Plasma proteome profiling identifies changes associated to AD but not to FTD.

BACKGROUND: Frontotemporal dementia (FTD) is caused by frontotemporal lobar degeneration (FTLD), characterized mainly by inclusions of Tau (FTLD-Tau) or TAR DNA binding43 (FTLD-TDP) proteins. Plasma biomarkers are strongly needed for specific diagnosis and potential treatment monitoring of FTD. We aimed to identify specific FTD plasma biomarker profiles discriminating FTD from AD and controls, and between FTD pathological subtypes. In addition, we compared plasma results with results in post-mortem frontal cortex of FTD cases to understand the underlying process. METHODS: Plasma proteins (n = 1303) from pathologically and/or genetically confirmed FTD patients (n = 56; FTLD-Tau n = 16; age = 58.2 ± 6.2; 44% female, FTLD-TDP n = 40; age = 59.8 ± 7.9; 45% female), AD patients (n = 57; age = 65.5 ± 8.0; 39% female), and non-demented controls (n = 148; 61.3 ± 7.9; 41% female) were measured using an aptamer-based proteomic technology (SomaScan). In addition, exploratory analysis in post-mortem frontal brain cortex of FTD (n = 10; FTLD-Tau n = 5; age = 56.2 ± 6.9, 60% female, and FTLD-TDP n = 5; age = 64.0 ± 7.7, 60% female) and non-demented controls (n = 4; age = 61.3 ± 8.1; 75% female) were also performed. Differentially regulated plasma and tissue proteins were identified by global testing adjusting for demographic variables and multiple testing. Logistic lasso regression was used to identify plasma protein panels discriminating FTD from non-demented controls and AD, or FTLD-Tau from FTLD-TDP. Performance of the discriminatory plasma protein panels was based on predictions obtained from bootstrapping with 1000 resampled analysis. RESULTS: Overall plasma protein expression profiles differed between FTD, AD and controls (6 proteins; p = 0.005), but none of the plasma proteins was specifically associated to FTD. The overall tissue protein expression profile differed between FTD and controls (7-proteins; p = 0.003). There was no difference in overall plasma or tissue expression profile between FTD subtypes. Regression analysis revealed a panel of 12-plasma proteins discriminating FTD from AD with high accuracy (AUC: 0.99). No plasma protein panels discriminating FTD from controls or FTD pathological subtypes were identified. CONCLUSIONS: We identified a promising plasma protein panel as a minimally-invasive tool to aid in the differential diagnosis of FTD from AD, which was primarily associated to AD pathophysiology. The lack of plasma profiles specifically associated to FTD or its pathological subtypes might be explained by FTD heterogeneity, calling for FTD studies using large and well-characterize cohorts.

Impaired Knowledge of Social Norms in Dementia and Psychiatric Disorders: Validation of the Social Norms Questionnaire-Dutch Version (SNQ-NL).

The Social Norms Questionnaire-Dutch version (SNQ-NL) measures the ability to understand and identify social boundaries. We examined the psychometric characteristics of the SNQ-NL and its ability to differentiate between patients with behavioral variant frontotemporal dementia (bvFTD; n = 23), Alzheimer's dementia (AD; n = 26), chronic psychiatric disorders (n = 27), and control participants (n = 92). Between-group differences in the Total score, Break errors, and Overadhere errors were examined and associations with demographic variables and other cognitive functions were explored. Results showed that the SNQ-NL Total Score and Break errors differed between patients with AD and bvFTD, but not between patients with bvFTD and psychiatric disorders. Modest correlations with age, sex, and education were observed. The SNQ-NL Total score and Break errors correlated significantly with emotion recognition and verbal fluency but not with processing speed or mental flexibility. In conclusion, the SNQ-NL has sufficient construct validity and can be used to investigate knowledge of social norms in clinical populations.

Exploring Abstract Semantic Associations in the Frontotemporal Dementia Spectrum in a Dutch Population.

