School-based targeted prevention for children with mild intellectual disabilities or borderline intellectual functioning and behaviour problems: A pilot implementation study.

BACKGROUND: We examined the implementation and potential effectiveness of a school-based targeted prevention programme addressing behaviour problems, adapted for children with mild intellectual disabilities or borderline intellectual functioning. METHOD: Thirteen children participated. The intervention was implemented in schools. We examined intervention dosage, reach, responsiveness, satisfaction, and comprehension, using questionnaires completed by children and trainers. We assessed child- and teacher-reported behaviour problems before and after the intervention. RESULTS: Trainers selected both children who did and did not meet the intervention eligibility criteria, suggesting problems in intervention reach. Intervention dosage, responsiveness, satisfaction, and comprehension were satisfactory. There were group-level behaviour problem decreases (i.e., Cohen's d). Individual-level behaviour problem changes (i.e., Reliable Change Indices) showed large heterogeneity and little reliable change. CONCLUSIONS: The results provide initial evidence that the intervention has potential for successful implementation in schools, but the current evidence for intervention effectiveness is inconclusive.

A rapidly growing fibroadenoma in a pregnant woman: A case report.

BACKGROUND: Fibroadenomas are the most common benign breast lesions in women. They present as a unilateral mass and can rapidly enlarge in size through hormonal changes. Fibroadenomas could be classified as small or giant, and as simple or complex. They are classified as 'giant' when the size exceeds 5 cm and/or weight 500 gram; and as 'complex' if one of the following characteristics is present: cysts with a size >3 mm, epithelial calcifications, sclerosing adenosis and papillary apocrine metaplasia. Giant fibroadenomas can cause compression of surrounding breast tissue or breast asymmetry, requiring surgical excision in order to preserve a normal breast shape. CASE: A 26-year-old pregnant woman was referred with a palpable mass of her right breast. The mass rapidly increased in size to a diameter of 13 cm during the second trimester of her pregnancy. A tru-cut biopsy confirmed a fibroadenoma. The rapid growth and compression of normal breast tissues indicated a lumpectomy during her pregnancy. The mass was easily excised without any consequences for the pregnancy. Pathological examination showed a complex giant fibroadenoma. CONCLUSION: A unique case of a pregnant woman with rapid progression of a fibroadenoma that met the criteria of a complex and giant fibroadenoma, was presented. This case emphasizes the importance of timely surgical intervention, even during pregnancy, to prevent permanent breast tissue damage.

The challenges of diagnosis and treatment of rare Prevotella-induced breast abscesses: A retrospective cohort study.

OBJECTIVE: Although the genus Prevotella is part of the general human microbiota, species of this anaerobic gram-negative bacterium have been described as causes of persisting nonpuerperal breast abscesses. Collecting punctate samples and testing these samples for anaerobic bacteria is not part of the common diagnostic workflow in atypical breast abscesses. The causative anaerobic micro-organism can remain unclear and patients can be treated with multiple inadequate antibiotics and/or extensive surgical procedures. The aim of this cohort study of Prevotella induced breast abscesses is to gain more insights into the diagnostic procedures and treatment. METHODS: Medical charts of patients with a Prevotella induced breast abscess between 2015 and 2021, were retrospectively reviewed on patient characteristics, diagnostic procedures, treatment and outcome. RESULTS: Twenty-one patients were included. Six subspecies of Prevotella were determined by culturing. High susceptibility was observed for amoxicillin/clavulanic acid (100%, n = 12). Nine patients (43%) were treated with antibiotics, eight patients (38%) with antibiotics and incision and drainage, and four patients (19%) with only incision and drainage. Recurrence was observed in nine patients (43%), of whom five patients were treated with antibiotics and three patients had surgery. The mean duration of antibiotic administration in patients with recurrence was significantly shorter compared to those without recurrence (5.6 days vs. 19.5 days, p = 0.039). CONCLUSION: Specific anaerobic culturing should be common practice in atypical breast abscesses to confirm Prevotella species. The high recurrence rate emphasizes the need of further research for optimal treatment. Prolonged duration of antibiotics could be considered and amoxicillin/clavulanic acid seems to be the first choice.

