Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disease of the central nervous system characterized by optic neuritis and longitudinal transverse myelitis.1 An NMOSD-specific antibody that selectively binds to the water channel protein aquaporin 4 (AQP4) was recently found in the sera of patients with NMOSD.2 In addition to the typical manifestations of the disease, which include vision abnormalities, muscle weakness in the limbs, and body numbness, cognitive impairment has recently been reported to be one of the more prominent symptoms of NMOSD. However, longitudinal information about the trajectories of cognitive function in NMOSD is still scarce.
Here, we report the first case of early-onset Alzheimer disease (EOAD) associated with NMOSD in a patient experiencing rapid cognitive decline.
A 55-year-old right-handed Japanese woman (height, 147.6 cm; weight, 31.0 kg) with an 11-year history of NMOSD (Supplementary data, Supplemental Digital Content 1, https://links.lww.com/WAD/A404) was referred to the memory clinic of the National Center for Geriatrics and Gerontology. She was diagnosed with NMOSD at 44 years of age based on a positive cell-based assay for serum AQP4 antibody (AQP4-IgG). She had been taking prednisolone and azathioprine since the last relapse at age 45. Her family noticed apraxia when she was 51 years old. Brain magnetic resonance imaging did not find significant atrophy, and her symptoms were monitored. Over the next 4 years, she had progressive apraxia, memory loss, and executive and visuospatial dysfunction, and her literacy and word-finding skills declined. Functional decline was evident in many tasks, including inability to use familiar devices (eg, microwave and smartphone), slow response to instructions, and difficulty writing. At age 54 years, she was admitted to a rehabilitation hospital with a femoral fracture sustained in a fall due to loss of balance. She did not have surgery to repair the fracture. During the hospital stay, she developed delirium and was diagnosed with dementia. Donepezil was prescribed. Neurocognitive assessment at the rehabilitation hospital revealed a Mini-Mental State Examination (MMSE) score of 15/30. She was discharged to a care home 6 months before visiting our memory clinic.
On neurological examination, we observed grade 4/5 muscle weakness affecting the lower limbs and hyperactive deep tendon reflexes at the knees. Her gait was irregular and unsteady. There was loss of proprioception and vibration sense in the hands and feet. She had no history of smoking or misuse of alcohol or other substances. Laboratory screening was normal. There was no first-degree family history of presenile dementia. She had normal hearing. She had 12 years of education and had worked part time until she was diagnosed with NMOSD. Neurocognitive assessment at the initial examination revealed an MMSE score of 12/30, Alzheimer Disease Assessment Scale (ADAS) score of 27/70, Frontal Assessment Battery (FAB) score of 5/18, Digit Span Forward test score of 2 on the Wechsler Adult Intelligence Scale, Digit Span Backward score of 3, and WMS-R Logical memory I and II scores of 2 and 0, respectively. There was no evidence of depression or psychotic symptoms.
Brain magnetic resonance imaging showed mild atrophy with left-sided predominance in the temporoparietal and frontal lobes (Fig. 1A). Brain perfusion single-photon emission computed tomography imaging showed bilateral hypoperfusion of the parietal and posterior temporal lobes, posterior cingulate cortex, and precuneus with left-sided predominance suggestive of Alzheimer disease (AD). Marked accumulation of amyloid beta (Aβ) was found on 18F-flutemetamol PET of the frontal, parietal and temporal lobes, posterior cingulate gyrus, and precuneus (Fig. 1B). On 18F-MK6240 tau PET, a high degree of tau deposition corresponding to Braak tangle stage V-VI was evident in the temporal, parietal, and frontal lobes; posterior cingulate gyrus; and precuneus (Fig. 1C). 18F-Fluorodeoxyglucose PET scans revealed decreased glucose metabolism from the inferior parietal lobule to the mid-anterior temporal lobe, frontal association cortex, posterior cingulate cortex, and precuneus, predominantly on the left side (Fig. 1D). Apolipoprotein E genotype molecular examination showed genotype E3/E3. Mutations in APP, PSEN1, PSEN2, PGRN, and MAPT were also tested. Whole-genome sequencing revealed synonymous variants (A23A, N43N, and H87H) in PSEN2 and a common missense variant (rs2258689) in MAPT. However, any mutations previously reported to lead to EOAD were not detected.
