Largen: a molecular regulator of mammalian cell size control.

Little is known about how mammalian cells maintain cell size homeostasis. We conducted a novel genetic screen to identify cell-size-controlling genes and isolated Largen, the product of a gene (PRR16) that increased cell size upon overexpression in human cells. In vitro evidence indicated that Largen preferentially stimulates the translation of specific subsets of mRNAs, including those encoding proteins affecting mitochondrial functions. The involvement of Largen in mitochondrial respiration was consistent with the increased mitochondrial mass and greater ATP production in Largen-overexpressing cells. Furthermore, Largen overexpression led to increased cell size in vivo, as revealed by analyses of conditional Largen transgenic mice. Our results establish Largen as an important link between mRNA translation, mitochondrial functions, and the control of mammalian cell size.

[Voluntary return of driver's license and the related activity of a neurocognitive center in Okayama prefecture].

Due to the rapid increase in traffic accidents caused by the old populations of ages 65-74 and more than 75 in Japan, the renewal of driver's licenses has become more difficult following the revision of traffic laws in March 2017. As part of the driver's license clinic at Kurashiki Heisei Hospital, the present study investigated the status of voluntary license surrender in Okayama Prefecture of Japan. From March 2017 to December 2019, the number of voluntary surrenders increased from 5,434 to 10,284 cases, or at a rate of 0.42% to 0.80%, among license holders, with the old-old accounting for 68%-77% of voluntary surrenders. The major reasons for surrender were a decline in physical ability (25%-38%), a decline in driving needs (28%-60%), and family's suggestion (14%-17%). The increase in voluntary license surrender over these 3 years was common across all municipalities within Okayama Prefecture, but the surrender rate was closely correlated with the aged-society rate for both old populations of ages 65-74 and more than 75 (r = -0.5508, **p = 0.002 and r = -0.3086, p = 0.110, respectively). The driver's license clinic at Kurashiki Heisei Hospital received 110 visits during the 3-year period, in which MCI (mild cognitive impairment) accounted for 67% of voluntary surrenders (21.8%). The present study suggests that the increase in the rate of voluntary license surrender during the 3-year period was closely related to the aged-society rate in Okayama Prefecture, and that a driver's license clinic provides a detailed dementia status among license holders who have voluntarily surrendered their license.

[Attitude survey among elderly outpatients in a hospital concerning driving after the implementation of a new road traffic act].

Following the passage of a new traffic law in March 2017, an inquiry survey was performed for 202 patients (men 60.9%, women 39.1%) in a medical center for neurocognitive disorders in Japan. Half of the 108 patients who currently had a driver's license had experienced traffic problems, including nearly crashing accidentally, in the past, but only a few of the men were willing to return their driver's license to the government, regardless of age (<75 and ≥75 years old). They mainly worried about how they would manage daily activities without a car, such as shopping for necessities, visiting the clinic, having the chance to get outside. They also worried about increasing the burden of other family members. In contrast, the other 94 patients who either did not have a driver's license or had already returned them to the government expected only slight issues due to the law, or even felt positive about losing their license. However, roughly half of those 94 patients did not get exchanging benefits (traffic discount card and license record card) on losing licenses probably due to less knowledge about such benefits. The present study revealed various aspects of elderly patients' thoughts concerning their driver's licenses in a local city of Japan.

The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease.

The recycling of the amyloid precursor protein (APP) from the cell surface via the endocytic pathways plays a key role in the generation of amyloid beta peptide (Abeta) in Alzheimer disease. We report here that inherited variants in the SORL1 neuronal sorting receptor are associated with late-onset Alzheimer disease. These variants, which occur in at least two different clusters of intronic sequences within the SORL1 gene (also known as LR11 or SORLA) may regulate tissue-specific expression of SORL1. We also show that SORL1 directs trafficking of APP into recycling pathways and that when SORL1 is underexpressed, APP is sorted into Abeta-generating compartments. These data suggest that inherited or acquired changes in SORL1 expression or function are mechanistically involved in causing Alzheimer disease.

