Parkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer’s disease and imposes a substantial burden on health and quality of life, affecting approximately 7 million people worldwide with an estimated prevalence of 100–300 cases per 100,000 population. The principal pathology in PD is the abnormal accumulation of fibrillary aggregates of alpha-synuclein, known as Lewy bodies and Lewy neurites, predominantly at the presynaptic level. These aggregates disrupt axonal transport and lead to neuronal loss in the substantia nigra pars compacta with subsequent dopaminergic depletion in the striatum. The cardinal motor features of PD—bradykinesia and rigidity, with or without resting tremor—typically emerge only after a 60–80% reduction in striatal dopamine terminals [1]. In addition to motor features, patients frequently experience non-motor symptoms such as hyposmia, constipation, depression, sleep disturbance and weight fluctuation, which are attributed to alpha-synuclein–mediated injury of non-dopaminergic pathways and, in part, to serotonergic system deficits [2,3,4].

The clinical features of PD overlap with those of atypical parkinsonian disorders such as the parkinsonian variant of multiple system atrophy (MSA-P), progressive supranuclear palsy (PSP), and with essential tremor, which complicates diagnosis. Neuroimaging can improve diagnostic precision. Structural magnetic resonance imaging (MRI) helps to distinguish PD from secondary and atypical parkinsonism, including striatonigral degeneration and MSA [5,6], while quantitative measurements of regional atrophy assist in the recognition of PSP [7,8]. Advanced diffusion techniques, including diffusion-weighted imaging and bi-tensor free-water analysis, detect microstructural and free-water changes in the substantia nigra and related structures and can differentiate the parkinsonian variant of MSA from PD [9,10]. Proton and phosphorus MR spectroscopic imaging has been explored for early diagnosis [11], arterial spin labelling can reveal altered cerebral perfusion and arterial arrival times [12], and resting-state functional MRI identifies disease-related spatial covariance patterns [13].

Molecular imaging further refines the evaluation of parkinsonism. Presynaptic dopaminergic imaging with 123I-labelled tracers (DaTSCAN) accurately differentiates degenerative parkinsonism and essential tremor and can unmask an early diagnosis [14,15,16,17]. Cardiac 123I-metaiodobenzylguanidine scintigraphy distinguishes PD from other neurodegenerative parkinsonism by detecting sympathetic denervation [18], 18F-fluorodeoxyglucose positron emission tomography (PET) enables metabolic pattern analysis [19], 11C-PK11195 PET images microglial activation [20], and phosphodiesterase 10A ligands track striatal signalling loss with disease progression [21]. Despite this substantial evidence base, none of these modalities is currently recommended for routine clinical use, and larger studies are required to establish their clinical role.

MR spectroscopy (MRS) is a non-invasive technique based on the principle of nuclear magnetic resonance that detects and quantifies brain metabolites, identifying the spectral signatures of compounds such as N-acetylaspartate (NAA), choline, myo-inositol and creatine. NAA is a marker of neuronal health and density, choline reflects membrane turnover, and creatine is relatively stable and serves as an internal reference. Proton (1H) MRS studies in PD have shown a consistent decrease in NAA in the basal ganglia and substantia nigra, often accompanied by increased choline and myo-inositol, indicating neuronal dysfunction, enhanced membrane turnover and glial proliferation. Reductions in the NAA/creatine ratio have been reported in the putamen and temporoparietal region, and NAA/choline reductions have been observed in treated compared with untreated patients, suggesting that medication may modulate the spectroscopic profile [22,23,24,25,26]. These changes support the validity of MRS as a tool for evaluating PD, from early diagnosis to the assessment of therapeutic response.

Levodopa (L-DOPA), a direct precursor of dopamine that crosses the blood–brain barrier, remains the primary pharmacological treatment for PD, replenishing striatal dopamine required for cortico-basal ganglia-thalamocortical motor control. Because the clinical manifestations of PD are characteristically asymmetric, with persistent asymmetry most affecting the side of onset, lateralised spectroscopic assessment is of particular interest [27,28,29]. One of the most promising applications of proton MRS lies in monitoring the biochemical effects of therapy. Accordingly, the present study was designed with two objectives: first, to analyse the association between the NAA-to-creatine ratio in the substantia nigra and globus pallidus and the Hoehn-Yahr stage and UPDRS score in patients with PD; and second, to assess the neurochemical profile of patients undergoing L-DOPA treatment in order to identify dopaminergic therapy–sensitive biomarkers after three months of treatment.

