A new educational tool for neuropsychological test raters in the dementia field: A Delphi study.

BACKGROUND: Neuropsychological testing is the primary endpoint of clinical research in the field of dementia, making it essential for the rater to accurately calculate test data for an extensive assessment. However, many raters lack adequate skill to complete neuropsychological tests with sufficient confidence. Therefore, we developed and examined the utility of a checklist and a manual as tools for educating raters on their basic behaviours when conducting comprehensive neuropsychological evaluations in the field of dementia. METHODS: We conducted a seven-step comprehensive study to develop rater training tools and examine their usefulness between April 2019 and February 2021 involving: 1. Development of a draft checklist, 2. Delphi review rounds, 3. Design of the final checklist, 4. Item weighting, 5. Examination of reliability, 6. Creating the manual, and 7. Examination of the usefulness of learning through rater educational tools (checklist and manual). RESULTS: The Delphi review round led to a highly reliable and valid checklist and manual. The total checklist score improved significantly (t = 2.37, P = 0.029) before and after manual learning. We found that the appropriate basic behaviours required by the rater to conduct neuropsychological testing skilfully within the dementia field could be acquired with this tool. CONCLUSIONS: Using a robust development process, we integrated expert knowledge and experience, and developed a checklist and a manual for learning the basic behaviours of neuropsychological test raters in the field of dementia. Establishing standards of basic behaviour for neuropsychological raters will help promote dementia research and advances in medicine.

Electromagnetic signatures of the preclinical and prodromal stages of Alzheimer's disease.

Biomarkers useful for the predementia stages of Alzheimer's disease are needed. Electroencephalography and magnetoencephalography (MEG) are expected to provide potential biomarker candidates for evaluating the predementia stages of Alzheimer's disease. However, the physiological relevance of EEG/MEG signal changes and their role in pathophysiological processes such as amyloid-ß deposition and neurodegeneration need to be elucidated. We evaluated 28 individuals with mild cognitive impairment and 38 cognitively normal individuals, all of whom were further classified into amyloid-ß-positive mild cognitive impairment (n = 17, mean age 74.7 ± 5.4 years, nine males), amyloid-ß-negative mild cognitive impairment (n = 11, mean age 73.8 ± 8.8 years, eight males), amyloid-ß-positive cognitively normal (n = 13, mean age 71.8 ± 4.4 years, seven males), and amyloid-ß-negative cognitively normal (n = 25, mean age 72.5 ± 3.4 years, 11 males) individuals using Pittsburgh compound B-PET. We measured resting state MEG for 5 min with the eyes closed, and investigated regional spectral patterns of MEG signals using atlas-based region of interest analysis. Then, the relevance of the regional spectral patterns and their associations with pathophysiological backgrounds were analysed by integrating information from Pittsburgh compound B-PET, fluorodeoxyglucose-PET, structural MRI, and cognitive tests. The results demonstrated that regional spectral patterns of resting state activity could be separated into several types of MEG signatures as follows: (i) the effects of amyloid-ß deposition were expressed as the alpha band power augmentation in medial frontal areas; (ii) the delta band power increase in the same region was associated with disease progression within the Alzheimer's disease continuum and was correlated with entorhinal atrophy and an Alzheimer's disease-like regional decrease in glucose metabolism; and (iii) the global theta power augmentation, which was previously considered to be an Alzheimer's disease-related EEG/MEG signature, was associated with general cognitive decline and hippocampal atrophy, but was not specific to Alzheimer's disease because these changes could be observed in the absence of amyloid-ß deposition. The results suggest that these MEG signatures may be useful as unique biomarkers for the predementia stages of Alzheimer's disease.

Age-Related Changes in Attentional Control Using an N-Back Working Memory Paradigm.