Usefulness of magnetic resonance imaging in differentiation between status epilepticus and acute ischemic stroke.

BACKGROUND: Status epilepticus, characterized by the temporal neurological deficits, often mimics acute ischemic stroke. We investigated the usefulness of magnetic resonance imaging for differentiation of status epilepticus from acute ischemic stroke. METHODS: A retrospective case series of patients with status epilepticus who underwent brain magnetic resonance imaging. For comparative analysis, a series of patients with acute ischemic stroke caused by unilateral middle cerebral artery occlusion was used. RESULTS: Ten patients (4 females and 6 males) with status epilepticus who underwent brain magnetic resonance imaging were included. The median age at diagnosis was 82 years (age range, 70-90 years). In all ten patients, hyperintensities in diffusion-weighted imaging with decreased apparent diffusion coefficient values, decreased venous intensity in susceptibility-weighted imaging, and hyperperfusion in arterial spin labeling perfusion were detected in the cortex of the affected side. Four patients showed an additional diffusion restriction in the thalamus. The apparent diffusion coefficient value of the lesional area was 13.1% less than the contralateral, which was less than one-third as acute ischemic stroke. Status epilepticus patients showed no change in medullary venous intensity of the affected area in susceptibility-weighted imaging, whereas acute ischemic stroke patients showed increased cortical and medullary venous intensity in affected hemisphere. Seven of eight patients with status epilepticus who underwent magnetic resonance angiography showed dilation of the cerebral arteries in the ipsilateral side. CONCLUSIONS: The combined use of diffusion-weighted imaging, susceptibility-weighted imaging, and arterial spin labeling perfusion may help accurate and prompt diagnosis of status epilepticus.

TMP21 is a presenilin complex component that modulates gamma-secretase but not epsilon-secretase activity.

The presenilin proteins (PS1 and PS2) and their interacting partners nicastrin, aph-1 (refs 4, 5) and pen-2 (ref. 5) form a series of high-molecular-mass, membrane-bound protein complexes that are necessary for gamma-secretase and epsilon-secretase cleavage of selected type 1 transmembrane proteins, including the amyloid precursor protein, Notch and cadherins. Modest cleavage activity can be generated by reconstituting these four proteins in yeast and Spodoptera frugiperda (sf9) cells. However, a critical but unanswered question about the biology of the presenilin complexes is how their activity is modulated in terms of substrate specificity and/or relative activities at the gamma and epsilon sites. A corollary to this question is whether additional proteins in the presenilin complexes might subsume these putative regulatory functions. The hypothesis that additional proteins might exist in the presenilin complexes is supported by the fact that enzymatically active complexes have a mass that is much greater than predicted for a 1:1:1:1 stoichiometric complex (at least 650 kDa observed, compared with about 220 kDa predicted). To address these questions we undertook a search for presenilin-interacting proteins that differentially affected gamma- and epsilon-site cleavage events. Here we report that TMP21, a member of the p24 cargo protein family, is a component of presenilin complexes and differentially regulates gamma-secretase cleavage without affecting epsilon-secretase activity.

Early detection of cognitive decline in mild cognitive impairment and Alzheimer's disease with a novel eye tracking test.

Due to an increasing number of dementia patients, the development of a rapid and sensitive method for cognitive assessment is awaited. Here, we examined the usefulness of a novel and short (3 min) eye tracking device to evaluate the cognitive function of normal control (NC, n = 52), mild cognitive impairment (MCI, n = 52), and Alzheimer's disease (AD, n = 70) subjects. Eye tracking total score declined significantly in MCI (**p < 0.01 vs NC) and AD (**p < 0.01 vs NC, ##p < 0.01 vs MCI), and correlated well with the mini-mental state examination (MMSE) score (r = 0.57, *p < 0.05). Furthermore, the eye tracking test, especially memory and deductive reasoning tasks, effectively discriminated NC, MCI and AD. The present novel eye tracking test clearly discriminated cognitive functions among NC, MCI, and AD subjects, thereby providing an advantage for the early detection of MCI and AD in screening.

