The striatum, the structure examined in the new study, is not a single functional unit but a set of anatomically and functionally segregated territories. The dorsal putamen receives its strongest inputs from motor cortical areas and is thought to support the execution and sequencing of movement, while the caudate nucleus is densely connected with prefrontal and limbic regions that govern executive control, motivation, and affect. This division explains why the topography of dopamine loss within the striatum can carry clinical meaning: when dopaminergic denervation remains confined largely to the putamen, the motor circuitry bears the brunt of the deficit, whereas extension into the caudate brings associative and limbic loops into the pathological process. The authors of the study exploited this organization by classifying patients according to whether their dopamine transporter imaging showed isolated putaminal involvement or combined putaminal and caudate involvement, and then asked whether that imaging signature predicted what happened to them clinically over the following five years.

Dopamine transporter imaging with single-photon emission computed tomography using the radioligand iodine-123 labeled FP-CIT has become a standard tool in the evaluation of parkinsonian syndromes. The technique measures the density of presynaptic dopamine transporters in the striatum, which fall as nigrostriatal dopaminergic neurons degenerate. Its established role is diagnostic: it reliably distinguishes parkinsonian syndromes associated with nigrostriatal degeneration from conditions such as essential tremor or drug-induced parkinsonism, in which transporter binding is preserved. What it cannot do, on its own, is separate Parkinson’s disease from dementia with Lewy bodies, because both conditions involve loss of nigrostriatal terminals and produce visually similar scans. The current study suggests that the regional pattern of that loss, rather than its mere presence, may carry prognostic information that transcends this diagnostic limitation.

The numbers reported in the study are striking in their separation between the two groups. Among the sixteen patients whose scans showed caudate involvement, roughly one in three already met criteria for cognitive impairment at the initial assessment, while none of the twelve patients with isolated putaminal involvement did. Five years later, the divergence had widened dramatically: the large majority of the caudate-involvement group scored below the validated Italian threshold for definite cognitive impairment on the Montreal Cognitive Assessment, whereas only a small fraction of the putamen-only group had crossed that line. The Montreal Cognitive Assessment is a brief screening instrument covering orientation, attention, executive function, language, abstraction, memory, and visuospatial abilities, and the Italian population-specific cut-off used in the study was chosen to reduce false positives that arise when thresholds derived from other populations are applied. The fact that group differences survived using a locally validated threshold strengthens the argument that the cognitive divergence was genuine rather than an artifact of scoring conventions.

The neuropsychiatric findings deserve particular attention. At baseline, psychiatric symptoms were already more prevalent among patients with caudate involvement, and during follow-up a subset of these patients developed visual hallucinations, a symptom classically associated with the dementia with Lewy bodies end of the Lewy body disease spectrum. This convergence of cognitive decline, psychiatric manifestations, and hallucinations in the same imaging-defined subgroup is consistent with the idea that caudate denervation is not an isolated radiological curiosity but a marker of more widespread disease involvement. Neuropathological work over several decades has described a caudal-to-rostral progression of Lewy body pathology through the brain, and dopaminergic depletion within the striatum does not advance uniformly: the putamen is typically affected earlier and more severely than the caudate in classical Parkinson’s disease. When the caudate is drawn into the degenerative process early, it plausibly signals a faster or more extensive ascending pathology, which would be expected to recruit the cortical and limbic networks that subserve cognition and behavior.

The connection between caudate dopamine loss and executive dysfunction has substantial independent support. Positron emission tomography and single-photon emission studies have repeatedly linked dopaminergic function in the caudate to performance on tasks of executive control and to global cognitive status in Parkinson’s disease, and longitudinal imaging work has associated early caudate dysfunction with accelerated cognitive decline and increased dementia risk. The new study adds a longitudinal clinical dimension to this literature by following patients for five years and showing that the imaging pattern at baseline anticipated not only cognitive trajectories but also the emergence of neuropsychiatric features. This is important because most prior evidence linking striatal subregions to cognition has been cross-sectional, which cannot establish whether the imaging finding precedes the clinical outcome.

Retrospective assessment of premotor symptoms adds another layer to the phenotype. The study screened for REM sleep behavior disorder using the One-Question Mayo Sleep Questionnaire, a validated instrument that asks about dream enactment behaviors and has high sensitivity for identifying probable REM sleep behavior disorder. This condition, in which patients physically act out their dreams because the normal muscle atonia of REM sleep is lost, is among the strongest known prodromal markers of synucleinopathy, often preceding the onset of motor parkinsonism by years or even decades. The study also gathered retrospective information on mood disorders predating motor symptoms, corroborated where possible through caregiver interviews and medical records. Incorporating these premotor features into the characterization of the two imaging groups reflects a growing recognition that the earliest stages of Lewy body disease unfold long before a motor diagnosis is possible, and that the constellation of prodromal symptoms may differ across patients who will ultimately follow different clinical trajectories.