Study design and setting This was a descriptive study conducted in the Department of Radio-diagnosis at hospitals attached to Bangalore Medical College and Research Institute, Bengaluru, over the period from August 2022 to January 2024. MR spectroscopy was performed at Victoria Hospital. The study was approved by the Institutional Ethics Committee, and written informed consent was obtained from every participant before enrolment. Participants Patients presenting to the affiliated hospitals who were newly diagnosed with Parkinson’s disease, started on L-DOPA for at least three months and referred for MR spectroscopy were eligible for inclusion, provided they were willing to give informed consent. Patients clinically diagnosed with Parkinson’s disease but not receiving L-DOPA, patients with drug-induced parkinsonism or Parkinson’s-plus syndromes, and patients unwilling to give informed consent were excluded. All 20 patients who met the inclusion criteria were enrolled, underwent baseline clinical and spectroscopic assessment, and completed the three-month follow-up assessment; there were no losses to follow-up. Sample size The sample size was estimated using nMaster software version 2.0. Based on the study by Wu and colleagues on proton MR spectroscopy for monitoring pathologic changes in the substantia nigra and globus pallidus in Parkinson’s disease, in which the mean UPDRS score was 40.5 ± 13.9, and applying the single-mean formula with an alpha of 0.05 (two-sided) and a relative precision of 15, the required sample size was 20 patients. Imaging technique / protocol All examinations were performed on a 1.5 T Siemens Magnetom Aventa MR system. Foam padding and paper tape were used to restrict head motion. Routine MRI and single-voxel 1H-MRS were acquired using point-resolved spectroscopy with an eight-channel phased-array head coil and turbo spin-echo and gradient-recalled echo sequences. MRI parameters were a matrix of 256 × 256, a slice thickness of 5 mm and an interlayer thickness of 1 mm. The 1H-MRS parameters were a repetition time of 1700 ms, an echo time of 135 ms, a volume of interest of 8 × 8 × 6 cm, a voxel of 2 × 2 × 1.5 cm and three excitations (Figure 1). Susceptibility-weighted imaging was used to localise the cross-section. Adequate local shimming was defined as a residual water peak linewidth of less than 16 Hz, and adequate water suppression as a full width at half maximum of less than 7 Hz. Post-processing included zero-filling, baseline correction, phase correction and frequency-shift correction, performed automatically in most cases and manually by a radiologist where the spectrum was significantly distorted. Time-domain processing included water-reference processing, filtering and zero-filling with an original vector size of 1024 and an extended vector size of 2048, followed by Fourier transformation, phase correction and semiquantitative curve fitting to calculate metabolite peaks and peak areas. The NAA-to-creatine ratio was calculated for the initially symptomatic side of the brain and compared according to the Hoehn-Yahr stage. Disease severity was assessed using the Modified Hoehn-Yahr scale and the Unified Parkinson’s Disease Rating Scale (UPDRS) Figure 1. Single-voxel proton MR spectroscopy planning in a 68-year-old man. T2-weighted MR localizer images show the spectroscopy voxel (yellow box) positioned over the symptom-onset side at the level of the substantia nigra in the sagittal (left), axial (middle) and coronal (right) planes. Statistical analysis Data were entered in Microsoft Excel 2016 and analysed using IBM SPSS Statistics for Windows, version 23.0 (IBM Corp, Armonk, NY). Categorical variables were summarised using frequencies and percentages, and continuous variables using means and standard deviations. Differences between two independent groups were tested with the unpaired t-test or the Mann-Whitney U test according to data distribution, and differences across multiple groups with analysis of variance or the Kruskal-Wallis test. Associations between categorical variables were tested with the chi-square or Fisher exact test. The Pearson correlation coefficient was used to assess the relationship between NAA/creatine ratios and UPDRS scores. A p value of less than 0.05 was considered statistically significant.

Demographic and clinical characteristics

Table 1. Demographic and clinical characteristics of the study population (n = 20).