New Ultrasound Measurements to Bridge the Gap between Prenatal and Neonatal Brain Growth Assessment.

BACKGROUND AND PURPOSE: Most ultrasound markers for monitoring brain growth can only be used in either the prenatal or the postnatal period. We investigated whether corpus callosum length and corpus callosum-fastigium length could be used as markers for both prenatal and postnatal brain growth. MATERIALS AND METHODS: A 3D ultrasound study embedded in the prospective Rotterdam Periconception Cohort was performed at 22, 26 and 32 weeks' gestational age in fetuses with fetal growth restriction, congenital heart defects, and controls. Postnatally, cranial ultrasound was performed at 42 weeks' postmenstrual age. First, reliability was evaluated. Second, associations between prenatal and postnatal corpus callosum and corpus callosum-fastigium length were investigated. Third, we created reference curves and compared corpus callosum and corpus callosum-fastigium length growth trajectories of controls with growth trajectories of fetuses with fetal growth retardation and congenital heart defects. RESULTS: We included 199 fetuses; 22 with fetal growth retardation, 20 with congenital heart defects, and 157 controls. Reliability of both measurements was excellent (intraclass correlation coefficient ≥ 0.97). Corpus callosum growth trajectories were significantly decreased in fetuses with fetal growth restriction and congenital heart defects (ß = -2.295; 95% CI, -3.320-1.270; P < .01; ß = -1.267; 95% CI, -0.972-0.562; P < .01, respectively) compared with growth trajectories of controls. Corpus callosum-fastigium growth trajectories were decreased in fetuses with fetal growth restriction (ß = -1.295; 95% CI, -2.595-0.003; P = .05). CONCLUSIONS: Corpus callosum and corpus callosum-fastigium length may serve as reliable markers for monitoring brain growth from the prenatal into the postnatal period. The clinical applicability of these markers was established by the significantly different corpus callosum and corpus callosum-fastigium growth trajectories in fetuses at risk for abnormal brain growth compared with those of controls.

Foetal fractional thigh volume: an early 3D ultrasound marker of neonatal adiposity.

BACKGROUND: The predisposition for obesity is suggested to originate in the prenatal period. Prenatal markers are needed to identify foetuses at risk for neonatal adiposity, as early marker of childhood obesity. OBJECTIVE: The aim of this study is to assess the association between foetal fractional thigh volume (TVol) and neonatal percentage fat mass from mid-gestation onward. METHODS: In this perinatal cohort study, singleton pregnancies with term born infants were included. Foetal TVol was measured on three-dimensional ultrasound scans (3D US) obtained at 22, 26 and 32 weeks of gestation. Neonatal body composition measurement (percentage body fat (%BF)) was planned between 42+0 and 42+6 -week postmenstrual age. Cross-sectional and longitudinal linear regression analyses were performed. RESULTS: Seventy-nine mother-child pairs were included. Median (interquartile range) TVol increased from 7.6 (7.1; 8.5) cm3 at 22 weeks to 36.5 (33.8; 40.9) cm3 at 32 weeks. Median neonatal %BF was 14.3% (11.7; 17.0). TVol at 22 weeks (ß = -1.58, 95% CI -2.45; -0.70, explained variance 31%) was negatively associated with %BF, but no associations were found at 26 and 32 weeks of gestation. TVol growth between 22 and 32 weeks of gestation (explained variance 18%) was also statistically significantly negatively associated with %BF. CONCLUSIONS: Foetal TVol is a promising 3D US marker for prediction of neonatal adiposity from mid-gestation onward.

Prenatal cerebellar growth trajectories and the impact of periconceptional maternal and fetal factors.

