The diagnosis of idiopathic normal pressure hydrocephalus (iNPH) is sometimes complicated by concomitant Alzheimer's disease (AD) pathology. The purpose of the present study is to identify an iNPH-specific cerebrospinal fluid (CSF) biomarker dynamics and to assess its ability to differentiate iNPH from AD. Total tau (t-tau), tau phosphorylated at threonine 181 (p-tau), amyloid-β (Aβ) 42 and 40, and leucine-rich α-2-glycoprotein (LRG) were measured in 93 consecutive CSF samples consisting of 55 iNPH (46 tap test responders), 20 AD, 11 corticobasal syndrome, and 7 spinocerebeller disease. Levels of t-tau and p-tau were significantly decreased in iNPH patients especially in tap test responders compared to AD. Correlation was observed between Mini-Mental State Examination scores and Aβ42 in AD (R = 0.44) and mildly in iNPH (R = 0.28). Although Aβ42/40 ratio showed no significant difference between iNPH and AD (p = 0.08), the levels of Aβ40 and Aβ42 correlated positively with each other in iNPH (R = 0.73) but much less in AD (R = 0.26), suggesting that they have discrete amyloid clearance and pathology. LRG levels did not differ between the two. Thus, our study shows that although CSF biomarkers of iNPH patients can be affected by concomitant tau and/or amyloid pathology, CSF t-tau and p-tau are highly useful for differentiation of iNPH and AD.

BackgroundIdiopathic normal pressure hydrocephalus (iNPH) is a treatable cause of dementia, gait disturbance, and urinary incontinence in elderly patients with ventriculomegaly. Its unique morphological feature, called disproportionately enlarged subarachnoid-space hydrocephalus (DESH), may also be a diagnostic feature. Lipocalin-type prostaglandin D synthase (L-PGDS) is a major cerebrospinal fluid (CSF) protein produced by arachnoid cells, and its concentration in the CSF is reportedly decreased in iNPH. L-PGDS acts as a prostaglandin D2-producing enzyme and behaves as a chaperone to prevent the neurotoxic aggregation of amyloid beta (Aβ) implicated in Alzheimer’s disease, a major comorbidity of iNPH. The aim of this study was to confirm the L-PGDS decrease in DESH-type iNPH and to clarify its relationship with clinico-radiological features or other CSF biomarkers.MethodsWe evaluated 22 patients (age: 76.4 ± 4.4 y; males: 10, females: 12) referred for ventriculomegaly without CSF pathway obstruction, and conducted a CSF tap test to determine the surgical indication. CSF concentrations of L-PGDS, Aβ42, Aβ40, and total tau (t-tau) protein were determined using enzyme-linked immunosorbent assays. Clinical symptoms were evaluated by the iNPH grading scale, mini-mental state examination, frontal assessment battery (FAB), and timed up and go test. The extent of DESH was approximated by the callosal angle, and the severity of parenchymal damage was evaluated by the age-related white matter change (ARWMC) score.ResultsL-PGDS and t-tau levels in CSF were significantly decreased in DESH patients compared to non-DESH patients (p = 0.013 and p = 0.003, respectively). L-PGDS and t-tau showed a significant positive correlation (Spearman r = 0.753, p < 0.001). Among the clinico-radiological profiles, L-PGDS levels correlated positively with age (Spearman r = 0.602, p = 0.004), callosal angle (Spearman r = 0.592, p = 0.004), and ARWMC scores (Spearman r = 0.652, p = 0.001), but were negatively correlated with FAB scores (Spearman r = 0.641, p = 0.004).ConclusionsOur data support the diagnostic value of L-PGDS as a CSF biomarker for iNPH and suggest a possible interaction between L-PGDS and tau protein. In addition, L-PGDS might work as a surrogate marker for DESH features, white matter damage, and frontal lobe dysfunction.

Even now, only a portion of leukodystrophy patients are correctly diagnosed, though various causative genes have been identified. In the present report, we describe a case of adult-onset leukodystrophy in a woman with ovarian failure. By whole-exome sequencing, a compound heterozygous mutation consisting of NM_020745.3 (AARS2_v001):c.1145C>A and NM_020745.3 (AARS2_v001):c.2255+1G>A was identified. Neither of the mutations has been previously reported, and this is the first report of alanyl-transfer RNA synthetase 2 mutation in Asia. We anticipate that further studies of the molecular basis of leukodystrophy will provide insight into its pathogenesis and hopefully lead to sophisticated diagnostic and treatment strategies.

We recently reported clinical anticipation in Japanese families with benign adult familial myoclonus epilepsy (BAFME). However, it remains unknown whether clinical anticipation is predominantly associated with paternal or maternal transmission. We investigated the relationship between gender of the transmitting parent and clinical anticipation in nine BAFME families. Clinical anticipation regarding either cortical tremor or generalised seizures was observed in all 12 parent/child pairs (8 mother/child pairs and 4 father/child pairs). Moreover, a higher degree of clinical anticipation was associated with maternal transmission than with paternal transmission (p=0.03). Although a causative gene for BAFME still remains unknown, our finding suggests that BAFME and diseases with unstable expanding repeats, including those in non‐coding regions, might share a similar molecular mechanism because such diseases often show clinical anticipation with maternal transmission.

Background. Brain dysfunction in Japanese benign adult familial myoclonus epilepsy (BAFME) has not been elucidated. Aim. To clarify diffuse brain dysfunction as indicated by posterior dominant rhythm (PDR) slowing in patients with BAFME. Methods. The frequency of PDR on EEG was studied in 19 BAFME patients (50.6±15.7 years) and 38 age‐matched control subjects (50.1±14.5 years). We investigated the relationship between age and PDR in both groups. Results. PDR frequency in the patient group (9.1±0.7 Hz) was significantly slower than that of age‐matched control subjects (10.4±1.1 Hz; p<0.0001), regardless of the use of anticonvulsants. There was no significant difference in PDR slowing with age between groups. Conclusion. These findings suggest that Japanese patients with BAFME have mild diffuse brain dysfunction with minimal progression.