OBJECTIVE: To investigate the differential ability of the "Test Relaties Abstracte Concepten" (TRACE), a Dutch test for abstract semantic knowledge, in frontotemporal dementia (FTD). METHODS: The TRACE was administered in patients with behavioral variant FTD (bvFTD; n = 16), nonfluent variant (nfvPPA; n = 10), logopenic variant (lvPPA; n = 10), and semantic variant primary progressive aphasia (svPPA; n = 9), and controls (n = 59). We examined group differences, performed correlational analyses with other neuropsychological tests and investigated discriminative ability. We compared the TRACE with a semantic association test for concrete stimuli (SAT). RESULTS: All patient groups, except nfvPPA, performed worse on the TRACE than controls (p < .01). svPPA patients performed worse than the other patient groups (p < .05). The TRACE discriminated well between patient groups, except nfvPPA, versus controls (all p < .01) and between svPPA versus other patient groups with high sensitivity (75-100%) and specificity (86%-92%). In bvFTD and nfvPPA the TRACE correlated with language tests (ρ > 0.6), whereas in svPPA the concrete task correlated (ρ ≥ 0.75) with language tests. Patients with bvFTD, nfvPPA and lvPPA performed lower on the TRACE than the SAT (p < .05), whereas patients with svPPA were equally impaired on both tasks (p = .2). DISCUSSION: We demonstrated impaired abstract semantic knowledge in patients with bvFTD, lvPPA, and svPPA, but not nfvPPA, with svPPA patients performing worse than the other subtypes. The TRACE was a good classifier between each patient group versus controls and between svPPA versus other patient groups. This highlights the value of incorporating semantic tests with abstract stimuli into standard neuropsychological assessment for early differential diagnosis of FTD subtypes.

Differences in Discriminability and Response Bias on Rey Auditory Verbal Learning Test Delayed Recognition in Behavioral Variant Frontotemporal Dementia and Alzheimer's Disease.

OBJECTIVE: Episodic memory is impaired in Alzheimer's disease (AD) dementia but thought to be relatively spared in behavioral variant frontotemporal dementia (bvFTD). This view is challenged by evidence of memory impairment in bvFTD. This study investigated differences in recognition memory performance between bvFTD and AD. METHOD: We performed a retrospective analysis on the recognition trial of the Rey Auditory Verbal Learning Test in patients with bvFTD (n = 85), AD (n = 55), and control participants (n = 59). Age- and education-adjusted between-group analysis was performed on the total score and indices of discriminative ability and response bias. Correlations between recognition and measures of memory, language, executive functioning, and construction were examined. RESULTS: Patients with AD had a significantly lower total recognition score than patients with bvFTD (control 28.8 ± 1.5; bvFTD 24.8 ± 4.5; AD 23.4 ± 3.6, p < .01). Both bvFTD and AD had worse discriminative ability than controls (A' control 0.96 ± 0.03; bvFTD 0.87 ± 0.03; AD 0.84 ± 0.10, p < .01), but there was no difference in response bias (B" control 0.9 ± 0.2; bvFTD 1.6 ± 1.47; AD 1.4± 1.4, p < .01). AD had worse discriminability than bvFTD (p < .05). Discriminability was associated with memory for both patient groups (median correlation coefficient r = .34) and additionally associated with language (r = .31), but not executive functioning (r = -.03) in bvFTD. Response bias was unrelated to other cognitive functions (r = -.02). CONCLUSIONS: Discriminability, but not response bias, differentiated patients with bvFTD from AD. The presence of an impaired discrimination index suggests a "pure" (recognition) memory deficit in bvFTD.

Correction to: Cognitive profiles discriminate between genetic variants of behavioral frontotemporal dementia.

The original version of this article unfortunately contained a mistake.

Cognitive profiles discriminate between genetic variants of behavioral frontotemporal dementia.

INTRODUCTION: Trials to test disease-modifying treatments for frontotemporal dementia are eagerly awaited and sensitive instruments to assess potential treatment effects are increasingly urgent, yet lacking thus far. We aimed to identify gene-specific instruments assessing clinical onset and disease progression by comparing cognitive functioning between bvFTD patients across genetic mutations. METHODS: We examined differences in 7 cognitive domains between bvFTD patients with GRN (n = 20), MAPT (n = 29) or C9orf72 (n = 31) mutations, and non-carriers (n = 24), and described longitudinal (M = 22.6 months, SD = 16.6) data in a subsample (n = 27). RESULTS: Patients showed overall cognitive impairment, except memory recall, working memory and visuoconstruction. GRN patients performed lower on executive function (mean difference - 2.1; 95%CI - 4.1 to - 0.5) compared to MAPT and lower on attention compared to MAPT (mean difference - 2.5; 95%CI - 4.7 to - 0.3) and C9orf72 (mean difference - 2.4; 95%CI - 4.5 to - 0.3). Only MAPT patients were impaired on delayed recall (mean difference - 1.4; 95%CI - 2.1 to - 0.7). GRN patients declined rapidly on attention and memory, MAPT declined in confrontation naming, whereas C9orf72 patients were globally impaired but remained relatively stable over time on all cognitive domains. DISCUSSION: This study shows gene-specific cognitive profiles in bvFTD, which underlines the value of neuropsychological tests as outcome measures in upcoming trials for genetic bvFTD.

