What if a questionnaire for autonomic symptoms could reveal a major signature of a rare neurodegenerative disease? In this study, autonomic dysfunction affected nearly all patients with NIID. Neuronal intranuclear inclusion disease, or NIID, is a rare neurodegenerative disease characterized by intranuclear inclusions in the central and peripheral nervous systems and in other organs.

In twenty nineteen, an expansion of GGC repeats in the five-prime untranslated region of the NOTCH2NLC gene was associated with individuals with NIID, mostly in people of Asian origin. Clinically, NIID symptoms are highly heterogeneous, including progressive dementia and cognitive impairment, parkinsonism, stroke-like episodes, encephalitic episodes, cerebellar ataxia, sensory disturbance, peripheral neuropathy, and autonomic dysfunction.

This study aimed to use SCOPA-AUT to investigate the prevalence and clinical characteristics of autonomic dysfunction in patients with NIID, along with correlations between autonomic dysfunction and other NIID symptoms in a large cohort. A total of one hundred twenty-two patients with genetically confirmed NIID were enrolled between January twenty eighteen and December twenty twenty-one, and all patients were evaluated by at least two neurologists.

NIID was diagnosed based on clinical features and abnormal GGC repeats greater than sixty-five within NOTCH2NLC. One hundred twenty-two age- and sex-matched healthy controls were enrolled, with genetic tests performed to exclude NIID. The study was approved by the Ethics Committee of Xiangya Hospital, Central South University, and written informed consent was obtained from all participants at enrollment.

Clinical manifestation data were collected during clinical examination interviews, and SCOPA-AUT was used to assess autonomic dysfunction in all participants. For patients, the Mini-Mental State Examination, Montreal Cognitive Assessment Scale, and Frontal Assessment Battery screened for cognitive impairments; the Neuropsychiatric Inventory assessed mental problems; and the Activities of Daily Living scale assessed daily living activities.

Repeat-primed PCR and GC-rich PCR assays were performed to confirm GGC expanded repeats within NOTCH2NLC. In patients with NIID, ninety-four point twenty-six percent, or one hundred fifteen of one hundred twenty-two, had autonomic dysfunction. The most frequently affected domain was urinary, followed by gastrointestinal, thermoregulatory, cardiovascular, pupillomotor, and sexual domains.

The median SCOPA-AUT score was eleven, with a range from four to eighteen. Compared with controls, patients with NIID displayed more severe autonomic dysfunction in the total SCOPA-AUT, gastrointestinal, urinary, cardiovascular, thermoregulatory, and pupillomotor domains.

Table two compares autonomic symptom severity in one hundred twenty-two patients and one hundred twenty-two controls, using the SCOPA-AUT scale and the percentage reporting each symptom. The total median score was eleven in patients versus two in controls, with adjusted p-values below zero point zero zero one; urinary symptoms were especially prominent, including nocturia in sixty-eight point zero three percent and incomplete bladder emptying in forty-nine point eighteen percent of patients.

This matters because it maps the broad autonomic burden across gastrointestinal, urinary, cardiovascular, thermoregulatory, pupillomotor, and sexual domains. To detect the diagnostic accuracy of SCOPA-AUT for autonomic dysfunction in NIID, ROC curve analysis was performed.

The highest area under the curve was for total SCOPA-AUT, at zero point eight four six, with sixty-nine point seven percent sensitivity, eighty-five point two percent specificity, and a cutoff value of four point five. The gastrointestinal domain had an area under the curve of zero point seven six five, while the urinary domain had an area under the curve of zero point seven seven six.

The area under the curve values for the other domains were below zero point seven, while SCOPA-AUT, gastrointestinal symptoms, and urinary symptoms showed high diagnostic performance in differentiating patients with NIID from healthy controls. Table three evaluates SCOPA-AUT for identifying autonomic dysfunction in NIID, using sensitivity, specificity, cutoff values, and ROC area under the curve.

The total score had an AUC of zero point eight four six, with a cutoff of four point five, while gastrointestinal and urinary domains had AUCs of zero point seven six five and zero point seven seven six. Most domains showed p-values below zero point zero zero one, whereas the sexual domain showed an AUC of zero point five one two and a p-value of zero point seven five two.

This figure shows receiver operating characteristic curves for the total SCOPA-AUT score and its gastrointestinal and urinary domains, assessing their ability to identify autonomic dysfunction in NIID. Each curve plots sensitivity against one minus specificity, with the dashed diagonal representing chance-level discrimination.

The authors report area-under-the-curve values of zero point eight four six for the total score, zero point seven six five for gastrointestinal functioning, and zero point seven seven six for urinary functioning, supporting SCOPA-AUT as a diagnostic assessment. Compared with a previous study, patients with multiple system atrophy had higher scores in total SCOPA-AUT, the urinary domain, and the sexual domain, while patients with NIID in this study had a higher score in the digestive system.

These findings suggest that the severity and involved domain of autonomic dysfunction differed between NIID and other neurodegenerative diseases. This study referred only to autonomic nervous dysfunction in patients with adult-onset NIID, and further longitudinal studies are needed to elucidate its mechanism and changes during disease duration.

The study did not combine the corresponding autonomic nerve function examination because some patients were in an acute stage and could not complete objective tests such as Quantitative Sudomotor Axon Reflex Tests or urodynamic studies. Only fourteen patients underwent bladder residual urine volume examination, of whom ten showed increased bladder residual urine volume.

For patients with NIID, objective examination of autonomic nervous function is necessary, and further studies with larger sample size are needed. SCOPA-AUT also had a limitation in assessing autonomic dysfunction in NIID: episodic vomiting, frequently observed in many patients with NIID, was not included.

Autonomic dysfunction was highly prevalent in this NIID cohort, with urinary and gastrointestinal symptoms especially prominent. SCOPA-AUT showed useful diagnostic performance, but objective and longitudinal testing is still needed.