J. C. van Swieten

Association of missense and 5 '-splice-site mutations in tau with the inherited dementia FTDP-17

Thirteen families have been described with an autosomal dominantly inherited dementia named frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), historically termed Picks disease. Most FTDP-17 cases show neuronal and/or glial inclusions that stain positively with antibodies raised against the microtubule-associated protein Tau, although the Tau pathology varies considerably in both its quantity (or severity) and characteristics,. Previous studies have mapped the FTDP-17 locus to a 2-centimorgan region on chromosome 17q21.11; the tau gene also lies within this region. We have now sequenced tau in FTDP-17 families and identified three missense mutations (G272V, P301L and R406W) and three mutations in the 5′ splice site of exon 10. The splice-site mutations all destabilize a potential stem–loop structure which is probably involved in regulating the alternative splicing of exon10 (ref. 13). This causes more frequent usage of the 5′ splice site and an increased proportion of tau transcripts that include exon 10. The increase in exon 10+ messenger RNA will increase the proportion of Tau containing four microtubule-binding repeats, which is consistent with the neuropathology described in several families with FTDP-17 (refs 12, 14).

Cerebral white matter lesions, vascular risk factors, and cognitive function in a population‐based study The Rotterdam Study

Cerebral white matter lesions are a common finding on MRI in elderly persons. We studied the prevalence of white matter lesions and their relation with classic cardiovascular risk factors, thrombogenic factors, and cognitive function in an age- and gender-stratified random sample from the general population that consisted of 111 subjects 65 to 84 years of age. Overall, 27% of subjects had white matter lesions. The prevalence and severity of lesions increased with age. A history of stroke or myocardial infarction, factor VIIc activity, and fibrinogen level were each significantly and independently associated with the presence of white matter lesions. Significant relations with blood pressure level, hypertension, and plasma cholesterol were present only for subjects aged 65 to 74 years. White matter lesions tended to be associated with lower scores on tests of cognitive function and were significantly associated with subjective mental decline. This study suggests that classic cardiovascular risk factors, as well as thrombogenic factors, are associated with white matter lesions in subjects over 65 years of age in the general population, and that these lesions may be related to cognitive function.

Clinical, genetic and pathological heterogeneity of frontotemporal dementia: a review

Frontotemporal dementia (FTD) is the second most common young-onset dementia and is clinically characterised by progressive behavioural change, executive dysfunction and language difficulties. Three clinical syndromes, behavioural variant FTD, semantic dementia and progressive non-fluent aphasia, form part of a clinicopathological spectrum named frontotemporal lobar degeneration (FTLD). The classical neuropsychological phenotype of FTD has been enriched by tests exploring Theory of Mind, social cognition and emotional processing. Imaging studies have detailed the patterns of atrophy associated with different clinical and pathological subtypes. These patterns offer some diagnostic utility, while measures of progression of atrophy may be of use in future trials. 30–50% of FTD is familial, and mutations in two genes, microtubule associated protein tau and Progranulin (GRN), account for about half of these cases. Rare defects in VCP, CHMP2B, TARDP and FUS genes have been found in a small number of families. Linkage to chromosome 9p13.2–21.3 has been established in familial FTD with motor neuron disease, although the causative gene is yet to be identified. Recent developments in the immunohistochemistry of FTLD, and also in amyotrophic lateral sclerosis (ALS), have led to a new pathological nomenclature. The two major groups are those with tau-positive inclusions (FTLD-tau) and those with ubiquitin-positive and TAR DNA-binding protein of 43 kDa (TDP-43) positive inclusions (FTLD-TDP). Recently, a new protein involved in familial ALS, fused in sarcoma (FUS), has been found in FTLD patients with ubiquitin-positive and TDP-43-negative inclusions. In this review, the authors discuss recent clinical, neuropsychological, imaging, genetic and pathological developments that have changed our understanding of FTD, its classification and criteria. The potential to establish an early diagnosis, predict underlying pathology during life and quantify disease progression will all be required for disease-specific therapeutic trials in the future.

Cognitive correlates of ventricular enlargement and cerebral white matter lesions on magnetic resonance imaging. The Rotterdam Study.