STUDY QUESTION: CAN WE assess human prenatal cerebellar growth from the first until the third trimester of pregnancy and create growth trajectories to investigate associations with periconceptional maternal and fetal characteristics? SUMMARY ANSWER: Prenatal growth trajectories of the human cerebellum between 9 and 32 weeks gestational age (GA) were created using three-dimensional ultrasound (3D-US) and show negative associations with pre-pregnancy and early first trimester BMI calculated from self-reported and standardized measured weight and height, respectively. WHAT IS KNOWN ALREADY: The cerebellum is essential for normal neurodevelopment and abnormal cerebellar development has been associated with neurodevelopmental impairments and psychiatric diseases. Cerebellar development is particularly susceptible to exposures during the prenatal period, including maternal folate status, smoking habit and alcohol consumption. STUDY DESIGN, SIZE, DURATION: From 2013 until 2015, we included 182 singleton pregnancies during the first trimester as a subgroup in a prospective periconception cohort with follow-up until birth. For the statistical analyses, we selected 166 pregnancies ending in live born infants without congenital malformations. PARTICIPANTS/MATERIALS, SETTING, METHODS: We measured transcerebellar diameter (TCD) at 9, 11, 22, 26 and 32 weeks GA on ultrasound scans. Growth rates were calculated and growth trajectories of the cerebellum were created. Linear mixed models were used to estimate associations between cerebellar growth and maternal age, parity, mode of conception, geographic origin, pre-pregnancy and first trimester BMI, periconceptional smoking, alcohol consumption, timing of folic acid supplement initiation and fetal gender. MAIN RESULTS AND THE ROLE OF CHANCE: In total, 166 pregnancies provided 652 (87%) ultrasound images eligible for TCD measurements. Cerebellar growth rates increased with advancing GA being 0.1691 mm/day in the first trimester, 0.2336 mm/day in the second trimester and 0.2702 mm/day in the third trimester. Pre-pregnancy BMI, calculated from self-reported body weight and height, was significantly associated with decreased cerebellar growth trajectories (ß = -0.0331 mm, 95% CI = -0.0638; -0.0024, P = 0.035). A similar association was found between cerebellar growth trajectories and first trimester BMI, calculated from standardized measurements of body weight and height (ß = -0.0325, 95% CI = -0.0642; -0.0008, P = 0.045, respectively). LIMITATIONS, REASONS FOR CAUTION: As the study population largely consisted of tertiary hospital patients, external validity should be studied in the general population. Whether small differences in prenatal cerebellar growth due to a higher pre-pregnancy and first trimester BMI have consequences for neurodevelopmental outcome needs further investigation. WIDER IMPLICATIONS OF THE FINDINGS: Our findings further substantiate previous evidence for the detrimental impact of a higher maternal BMI on neurodevelopmental health of offspring in later life. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the Department of Obstetrics and Gynecology, Erasmus MC University Medical Centre and Sophia Children's Hospital Fund, Rotterdam, The Netherlands (SSWO grant number 644). No competing interests are declared.

Functional connectivity and microstructural white matter changes in phenocopy frontotemporal dementia.

OBJECTIVES: Phenocopy frontotemporal dementia (phFTD) is a rare and poorly understood clinical syndrome. PhFTD shows core behavioural variant FTD (bvFTD) symptoms without associated cognitive deficits and brain abnormalities on conventional MRI and without progression. In contrast to phFTD, functional connectivity and white matter (WM) microstructural abnormalities have been observed in bvFTD. We hypothesise that phFTD belongs to the same disease spectrum as bvFTD and investigated whether functional connectivity and microstructural WM changes similar to bvFTD are present in phFTD. METHODS: Seven phFTD patients without progression or alternative psychiatric diagnosis, 12 bvFTD patients and 17 controls underwent resting state functional MRI (rs-fMRI) and diffusion tensor imaging (DTI). Default mode network (DMN) connectivity and WM measures were compared between groups. RESULTS: PhFTD showed subtly increased DMN connectivity and subtle microstructural changes in frontal WM tracts. BvFTD showed abnormalities in similar regions as phFTD, but had lower increased DMN connectivity and more extensive microstructural WM changes. CONCLUSIONS: Our findings can be interpreted as neuropathological changes in phFTD and are in support of the hypothesis that phFTD and bvFTD may belong to the same disease spectrum. Advanced MRI techniques, objectively identifying brain abnormalities, would therefore be potentially suited to improve the diagnosis of phFTD. KEY POINTS: • PhFTD shows brain abnormalities that are similar to bvFTD. • PhFTD shows increased functional connectivity in the parietal default mode network. • PhFTD shows microstructural white matter abnormalities in the frontal lobe. • We hypothesise phFTD and bvFTD may belong to the same disease spectrum.

