Motor difficulties from childhood to midlife: A 40-year cohort study.

BACKGROUND: There are few studies of the persistence of childhood motor difficulties (MD) into adulthood. AIMS: To investigate the association of childhood MD with motor skills and body mass index (BMI) in midlife. METHODS AND PROCEDURES: We studied 324 adults aged 40 from a cohort born in 1971-1974. At age 9, they had undergone the Test of Motor Impairment, used to classify them into groups: childhood MD (cMD), borderline cMD (bcMD), or no cMD. At age 40, participants comprised 23 with cMD, 47 with bcMD, and 254 with no cMD. Participants completed motor tests of balance, manual dexterity, and visuomotor speed, followed by recording of their BMI. OUTCOMES AND RESULTS: At age 40, the cMD group performed worse than the no-cMD group on all motor tests (p < .001-.008). The bcMD group had slower visuomotor speed than the no-cMD group (p = .025). The groups differed in BMI (p = .002). Having cMD was associated with obesity in midlife (p < .001). After adjusting for sex, childhood socioeconomic status, and BMI at age 9, both cMD and bcMD were associated with obesity in midlife (p = .015). CONCLUSIONS AND IMPLICATIONS: Childhood MD are associated with poor motor skills, overweight, and obesity in midlife. This emphasises the importance of early intervention and follow-up when a child exhibits MD. WHAT THIS PAPER ADDS: This prospective longitudinal study presents novel evidence that individuals with a history of comprehensively and objectively assessed childhood motor difficulties (MD) have worse motor skills and a higher risk of obesity in midlife than do those with no childhood MD. There is a growing literature on adults with developmental coordination disorder or a history of MD. There is, however, a scarcity of longitudinal studies of childhood MD that continue beyond early adulthood, into midlife. In a systematic search, we could identify only one longitudinal study of objectively measured childhood MD with a reassessment of motor skills in those same participants in adulthood, and no study with a reassessment after age 20. Furthermore, longitudinal studies of the association of comprehensively and objectively assessed childhood MD with BMI in midlife have been lacking.

The shared ancestry between the C9orf72 hexanucleotide repeat expansion and intermediate-length alleles using haplotype sharing trees and HAPTK.

The C9orf72 hexanucleotide repeat expansion (HRE) is a common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The inheritance is autosomal dominant, but a high proportion of subjects with the mutation are simplex cases. One possible explanation is de novo expansions of unstable intermediate-length alleles (IAs). Using haplotype sharing trees (HSTs) with the haplotype analysis tool kit (HAPTK), we derived majority-based ancestral haplotypes of HRE samples and discovered that IAs containing ≥18-20 repeats share large haplotypes in common with the HRE. Using HSTs of HRE and IA samples, we demonstrate that the longer IA haplotypes are largely indistinguishable from HRE haplotypes and that several ≥18-20 IA haplotypes share over 5 Mb (>600 markers) haplotypes in common with the HRE haplotypes. These analysis tools allow physical understanding of the haplotype blocks shared with the majority-based ancestral haplotype. Our results demonstrate that the haplotypes with longer IAs belong to the same pool of haplotypes as the HRE and suggest that longer IAs represent potential premutation alleles.

C9orf72 hexanucleotide repeat allele tagging SNPs: Associations with ALS risk and longevity.

