I. de Koning

Phenotypic Variation in Hereditary Frontotemporal Dementia with Tau Mutations

Several mutations in the tau gene have been found in families with hereditary frontotemporal dementia and parkinsonism linked to chromosome 17q21‐22 (FTDP‐17). This study is the first attempt to correlate genotype and phenotype in six families with FTDP‐17 with mutations in the tau gene (ΔK280, G272V, P301L, and R406W). We have investigated tau pathology in 1 P301L and 1 R406W patient. The R406W family showed a significantly higher age at onset (59.2 ± 5.5 years) and longer duration of illness (12.7 ± 1.5 years) than the families with the other mutations. The six families showed considerable variation in clinical presentation, but none of them had early parkinsonism. Mutism developed significantly later in the R406W family than in the other families. Frontotemporal atrophy on neuroimaging in the R406W family was less severe than in the P301L and ΔK280 families. The P301L brain contained many pretangles in the frontal and temporal cortex, and the dentate gyrus of hippocampus, showing three tau bands (64, 68, and 72 kd) of extracted tau from the frontal cortex. The presence of many neurofibrillary tangles, many diffuse and classic neuritic plaques in the temporal and parietal cortex, and the hippocampus of the same P301L brain correlated with the presence of four sarkosyl‐insoluble (60, 64, 68, and 72 kd) tau bands. The coexistence of characteristic P301L and Alzheimer pathology in the same brain needs further explanation. The R406W brain showed abundant neurofibrillary tangles in several brain regions, and four tau bands (60, 64, 68, and 72 kd) of extracted tau from these regions. The slower progression of the disease in the R406W family might be explained by the microtubule‐binding properties of the mutant protein.

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 (Aβ42). Patients also were assessed with a brief neuropsychological battery. Results: CSF total tau level and the ratio of CSF total tau to Aβ42 (tau/Aβ42) were significantly lower in FTLD than in AD. Receiver operating characteristic curve analyses confirmed that the CSF tau/Aβ42 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/Aβ42 is a sensitive and specific biomarker at discriminating frontotemporal lobar degeneration from Alzheimer disease in patients with known pathology.

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. GLOSSARY: CA1 = cornu ammonis field 1; FTD = frontotemporal dementia; FTD-bv = behavioral variant of FTD; FTD+MND = FTD with motor neuron disease; FTLD = frontotemporal lobe degeneration; FTLD-tau = FTLD with tau-positive pathology; FTLD-U = FTLD with tau-negative, ubiquitin-positive inclusions; HS = hippocampal sclerosis; PNFA = progressive nonfluent aphasia; TDP-43 = TAR-DNA binding protein 43.

The diagnostic value of SPECT with Tc 99m HMPAO in Alzheimer's disease: A population‐based study

We studied the diagnostic accuracy of single-photon emission computed tomography (SPECT) with technetium 99m-labeled hexamethylpropylene amine oxime (Tc 99m HMPAO) in 48 patients with probable Alzheimers disease (AD) according to NINCDS-ADRDA criteria and in 60 controls recruited from a population-based study. With logistic regression, we identified decreased temporal regional cerebral blood flow as the best discriminating variable between patients and controls. Receiver-operator characteristic curves showed that the discriminative ability of SPECT improved with increasing dementia severity. With specificity set at 90%, sensitivity figures were 42% in mild, 56% in moderate, and 79% in severe AD. The diagnostic gain as a function of the prior probability of the disease being present was computed for those with mild AD. When the prior probability varied at around 50%, the diagnostic gain for mild AD patients was substantial (a maximum of 34%) for a positive test result but poor for a negative test result. The results suggest that the practical usefulness of SPECT as a diagnostic adjunct in patients suspected of having mild AD is confined to situations in which, on clinical grounds, there is considerable diagnostic doubt.

Abnormal amino acid metabolism in patients with early stage Alzheimer dementia

Summary. Plasma levels of several amino acids were studied in 14 patients with early stage probable Alzheimers disease (AD) and 17 age-matched controls. In the AD patients a possible relationship between amino acid levels and behavioural symptomatology was also investigated. We found significantly reduced levels of tryptophan and methionine in plasma samples from the AD patients compared to the control subjects. Moreover, plasma tyrosine/large neutral amino acids (LNAA) ratio and the ratio of plasma taurine and the product of the plasma levels of methionine and serine (TSM-ratio) were significantly increased in the AD patients in comparison with the controls. However, no difference was found in plasma tryptophan/LNAA ratio and in homocysteine levels between both groups. Concerning the behavioural symptomatology no significant correlation was found between the Reisberg Behave AD scale and plasma amino acid levels or ratios. The reported findings suggest that abnormal amino acid metabolism is present in the early stages of AD. We hypothesize that this abnormality could play a role in the pathogenesis of behavioural changes occurring in later stages of AD.

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

van de Kamp JM, Mancini GMS, Pouwels PJW, Betsalel OT, van Dooren SJM, de Koning I, Steenweg ME, Jakobs C, van der Knaap MS, Salomons GS. Clinical features and X‐inactivation in females heterozygous for creatine transporter defect.

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.

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

ObjectivesTo investigate cognitive functioning shortly after multiple sclerosis (MS) diagnosis and to examine the relationship with disability, depression and anxiety.MethodsData 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).ResultsPatients 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 ≥ 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.ConclusionWithin 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.

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

Impaired cognition in later life may result from Alzheimers 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.

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.