BACKGROUND/STUDY CONTEXT: Older adults tend to be affected by task-irrelevant distracters. However, whether or not this aging effect is evident when task-irrelevant and relevant stimuli are presented across different sensory modalities is still a subject of debate. The purpose of the present study was to clarify age-related differences in the effects of auditory distraction on visual information processing. METHODS: Participants included 20 young individuals, 20 younger-old individuals in their 60s, and 20 older-old individuals in their 70s. Visual n-back (1-back, 2-back) working memory (WM) tasks using Japanese words were examined with and without auditory distracter conditions. Participants' performances were analyzed using a three-way analysis of variance: 3 (age group) × 2 (distraction) × 2 (working memory load). RESULTS: The effects of auditory distractions were influenced by aging and WM load. Auditory distractions disturbed WM performances preferentially in older adults. Further, participants in the older-old group were more affected by auditory distractions than those in the younger-old group, especially during the 2-back task. CONCLUSION: These results suggested that the WM performances for visual n-back tasks were largely disturbed by auditory distractions in older adults but not in young adults.

Psychological status of patients with mucopolysaccharidosis type II and their parents.

BACKGROUND: The aim of the present study was to delineate the psychological status of 10 patients with the attenuated phenotype of mucopolysaccharidosis type II (MPS-II) and their parents (six fathers and five mothers) for the improvement of clinical management. METHODS: Intellectual ability was evaluated using the Wechsler Intelligence Scale. Activities of daily living (ADL) was assessed using the Functional Independence Measure. The personality and psychiatric aspects were analyzed using the Yatabe-Guilford Personality test (Y-G test) and the Tree-Drawing Test. Mental health was assessed using the General Health Questionnaire 60 (GHQ-60) and State-Trait Anxiety Inventory (STAI). RESULTS: Intellectual background, measured with full-scale, verbal and performance IQ, were 72.8, 76.1 and 79.3, respectively. Nine of 10 patients were not judged as having neurosis and a psychotic tendency with the Y-G test. In the tree-drawing test, many patients drew a tree without ground, suggesting that they have difficulties in making relationships with surrounding people and the community. The child patient with a psychosis pattern on the Y-G test, drew a bizarre tree, suggesting psychological problems. GHQ-60 and STAI survey indicated that the patients and their parents had higher levels of anxiety. A significant negative correlation between GHQ-60 score and ADL (R = -0.77) was identified, suggesting that the psychological status may worsen as ADL decreases. CONCLUSIONS: Patients with MPS-II and their parents had higher risks for mental problems. Understanding psychological status is essential when providing genetic counseling or therapeutic intervention.

Parents of childhood X-linked adrenoleukodystrophy: high risk for depression and neurosis.

The purpose of this study was to assess mental health in parents of patients with the childhood cerebral form of X-linked adrenoleukodystrophy (CCALD) and to investigate factors relating to psychological problems in order to improve clinical management and quality of life. Sixteen fathers and 21 mothers of patients with CCALD completed a battery of psychological examinations including the Beck Depression Inventory second edition (BDI-II), the General Health Questionnaire 60 (GHQ60), and the State-Trait Anxiety Inventory (STAI). Three fathers and 11 mothers showed high scores on the BDI-II, suggesting that they were in a depressive state. Depression in the mothers was serious as compared with previous reports. Six fathers and 11 mothers were considered to be in a state of neurosis, according to the results of the GHQ60. Four fathers and 8 mothers showed high levels of anxiety on the STAI. Health and social status of the mothers correlated with their mental health, and younger mothers with young patients tended to be more depressed. Thus, parents of patients with CCALD have a high risk of depression and neurosis. Understanding the mental state of these parents and improvements in the social support system including mental counseling, home nursing care, supports in workplace and community are necessary to prevent and treat psychological problems. Especially, early intervention for mental health problems should be provided for younger mothers with few years since the child's diagnosis.

Evaluation of ADL in patients with Hunter disease using FIM score.