A New Ultrasound Marker for Bedside Monitoring of Preterm Brain Growth.

BACKGROUND AND PURPOSE: Preterm neonates are at risk for neurodevelopmental impairment, but reliable, bedside-available markers to monitor preterm brain growth during hospital stay are still lacking. The aim of this study was to assess the feasibility of corpus callosum-fastigium length as a new cranial sonography marker for monitoring of preterm brain growth. MATERIALS AND METHODS: In this longitudinal prospective cohort study, cranial ultrasound was planned on the day of birth, days 1, 2, 3, and 7 of life; and then weekly until discharge in preterm infants born before 29 weeks of gestational age. Reproducibility and associations between clinical variables and corpus callosum-fastigium growth trajectories were studied. RESULTS: A series of 1-8 cranial ultrasounds was performed in 140 infants (median gestational age at birth, 27(+2) weeks (interquartile range, 26(+1) to 28(+1); 57.9% male infants). Corpus callosum-fastigium measurements showed good-to-excellent agreement for inter- and intraobserver reproducibility (intraclass correlation coefficient >0.89). Growth charts for preterm infants between 24 and 32 weeks of gestation were developed. Male sex and birth weight SD score were positively associated with corpus callosum-fastigium growth rate. CONCLUSIONS: Corpus callosum-fastigium length measurement is a new reproducible marker applicable for bedside monitoring of preterm brain growth during neonatal intensive care stay.

Growth trajectories of the human embryonic head and periconceptional maternal conditions.

STUDY QUESTION: Can growth trajectories of the human embryonic head be created using 3D ultrasound (3D-US) and virtual reality (VR) technology, and be associated with second trimester fetal head size and periconceptional maternal conditions? SUMMARY ANSWER: Serial first trimester head circumference (HC) and head volume (HV) measurements were used to create reliable growth trajectories of the embryonic head, which were significantly associated with fetal head size and periconceptional maternal smoking, age and ITALIC! in vitro fertilization (IVF)/intra-cytoplasmic sperm injection (ICSI) treatment. WHAT IS KNOWN ALREADY: Fetal growth is influenced by periconceptional maternal conditions. STUDY DESIGN, SIZE, DURATION: We selected 149 singleton pregnancies with a live born non-malformed fetus from the Rotterdam periconception cohort. PARTICIPANTS/MATERIALS, SETTING, METHODS: Bi-parietal diameter and occipital frontal diameter to calculate HC, HV and crown-rump length (CRL) were measured weekly between 9 + 0 and 12 + 6 weeks gestational age (GA) using 3D-US and VR. Fetal HC was obtained from second trimester structural anomaly scans. Growth trajectories of the embryonic head were created with general additive models and linear mixed models were used to estimate associations with maternal periconceptional conditions as a function of GA and CRL, respectively. MAIN RESULTS: A total of 303 3D-US images of 149 pregnancies were eligible for embryonic head measurements (intra-class correlation coefficients >0.99). Associations were found between embryonic HC and fetal HC ( ITALIC! ρ = 0.617, ITALIC! P < 0.001) and between embryonic HV and fetal HC ( ITALIC! ρ = 0.660, ITALIC! P < 0.001) in ITALIC! Z-scores. Maternal periconceptional smoking was associated with decreased, and maternal age and IVF/ICSI treatment with increased growth trajectories of the embryonic head measured by HC and HV (All ITALIC! P < 0.05). LIMITATIONS, REASONS FOR CAUTION: The consequences of the small effect sizes for neurodevelopmental outcome need further investigation. As the study population consists largely of tertiary hospital patients, external validity should be studied in the general population. WIDER IMPLICATIONS OF THE FINDINGS: Assessment of growth trajectories of the embryonic head may be of benefit in future early antenatal care. STUDY FUNDING/COMPETING INTERESTS: This study was funded by the Department of Obstetrics and Gynaecology, Erasmus MC University Medical Centre and Sophia Foundation for Medical Research, Rotterdam, The Netherlands (SSWO grant number 644). No competing interests are declared.

