NIID can look like many different diseases, but a distinctive diffusion MRI pattern may reveal what is really happening. This study asks how clinical symptoms and several imaging methods fit together. Neuronal intranuclear inclusion disease, or NIID, is a rare progressive neurodegenerative condition characterized by widespread eosinophilic intranuclear inclusions in cells of the nervous system and visceral organs.

Its clinical manifestations are significantly heterogeneous and can be classified as central, peripheral, or autonomic nervous system symptoms. NIID is categorized into infantile, adolescent, and adult types, and adult NIID is further categorized into familial and disseminated types based on genetic characteristics.

Clear diagnostic criteria for NIID have yet to be established. The three main bases for clinical diagnosis are a characteristic high diffusion-weighted imaging signal in the corticomedullary junction area, eosinophilic intranuclear inclusion bodies in skin biopsy, and abnormal amplification of the GGC sequence in the five-prime untranslated region of the NOTCH2NLC gene.

The high signal at the corticomedullary junction on diffusion-weighted imaging is used as the strongest and most readily available evidence guiding further skin biopsy and diagnosis. That is why early recognition of NIID imaging features is significant. The study aimed to analyze the clinical and imaging manifestations of 40 adult-onset NIID patients to provide information for early and accurate diagnosis.

It also aimed to investigate NIID-specific neuroimaging biomarkers through multimodal imaging findings and chronologically varying dynamic MRI evolution patterns. Finally, it aimed to investigate factors influencing white matter hyper-signalization and produce new imaging perspectives on the neuropathological mechanisms of the disease.

Forty patients, including 15 males and 25 females aged between 31 and 77 years, were retrospectively enrolled from Qilu Hospital of Shandong University between January 2019 and January 2024. The patients consisted of three patients from one pedigree and 37 individuals affected sporadically.

Magnetic resonance imaging was performed on a Siemens Magnetom Verio 3.0 Tesla scanner with a standard 20-channel receive head and neck coil. During scanning, participants were instructed to keep their eyes closed and remain still.

MRI scanning included T1-weighted fluid-attenuated inversion recovery, fast spin-echo T2-weighted imaging, fluid-attenuated inversion recovery, and diffusion-weighted imaging for all patients. Each patient’s Fazekas grade was then categorized into three severity groups based on fluid-attenuated inversion recovery imaging.

Categorical variables were summarized with frequencies and percentages, while numerical variables were summarized with medians and ranges. All quantitative data were tested for normality using the Shapiro-Wilk test.

T-tests were used for normally distributed data, while Mann-Whitney U or Kruskal-Wallis tests were used for non-normally distributed data. For categorical variables, the chi-squared test was employed. Symptoms varied from single to multiple presentations across individuals, with cognitive impairment observed in 30 patients and reported as the initial symptom by 10 patients.

Idiopathic tremor was the initial diagnosis in three cases. Nearly half of the participants experienced paroxysmal symptoms, with episodic headaches accompanied by nausea and vomiting being the most prevalent. Autonomic dysfunction was significant, with up to 20 percent of patients experiencing dysuria or urinary incontinence, and these symptoms sometimes preceded central nervous system manifestations by several years.

Table One profiles forty patients with NIID, diagnosed at a median age of sixty-three years, with fifteen men and twenty-five women. Cognitive impairment affected thirty patients, or seventy-five percent; among the twenty-eight who completed testing, the median MMSE was twenty-one and the median MoCA was fourteen.

The table also documents movement disorders in twenty-one patients, paroxysmal symptoms in eighteen, and smaller groups with autonomic or other symptoms, showing the broad clinical range of NIID. The most characteristic imaging manifestation was a curvilinear high signal in the corticomedullary junction area on diffusion-weighted imaging.

A typical subcortical lace sign appeared in 32 of 40 patients, or 80 percent, and it was most commonly observed in the frontal lobes. Most cases, 29 of 32, showed a symmetrical distribution extending along the subcortex without deep white matter involvement, while three patients had an asymmetric high signal in one frontal lobe.

Diffusion-weighted imaging hyperintensity also appeared in the corpus callosum in 22 of 40 patients, or 55 percent, and in the cerebellum in 15 of 40 patients, or 37.5 percent. Figure one assembles the major brain-imaging and pathological features reported in neuronal intranuclear inclusion disease.

Diffusion-weighted images show the characteristic subcortical lace-like signal at the corticomedullary junction, along with involvement of the corpus callosum and middle cerebellar peduncle, while other panels illustrate diffuse white-matter signal or an absent typical DWI pattern.

FLAIR, diffusion-tensor imaging, magnetic resonance spectroscopy, and skin biopsy add evidence of leukoencephalopathy, fiber thinning, no significant metabolic abnormality, and eosinophilic nuclear inclusions. Dynamic MRI changes were evaluated in 19 patients with NIID.

Eight patients exhibited alterations in abnormally high diffusion-weighted imaging signal intensities, mainly showing persistence and gradual progression with disease progression. Signals disappeared in several cases during follow-up. The remaining 11 patients showed no significant MRI changes during follow-up.

Diffusion tensor imaging revealed extensive damage to white matter fiber bundles, including U-shaped fibers, the corpus callosum, and pyramidal tracts. Five patients’ proton magnetic resonance spectra showed no significant abnormal metabolism compared to healthy controls, despite high signal intensity on diffusion-weighted imaging in the corticomedullary junction area.

NIID is a highly heterogeneous disease with variable, nonspecific clinical manifestations. Cognitive impairment was the most common manifestation, and the Montreal Cognitive Assessment was more sensitive in identifying cognitive impairment in NIID patients.

Half of the patients presented with paroxysmal symptoms, and headache accompanied by nausea and vomiting was frequently misdiagnosed because of its lack of specificity. Bladder dysfunction was the most common autonomic symptom, and urinary incontinence may develop six to eight years before the onset of cognitive symptoms.

Figure three examines brain age against chronological age in patients with neuronal intranuclear inclusion disease, using three views. The left panel compares estimated brain age with the identity line, the middle shows the brain-age gap, and the right shows the relative difference.

Most plotted observations lie above zero in the gap and relative-difference panels, indicating that the figure reports brain-age estimates exceeding patients’ chronological ages, supporting brain age as a way to characterize age-related brain changes in NIID. The cohort of NIID patients was limited in size, and neuropsychological assessment data were incomplete for some patients.

The study used only the MMSE and MoCA scales to assess the presence of cognitive impairment, and these scales may not comprehensively detect all aspects of cognitive profile, particularly among younger patients. There was also a lack of longitudinal follow-up of functional imaging performance.

Further research is needed to explore alterations in brain microstructure and substance metabolism to understand the pathogenesis of this condition better. Adult-onset NIID showed broad clinical variation, but diffusion MRI frequently revealed a characteristic corticomedullary junction signal, alongside white-matter damage and advanced estimated brain aging.