Discrepancy of subjective and objective sleep problems in Alzheimer's disease and mild cognitive impairment detected by a home-based sleep analysis.

There is a strong relationship between Alzheimer's disease (AD) and sleep problems, and a sleep condition is informative for evaluating the AD status. In the present study, we evaluated subjective sleep problems in AD and mild cognitive impairment (MCI) with self-check questionnaires and objective sleep problems with a convenient home-based portable device, WatchPAT. A total of 63 subjects with normal cognition (NC) (n = 22), MCI (n = 20), and AD (n = 21) were cross-sectionally investigated. AD patients showed a better self-check Pittsburgh sleep quality index (PSQI) score (*p < 0.05) than NC and MCI patients. On the other hand, WatchPAT analysis showed a significantly reduced rapid eye movement (REM) sleep (*p < 0.05) and increased light sleep in AD patients (*p < 0.05) compared with NC subjects, and mildly reduced REM and increased light sleep in MCI subjects. The present study revealed a gap between the subjective self-check sleep questions and the objective WatchPAT analysis in AD patients. Thus, a home-based sleep study with WatchPAT is a useful tool to detect an objective sleep problem in AD and the risk of MCI conversion into AD.

A New Serum Biomarker Set to Detect Mild Cognitive Impairment and Alzheimer's Disease by Peptidome Technology.

BACKGROUND: Because dementia is an emerging problem in the world, biochemical markers of cerebrospinal fluid (CSF) and radio-isotopic analyses are helpful for diagnosing Alzheimer's disease (AD). Although blood sample is more feasible and plausible than CSF or radiological biomarkers for screening potential AD, measurements of serum amyloid- ß (Aß), plasma tau, and serum antibodies for Aß1 - 42 are not yet well established. OBJECTIVE: We aimed to identify a new serum biomarker to detect mild cognitive impairment (MCI) and AD in comparison to cognitively healthy control by a new peptidome technology. METHODS: With only 1.5µl of serum, we examined a new target plate "BLOTCHIP®" plus a matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF/MS) to discriminate control (n = 100), MCI (n = 60), and AD (n = 99). In some subjects, cognitive Mini-Mental State Examination (MMSE) were compared to positron emission tomography (PET) with Pittsburgh compound B (PiB) and the serum probability of dementia (SPD). The mother proteins of candidate serum peptides were examined in autopsied AD brains. RESULTS: Apart from Aß or tau, the present study discovered a new diagnostic 4-peptides-set biomarker for discriminating control, MCI, and AD with 87% of sensitivity and 65% of specificity between control and AD (***p < 0.001). MMSE score was well correlated to brain Aß deposition and to SPD of AD. The mother proteins of the four peptides were upregulated for coagulation, complement, and plasticity (three proteins), and was downregulated for anti-inflammation (one protein) in AD brains. CONCLUSION: The present serum biomarker set provides a new, rapid, non-invasive, highly quantitative and low-cost clinical application for dementia screening, and also suggests an alternative pathomechanism of AD for neuroinflammation and neurovascular unit damage.

Impaired comprehension of metaphorical expressions in very mild Alzheimer's disease.