The patient’s history, neuroimaging results, and cognitive test results all satisfied the National Institute on Aging and Alzheimer’s Association criteria for probable AD dementia with evidence of the AD pathophysiological process. Memantine was prescribed at AD diagnosis in addition to donepezil. In the 6 months after the diagnosis, the patient’s memory loss, executive and visuospatial function, and apraxia worsened. She became increasingly absentminded and got lost in the care home more often. Her mood swings became more extreme, and her decision-making skills declined. Memantine was increased to 10 mg/d. One year after the AD diagnosis, at age 56 years, neurocognitive assessment revealed continuing decline, with scores of 7/30 on the MMSE, 38/70 on the ADAS, 6/18 on the FAB, 3 on the Digit Span Forward test, 0 on the Digit Span Backward test, and 0 on both the WMS-R Logical memory I and II. She did not want to bathe, could not change her clothes, could not speak or eat on her own initiative, and had worsening incontinence.
This is the first report of NMOSD in a patient diagnosed with sporadic EOAD. The clinical relevance in this case is that, despite being rare, complications of AD should be considered when patients with NMOSD show rapid cognitive decline.
No previous reports have described patients with NMOSD and AD pathology in the brain3 or suspected AD based on cerebrospinal fluid findings. However, EOAD is the most common early-onset neurodegenerative dementia and the vast majority of cases are nonfamilial, accounting for about 4% to 6% of all AD cases. EOAD often has an atypical presentation and diagnosis is missed, resulting in about a 1.6-year delay in diagnosis on average compared with older patients.4 Our patient was observed for 4 years following the onset of cognitive impairment. Several studies have indicated that the clinical course of EOAD is more rapid than that of late-onset AD.5 A previous study showed that MMSE score in patients with EOAD decreased by 1 point at 1 year after onset and by 3 points at 2 years compared with respective decreases of 0.5 and 2.2 points in patients with late-onset AD.5 On the other hand, cognitive disorders have been found in 35% to 67% of patients with NMOSD, mainly in memory, attention, and information processing speed.6 The trajectories of cognitive function have been often compared with those in MS.7 The progression of NMOSD including cognitive impairment is considered relatively slow compared with MS, but the progression of cognitive decline in MS is known to vary depending on relapse.8 Although cognitive impairment is detected in most patients with NMOSD, little is known about the course of cognitive decline.
Based on these previous reports, our patient showed a more rapid progression of cognitive impairment than would be typical in NMOSD or EOAD alone. Clinical and demographic factors such as age, level of education, level of neurological disability, mood disorders, and disease duration may influence cognitive dysfunction in NMOSD patients,9 but in our case, only a long history of NMOSD was identified as a risk factor for cognitive decline.
Recent studies have revealed that AQP4 plays an important role in the clearance of amyloid from the brain via lymphatic function, clearance, transcytosis delivery, and glial degradation, as well as in synaptic function. In fact, an increase in Aβ deposition has been observed in AQP4-knockout mice with a predisposition to AD (APP/PS1 mice).10 Although it is not clear why our patient had such rapid cognitive decline, defects in the abovementioned mechanisms due to the presence of AQP4-IgG might have contributed to the accumulation of Aβ or rapid progression of cognitive impairment. Although no other cases of NMOSD associated with EOAD have been reported, there may have been cases of NMOSD in which EOAD was suspected but tests for biomarkers of AD, including PET, were not available. More longitudinal studies on NMOSD with cognitive impairment are needed.
In conclusion, this is the first report of a case of NMOSD associated with sporadic EOAD. Despite its rarity, this case suggests that complications of AD be considered when patients with NMOSD exhibit rapid cognitive decline.
The authors thank the Biobank and National Center for Geriatrics and Gerontology for quality control of the clinical samples and data.
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