C9orf72 hexanucleotide repeat expansion is a common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The C9orf72 locus may harbor residual risk outside the hexanucleotide repeat expansion, but the evidence is conflicting. Here, we first compared 683 unrelated amyotrophic lateral sclerosis cases and 3,196 controls with Finnish ancestry to find best single nucleotide polymorphisms that tag the C9orf72 hexanucleotide repeat expansion and intermediate-length alleles. Rs2814707 was the best tagging single nucleotide polymorphisms for intermediate-length alleles with ≥7 repeats (p = 5 × 10-307) and rs139185008 for the hexanucleotide repeat expansion (p = 7 × 10-114) as well as alleles with ≥20 repeats. rs139185008*C associated with amyotrophic lateral sclerosis after removing cases with the hexanucleotide repeat expansion, especially in the subpopulation homozygous for the rs2814707*T (p = 0.0002, OR = 5.06), which supports the concept of residual amyotrophic lateral sclerosis risk at the C9orf72 haplotypes other than the hexanucleotide repeat expansion. We then leveraged Finnish biobank data to test the effects of rs2814707*T and rs139185008*C on longevity after removing individuals with amyotrophic lateral sclerosis / frontotemporal dementia diagnoses. In the discovery cohort (n = 230,006), the frequency of rs139185008*C heterozygotes decreased significantly with age in the comparisons between 50 and 80 years vs. >80 years (p = 0.0005) and <50 years vs. >80 years (p = 0.0001). The findings were similar but less significant in a smaller replication cohort (2-sided p = 0.037 in 50-80 years vs. >80 years and 0.061 in <50 years vs. >80 years). Analysis of the allele frequencies in 5-year bins demonstrated that the decrease of rs139185008*C started after the age of 70 years. The hexanucleotide repeat expansion tagging single nucleotide polymorphisms decreasing frequency with age suggests its' association with age-related diseases probably also outside amyotrophic lateral sclerosis / frontotemporal dementia.

No Clinically Relevant Memory Effects in Perinatal Hyperglycemia and Hypoglycemia: A 40-Year Follow-Up of a Small Cohort.

Maternal diabetes mellitus in pregnancy is associated with impairments in memory functions of the offspring in childhood and adolescence but has not been studied in adulthood. The association of perinatal hypoglycemia with memory has not been studied in adulthood either. The combined sequelae of these two risk factors have not been directly compared. We studied general cognitive ability and memory functions in a prospective follow-up of a cohort born in 1971 to 1974. The sample included participants exposed to prenatal hyperglycemia (n = 24), perinatal hypoglycemia (n = 19), or both (n = 7). It also included controls with no early risks (n = 82). We assessed the participants' Intelligence quotient (IQ), working memory, and immediate and delayed recall of both verbal and visual material at the age of 40. We did not find significant differences in IQ or the memory tests between the groups. We did identify an interaction (p = 0.03) of the early risk with the type of digit span task: compared to the controls, the participants exposed to perinatal hypoglycemia had a larger difference between the forward digit span, a measure of attention, and the backward digit span, a measure of working memory processing (p = 0.022). The interaction remained significant when birth weight was controlled for (p = 0.026). Thus, in this small cohort, prenatal hyperglycemia, perinatal hypoglycemia, and their combination appeared relatively benign disorders. The association of these conditions with neurocognitive impairments in adulthood remains unconfirmed. The significance of the working memory difference needs to be verified with a larger sample.

Mortality in individuals with childhood ADHD or subthreshold symptoms - a prospective perinatal risk cohort study over 40 years.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is associated with negative life outcomes and recent studies have linked it to increased mortality. These studies have examined nationwide registers or clinic-referred samples and mostly included participants up until the age of 30. No studies have investigated mortality associated with subthreshold levels of ADHD symptoms. Our aim was to analyze mortality in a perinatal risk cohort of 46-year-old adults with childhood ADHD (cADHD) and milder childhood attention problems (including hyperactivity and inattention; cAP) compared with a group with similar birth risks but no or low levels of childhood ADHD symptoms (Non-cAP). Causes of death obtained from a national register were examined. METHODS: Mortality was analyzed with Cox proportional hazard models for all-cause mortality, cause-specific mortality (natural and unnatural causes), and age-specific mortality (under and over age 30). All models were adjusted with gender. The total n in the study was 839 (cADHD n = 115; cAP n = 216; Non-cAP n = 508). RESULTS: By the age of 46, 11 (9.6%) deaths occurred in the cADHD group, 7 (3.2%) in the cAP group, and 20 (3.9%) in the Non-cAP group. The cADHD group had the highest mortality risk (adjusted hazard ratio = 2.15; 95% CI 1.02, 4.54). Mortality was not elevated in the cAP group (adjusted hazard ratio = 0.72; 95% CI .30, 1.72). Mortality in the cADHD group was mainly attributed to unnatural causes of death (adjusted hazard ratio = 2.82; 95% CI 1.12, 7.12). The mortality risk in the cADHD group was sixfold before age 30 (adjusted hazard ratio = 6.20; 95% CI 1.78, 21.57). CONCLUSIONS: Childhood ADHD was associated with a twofold risk of premature death by the age of 46 in this prospective longitudinal cohort study. Our results corroborate previous findings and the morbidity of ADHD. Subthreshold levels of childhood ADHD symptoms were not linked to increased mortality. Our results suggest that mortality risk is higher in young than middle adulthood. Future studies should examine mortality associated with ADHD in different ages in adulthood to identify those in greatest risk of premature death.