The study included 20 patients with clinically diagnosed Parkinson’s disease who had been on L-DOPA for at least three months. The mean age was 68.9 ± 6.46 years, the gender distribution was 65% male (n = 13) and 35% female (n = 7), and the mean Hoehn-Yahr stage was 3, indicating moderate disease progression (Table 1). Patients spanned all five Modified Hoehn-Yahr stages, with the largest group at stage 3 (Figure 6).

Figure 6. Distribution of the 20 patients across Modified Hoehn-Yahr stages, showing that most patients were at moderate stages (stage 3, n = 8) (data from Tables 9 and 10).

Baseline NAA/creatine ratios

Table 2. Baseline NAA and creatine values and NAA/creatine ratios in the substantia nigra.

Table 3. Baseline NAA and creatine values and NAA/creatine ratios in the globus pallidus.

Table 4. NAA and creatine values and NAA/creatine ratios in the substantia nigra after three months of L-DOPA treatment.

Table 5. NAA and creatine values and NAA/creatine ratios in the globus pallidus after three months of L-DOPA treatment.

At baseline, the mean NAA/creatine ratio in the substantia nigra was 0.8825 ± 0.725 on the right and slightly higher at 1.12734 ± 0.45135 on the left. The corresponding NAA and creatine values are shown in Table 2. In the globus pallidus, the baseline ratio was 0.98457 ± 0.545 on the right and 1.2489 ± 0.0335 on the left (Table 3). The mild asymmetry between the two sides is consistent with the asymmetric nature of Parkinson’s disease. Representative pre-treatment single-voxel spectra are shown in Figures 2–4.

Figure 2. Pre-treatment single-voxel proton MR spectrum from the left globus pallidus in a 75-year-old man. The spectrum shows the N-acetylaspartate (NAA), choline (Cho) and creatine (Cr1, Cr2) peaks, with the corresponding voxel location displayed on the axial, sagittal and coronal localizer images (right).

Figure 3. Pre-treatment single-voxel proton MR spectrum from the left substantia nigra in a 72-year-old man, demonstrating the NAA, choline and creatine peaks with the voxel position shown on the localizer images (right).

Figure 4. Pre-treatment single-voxel proton MR spectrum from the left substantia nigra in a second 72-year-old man, showing the NAA, creatine, choline and myo-inositol peaks with the voxel location on the localizer images (right).

Post-treatment NAA/creatine ratios

After three months of L-DOPA treatment, the NAA/creatine ratio in the substantia nigra increased to 1.745 ± 0.206 on the right and 1.58365 ± 0.1556 on the left (Table 4). In the globus pallidus, the ratio increased to 1.6935 ± 0.111 on the right and 1.69365 ± 0.1917 on the left (Table 5). In both regions, the rise in the ratio was driven by an increase in NAA together with a fall in creatine (Figure 5).

Figure 5. Post-treatment single-voxel proton MR spectrum from the right globus pallidus in a 74-year-old man after three months of L-DOPA treatment, showing the NAA, creatine and choline peaks with a prominent NAA peak; the voxel location is displayed on the localizer images (right).

Comparison of pre- and post-treatment ratios

Table 6. Comparison of NAA/creatine ratios before and after L-DOPA treatment in the substantia nigra.

Table 7. Comparison of NAA/creatine ratios before and after L-DOPA treatment in the globus pallidus.

The increases in NAA/creatine ratios were statistically significant. In the substantia nigra, the ratio increased from 0.8825 ± 0.725 to 1.745 ± 0.206 on the right and from 1.12734 ± 0.45135 to 1.58365 ± 0.1556 on the left (both p < 0.01; Table 6). In the globus pallidus, the ratio increased from 0.98457 ± 0.545 to 1.6935 ± 0.111 on the right and from 1.2489 ± 0.0335 to 1.69365 ± 0.1917 on the left (both p < 0.01; Table 7). The consistent post-treatment rise across all four regions is shown in Figure 7.

Figure 7. Mean NAA/creatine ratios in the right and left substantia nigra (SN) and globus pallidus (GP) before and after three months of L-DOPA treatment; the ratio rose significantly in every region (all p < 0.01) (data from Tables 6 and 7).

UPDRS scores

Table 8. UPDRS scores before and after L-DOPA treatment.