BACKGROUND: Brain-damaged patients often have difficulty understanding non-literal language. However, whether patients with Alzheimer's disease (AD) have comprehension deficits of metaphorical expressions, in contrast with non-metaphorical (literal) expressions, remains unclear. PATIENTS AND METHODS: The subjects were 40 AD patients; 20 had mild AD (17-23 points on the Mini-Mental State Examination [MMSE]), and 20 had very mild AD (≥24 points). Twenty normal elderly controls were also enrolled as a control group. Thirty sentences that contained novel similes (Items) were prepared. For each Item, four explanatory choices, consisting of one correct response and three foils, were provided. The participants were asked to choose the written statement that best represented the Item's meaning. In addition, all the subjects completed the Token Test. RESULTS: The patients with mild AD had significantly lower scores than the normal controls on both the simile comprehension test and the Token Test. However, the patients with very mild AD exhibited significantly lower scores on the simile comprehension test, but not on the Token Test. The distributions of error types for the simile test differed between the mild AD group and the other groups. The mild AD patients made more errors that were "far" from the correct responses. CONCLUSION: Patients with AD are more likely to have comprehension deficits of metaphorical expressions than comprehension deficits of non-metaphorical expressions. Pragmatic language dysfunction may precede formal language dysfunction during the progression of AD.

Female dominant association of sarcopenia and physical frailty in mild cognitive impairment and Alzheimer's disease.

Associations of sarcopenia and physical frailty in cognitive and affective (depression, apathy, and behavioral and psychological symptoms of dementia) functions of mild cognitive impairment (MCI) and Alzheimer's disease (AD) were not fully evaluated previously, especially not for gender differences. 165 AD, 84 MCI, and 48 control participants (175 female, 122 male) were evaluated for cognitive, affective, activities of daily living (ADL), and physical functions associated with sarcopenia and physical frailty. In both sexes, cognitive and affective functions, ADL, and physical functions worsened in MCI and AD compared to control subjects. Physical dysfunctions, especially slow gait speed (3 m up and go test), were significantly associated with cognitive, affective, and ADL declines in participants (control subjects, MCI, and AD) of each gender, which were especially noticeable in females. The present study may be the first to suggest significant associations of sarcopenia and physical frailty with cognitive and affective functions of MCI and AD, especially in females.

Social problems in daily life of patients with dementia.

AIM: Most patients with dementia frequently encounter various problems in their daily lives. Those troubles embarrass both the patients and their families, and cause problems for society. However, there have been few scientific reports on the difficulties in the daily life of patients with dementia. Therefore, we tried to clarify the frequency and characteristics of troubles experienced by patients with dementia. METHODS: Seven medical centers treating dementia patients in Okayama Prefecture, Japan, participated in this survey. A total of 737 patients were placed in one of the three groups: a dementia group (n = 478), a mild cognitive impairment group (n = 199) and a control group (n = 60). The frequency of 13 difficulties was scored for each patient. RESULTS: Among normal participants, no person caused these problems once a year or more frequently. "Massive, recurrent buying" and "acts that risk causing a fire" were reported once a year or more for >10% of mild cognitive impairment patients. "Troubles with wealth management" and "troubles with money management" were the most frequent problems of dementia patients. CONCLUSIONS: Several problems are already sometimes encountered in patients with mild cognitive impairment. It would be useful to know which social difficulties are often seen in dementia patients in order to protect the safety of the patients. It is always difficult to balance respecting the autonomy of dementia patients and ensuring their safely. Geriatr Gerontol Int 2019; 19: 113-118.

Efficacy, Safety, and Tolerability of Switching from Oral Cholinesterase Inhibitors to Rivastigmine Transdermal Patch with 1-Step Titration in Patients with Mild to Moderate Alzheimer's Disease: A 24-Week, Open-Label, Multicenter Study in Japan.