Brain perfusion patterns in familial frontotemporal lobar degeneration.

OBJECTIVE: Frontotemporal lobar degeneration (FTLD) is a clinically, genetically, and pathologically heterogeneous disorder. The aim of this study was to compare clinical features and perfusion patterns on SPECT of patients with familial FTLD-TAR DNA binding protein 43 kDa (TDP) and MAPT mutations. METHODS: Patients were included if they had MAPT or GRN mutations, positive family history with pathologically proven FTLD in the patient or first-degree relative, or were part of FTD-MND families. All patients and 10 age- and gender-matched controls underwent measurement of brain perfusion using (99m)Tc-HMPAO SPECT. We used SPM8 to perform image processing and voxel-based group analyses (p < 0.001). Gender and age were included as nuisance variables in the design matrices. RESULTS: Of the 29 patients with familial FTLD, 19 had familial FTLD-TDP (GRN mutations in 6), and 10 had MAPT mutations. At clinical presentation, familial FTLD-TDP patients were older at onset (p = 0.030) and had more memory deficits (p = 0.011), whereas patients with MAPT had more naming deficits (p < 0.001) and obsessive-compulsive behavior (p = 0.001). The between-groups SPECT analyses revealed significantly less perfusion in the right frontal lobe, precuneus, cuneus, and inferior parietal lobule in familial FTLD-TDP, whereas significantly less perfusion was found in the left temporal and inferior frontal gyri in MAPT. Post hoc analysis of familial FTLD-TDP with unknown genetic defect vs MAPT revealed less perfusion in the right frontal and parietal lobe. CONCLUSION: Familial FTLD-TDP shows relatively more posterior hypoperfusion, including the precuneus and inferior parietal lobule, possibly related to significant memory impairment. Patients with MAPT were characterized by impaired perfusion of the temporal regions and naming deficits.

Genetic risk factors for cerebral small-vessel disease in hypertensive patients from a genetically isolated population.

BACKGROUND: Asymptomatic cerebral lesions on MRI such as white matter lesions (WML), lacunes and microbleeds are commonly seen in older people. We examined the role of a series of candidate genes involved in blood pressure regulation and amyloid metabolism. MATERIALS AND METHODS: The study was embedded in a family-based cohort sampled from a Dutch genetically isolated population. We selected individuals between 55 and 75 years of age with hypertension (N=129). Volumes of WML and presence of lacunes and microbleeds were assessed with MRI. We studied three genes involved in blood pressure regulation (angiotensin, angiotensin II type 1 receptor, α-adducin) and two genes involved in the amyloid pathway (apolipoprotein E (APOE) and sortilin-related receptor gene (SORL1)). RESULTS: All participants had WML (median volume, 3.1 ml; interquartile range, 1.5-6.5 ml); lacunar infarcts were present in 15.5% and microbleeds in 23.3%. Homozygosity for the APOE ε4 allele was associated with lacunes (OR, 4.8; 95% CI, 1.2 to 19.3). Individuals carrying two copies of the variant allele of four single nucleotide polymorphism (SNPs) located at the 3'-end of SORL1 (rs1699102, rs3824968, rs2282649, rs1010159) had significantly more often microbleeds (highest OR, 6.87; 95% CI, 1.78 to 26.44). CONCLUSION: The association of SORL1 with microbleeds suggests that the amyloid cascade is involved in the aetiology of microbleeds in populations with hypertension.

Clinical features and X-inactivation in females heterozygous for creatine transporter defect.

