Christian Andersen

Clinic-Based Cases with Frontotemporal Dementia Show Increased Cerebrospinal Fluid Tau and High Apolipoprotein E ε4 Frequency, but No Tau Gene Mutations

Frontotemporal dementia (FTD) belongs to a group of neurodegenerative disorders known as tauopathies, characterized by intracellular aggregation of hyperphosphorylated tau protein in the brain. Some tauopathies, like Alzheimers disease (AD), consistently show increased levels of tau protein in cerebrospinal fluid (CSF). However, similar studies in FTD populations have shown variable results, although mutations in the tau gene are identified as causes of disease in certain FTD families. In the present study, a Swedish clinic-based FTD population was investigated with respect to CSF tau levels, apolipoprotein E (APOE) genotype distribution and occurrence of mutations in the tau gene. CSF tau levels were significantly increased among FTD patients (534 +/- 235 pg tau/ml, P < 0.001) (n = 47) compared to controls (316 +/- 137 pg tau/ml) (n = 51). Furthermore, a strong increase in the APOE epsilon4 allele frequency was found in the FTD population, as 52% were epsilon4 carriers, compared to 21% of the controls. However, no mutations in the tau gene were identified. These findings support the present notion of a common pathogenic pathway in the disease processes for several tauopathies, with both APOE epsilon4 and CSF tau being a pathological link between the different disorders. Furthermore, we conclude that mutations in the tau gene are a rare cause of FTD. .

Quantitative EEG abnormalities and cognitive dysfunctions in frontotemporal dementia and Alzheimer's disease.

Objective: To investigate the relationship between quantitative EEG (qEEG) measurements in frontotemporal dementia (FTD), Alzheimer’s disease (AD) and healthy controls and to study to what extent qEEG in FTD and AD or neuropsychological test results of FTD and AD patients or a combination of both contribute to classification accuracy. Method: The FTD sample consisted of 19 patients, the AD sample of 16 patients, and the control group of 19 subjects. Groups were matched on the group level with respect to demographic variables. For qEEG the global field power was calculated for six frequency bands: δ (1.0–3.5 Hz), Θ (4.0–7.5 Hz), α (8.0–11.0 Hz), β1 (12.0–15.5 Hz), β2 (16.0–19.5 Hz), β3 (20.0–23.5 Hz), and spectral ratio as the ratio of the sum of fast frequency bands α + β1 + β2 + β3 and slow frequency bands δ + Θ. Results: In comparison to controls FTD patients were marked by an absence of an increase in slow qEEG activities and a decrease in fast activities, whereas AD patients were marked by an increase in slow activities and a smaller decrease in fast activities. According to the Mann-Whitney U test the cognitive functions of attention, visuospatial thinking and episodic memory were significantly better in FTD than in AD. Using logistic regression analysis the best predictors of FTD and AD were in a model using the δ and Θ activities, and high levels of visuospatial ability and episodic memory. Classification accuracy of the model was 93.3%. Conclusion: FTD patients reveal a different pattern of qEEG changes than AD patients. This result demonstrates the importance of qEEG for FTD diagnosis. Cognition is selectively better in FTD than in AD. A combination of qEEG and neuropsychology is recommended for differential diagnoses of FTD and AD.

Caudate Nucleus Volumes in Frontotemporal Lobar Degeneration: Differential Atrophy in Subtypes

BACKGROUND AND PURPOSE: Frontostriatal circuits involving the caudate nucleus have been implicated in frontotemporal lobar degeneration (FTLD). We assessed caudate nucleus volumetrics in FTLD and subtypes: frontotemporal dementia (FTD, n = 12), semantic dementia (SD, n = 13), and progressive nonfluent aphasia (PNFA, n = 9) in comparison with healthy controls (n = 27) and subjects with Alzheimer disease (AD, n = 19). MATERIALS AND METHODS: Diagnoses were based on accepted clinical criteria. Manual volume measurement of the head and body of the caudate, excluding the tail, was conducted on T1-weighted brain MR imaging scans, using a published protocol, by a single analyst blinded to the diagnosis. RESULTS: Paired t tests (P < .05) showed that the right caudate nucleus volume was significantly larger than the left in controls and PNFA. No hemispheric asymmetry was found in AD, FTD, and SD. Across the groups, there was a positive partial correlation between the left caudate nucleus volume and Mini-Mental State Examination (MMSE) scores (r = 0.393, n = 76, P = .001) with higher left caudate volumes associated with higher MMSE scores. Multivariate analysis of covariance was used to assess the statistical significance between the subject groups (AD, FTD, SD, PNFA, and controls) as independent variables and raw right/left caudate volumes at the within-subject level (covariates: age and intracranial volume; P < .05). Control volume was largest, followed by AD (93% of control volume), SD (92%), PNFA (79%), and FTD (75%). CONCLUSIONS: Volume of the head and body of the caudate nucleus differs in subtypes of FTLD, due to differential frontostriatal dysfunction in subtypes being reflected in structural change in the caudate, and is correlated with cognition.

Increased risk for frontotemporal dementia through interaction between tau polymorphisms and apolipoprotein E ε4

The tau gene has an important role in frontotemporal dementia (FTD) as pathogenic mutations have been found in hereditary forms of the disease. Furthermore, a certain extended tau haplotype has been shown to increase the risk for progressive supranuclear palsy, corticobasal degeneration, Parkinsons disease and, in interaction with the apolipoprotein E (apoE) &epsis;4 allele, Alzheimers disease. By microsatellite analysis we investigated an intronic tau polymorphism, in linkage disequilibrium with the extended tau haplotype, in FTD patients (n = 36) and healthy controls (n = 39). No association between any of the tau alleles/genotypes and FTD was seen, but certain tau alleles and apoE &epsis;4 interactively increased the risk of FTD (p = 0.006). We thus propose that this extended tau haplotype in combination with apoE &epsis;4 is a genetic risk factor for FTD.