BACKGROUND: Few studies have investigated treatment options for patients with Alzheimer's disease (AD) showing a poor response to oral cholinesterase inhibitors (ChEIs) in Japan. OBJECTIVE: To investigate the efficacy and safety of switching from oral ChEIs to rivastigmine transdermal patch in patients with AD. METHODS: In this multicenter, open-label, phase IV study in outpatient clinics in Japan, patients with mild-moderate AD who had a poor response to or experienced difficulty in continuing donepezil or galantamine were switched to rivastigmine transdermal patch (5 cm2; loaded dose 9 mg, delivery rate 4.6 mg/24 h) with a 1-step titration in week 4 (10 cm2; loaded dose 18 mg, delivery rate 9.5 mg/24 h), which was continued for 4 weeks in the titration period and 16 weeks in a maintenance period. The primary endpoint was the change in Mini-Mental State Examination (MMSE) total score from baseline to week 24. RESULTS: A total of 118 patients were enrolled and switched to rivastigmine, of which 102 completed the 24-week study. The MMSE total score was essentially unchanged during the study, with a least-square mean change (SD) of -0.35 (2.64) at week 24 (p = 0.1750). Exploratory analysis with a mixed-effect model comparing changes in MMSE between the pre- and post-switch periods suggested that switching to rivastigmine prevented a worsening of MMSE. Application site skin reactions/irritations occurred in 30.5% of patients overall, in 22.0% in the 8-week titration period, and in 10.2% in the 16-week maintenance period. CONCLUSION: Within-class switching from an oral ChEI to rivastigmine transdermal patch might be an efficacious and tolerable option for AD patients showing a poor or limited response to a prior oral ChEI.

Clinical Benefits of Antioxidative Supplement Twendee X for Mild Cognitive Impairment: A Multicenter, Randomized, Double-Blind, and Placebo-Controlled Prospective Interventional Study.

Oxidative stress is part of the entire pathological process that underlies the development of Alzheimer's disease (AD), including the mild cognitive impairment (MCI) stage. Twendee X (TwX) is a supplement containing a strong antioxidative mix of eight antioxidants, which has been shown to have a clinical and therapeutic benefit in AD model mice. Here, we conducted a multicenter, randomized, double-blind, and placebo-controlled prospective interventional study to evaluate the efficacy of TwX in mitigating MCI. The primary outcomes were differences in Mini-Mental State Examination (MMSE) and Hasegawa Dementia Scale-revised (HDS-R) scores between baseline and six months for placebo and TwX groups. Seventy-eight subjects with MCI were randomized into placebo (n = 37) and TwX (n = 41) groups. MMSE scores at six months differed significantly between the TwX and placebo groups (p = 0.018), and HDS-R scores for the TwX group exhibited a significant improvement at six months relative to baseline (p = 0.025). The TwX group did not show any change in affective or activities of daily living scores at six months. The present study indicates that strong antioxidative supplement TwX is clinical beneficial for cognitive function in subjects with MCI.

Age-at-onset linkage analysis in Caribbean Hispanics with familial late-onset Alzheimer's disease.

The aim of the study was to identify chromosomal regions that may harbor putative genetic variants influencing age at onset in familial late-onset Alzheimer's disease (LOAD). Data from a genome-wide scan that included genotyping of APOE were analyzed in 1,161 individuals from 209 families of Caribbean Hispanic ancestry with a mean age at onset of 73.3 years multiply affected by LOAD. Two-point and multipoint analyses were conducted using variance component methods using 376 microsatellite markers with an average intermarker distance of 9.3 cM. Family-based test of association was also conducted for the same set of markers. Age at onset of symptoms among affected individuals was used as the quantitative trait. Our results showed that the presence of APOE-epsilon4 lowered the age at onset by 3 years. Several candidate loci were identified. Using linkage analysis strategy, the highest logarithm of odds (LOD) scores were obtained using a conservative definition of LOAD at 5q15 (LOD = 3.1), 17q25.1 (LOD = 2.94), 14q32.12 (LOD = 2.36), and 7q36.3 (LOD = 2.29) in a model that adjusted for APOE-epsilon4 and other covariates. Both linkage and family-based association identified 17p13 as a candidate region. Family-based association analysis showed markers at 12q13 (p = 0.00002), 13q33 (p = 0.00043), and 14q23 (p = 0.00046) to be significantly associated with age at onset. The current study supports the hypothesis that there are additional genetic loci that could influence age at onset of late onset Alzheimer's disease. The novel loci at 5q15, 17q25.1, 13q33, and 17p13 and the previously reported loci at 7q36.3, 12q13, 14q23, and 14q32 need further investigation.