The creatine transporter defect is an X-linked cause of mental retardation. We investigated the clinical features and pattern of X-inactivation in a Dutch cohort of eight female heterozygotes. We show that symptoms of the creatine transporter defect (mental retardation, learning difficulties, and constipation) can be present in female heterozygotes. We further show that the diagnosis in females is not straightforward: (i) The creatine/creatinine ratio in urine was elevated only in three of eight females. (ii) Although as a group the females had a significantly decreased cerebral creatine concentration, individual females had creatine concentrations overlapping with normal controls. (iii) Skewed X-inactivation was found in the cultured fibroblasts, in favour of either the mutated or the wild-type allele, leading to either deficient or normal results in the creatine uptake studies in fibroblasts. Thus, screening by these tests is unreliable for the diagnosis. In addition, we found no consistent skewing of the X-inactivation in peripheral tissues indicating that there is no selection against the creatine transporter defect. We conclude that testing for creatine transporter defect should be considered in females with (mild) mental retardation. Screening by DNA analysis of the SLC6A8 gene is recommended.

Insulin-resistance and metabolic syndrome are related to executive function in women in a large family-based study.

While type 2 diabetes is well-known to be associated with poorer cognitive performance, few studies have reported on the association of metabolic syndrome (MetS) and contributing factors, such as insulin-resistance (HOMA-IR), low adiponectin-, and high C-reactive protein (CRP)-levels. We studied whether these factors are related to cognitive function and which of the MetS components are independently associated. The study was embedded in an ongoing family-based cohort study in a Dutch population. All participants underwent physical examinations, biomedical measurements, and neuropsychological testing. Linear regression models were used to determine the association between MetS, HOMA-IR, adiponectin levels, CRP, and cognitive test scores. Cross-sectional analyses were performed in 1,898 subjects (mean age 48 years, 43% men). People with MetS had significantly higher HOMA-IR scores, lower adiponectin levels, and higher CRP levels. MetS and high HOMA-IR were associated with poorer executive function in women (P = 0.03 and P = 0.009). MetS and HOMA-IR are associated with poorer executive function in women.

Distinct genetic forms of frontotemporal dementia.

BACKGROUND: Frontotemporal dementia (FTD) is the second most common type of presenile dementia and can be distinguished into various clinical variants. The identification of MAPT and GRN defects and the discovery of the TDP-43 protein in FTD have led to the classification of pathologic and genetic subtypes. In addition to these genetic subtypes, there exist familial forms of FTD with unknown genetic defects. METHODS: We investigated the frequency, demographic, and clinical data of patients with FTD with a positive family history in our prospective cohort of 364 patients. Genetic analysis of genes associated with FTD was performed on all patients with a positive family history. Immunohistochemical studies were carried out with a panel of antibodies (tau, ubiquitin, TDP-43) in brains collected at autopsy. RESULTS: In the total cohort of 364 patients, 27% had a positive family history suggestive for an autosomal mode of inheritance, including MAPT (11%) and GRN (6%) mutations. We identified a new Gln300X GRN mutation in a patient with a sporadic FTD. The mean age at onset in GRN patients (61.8 +/- 9.9 years) was higher than MAPT patients (52.4 +/- 5.9 years). In the remaining 10% of patients with suggestive autosomal dominant inheritance, the genetic defect has yet to be identified. Neuropathologically, this group can be distinguished into familial FTLD+MND and familial FTLD-U with hippocampal sclerosis. CONCLUSION: Future genetic studies need to identify genetic defects in at least two distinct familial forms of frontotemporal dementia (FTD) with unknown genetic defects: frontotemporal lobe degeneration with ubiquitin-positive inclusions with hippocampal sclerosis and frontotemporal lobe degeneration with motor neuron disease.

The role of disability and depression in cognitive functioning within 2 years after multiple sclerosis diagnosis.