ALS in Finland: Major Genetic Variants and Clinical Characteristics of Patients With and Without the C9orf72 Hexanucleotide Repeat Expansion.

Background and Objectives: To analyze the frequencies of major genetic variants and the clinical features in Finnish patients with amyotrophic lateral sclerosis (ALS) with or without the C9orf72 hexanucleotide repeat expansion. Methods: A cohort of patients with motor neuron disease was recruited between 1993 and 2020 at the Helsinki University Hospital and 2 second-degree outpatient clinics in Helsinki. Finnish ancestry patients with ALS fulfilled the diagnosis according to the revised El Escorial criteria and the Awaji-criteria. Two categories of familial ALS (FALS) were used. A patient was defined FALS-A if at least 1 first- or second-degree family member had ALS, and FALS-NP, if family members had additional neurologic or psychiatric endophenotypes. Results: Of the 815 patients, 25% had FALS-A and 45% FALS-NP. C9orf72 expansion (C9pos) was found in 256 (31%) of all patients, in 58% of FALS-A category, in 48% of FALS-NP category, and in 23 or 17% of sporadic cases using the FALS-A or FALS-NP definition. C9pos or SOD1 p.D91A homozygosity was found in 328 (40%) of the 815 patients. We compared demographic and clinical characteristics between C9pos and patients with unknown cause of ALS (Unk). We found that the age at onset was significantly earlier and survival markedly shorter in the C9pos vs Unk patients with ALS. The shortest survival was found in bulbar-onset male C9pos patients, whereas the longest survival was found in Unk limb-onset males. Older age at onset associated consistently with shorter survival in C9pos and Unk patients in both limb-onset and bulbar-onset groups. There were no significant differences in the frequencies of bulbar-onset and limb-onset patients in C9pos and Unk groups. ALS-frontotemporal dementia (FTD) was more common in C9pos (17%) than in Unk (4%) patients, and of all patients with ALS-FTD, 70% were C9pos. Discussion: These results provide further evidence for the short survival of C9orf72-associated ALS. A prominent role of the C9orf72 and SOD1 variants was found in the Finnish population. An unusually high frequency of C9pos was also found among patients with sporadic ALS. The enrichment of these 2 variants likely contributes to the high incidence of ALS in Finland.

Carriership of two copies of C9orf72 hexanucleotide repeat intermediate-length alleles is a risk factor for ALS in the Finnish population.

The hexanucleotide repeat expansion in intron 1 of the C9orf72 gene causes amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. In addition to the effects of the pathogenic expansion, a role of intermediate-length alleles has been suggested in ALS, corticobasal degeneration and Parkinson's disease. Due to the rarity of intermediate-length alleles with over 20 repeats and the geographical variability in their frequency, large studies that account for population stratification are needed to elucidate their effects. To this aim, we used repeat-primed PCR and confirmatory PCR assays to determine the C9orf72 repeat allele lengths in 705 ALS patients and 3958 controls from Finland. After exclusion of expansion carriers (25.5% of the ALS patients and 0.2% of the controls), we compared the frequency of intermediate-length allele carriers of 525 ALS cases and 3950 controls using several intermediate-length allele thresholds (7-45, 17-45, 21-45, 24-45 and 24-30). The carriership of an intermediate-length allele did not associate with ALS (Fisher's test, all p ≥ 0.15) nor was there any association with survival (p ≥ 0.33), when we divided our control group into three age groups (18-65, 66-84 and 85-105 years). Carriership of two intermediate-length alleles was associated with ALS, when the longer allele was ≥ 17 repeats (p = 0.002, OR 5.32 95% CI 2.02-14.05) or ≥ 21 repeats (p = 0.00016, OR 15.21 95% CI 3.79-61.0). Our results show that intermediate-length alleles are a risk factor of ALS when present in both alleles, whereas carrying just one intermediate-length allele was not associated with ALS or survival.