The study’s design carries both strengths and limitations that readers should weigh. Its longitudinal nature, with five years of clinical follow-up, is a considerable advantage over the cross-sectional designs that dominate much of the imaging literature in parkinsonism. The cohort, however, was modest in size, with twenty-eight patients divided into two groups, and the patients were recruited from a single movement disorders center in Italy. Small samples limit statistical power and precision, and the reported proportions, such as the eighty-three percent versus nine percent divergence in cognitive impairment at five years, should be interpreted as hypothesis-generating rather than definitive estimates of effect size. The classification into putamen-only versus combined involvement was based on manual placement of regions of interest with the occipital cortex as reference tissue, a semi-quantitative approach that is practical in clinical settings but less standardized than fully automated quantitative pipelines. In addition, all patients initially fulfilled clinical diagnostic criteria for Parkinson’s disease, so the cohort by design excluded patients presenting with overt dementia at onset, which means the findings speak to early-stage disease rather than to the full breadth of the Lewy body spectrum.

The concept that Parkinson’s disease and dementia with Lewy bodies represent poles of a single disease continuum rather than discrete entities has gained substantial traction in recent years. The two disorders share the hallmark neuronal inclusions composed of alpha-synuclein, and clinical features overlap extensively: cognitive impairment, visual hallucinations, REM sleep behavior disorder, autonomic dysfunction, and parkinsonism occur in both, differing mainly in the timing of their appearance relative to one another. The one-year rule, under which dementia beginning within a year of motor symptoms points toward dementia with Lewy bodies and dementia arising later points toward Parkinson’s disease dementia, remains the conventional clinical distinction, but it is widely acknowledged to be an arbitrary boundary on a continuous landscape. Biomarkers that can position an individual patient along this continuum earlier in the disease course would therefore be valuable both for prognosis and for the design of clinical trials, in which cognitive trajectory is increasingly recognized as a key outcome.

Against that background, the study’s central message is that dopamine transporter imaging, an investigation already performed routinely in the diagnostic workup of parkinsonism, may yield prognostic information at no additional cost or burden to the patient. Rather than serving solely to confirm or exclude nigrostriatal degeneration, the scan’s regional pattern could help clinicians identify, at the time of diagnosis, which patients are likely to experience cognitive and neuropsychiatric deterioration over the coming years. Such identification has practical consequences: patients flagged as being on a faster-declining trajectory could be prioritized for closer cognitive monitoring, earlier consideration of interventions targeting cognition, more careful management of medications with potential cognitive or psychiatric side effects, and earlier counseling of patients and families about what to expect. It could also inform stratification in research settings, ensuring that trials of disease-modifying or cognitive therapies enroll cohorts defined not only by motor severity but by predicted trajectory.

Several questions remain open for future research. It is not yet known whether the caudate-involvement phenotype corresponds to a specific underlying pathological substrate that could be confirmed by emerging alpha-synuclein biomarkers in cerebrospinal fluid or by other imaging modalities. Nor is it clear whether the pattern is stable over time or whether patients with isolated putaminal involvement eventually develop caudate denervation as their disease progresses, which would make the baseline distinction a matter of timing rather than of fundamentally different disease types. Replication in larger, multicenter cohorts with longer follow-up would be needed to establish the finding’s robustness and to determine whether the imaging pattern adds prognostic value beyond established clinical predictors such as age, baseline cognition, and the presence of REM sleep behavior disorder. Combining striatal topography with other biomarkers, including cardiac sympathetic imaging, olfactory testing, and fluid-based markers of synuclein pathology, may ultimately yield a multidimensional staging framework in which no single test is decisive but convergent evidence positions each patient along the spectrum with useful confidence.

For clinicians seeing patients with early parkinsonism, the study offers a concrete and immediately applicable observation: when reviewing a dopamine transporter scan, attention to whether the caudate nucleus is spared or involved may be as informative as the overall degree of putaminal signal reduction. For patients and families, the finding underscores that the earliest years after diagnosis are not clinically uniform, and that individual trajectories can differ substantially in the pace at which thinking, mood, and perception are affected. For the research community, it reinforces the view that heterogeneity within the Lewy body diseases is not noise to be averaged away but signal to be decoded, and that the anatomical fingerprint of dopaminergic degeneration visible on a routine nuclear medicine scan may be one of the more accessible keys to that decoding.

Subject of Research: Striatal dopaminergic denervation patterns as prognostic markers in Lewy body disease

Article Title: Early caudate involvement marks a Lewy body spectrum phenotype in parkinsonism: a 5-year longitudinal study

Article References: Early caudate involvement marks a Lewy body spectrum phenotype in parkinsonism: a 5-year longitudinal study. (n.d.). https://doi.org/10.3389/fneur.2026.1895109

Image Credits: AI Generated

DOI: 10.3389/fneur.2026.1895109

Keywords: Parkinson's disease, dementia with Lewy bodies, DAT-SPECT, caudate nucleus, cognitive decline, Lewy body disease, parkinsonism, visual hallucinations, neuropsychiatric symptoms, putamen, MoCA, longitudinal study