Von Economo neurons are part of a larger neuronal population that are selectively vulnerable in C9orf72 frontotemporal dementia.

AIMS: The behavioural variant of frontotemporal dementia with a C9orf72 expansion (C9-bvFTD) is characterised by early changes in social-emotional cognition that are linked to the loss of von Economo neurons (VENs). Together with a subset of neighbouring pyramidal neurons, VENs express the GABA receptor subunit theta (GABRQ). It is not known if the selective vulnerability of VENs in C9-bvFTD also includes this GABRQ-expressing population. METHODS: We quantified VENs and GABRQ immunopositive neurons in the anterior cingulate cortex (ACC) in C9-bvFTD (n = 16), controls (n = 12) and Alzheimer's disease (AD) (n = 7). Second, we assessed VENs and GABRQ-expressing populations in relation to the clinicopathological profiles. RESULTS: We found the number of VENs and GABRQ-expressing neurons and their ratio over the total layer 5 neuronal population was lower in C9-bvFTD compared to control and AD. C9-bvFTD donors with underlying TDP43 type A pathology in the ACC showed the highest loss of GABRQ-expressing neurons. C9-bvFTD donors that did not present with motor neuron disease (MND) symptoms in the first half of their disease course showed a prominent loss of GABRQ-expressing neurons compared to controls. C9-bvFTD donors with no symptoms of psychosis showed a higher loss compared to controls. Across all donors, the number of VENs correlated strongly with the number of GABRQ-expressing neurons. CONCLUSION: We show that VENs, together with GABRQ-expressing neurons, are selectively vulnerable in C9-bvFTD but are both spared in AD. This suggests they are related and that this GABRQ-expressing population of VENs and pyramidal neurons, is a key modulator of social-emotional functioning.

Exploring quantitative group-wise differentiation of Alzheimer's disease and behavioural variant frontotemporal dementia using tract-specific microstructural white matter and functional connectivity measures at multiple time points.

OBJECTIVES: This study explored group-wise quantitative measures of tract-specific white matter (WM) microstructure and functional default mode network (DMN) connectivity to establish an initial indication of their clinical applicability for early-stage and follow-up differential diagnosis of Alzheimer's disease (AD) and behavioural variant frontotemporal dementia (bvFTD). METHODS: Eleven AD and 12 bvFTD early-stage patients and 18 controls underwent diffusion tensor imaging and resting state functional magnetic resonance imaging at 3 T. All AD and 6 bvFTD patients underwent the same protocol at 1-year follow-up. Functional connectivity measures of DMN and WM tract-specific diffusivity measures were determined for all groups. Exploratory analyses were performed to compare all measures between the three groups at baseline and between patients at follow-up. Additionally, the difference between baseline and follow-up diffusivity measures in AD and bvFTD patients was compared. RESULTS: Functional connectivity of the DMN was not different between groups at baseline and at follow-up. Diffusion abnormalities were observed widely in bvFTD and regionally in the hippocampal cingulum in AD. The extent of the differences between bvFTD and AD was diminished at follow-up, yet abnormalities were still more pronounced in bvFTD. The rate of change was similar in bvFTD and AD. CONCLUSIONS: This study provides a tentative indication that quantitative tract-specific microstructural WM abnormalities, but not quantitative functional connectivity of the DMN, may aid early-stage and follow-up differential diagnosis of bvFTD and AD. Specifically, pronounced microstructural changes in anterior WM tracts may characterise bvFTD, whereas microstructural abnormalities of the hippocampal cingulum may characterise AD. KEY POINTS: • The clinical applicability of quantitative brain imaging measures for early-stage and follow-up differential diagnosis of dementia subtypes was explored using a group-wise approach. • Quantitative tract-specific microstructural white matter abnormalities, but not quantitative functional connectivity of the default mode network, may aid early-stage and follow-up differential diagnosis of behavioural variant frontotemporal dementia and Alzheimer's disease. • Pronounced microstructural white matter (WM) changes in anterior WM tracts characterise behavioural variant frontotemporal dementia, whereas microstructural WM abnormalities of the hippocampal cingulum in the absence of other WM changes characterise Alzheimer's disease.