The mean UPDRS score decreased significantly from 40.5 ± 13.9 before treatment to 28.3 ± 12.1 after treatment (p < 0.01), indicating a marked reduction in symptom severity (Table 8, Figure 8).

Figure 8. Mean Unified Parkinson’s Disease Rating Scale (UPDRS) score before and after three months of L-DOPA treatment; the score fell significantly (p < 0.01) (data from Table 8).

NAA/creatine ratio by Hoehn-Yahr stage

Table 9. Pre-treatment NAA/creatine ratio by Hoehn-Yahr stage in the substantia nigra.

Table 10. Pre-treatment NAA/creatine ratio by Hoehn-Yahr stage in the globus pallidus.

Pre-treatment NAA/creatine ratios varied across Hoehn-Yahr stages in both the substantia nigra (Table 9) and the globus pallidus (Table 10), with generally lower ratios in the most advanced stage, reflecting more pronounced neuronal loss (Figure 9).

Figure 9. Pre-treatment NAA/creatine ratios across Modified Hoehn-Yahr stages in the right and left substantia nigra (SN) and globus pallidus (GP); ratios were generally lowest at the most advanced stage (data from Tables 9 and 10).

Correlation between NAA/creatine ratios and UPDRS score

Table 11. Correlation between NAA/creatine ratios and UPDRS score.

A significant negative correlation was found between NAA/creatine ratios and UPDRS scores, with Pearson coefficients of -0.65 for the right and -0.58 for the left substantia nigra, and -0.62 for the right and -0.60 for the left globus pallidus (all p < 0.01; Table 11, Figure 10). Higher NAA/creatine ratios were therefore associated with lower (better) UPDRS scores.

Figure 10. Pearson correlation coefficients between regional NAA/creatine ratios and UPDRS score; all four regions showed a significant negative correlation (all p < 0.01) (data from Table 11).

Adverse events

Table 12. Adverse events after L-DOPA treatment.

Adverse events after L-DOPA treatment were mild and infrequent: three patients (15%) reported headache, two (10%) dizziness and one (5%) nausea, while 14 patients (70%) reported no adverse events (Table 12).

