associated with a greater likelihood of receiving a dementia diagnosis at follow-up, even after adjusting for age, baseline MMSE score, functional status and co-morbidities. Although a surveillance bias might account for this observation if patients with more NPS are more closely followed than those with fewer NPS, this is unlikely because follow-up was similar in our cohort for patients with high and low numbers of NPS. Our findings beg the question of whether treatment of NPS in MCI might delay or even prevent progression to dementia. Further research is needed to address this possibility.
Some limitations in our study design warrant consideration. First, although a clinician administered the MUDS questionnaire to ascertain the presence of NPS, no validated scale such as the Neuropsychiatric Inventory34
was used. In addition, a lack of data on the duration of participants' NPS precluded us from investigating whether NPS duration predicted progression to dementia. Furthermore, follow-up data was incomplete in the present study, raising the possibility of selection bias. Finally, because patients were seen at university-based referral centers, results may not be generalizable to patients seen at clinics without an academic affiliation.
In conclusion, our findings suggest that patients with elevated NPS are more likely to have the amnestic subtype of MCI, and that depressive symptoms are especially common in patients with amnestic MCI. Our results also indicate that patients with MCI who have an elevated number of NPS may have more than twice the odds of progression to dementia than those with fewer NPS. Additional studies are needed to determine the extent to which NPS duration and severity predict progression from MCI to dementia.