Recognizing and Treating Neuropsychiatric Symptoms in Parkinson's Disease

Apathy has been associated with longer disease duration, male gender [40], higher daily levodopa doses [41], more severe parkinsonism [38], and lower education status, though the latter feature remains under debate. Early cognitive deficits appear to be a risk factor for development of apathy [42]. The patterns of cognitive dysfunction and apathy remain unsettled in the literature.

Pathology

The pathology of atrophy remains unexplained and is unlikely to be reduced to a simple atrophy of one nucleus or the tone of one circuit. However, in a small neuroimaging study, severity of apathy correlated with atrophy of the bilateral nucleus accumbens [43], and it is notable that one major input to the nucleus accumbens is the amygdala. According to Braak staging, by stage 4 significant involvement of the amygdala by Lewy bodies has occurred. Others have found changes in grey matter density that could correlate with deficits of the prefrontal-basal ganglia circuitry to produce dysfunction of segregated frontal-subcortical loops. These may correlate with the “autoactivation” deficit pattern of apathy in which patients have a lack of self-initiated actions, even thoughts, though appear more normal when giving externally prompted responses [37,44].

Assessment

Clinically, the relationship between apathy and depression can be hard to disentangle, especially since many studies have found an association between them, especially with regards to apathy and anhedonia. Depression may feature negative self thoughts and sadness while apathy is notable for lack of initiation and effort. Viewed over a longer period of time, apathy tended to worsen in a linear fashion, where depression tended to fluctuate with improvements and exacerbations.

The Movement Disorders Society task force has recommended the Lille Apathy Rating Scale (LARS) for assessment of apathy; English and French versions have been validated in PD patients. It uses a semi-structured interview format assessing 4 dimensions of apathy: self awareness, intellectual curiosity, emotion, and action initiation [45–47].

The impact of apathy cannot be underestimated as this poor show of motivation or effort leads to lack of engagement in old activities or interest in new ones. Spouses may misinterpret this change in behavior as laziness or deliberate social withdrawal, or perhaps entitlement. It is not surprising that apathy routinely shows up on quality of life (QoL) questionnaires as highly impacting patients and families. In one study, apathy was the nonmotor symptom most likely to cause caregiver distress in PD [40,48–50].

Treatment

No approved drugs exist for treatment of apathy. However, clinical experience often confirms that dopaminergic modulation can be helpful in the treatment of apathy as indirect evidence suggests. A meta-analysis of controlled trials using pramipexole and Part I of the Unified Parkinson's disease rating scale (UPDRS) (secondary measure) showed the medication improved scores on this measure of motivation and mood in non-depressed subjects [51] with PD. Rare patients undergoing subthalamic deep brain stimulation have been reported to experience new and sometimes severe apathy after surgery [52]. This was posited at least in part to be the result of reduction of dopaminergic medication due to surgery.

Nondopaminergic pharmacotherapy of apathy is in its infancy. A recent controlled trial of rivastigmine in 31 French subjects with moderate to severe apathy based on LARS showed that 6 months of treatment at 9.5 mg/day improved average scores from –11.5 to –20 compared with placebo. While quality of life did not improve, caregiver burden did. The investigators found in this group of subjects that apathy was a possible herald for early dementia in PD [53].