This study evaluated the utility of proton MRS in monitoring Parkinson’s disease and the therapeutic response to L-DOPA. The cohort of 20 patients had a mean age of 68.9 ± 6.46 years and a slight male predominance (65%), with a mean Hoehn-Yahr stage of 3, a profile that is consistent with the epidemiology of PD, which predominantly affects older adults and shows a higher risk in men. The reasons for the increased risk in men are incompletely understood and may relate to environmental exposures, the neuroprotective effect of oestrogen, mitochondrial factors, or a putative susceptibility locus on the X chromosome. Age and disease severity are important because more advanced age and stage are associated with greater neuronal loss, which influences both baseline and post-treatment metabolite levels. Proton MRS provides metabolic information non-invasively, and in this study we focused on the NAA/creatine ratio in the substantia nigra and globus pallidus, regions central to the pathophysiology of PD. NAA is a marker of neuronal health and density, whereas creatine is relatively stable and serves as an internal reference. The baseline ratios in our cohort—0.8825 and 1.12734 in the right and left substantia nigra and 0.98457 and 1.2489 in the right and left globus pallidus—indicate neuronal dysfunction in these structures and are in keeping with the reduced NAA/creatine ratios reported in previous 1H-MRS series of PD [23,24,25,26]. The mild right–left asymmetry observed at baseline mirrors the clinical asymmetry that characterises PD, in which symptoms and neurodegeneration are typically more severe on one side; this laterality has been demonstrated spectroscopically and is recognised in diagnostic criteria [27,28,29]. The globus pallidus is integral to basal ganglia circuitry, and the baseline abnormalities in this region are directly relevant to the motor manifestations of the disease. The central finding of this study is that three months of L-DOPA treatment produced significant increases in the NAA/creatine ratio in both the substantia nigra (right 0.8825 to 1.745; left 1.12734 to 1.58365) and the globus pallidus (right 0.98457 to 1.6935; left 1.2489 to 1.69365), all with p < 0.01. Because NAA reflects neuronal integrity, these increases suggest that dopaminergic therapy improves neuronal health and function, likely by replenishing dopamine and mitigating aspects of the neurodegenerative process. This interpretation is consistent with earlier reports that the reduced NAA-based ratios seen in untreated patients may be partially reversible with L-DOPA, providing a potentially reversible marker of striatal neuronal dysfunction. Several MRS studies have similarly evaluated the effect of L-DOPA on brain metabolism, examining dopamine-related metabolite turnover, NAA and choline changes in the basal ganglia, and energy-metabolism markers such as creatine and lactate, and have used advanced multi-voxel and spectroscopic imaging techniques to localise the regions most responsive to therapy. The metabolic improvements were mirrored by clinical improvement. The mean UPDRS score fell significantly from 40.5 ± 13.9 to 28.3 ± 12.1 (p < 0.01), and NAA/creatine ratios correlated negatively with UPDRS scores in all four regions (right substantia nigra r = -0.65, left -0.58; right globus pallidus -0.62, left -0.60; all p < 0.01). The concordance between rising NAA/creatine ratios and falling UPDRS scores strengthens the case that the spectroscopic change reflects a genuine, clinically meaningful treatment response rather than measurement noise, and supports the NAA/creatine ratio as a biomarker of both disease severity and therapeutic response. The analysis of NAA/creatine ratios by Hoehn-Yahr stage showed variation across stages in both regions, with the lowest ratios in the single stage 5 patient, in keeping with the expectation that more advanced disease is associated with greater neuronal loss or dysfunction. The relatively small number of patients within individual stages limits firm conclusions about stage-wise trends, but the overall pattern is consistent with the use of the NAA/creatine ratio as a marker of disease severity and progression. Prior work has drawn attention to the value of laterality in this context, noting that persistent asymmetry most often affects the side of symptom onset and that the difference in NAA/creatine ratios between the two hemispheres may relate to the course of the disease [27,28]. L-DOPA was generally well tolerated in this cohort. Adverse events were mild and infrequent, comprising headache in three patients (15%), dizziness in two (10%) and nausea in one (5%), with 70% of patients reporting no adverse events. This favourable tolerability profile is in line with the established safety of L-DOPA and supports its continued role as first-line therapy, while long-term use is known to carry a risk of motor fluctuations and dyskinesias mediated in part by serotonergic mechanisms [22]. Taken together, these findings indicate that proton MRS can non-invasively capture treatment-related neurochemical change in PD and that the NAA/creatine ratio in the substantia nigra and globus pallidus is a promising candidate biomarker for monitoring disease progression and response to dopaminergic therapy. The differential response between sides observed in some patients underscores the potential value of lateralised, individualised assessment, and the more marked changes in earlier-stage patients highlight the importance of timely intervention. Future work should include larger, multi-centre and longitudinal studies, the integration of MRS with complementary modalities such as PET and functional MRI, and the evaluation of additional metabolites such as choline and myo-inositol to improve sensitivity and specificity. STRENGTHS AND LIMITATIONS The principal strengths of this study are its prospective before-and-after design with complete follow-up, the paired within-patient comparison that controls for individual variability, and the combined use of a quantitative imaging biomarker (the NAA/creatine ratio) alongside a validated clinical instrument (the UPDRS), which allowed the metabolic and clinical responses to be directly correlated. The study also has important limitations. The sample size was small (n = 20) and drawn from a single centre, the follow-up was limited to three months, and the analysis focused on a single metabolite ratio, which constrains the assessment of longer-term and broader neurochemical change. The absence of a healthy control group and the uneven distribution of patients across Hoehn-Yahr stages further limit the strength of the stage-wise comparisons. These limitations should be addressed in larger, controlled, longitudinal studies.

This study demonstrates that three months of L-DOPA treatment significantly increased NAA/creatine ratios in the substantia nigra and globus pallidus of patients with Parkinson’s disease, and that these metabolic improvements correlated strongly with clinical improvement measured by the UPDRS. Proton MRS is therefore a promising non-invasive biomarker for monitoring disease progression and treatment response in PD, and treatment was generally well tolerated with minimal adverse events. Larger, multi-centre studies with longer follow-up and standardised protocols are needed to confirm these findings and to support the wider clinical adoption of MRS in the management of Parkinson’s disease.

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