Moderate alcohol use is associated with decreased brain volume in early middle age in both sexes.

The aim was to examine cross-sectional association between moderate alcohol consumption and total brain volume in a cohort of participants in early middle-age, unconfounded by age-related neuronal change. 353 participants aged 39 to 45 years reported on their alcohol consumption using the AUDIT-C measure. Participants with alcohol abuse were excluded. Brain MRI was analyzed using a fully automated method. Brain volumes were adjusted by intracranial volume expressed as adjusted total brain volume (aTBV). AUDIT-C mean of 3.92 (SD 2.04) indicated moderate consumption. In a linear regression model, alcohol consumption was associated with smaller aTBV (B = - 0.258, p < .001). When sex and current smoking status were added to the model, the association remained significant. Stratified by sex, the association was seen in both males (B = - 0.258, p = 0.003) and females (B = - 0.214, p = 0.011). Adjusted for current smoking, the association remained in males (B = - 0.268, p = 0.003), but not in females. When alcohol consumption increased, total brain volume decreased by 0.2% per one AUDIT-C unit already at 39-45 years of age. Moderate alcohol use is associated with neuronal changes in both males and females suggesting health risks that should not be overlooked.

ADHD and subthreshold symptoms in childhood and life outcomes at 40 years in a prospective birth-risk cohort.

We investigated ADHD symptoms and life outcomes in adulthood and their association with childhood ADHD and subthreshold symptoms in a prospectively followed cohort with perinatal risks. We identified participants with childhood ADHD (cADHD, n = 37), subthreshold symptoms defined as attention problems (cAP, n = 64), and no ADHD or cAP (Non-cAP, n = 217). We compared the groups and a control group with no perinatal risks (n = 64) on self-reported ADHD symptoms, executive dysfunction, and life outcomes in adulthood. At age 40, 21.6% of the cADHD, 6.3% of the cAP, 6.0% of the Non-cAP group, and 1.6% of the controls reached a screener cutoff for possible ADHD. The cADHD group had lower educational level, more ADHD symptoms and executive dysfunction, and higher rates of drug use than the other groups. Childhood ADHD associated with perinatal risks persists into midlife whereas childhood subthreshold ADHD symptoms in this cohort were not associated with negative outcomes in adulthood.

A Prospective 30-Year Follow-Up of ADHD Associated With Perinatal Risks.

OBJECTIVE: Longitudinal follow-up of ADHD suggests a poorer outcome in those affected. Studies extending to 30 years however are rare. We investigated the adult outcome of ADHD associated with perinatal risks (PRs), treated non-pharmacologically. METHOD: A study group of 122 participants (86 men, 36 women) with PR-associated ADHD was followed-up from birth and compared with a control group also prospectively studied. RESULTS: The study group showed more cognitive, motor perception, and learning impairments as well as psychiatric problems at ages 5, 9, and 16. At age 30, the study group reported less education, more involuntary job dismissals and more alcohol abuse. Self-reported ADHD symptoms were still prevalent in adulthood. CONCLUSION: ADHD symptoms persist and impair the long-term educational, occupational, and psychiatric outcome. ADHD in participants with PR appears to follow a course seen in studies of unselected ADHD.

