Introduction
Apathy, a profound loss of initiative, motivation, and persistence, is the most common behavioral problem in patients with dementia (Lyketsos et al., Reference Lyketsos, Lopez, Jones, Fitzpatrick, Breitner and Dekosky2002). The presence of apathy is associated with functional deficits, higher caregiver burden, and worsening neurodegenerative trajectory (Marin, Reference Marin1991). Frontal lobe dysfunction, poor neuronal integrity, and hypo-dopaminergic state in the frontal lobe and reward circuitry are considered etiologic factors for apathy (Benoit et al., Reference Benoit, Koulibaly, Migneco, Darcourt, Pringuey and Robert2002). Dopaminergic reuptake inhibitors such as methylphenidate (MPH) have been found to be effective in treating apathy in well-controlled randomized clinical trials (Padala et al., Reference Padala2017; Rosenberg et al., Reference Rosenberg2013). It is unknown if MPH treatment of apathy in those with dementia changes frontal lobe metabolites which are a proxy for neuronal integrity. Use of MPH in children has shown increase in N-acetylaspartate (nAA), a marker of healthy, normally functioning neurons (Wiguna et al., Reference Wiguna, Guerrero, Wibisono and Sastroasmoro2012). To date, no studies have been conducted on the effect of MPH on brain metabolites in patients with concomitant apathy and dementia. We hypothesized that nAA levels would increase in the right medial frontal (RMF) but not right parietal (RP) cortex as MPH is known to have preferential dopamine enhancement effects on the frontal cortex.
Figure 1. MRS changes after 12 weeks of MPH treatment.
Methods
Mr. A, 74-year-old Caucasian male, was referred for management of Alzheimer’s dementia (AD) with behavioral problems. The diagnosis of dementia was confirmed via a comprehensive evaluation in an interdisciplinary memory disorders clinic. Memory and behaviors were assessed with Mini Mental State Examination (MMSE), Neuropsychiatric Inventory (NPI), and the Apathy Evaluation Scale-Clinician version (AES-C) (Marin et al., Reference Marin, Biedrzycki and Firinciogullari1991). Patient scored 23 on MMSE, 56 on AES-C, which is considered clinically significant apathy, and the NPI was positive for clinically significant apathy and irritability. MPH was started at 5 mg BID and titrated to 10 mg BID at 2 weeks. MPH was continued for 12 weeks.
Magnetic resonance spectroscopy (MRS) was performed before and after treatment using a 3 Tesla GE scanner. Single voxel spectra 2 × 2 × 2 cm point-resolved spectroscopy sequences (PRESS) at short echo time (35/2000 ms) were acquired and processed by fitting using the LC Model software package. Anatomic images were used to place the voxel at the same location pre- and post-intervention. Metabolite quantitation and database development were performed using water as an internal standard. nAA levels were measured pre-and post-treatment in the RMF and RP. Hunter’s angle was calculated. It is a quick visual method for assessing the relative peak heights of major metabolites with the three largest spectral peaks (choline, creatine, and nAA) making a 45° angle (Lin et al., Reference Lin, Ross, Harris and Wong2005). In dementia, this is disrupted due to the relative high proportion of choline and is typically 15° (Lin et al., Reference Lin, Ross, Harris and Wong2005).
Results
No adverse events were reported. There was a clinically significant improvement in apathy at 12 weeks by both outcome measures (AES-C 33, 41% improvement and NPI apathy domain). nAA levels increased in the RMF region from 6.3 to 7.6 (20% improvement). nAA levels decreased in the RP region from 7.4 to 6.7 (9% decline). In our subject, the Hunter’s angle was 15° at baseline and neared 45° after 12 weeks of MPH treatment (Figure 1).
Discussion
MRS is a safe and noninvasive tool that can be used to study aspects of brain chemistry and metabolism. nAA levels decline with neurodegeneration, with lowest levels noted in AD patients, followed by mild cognitive impairment (MCI) patients, compared to healthy controls (Gao and Barker, Reference Gao and Barker2014). Lower nAA levels in the right frontal lobe and anterior cingulate are seen in those with apathy (Shinno et al., Reference Shinno2014). In this subject, apathy improved significantly with MPH treatment. Improvement in nAA levels was seen in the RMF cortex but not in the RP cortex. Improvement in the neuronal integrity of the frontal cortex could potentially be the mechanism of action of MPH leading to improvement and apathy. This is consistent with ADHD literature (Wiguna et al., Reference Wiguna, Guerrero, Wibisono and Sastroasmoro2012). This preliminary finding needs to be confirmed by larger studies.
Conflict of interest
This research was funded by grant number, MXH/99-925-1314, Clinical Research Center, UNMC (PRP). The Nancy and Ronald Reagan Alzheimer’s Research Award (PRP).
Acknowledgement
We acknowledge the role of Michael Boska, PhD, a great mentor and a friend, in this project and dedicate the work in his memory.