Background and Purpose Ventricular enlargement and white matter lesions are frequent findings on cerebral magnetic resonance imaging scans of elderly subjects. In demented subjects they seem related to the severity of the dementia, but in nondemented subjects their clinical significance is less clear. We investigated the relation of size of the lateral ventricles and white matter lesions with cognitive function in a population-based random sample of nondemented elderly persons. Methods The study population consisted of 90 subjects, aged 65 to 84 years, who were randomly selected from the cohort of the Rotterdam Study, and who were not demented. The presence of white matter lesions and the ventricle-to-brain ratio were assessed on magnetic resonance scans. Participants were tested with a neuropsychological battery that covered a broad range of cognitive functions. Results Ventricular enlargement and white matter lesions were both and independently associated with poorer performance on all tests. After adjustment for age and sex, ventricular enlargement was significantly associated with worse scores on tests assessing global cognitive function (Mini-Mental State Examination, P=.02; Groninger Intelligence Test, P=.01), memory (Word List Learning delayed recall, P = .03), and executive control functions (Stroop part II, P=.02; Trail Making Test B, P<.01); for white matter lesions the differences were significant for tests measuring executive control functions and mental speed (Trail Making Test A and B, P=.01 and P<.01, respectively; verbal fluency, P=.01), and memory (Word List Learning delayed recall, P=.04). Conclusions This study suggests that white matter lesions are primarily related to impairment of subcorticofrontal functions, whereas enlargement of the lateral ventricles is associated with disturbances of cortical functions as well.

Cerebral white matter lesions and atherosclerosis in the Rotterdam Study

Cerebral white matter lesions (WML) seen on magnetic resonance imaging scans are associated with cardiovascular disease and vascular risk factors. To assess the association between WML and atherosclerosis, we studied 111 people, aged 65 to 85 years, randomly sampled, and stratified by age and sex, from participants in the Rotterdam Study. Cerebral T2-weighted magnetic resonance images in the axial plane were obtained for all subjects. Carotid atherosclerosis was ultrasonographically assessed by the presence of stenosis, measurement of intima to media wall thickness (IMT), and the presence of atherosclerotic plaques. A possible or definite myocardial infarction on an electrocardiogram was used as an indicator of coronary atherosclerosis. The ankle to arm systolic blood pressure ratio (ABI) was determined, and peripheral arterial disease was defined as an ABI lower than 0.90 in at least one side. Carotid atherosclerosis was significantly more pronounced in people with WML. The difference in common carotid IMT was 0.13 mm (95% confidence interval [CI] 0.04-0.21), whereas the odds ratio of WML associated with plaques in the carotid bifurcation was 3.9. The degree of internal carotid artery stenosis was not, however, associated with WML. The mean ABI was significantly lower in people with WML than in those without lesions with a difference of -0.11 (95% CI -0.21 to -0.01). The odds ratio of WML associated with peripheral arterial disease and a possible or definite myocardial infarction was 2.4 and 3.1, respectively. We conclude that atherosclerosis, indicated by increased common carotid IMT, carotid plaques, and a lower ABI, is related to WML.

PARK7, a Novel Locus for Autosomal Recessive Early-Onset Parkinsonism, on Chromosome 1p36

Although the role of genetic factors in the origin of Parkinson disease has long been disputed, several genes involved in autosomal dominant and recessive forms of the disease have been localized. Mutations associated with early-onset autosomal recessive parkinsonism have been identified in the Parkin gene, and recently a second gene, PARK6, involved in early-onset recessive parkinsonism was localized on chromosome 1p35-36. We identified a family segregating early-onset parkinsonism with multiple consanguinity loops in a genetically isolated population. Homozygosity mapping resulted in significant evidence for linkage on chromosome 1p36. Multipoint linkage analysis using MAPMAKER-HOMOZ generated a maximum LOD-score of 4.3, with nine markers spanning a disease haplotype of 16 cM. On the basis of several recombination events, the region defining the disease haplotype can be clearly separated, by > or =25 cM, from the more centromeric PARK6 locus on chromosome 1p35-36. Therefore, we conclude that we have identified on chromosome 1 a second locus, PARK7, involved in autosomal recessive, early-onset parkinsonism.

DJ-1( PARK7), a novel gene for autosomal recessive, early onset parkinsonism

Abstract.Four chromosomal loci (PARK2, PARK6, PARK7, and PARK9) associated with autosomal recessive, early onset parkinsonism are known. We mapped the PARK7 locus to chromosome 1p36 in a large family from a genetically isolated population in the Netherlands, and confirmed this linkage in an Italian family. By positional cloning within the refined PARK7 critical region we recently identified mutations in the DJ-1 gene in the two PARK7-linked families. The function of DJ-1 remains largely unknown, but evidence from genetic studies on the yeast DJ-1 homologue, and biochemical studies in murine and human cell lines, suggests a role for DJ-1 as an antioxidant and/or a molecular chaperone. Elucidating the role of DJ-1 will lead to a better understanding of the pathogenesis of DJ-1-related and common forms of Parkinson’s disease.