Adult with Middle Interhemispheric Variant of Holoprosencephaly: Neuropsychological, Clinical, and Radiological Findings.

OBJECTIVE: The middle interhemispheric variant of holoprosencephaly (MIHV) is a mild, rare variant of holoprosencephaly. Only a few cases of children with MIHV have been reported. Here we report in detail an adult case. METHOD: The patient is a female in her 30s. The patient underwent an extensive neuropsychological examination, a neurological examination and a magnetic resonance imaging. RESULTS: Neuroradiologically, the patient had a typical finding of MIHV, with the absence of the central corpus callosum and union of posterior frontal and anterior parietal gyri. In neuropsychological examination, the patient had average or above average performance in verbal comprehension, naming, reading and writing, and below average performance in perceptual reasoning, visuospatial abilities, processing speed and memory. Also difficulties in mathematical abilities, psychomotor skills, and executive functions were found. No gross neurological involvement was noted. She was diagnosed with atypical depression, post-traumatic stress disorder and a dissociative disorder in early adulthood. Despite cognitive deficits, she was able to achieve a tertiary level education. CONCLUSIONS: This is the first adult case of MIHV described in detail. Our case emphasizes the possibility of a missed diagnosis of marked brain malformations in patients with craniofacial abnormalities. More cases and prospective follow-up studies are needed to understand the evolvement of both neuropsychological and psychiatric symptoms in these patients.

Attrition in a 30-year follow-up of a perinatal birth risk cohort: factors change with age.

Background. Attrition is a major cause of potential bias in longitudinal studies and clinical trials. Attrition rate above 20% raises concern of the reliability of the results. Few studies have looked at the factors behind attrition in follow-ups spanning decades. Methods. We analyzed attrition and associated factors of a 30-year follow-up cohort of subjects who were born with perinatal risks for neurodevelopmental disorders. Attrition rates were calculated at different stages of follow-up and differences between responders and non-responders were tested. To find combinations of variables influencing attrition and investigate their relative importance at birth, 5, 9, 16 and 30 years of follow-up we used the random forest classification. Results. Initial loss of potential participants was 13%. Attrition was 16% at five, 24% at nine, 35% at 16 and 46% at 30 years. The only group difference that emerged between responders and non-responders was in socioeconomic status (SES). The variables identified by random forest classification analysis were classified into Birth related, Development related and SES related. Variables from all these categories contributed to attrition, but SES related variables were less important than birth and development associated variables. Classification accuracy ranged between 0.74 and 0.96 depending on age. Discussion. Lower SES is linked to attrition in many studies. Our results point to the importance of the growth and development related factors in a longitudinal study. Parents' decisions to participate depend on the characteristics of the child. The same association was also seen when the child, now grown up, decided to participate at 30 years. In addition, birth related medical variables are associated with the attrition still at the age of 30. Our results using a data mining approach suggest that attrition in longitudinal studies is influenced by complex interactions of a multitude of variables, which are not necessarily evident using other multivariate techniques.

Adult neurobehavioral outcome of hyperbilirubinemia in full term neonates-a 30 year prospective follow-up study.