The G2019S LRRK2 mutation in Brazilian patients with Parkinson's disease: phenotype in monozygotic twins.

Mutations in the Leucine-Rich Repeat Kinase 2 gene (LRRK2) are mainly responsible for idiopathic Parkinson's disease (PD) with either a dominant pattern of transmission or a sporadic occurrence due to the reduced penetrance. A majority of LRRK2 kindreds demonstrate an extremely variable age-at-onset in affected members of the same family. The G2019S is the most common LRRK2 mutation, which accounts for 1-5% PD patients in North America, and up to 40% of patients from an isolated Arab population. We assessed the frequency of the G2019S mutation in 83 Brazilian PD patients originally preselected for having an early age-at-onset (<50 years) and/or a positive family history. The mutation was detected in three probands (3.5%). Our clinical findings in these kindreds include the first description of the phenotype in identical twins discordant for handedness (a general phenomenon found in approximately 25% monozygotic twins). However, both twins developed right asymmetric PD. The clinical presentation of twins was strikingly similar including an identical PD onset at age 60. This observation may suggest that genetic factors predominantly determine age-at-onset.

Sugar chains of cerebrospinal fluid transferrin as a new biological marker of Alzheimer's disease.

BACKGROUND/AIMS: Alzheimer's disease (AD) is a well-known type of dementia. However, it remains difficult to identify AD in the early stage and to distinguish it from other dementing disorders. We examined glycoproteins in cerebrospinal fluid (CSF) as potential biological markers of AD. METHODS: CSF samples were collected from AD, other dementia and nondemented patients. Glycoproteins in CSF were detected by lectin blotting using wheat germ agglutinin (WGA), and sugar chain analysis was performed by isoelectric focusing. RESULTS: In Alzheimer's CSF, several glycoproteins had lower WGA-binding activities, one of which was sufficiently sensitive and specific to distinguish AD from nondemented controls and other dementias. Further analysis identified this glycosylated protein as transferrin, and altered sugar chain composition of transferrin isoforms was observed despite normal protein levels in CSF. CONCLUSION: The decreased WGA-binding activity of transferrin in AD is probably due to altered glycosylation of transferrin molecules. Transferrin glycosylation is thus a potential biological marker for AD diagnosis, and changes in this glycosylation may play an important role in the pathophysiology of AD.

Clinical characteristics of patients with dementia in a local emergency clinic in Japan.

AIM: The present study aimed to clarify the clinical characteristics of patients with dementia in an emergency clinic. METHODS: We retrospectively examined patients with dementia who visited the emergency clinic at Kurashiki Heisei Hospital, Okayama, Japan. Among 16 764 patients who visited our emergency clinic in the 3 years from 2014 to 2017, we focused on 2574 (15.4%) patients with dementia. RESULTS: The mean age of patients with dementia was 84.9 ± 0.1 years, which was much older than the age of the total emergency patients (58.1 ± 0.2 years). The hospitalization rate was 54.9% for patients with dementia, which was more than double that of patients without dementia (23.3%; P <0.01), and was higher than that (44.3%) of patients who were aged ≥75 years without dementia. Infection (42.4%) and falls (20.9%) were the most common causes for emergency visits and hospitalization in the present study. Hospitalized patients with dementia spent a longer time in hospital for stroke (64.0 ± 5.3 days) and falls (51.9 ± 2.1 days) than those with infection, epilepsy, syncope, loss of consciousness, other causes (all P <0.01) or dehydration (P ≤ 0.05). CONCLUSIONS: Patients with dementia commonly attend our emergency clinic. These patients are older in age, have a higher hospitalization rate and have a longer hospitalization, especially due to stroke and falls, than patients without dementia. Geriatr Gerontol Int 2018; 18: 1383-1387.