OBJECTIVES: To investigate cognitive functioning shortly after multiple sclerosis (MS) diagnosis and to examine the relationship with disability, depression and anxiety. METHODS: Data were available for 101 recently diagnosed MS patients and 117 healthy controls. Neuropsychological and clinical assessment included Rao's Brief Repeatable Battery, Expanded Disability Status Scale (EDSS), and Hospital Anxiety and Depression scale (HADS). RESULTS: Patients had lower scores than controls on timed tasks (Paced Auditory Serial Addition Test (PASAT3, p-value adjusted for age, sex and education = 0.04; PASAT2, p = 0.001), Word List Generation Test (WLG, p = 0.04)). Scores on Symbol Digit Modalities Test (SDMT; p = 0.001), PASAT3 (p = 0.01) and PASAT2 (p < 0.001) showed significant association with EDSS. Patients with EDSS >or= 3.0 had significantly lower scores on Selective Reminding Test (SRTC, p = 0.04), SDMT (p = 0.002), PASAT3 (p = 0.002), PASAT2 (p < 0.001) and WLG (p = 0.01) than controls from the general population. Patients with clinically borderline scores of depression scored lower on SDMT (49.5 versus 57.1, p = 0.06) and PASAT3 (39.8 versus 47.1, p = 0.03). However, after adjustment for EDSS and time since disease onset, these differences were not statistically significant. CONCLUSION: Within two years after diagnosis, patients with MS had lower scores compared to healthy controls on timed tasks, suggesting cognitive slowing in patients with early MS. Cognitive impairment was associated with symptoms of depression, but this association could be explained by differences in disability.

CSF biomarkers in frontotemporal lobar degeneration with known pathology.

OBJECTIVE: To evaluate the diagnostic value of CSF biomarkers in patients with known pathology due to frontotemporal lobar degeneration (FTLD). BACKGROUND: It is important to distinguish FTLD from other neurodegenerative diseases like Alzheimer disease (AD), but this may be difficult clinically because of atypical presentations. METHODS: Patients with FTLD (n = 30) and AD (n = 19) were identified at autopsy or on the basis of genetic testing at University of Pennsylvania and Erasmus University Medical Center. CSF was obtained during a diagnostic lumbar puncture and was analyzed using assays for total tau and amyloid-beta 1-42 (A beta(42)). Patients also were assessed with a brief neuropsychological battery. RESULTS: CSF total tau level and the ratio of CSF total tau to A beta(42) (tau/A beta(42)) were significantly lower in FTLD than in AD. Receiver operating characteristic curve analyses confirmed that the CSF tau/A beta(42) ratio is sensitive and specific at discriminating between FTLD and AD, and is more successful at this than CSF total tau alone. Although some neuropsychological measures are significantly different in autopsy-proven FTLD and AD, combining these neuropsychological measures with CSF biomarkers did not improve the ability to distinguish FTLD from AD. CONCLUSIONS: The ratio of CSF tau/A beta(42) is a sensitive and specific biomarker at discriminating frontotemporal lobar degeneration from Alzheimer disease in patients with known pathology.

Cerebrovascular risk factors do not contribute to genetic variance of cognitive function: the ERF study.

Impaired cognition in later life may result from Alzheimer's disease-related pathology, but also from vascular pathology. We studied to what extent vascular risk explained heritability of cognition in 780 individuals, related in one extended pedigree in a genetically isolated population, in the ERF study. Heritability was estimated using variance components modelling (SOLAR). Univariate analyses included models with and without vascular disease; bivariate analyses included both cognitive and vascular traits, such as blood pressure, serum glucose or lipids. Heritability for immediate and delayed recall, recognition, semantic fluency, Trail making B and Stroop tests was significant, with estimates from 0.16 to 0.36. Vascular factors did not affect cognitive functions, except immediate recall and the Stroop test. Heritability estimates did not change significantly when adjusted for vascular disease. We found no genetic correlation between cognition and vascular traits. Therefore, in this population vascular disease is mildly associated with cognitive dysfunction, and in those with vascular disease, the underlying genetic risk factors are not likely to account for the genetic variation in cognition at adult age.

Diagnostic value of the Rotterdam-CAMCOG in post-stroke dementia.