Cortical Morphometric Subclassification of Frontotemporal Lobar Degeneration

BACKGROUND AND PURPOSE: Frontotemporal lobar degeneration (FTLD) is a primary neurodegenerative disease comprising 3 clinical subtypes: frontotemporal dementia (FTD), semantic dementia (SD), and progressive nonfluent aphasia (PNFA). The subdivision is primarily based on the characteristic clinical symptoms displayed by each subtype. We hypothesized that these symptoms would be correlated to characteristic patterns of brain atrophy, which could be indentified and used for subclassification of subjects with FTLD. MATERIALS AND METHODS: Volumes of 9 cortical regions were manually parcellated and measured on both hemispheres on 27 controls, 12 patients with FTD, 9 patients with PNFA, and 13 patients with SD. The volumetric data were analyzed by traditional t tests and by a multivariate discriminant analysis (partial least squares discriminant analysis). RESULTS: The ensemble or pattern of atrophy was a good discriminator in pair-wise comparison between the subtypes: FTD compared with SD (sensitivity 100% [12/12], specificity 100% [13/13]); FTD compared with PNFA (sensitivity 92% [11/12], specificity 89% [8/9]); and SD compared with PNFA (sensitivity 86% [11/13], specificity 100% [9/9]). Temporal-versus-frontal atrophy was the most important pattern for discriminating SD from the other 2 subtypes. Right-sided versus left-sided atrophy was the most important pattern for discriminating between subjects with FTD and PNFA. CONCLUSIONS: FTLD subtypes generally display a characteristic pattern of atrophy, which may be considered in diagnosing patients with FTLD.

Amyloid Aβ40 Csf concentrations correlate to frontal lobe atrophy in frontotemporal dementia

We wanted to further study amyloid Abeta protein alterations in non-AD neurodegenerative diseases. Cerebrospinal fluid concentrations of the amyloid Abeta protein with 40 (Abeta40) and 42 (Abeta42) amino acid residues were measured in eleven patients with frontotemporal dementia (FTD). Abeta40 and Abeta42 concentrations were related to the degree of frontal lobe atrophy as assessed with MRI volumetry. Abeta40 concentrations showed a statistically significant linear correlation with degree of frontal lobe atrophy (r = -0.77, p<0.02). Similar results have not been found in previous studies of CSF Abeta40 concentrations and atrophy in patients with AD which suggest that the role of Abeta40 differs between the pathological processes of FTD and AD.

Tau protein in cerebrospinal fluid from semantic dementia patients

Apolipoprotein E (APOE) genotypes and cerebrospinal fluid (CSF) tau protein concentration were evaluated in patients suffering from semantic dementia, with the aim of determining whether these markers could help to differentiate this condition from Alzheimers disease (AD) in early stages. By strictly following diagnostic criteria for semantic dementia, we found a clinically homogeneous group comprising eight patients from a total population of 621 subjects referred for dementia investigation. CSF tau protein concentrations were moderately increased with a small intraindividual variation 437+/-36 pg/ml (mean+/-SD) compared to healthy control individuals. APOE genotype distribution showed an over representation of the epsilon4 allele (69% epsilon3, 31% epsilon4 and no epsilon2), a pattern similar to that found in AD. These results indicate that semantic dementia is a rather uncommon but clinically distinct condition which shows a moderate increase of CSF tau protein levels and for which the epsilon4 allele is a risk factor.

Reliability of interactive three-dimensional brain volumetry using MP-RAGE magnetic resonance imaging.

We assessed the reliability of an interactive 3-dimensional methodology for magnetic resonance imaging (MRI) brain tissue segmentation and volumetry using a 3-dimensional magnetization prepared rapid gradient echo pulse sequence (3D MP-RAGE). The methodology was intended to be practically useful to study structural brain changes in larger groups of patients investigated for suspected dementia. The pulse sequence combines volume acquisition, excellent tissue contrast and short patient scan-time. The volumetric method is fully interactive, requiring a minimum of image pre-processing. Ten healthy controls and 10 patients with dementia were included in the study. Six healthy controls were scanned twice. The method is based on thresholding combined with manual tracing in a 3D volume. The 3-dimensional measurement method reduces the measurement time considerably compared to that of slice by slice measurement and permits 3-dimensional display of measured volumes. For different brain regions the intra-study (0.5-1.3%), study-study (1.8-4.7%) and inter-operator (7.1%) variability of this method compared favourably with other manual or automated methods reported. The major advantages of the method are its simplicity and speed, which permits measurement and display of regional brain volumes and tissues in larger patient groups.

Amyloid Aβ40 CSF concentrations correlate to frontal lobe atrophy in frontotemporal dementia

We wanted to further study amyloid Aβ protein alterations in non-AD neurodegenerative diseases. Cerebrospinal fluid concentrations of the amyloid Aβ protein with 40 (Aβ40) and 42 (Aβ42) amino acid residues were measured in eleven patients with frontotemporal dementia (FTD). Aβ40 and Aβ42 concentrations were related to the degree of frontal lobe atrophy as assessed with MRI volumetry. Aβ40 concentrations showed a statistically significant linear correlation with degree of frontal lobe atrophy (r = −0.77, p <0.02). Similar results have not been found in previous studies of CSF Aβ40 concentrations and atrophy in patients with AD which suggest that the role of Aβ40 differs between the pathological processes of FTD and AD.