MPS type II (Hunter disease) results from deficiency of the lysosomal enzyme iduronate-2-sulfate sulfatase. Two forms of the disease have been recognized, based on absence or presence of progressive intellectual deterioration. This study aimed to assess activities of daily life (ADL) in 27 Hunter disease-affected Japanese patients, using a modified version of the functional independence measure (FIM). Scores of ADL for patients with a severe phenotype were significantly lower than those of control children. Total scores were highest around 5-7 years old, then progressively decreased, and scores <40 were obtained with patients aged 9 years or more. In contrast to motor scores, cognitive scores decreased rapidly, generally reaching a minimum score at around 7 years old. On the other hand, in children with attenuated phenotype, total scores increased progressively with age similar to control children. Two children who had the highest grades at elementary school showed maximum scores. However, all adult patients did not show maximum total scores, and 3 of 4 patients over 25 years old showed decreasing scores. Two children and two adults showed significant lower scores compared with other patients, suggesting an intermediate form from the view of ADL. This study elucidated the precise clinical state of Hunter disease with distinct numerical scores, in addition to previously described narrative data. To maintain the QOL of the patients better, they and their family need to know what specific difficulties they encounter, in which period they encounter them, and what support can fix them. Further ADL investigations with larger populations and/or long-term sequential examination could help the patients and family to understand them well.

Early functional network alterations in asymptomatic elders at risk for Alzheimer's disease.

Amyloid-ß (Aß) deposition is known to starts decades before the onset of clinical symptoms of Alzheimer's disease (AD), however, the detailed pathophysiological processes underlying this preclinical period are not well understood. This study aimed to investigate functional network alterations in cognitively intact elderly individuals at risk for AD, and assessed the association between these network alterations and changes in Aß deposition, glucose metabolism, and brain structure. Forty-five cognitively normal elderly subjects, who were classified into Aß-positive (CN+) and Aß-negative (CN-) groups using 11C-Pittsburgh compound B PET, underwent resting state magnetoencephalography measurements, 18F-fluorodeoxyglucose PET (FDG-PET) and structural MRI. Results demonstrated that in the CN+ group, functional connectivity (FC) within the precuneus was significantly decreased, whereas it was significantly enhanced between the precuneus and the bilateral inferior parietal lobules in the low-frequency bands (theta and delta). These changes were suggested to be associated with local cerebral Aß deposition. Most of Aß+ individuals in this study did not show any metabolic or anatomical changes, and there were no significant correlations between FC values and FDG-PET or MRI volumetry data. These results demonstrate that functional network alterations, which occur in association with Aß deposition, are detectable using magnetoencephalography before metabolic and anatomical changes are seen.

Portal hypertension in a patient with Hunter disease.

Hepatosplenomegaly is one of the cardinal signs of Hunter disease; however, portal hypertension has not been described. We report portal hypertension in an adult Hunter patient with the attenuated phenotype.

Mutational and structural analysis of Japanese patients with mucopolysaccharidosis type II.

We investigated mutations of the iduronate-2-sulfatase (I2S) gene and structural characteristics of I2S to clarify genotype/phenotype relationships in 18 Japanese patients with mucopolysaccharidosis type II. The I2S gene was analyzed in five patients with a severe phenotype and in 13 patients with an attenuated phenotype. The tertiary structural model of the human I2S was constructed by homology modeling using the arylsulfatase structure as a template. We identified four missense mutations and a nonsense mutation in the severe phenotype; four missense, two nonsense, three frame shifts, and one each of splice and amino acid deletion in the attenuated phenotype. Seven of them (L73del, Q75X, G140R, C171R, V401 fs, C422 fs, and H441 fs) were novel mutations. Structural analysis indicated that the residues of the mutations found in the severe phenotype would have direct interactions with the active site residues or should break the hydrophobic core domain of I2S, whereas residues of the missense mutations found in the attenuated phenotype were located in the peripheral region. In addition, effects by deletion or frameshift mutations could also be interpreted by the structure. Structural analysis of mutant proteins would help in understanding the genotype/phenotype relationships of Hunter disease.