BACKGROUND AND OBJECTIVE: Specific screening tests to detect post-stroke dementia are lacking. We recently reported that an adaptation of the Cambridge Cognitive Examination (CAMCOG), the Rotterdam-CAMCOG, had excellent sensitivity and specificity for detecting post-stroke dementia. In this study, we externally validated the diagnostic accuracy of the R-CAMCOG in a new, representative cohort of stroke patients. METHODS: The R-CAMCOG and an extensive neuropsychological examination were administered, independently of each other, in 121 patients aged 55 and over with a stroke in the preceding three to nine months. The gold standard diagnosis of dementia was based on the results of the extensive neuropsychological examination, clinical presentation, and information from a close relative, as well as DSM-IV criteria. RESULTS: Of the 121 patients, 35 had dementia (29%). The diagnostic accuracy at the pre-specified cut-off point of 33/34 was established through receiver operating characteristic (ROC) analyses (sensitivity 66%, specificity 94%). At a cut-off point of 36/37 sensitivity would be 83% and specificity 78%. CONCLUSION: The R-CAMCOG is a useful screening tool for post-stroke dementia in a clinical setting.

Complex compulsive behaviour in the temporal variant of frontotemporal dementia.

OBJECTIVE: As metabolic and structural changes in frontotemporal-subcortical pathways have been reported in patients with obsessive-compulsive disorders, we investigated the correlation between complex compulsive behaviour (CCB) and the distribution of atrophy in a group of 90 patients with frontotemporal dementia (FTD). METHODS: CCB was defined as complex, intentional, and time consuming repetitive behaviour, which was distinguished from simple compulsive behaviour (SCB), such as verbal and motor repetitions and utilisation behaviour. Cortical atrophy on CT and/or MRI was semi-quantitatively assessed in frontal, temporal, parietal and occipital regions, and the pattern of atrophy was compared between patients with and without CCB or SCB. Linear measures were used to establish the presence of caudate atrophy (bicaudate ratio) and ventricular enlargement (bifrontal ratio). RESULTS: CCB was reported in 18 (21%) and SCB in 53 (61%) FTD patients. Frontotemporal atrophy was present in 64 patients (74%), and predominant temporal atrophy in 23 (26%). The pattern of atrophy was asymmetric in 25 patients (29%). Logistic regression analysis showed that temporal lobe atrophy (p < 0.005), as well as asymmetry of atrophy (p < 0.05) were independently associated with CCB, after adjusting for age at onset, gender, duration of symptoms at the time of imaging, severity of atrophy, and bicaudate and bifrontal ratio. No relationship was found between the presence of SCB and the distribution of atrophy, although patients with SCB tended to have more caudate atrophy (p < 0.1). CONCLUSION: Temporal lobe atrophy appears to mediate CCB in patients with FTD, especially if asymmetry of atrophy is present. Future studies with quantitative and volumetric measurements of the cortical and subcortical structures may further clarify the aetiology of CCB in FTD.

Presentation of amyloidosis in carriers of the codon 692 mutation in the amyloid precursor protein gene (APP692).

Several mutations in the amyloid precursor protein (APP) gene may lead to either Alzheimer's disease or cerebral haemorrhage due to congophilic amyloid angiopathy (CAA). A single family is known in which both types of pathology are expressed because of a missense mutation at codon 692 of the APP gene (APP692). Here we describe the clinical and pathological expression of APP692 in eight patients with the mutation. Furthermore, 21 first-degree relatives with an a priori risk of 50% of being a carrier were tested for the APP692 mutation and studied for presymptomatic signs by neurological examination, neuropsychological testing and brain MRI. Patients with APP692 presented with haemorrhage, dementia or both. The dementia in patients with the APP692 mutation was compatible with Alzheimer's disease both clinically and neuropathologically. Of the 21 healthy relatives at 50% risk, five carried the APP692 mutation. The presymptomatic carriers showed a subtle, non-significant impairment of cognitive function compared with relatives without APP692. A significant increase in the number of periventricular and subcortical white matter lesions at young age was seen in presymptomatic carriers (mean age 26.4 years). The findings of this study suggest that a single (genetic) mechanism may underlie the pathology of Alzheimer's disease and CAA. These diseases are manifested subclinically by white matter pathology. Further insight into the relationship between CAA and Alzheimer's disease may provide clues about the aetiology of Alzheimer's disease.