Background. Neonatal hyperbilirubinemia (HB) may cause severe neurological damage, but serious consequences are effectively controlled by phototherapy and blood exchange transfusion. HB is still a serious health problem in economically compromised parts of the world. The long term outcome has been regarded favorable based on epidemiological data, but has not been confirmed in prospective follow-up studies extending to adulthood. Methods. We studied the long term consequences of HB in a prospective birth cohort of 128 HB cases and 82 controls. The cases are part of a neonatal at-risk cohort (n = 1196) that has been followed up to 30 years of age. HB cases were newborns ≥ 2500 g birth weight and ≥ 37 weeks of gestation who had bilirubin concentrations > 340 µmol/l or required blood exchange transfusion. Subjects with HB were divided into subgroups based on the presence (affected HB) or absence (unaffected HB) of diagnosed neurobehavioral disorders in childhood, and compared with healthy controls. Subjects were seen at discharge, 5, 9 and 16 years of life and parent's and teacher's assessments were recorded. At 30 years they filled a questionnaire about academic and occupational achievement, life satisfaction, somatic and psychiatric symptoms including a ADHD self-rating score. Cognitive functioning was tested using ITPA, WISC, and reading and writing tests at 9 years of life. Results. Compared to controls, the odds for a child with HB having neurobehavioral symptoms at 9 years was elevated (OR = 4.68). Forty-five per cent of the HB group were affected by cognitive abnormalities in childhood and continued to experience problems in adulthood. This was apparent in academic achievement (p < 0.0001) and the ability to complete secondary (p < 0.0001) and tertiary (p < 0.004) education. Also, the subgroup of affected HB reported persisting cognitive complaints e.g., problems with reading, writing and mathematics. Childhood symptoms of hyperactivity/impulsivity (p < 0.0001) and inattention (p < 0.02) were more common in HB groups, but in adulthood the symptoms were equal. The affected HB had lower scores in parameters reflecting life satisfaction, less controlled drinking, but not increased substance abuse. Discussion. Our results indicate that neonatal HB has negative consequences in adult age. A prospectively collected cohort with strict inclusion criteria enables to control most of the bias factors involved with retrospective data. The control and HB groups were remarkably similar at birth in terms of medical data, and the growth environment of the children, as well as the parents' social groups, education, size of family, type of housing at birth and at 9 years of age. Our findings bear resemblance to disorders of the fronto-striatal network, and also symptoms of the ADHD spectrum were frequent in the HB group suggesting a link of HB to other neurodevelopmental disorders.

The Perinatal Adverse events and Special Trends in Cognitive Trajectory (PLASTICITY) - pre-protocol for a prospective longitudinal follow-up cohort study.

Prospective follow-up studies on long term effects of pre- and perinatal adverse conditions in adulthood are rare. We will continue to follow the prospective cohort of initially 1196 subjects with predefined at-delivery risk factors out of 22,359 consecutive deliveries during 1971-74 at a single maternity hospital. The risk cohort and 93 controls have been followed up with a comprehensive clinical program at 5, 9, and 16 years of age and by questionnaire at the age of 30 years. Major medical events known to affect the development and growth of the brain, or cognitive functions and personality have been documented. Here we present a pre-protocol for the project, which we will call PLASTICITY, whose aim is to follow consenting subjects and controls into mid-adulthood and beyond, and to explore how the neonatal risk factors modulate neurodevelopmental and neurodegenerative processes such as learning disabilities, ADHD, aging, early onset mild cognitive impairment and even dementia. Our first focus is on the neurological and cognitive outcomes at age 40 years, using detailed neurological, neuropsychological, neuroimaging, genetic, blood chemistry and registry based methods. Results will be expected to offer information on the risk of neurological, psychiatric, metabolic and other medical consequences as well as the need for health and social services at the brink of middle age, when new degenerative phenomena are known to emerge. The evaluation at age 40 years will serve as a baseline for later aging studies. We welcome all comments and suggestions, which we will apply in finalizing details and inviting collaboration.

Neuropsychological sequelae of acute-onset sporadic viral encephalitis.

Acute encephalitis is an inflammation of the brain parenchyma. In the USA, by estimation, 20,000 cases occur every year. A variety of cognitive deficits may persist after the acute stage, and they are often the sole cause of disability. Recent literature demonstrates the heterogeneity of both amnestic disorders and the outcome following encephalitis. Herpes simplex virus is the most commonly recognised single aetiology of sporadic encephalitis and it may be the cause of the most severe symptoms. Antiviral medication, however, seems to have improved the cognitive outcome when compared to the historical, untreated cases. The cognitive sequelae following herpes simplex virus encephalitis (HSVE) are best known and most commonly described, e.g., in textbooks, but they do not represent the typical symptomatology of encephalitis in general. Much less is unfortunately known about other types of encephalitis, those that account perhaps up to 80% of all cases, where both mild and severe defects have been observed. This article summarises the current knowledge.