Diet and risk of dementia: Does fat matter?: The Rotterdam Study

Objective: To examine whether high intake of total fat, saturated fatty acids (saturated fat), trans fatty acids (trans fat), and cholesterol and low intake of monounsaturated fatty acids (MUFA), polyunsaturated fatty acids (PUFA), n-6 PUFA, and n-3 PUFA are associated with increased risk of dementia and its subtypes. Method: Data from the Rotterdam Study, a prospective cohort study among elderly, were used. At baseline (1990 to 1993), 5,395 subjects had normal cognition, were noninstitutionalized, and underwent complete dietary assessment by a semiquantitative food-frequency questionnaire. The cohort was continuously monitored for incident dementia, and re-examinations were performed in 1993 to 1994 and 1997 to 1999. The association between fat intake and incident dementia was examined by Cox’s proportional hazards models. Results: After a mean follow-up of 6.0 years, 197 subjects developed dementia (146 AD, 29 vascular dementia). High intake of total, saturated, trans fat, and cholesterol and low intake of MUFA, PUFA, n-6 PUFA, and n-3 PUFA were not associated with increased risk of dementia or its subtypes. Rate ratios of dementia per standard deviation increase in intake were for total fat 0.93 (95% CI 0.81 to 1.07), for saturated fat 0.91 (95% CI 0.79 to 1.05), for trans fat 0.90 (95% CI 0.77 to 1.06), for cholesterol 0.93 (95% CI 0.80 to 1.08), for MUFA 0.96 (95% CI 0.84 to 1.10), for PUFA 1.05 (95% CI 0.80 to 1.38), for n-6 PUFA 1.03 (95% CI 0.77 to 1.36), and for n-3 PUFA 1.07 (95% CI 0.94 to 1.22). Conclusion: High intake of total, saturated, and trans fat and cholesterol and low intake of MUFA, PUFA, n-6 PUFA, and n-3 PUFA were not associated with increased risk of dementia or its subtypes.

Grading white matter lesions on CT and MRI: a simple scale.

We developed and tested a simple three-point scale for grading white matter lesions in anterior and posterior regions of the brain. Twenty four CT scans and 24 MRI scans were separately judged by 11 and five observers, respectively, on the presence and severity of white matter lesions. The observers were radiologists and neurologists. For CT scans, these periventricular changes were graded according to their extent as absent, or partly involving the white matter, or extending up to the subcortical region. The MRI lesions were graded as no lesion or only a single one, multiple focal lesions, and multiple confluent lesions. The pairwise agreements of all possible combinations of observers for each scan were corrected for chance (kappa statistics; maximal agreement 1.0). The weighted kappa value, for anterior and posterior regions combined, was 0.63 for CT scans, and 0.78 for MRI scans. This three-point scale for two separate regions seems suitable as a basis for cross-sectional or longitudinal studies of large series of patients.

Tau pathology in two Dutch families with mutations in the microtubule-binding region of tau.

Different mutations in the microtubule-associated tau protein gene have recently been identified in several families with hereditary frontotemporal dementia and Parkinsonism (FTDP-17) linked to chromosome 17q21-22. Some families show neuronal and glial deposits containing hyperphosphorylated tau in several brain regions. We have investigated the presence of tau deposits by using a panel of anti-tau antibodies in three brains of a family with the P301L mutation (HFTD1) and in another family with the G272V mutation (HFTD2) of the tau gene. Numerous intracytoplasmic tau deposits in neurons, glial cells, and neurites were found in hippocampal formation, neocortex, and substantia nigra. These deposits in three patients from HFTD1 consisted of slender twisted filaments 15 nm wide with variable periodicity and a few straight filaments. Tau extracted from these filaments appeared as two major bands of 64 and 68 kd and a minor band of 72 kd that, after alkaline phosphatase treatment, proved to consist mainly of 4-repeat tau isoforms and one of the 3-repeat isoforms. In three patients from HFTD2 numerous Pick-like bodies were present. The conclusion is that the type and distribution of tau deposits in HFTD1 and HFTD2, the physical structure of filaments, and tau isoform composition in HFTD1 differ from Alzheimers disease and an FTDP-17 family with a V337M mutation in the tau gene.