Agenesis of the corpus callosum (AgCC) may occur with colpocephaly. ^{Reference Parker, Eilbert and Meehan1} We present a case of elevated neurodegenerative biomarker levels in a patient with colpocephaly and partial AgCC.

A patient in their 50s complained of behavioral and progressive memory and cognitive issues beginning in their mid-forties after having sustained a fall related mild traumatic brain injury (mTBI). Post-concussion symptoms developed including headache, vertigo and dizziness. The physical symptoms largely resolved but the cognitive complaints slowly worsened. Although working full time, the patient reported difficulties remembering recent training sessions, and misplacing objects. They endorsed issues with word-finding, phonemic substitution and following conversations with multiple participants. The patient expressed frustration with multi-tasking, problem-solving, planning and navigating in familiar places.

The patient was independent for basic and most instrumental activities of daily life but their partner was managing finances due to reduced organizational skills. Although irritable, the patient denied other neuropsychiatric symptoms. They reported body, hands and legs paresthesia and pain in the right arm, bilateral legs and lower back. They had tension type headaches once a week, positional vertigo and right ear tinnitus.

The patient had normal physical and psychomotor development and no dysmorphic features were found on the exam. They smoked until their early 20s and drank wine and beer occasionally. The patient used CPAP 4–6 hours/night for their sleep apnea and oral cannabinoids for chronic pain but was on no other medications. There was no familial history of neurodegenerative disease, developmental delay, cognitive impairment, epilepsy or genetic syndromes, but the patient’s father passed away from a stroke at age 60. The patient’s mother was alive at first assessment.

The patient underwent four consecutive, yearly visits consisting of a neuropsychological assessment (Toronto Cognitive Assessment [TORCA]) ^{Reference Freedman, Leach and Tartaglia2} or Montreal Cognitive Assessment (MOCA) and neurological exam. A lumbar puncture was performed according to Alzheimer’s Disease Neuroimaging Initiative protocol. ^{Reference Jack, Bernstein and Fox3} Laboratory investigations included an evaluation of Alzheimer’s disease (AD) biomarkers using an enzyme-linked immunosorbent assay to measure phosphorylated tau (pTau) (Innotest phospho-tau 181p, Fujirebio), total tau (T-Tau) (Innotest hTau-Ag, Fujirebio) and Amyloid beta 1-42 (Ab1-42) (Innotest B-Amyloid 1-42, Fujirebio) following the manufacturer’s instruction. A SIMOA immunoassay Neurology 2-Plex B assay kit was performed on an SR-X instrument (Quanterix) to measure cerebrospinal fluid (CSF) neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP).

During visit one, the patient scored 311/330 on the TorCA, which is in the normal range, but verbal memory on CERAD was low (Supplementary table 1). One year later, the patient scored 19/22 on a telephone Blind MOCA (lost 2 points for delayed recall, 1 for serial 7s). One year afterwards, the patient scored 23/30 (lost 1 point for clock, 1 for serial 7s and 5 points for delayed recall). A repeat TorCA performed four years after the first time point showed no change in score (308/330) and better performance on CERAD (Supplementary table 1). Neurological exam revealed mild atrophy in the right hypothenar eminence with occasional fasciculations with full power, normal tone, symmetrical 2+ reflexes and downgoing plantar response. Their partner helps open jars and cut their food. EMG/NCS performed in Oct. 2019 was normal. An MRI of the brain was ordered to investigate the patient’s reported dizziness. Incidentally, the T1 weighted 1.5T MRI showed partial AgCC and symmetrical biparietal atrophy (Fig. 1). Alzheimer’s biomarkers (Ab1-42, phospho tau, total tau), neurodegenerative and astrocytic markers (Table 1), suggest that the patient was negative for AD.

Figure 1: T1 weighted MRI images of a 51-year-old man with partial agenesis of the corpus callosum and colpocephaly. (a) Sagittal image showing dysgenesis of the corpus callosum with absent splenium.(b) Axial image illustrating the widely spaced bodies of the lateral ventricles (racing car sign) and the dilatation of the occipital horns of the lateral ventricles. (c) Axial image showing bilateral and symmetric parietal atrophy.

Table 1: Laboratory values of neurodegenerative markers found in the patient

ATI = Amyloid Beta/Tau Ratio; NfL = Neurofilament light chain; CSF GFAP = Cerebrospinal Fluid Glial fibrillary acidic protein.

To the best of our knowledge, this is the first description of elevated levels of CSF T-Tau, NfL and GFAP in a patient with partial AgCC and colpocephaly that was AD biomarker negative. While tau protein promotes the assembly of axonal microtubules, tau hyperphosphorylation results in pathological aggregation into neurofibrillary tangles, which is a neurodegenerative process. ^{Reference Wolfe9} NfL proteins aid neuronal stability but NfL is increased in neurodegenerative diseases. ^{Reference Gaetani, Blennow and Calabresi10} GFAP acts to support cytoskeletal structure within astrocytes. ^{Reference Benedet, Milà-Alomà and Vrillon8} Neurodegenerative disease may injure astrocytes resulting in the extracellular release of GFAP. ^{Reference Benedet, Milà-Alomà and Vrillon8}

The patient reported experiencing a singular mTBI over five years prior to the assessment. While mTBI can lead to neuronal-axonal damage, and is associated with increased levels of NfL and GFAP following an injury, they return to baseline in most cases of mTBI. ^{Reference Shahim, Zetterberg and Tegner11} Notably, a study on Swedish hockey players with mTBI, found that while serum Nfl levels are initially elevated, the levels normalized close to return to play. ^{Reference Shahim, Zetterberg and Tegner11} Therefore this patient’s elevated NfL and GFAP are unlikely related to mTBI. While previous cases of AgCC and colpocephaly did not measure neurodegenerative markers, ^{Reference Parker, Eilbert and Meehan1,Reference Kosky, Phenis and Kiselica12} the patient described by Kosky et al 2022, had symptoms that may be secondary to accelerated aging. ^{Reference Kosky, Phenis and Kiselica12} The gentleman reported forgetting events, and complained of issues with attention and multitasking. ^{Reference Kosky, Phenis and Kiselica12} While the investigators concluded that the cognitive issues were likely to remain stable as the patient ages, ^{Reference Kosky, Phenis and Kiselica12} testing for neurodegenerative markers may have provided valuable information.

In conclusion, we present the first case of elevated neurodegenerative biomarkers in a patient with colpocephaly and partial AgCC despite being negative for AD biomarkers. It is unclear whether these markers reflect the colpocephaly and partial AgCC, which may be a form of brain injury with astrocytic reaction. While our patient had a mTBI, it is unlikely to be related as it was a single injury many years before assessment. Our current understanding of the long-term impact of AgCC and colpocephaly remains poor. It is notable that both NfL and GFAP are elevated in this patient. An increasing number of MRIs may lead to further incidental cases being discovered, and prompt subsequent biofluid analysis of neurodegenerative markers to better capture the pathophysiology of this condition. While this is a developmental lesion, there may be evidence of neuro-axonal injury and astrogliosis in patients who present with AgCC. The long term effects of developmental abnormalities are not well understood and may be associated with accelerated neurodegeneration that is detectable through cerebrospinal fluid analysis. Therefore, further research investigating the significance of these elevated markers in AgCC and colpocephaly is warranted.