Review: Fluid biomarkers for frontotemporal dementias.

Frontotemporal dementias (FTDs) are clinically, genetically and pathologically heterogeneous neurodegenerative disorders that affect the frontal and anterior temporal lobes of the brain. They are relatively common causes of young-onset dementia and usually present with behavioural disturbance (behavioural variant FTD) or language impairment (primary progressive aphasia), but there is also overlap with motor neurone disease and the atypical parkinsonian disorders, corticobasal syndrome and progressive supranuclear palsy. At post mortem, neuronal inclusions containing tau, TDP-43 or infrequently FUS protein are seen in most cases. However, a poor correlation between clinical syndrome and underlying pathology means that it is difficult to diagnose the underlying molecular basis using clinical criteria. At this point, biomarkers for the underlying pathology come into play. This paper provides a brief update on fluid biomarkers for FTDs that may be useful to dissect the underlying molecular changes in patients presenting with signs of frontal and/or temporal lobe dysfunction. The hope is that such biomarkers, together with genetics and imaging, would be useful in clinical trials of novel drug candidates directed against specific pathologies and, in the long run, helpful in clinical practice to select the most appropriate treatment at the right dose for individual patients.

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.

Mutation frequency of PRKAR1B and the major familial dementia genes in a Dutch early onset dementia cohort.

Genetic factors are important in all forms of dementia, especially in early onset dementia. The frequency of major gene defects in dementia has not been investigated in the Netherlands. Furthermore, whether the recently in a FTD family identified PRKAR1B gene is associated with an Alzheimer's disease (AD) like phenotype, has not been studied. With this study, we aimed to investigate the mutation frequency of the major AD and FTD genes and the PRKAR1B gene in a well-defined Dutch cohort of patients with early onset dementia. Mutation analysis of the genes PSEN1, APP, MAPT, GRN, C9orf72 and PRKAR1B was performed on DNA of 229 patients with the clinical diagnosis AD and 74 patients with the clinical diagnosis FTD below the age of 70 years. PSEN1 and APP mutations were found in, respectively 3.5 and 0.4 % of AD patients, and none in FTD patients. C9orf72 repeat expansions were present in 0.4 % of AD and in 9.9 % of FTD patients, whereas MAPT and GRN mutations both were present in 0.4 % in AD patients, and in 1.4 % resp. 2.7 % in FTD patients. We did not find any pathogenic mutations in the PRKAR1B gene. PSEN1 mutations are the most common genetic cause in Dutch AD patients, whereas MAPT and GRN mutations were found in less than 5 percent. C9orf72 repeat expansions were the most common genetic defect in FTD patients. No pathogenic PRKAR1B mutations were found in the early onset AD and FTD patients of our study.

Neuropathology of the hippocampus in FTLD-Tau with Pick bodies: a study of the BrainNet Europe Consortium.

AIMS: Frontotemporal lobar degeneration with Pick bodies (Pick's disease) is characterized by the presence of tau immunoreactive spherical structures in the cytoplasm of neurones. In view of confusion about the molecular pathology of Pick's disease, we aimed to evaluate the spectrum of tau pathology and concomitant neurodegeneration-associated protein depositions in the characteristically affected hippocampus. METHODS: We evaluated immunoreactivity (IR) for tau (AT8, 3R, 4R), α-synuclein, TDP43, p62, and ubiquitin in the hippocampus, entorhinal and temporal cortex in 66 archival cases diagnosed neuropathologically as Pick's disease. RESULTS: Mean age at death was 68.2 years (range 49-96). Fifty-two (79%) brains showed 3R immunoreactive spherical inclusions in the granule cells of the dentate gyrus. These typical cases presented mainly with the behavioural variant of frontotemporal dementia, followed by progressive aphasia, mixed syndromes or early memory disturbance. α-Synuclein IR was seen only in occasional spherical tau-positive inclusions, TDP-43 IR was absent, and 4R IR was present only as neurofibrillary tangles in pyramidal neurones. Aß IR was observed in 16 cases; however, the overall level of Alzheimer's disease-related alterations was mainly low or intermediate (n = 3). Furthermore, we identified six cases with unclassifiable tauopathy. CONCLUSIONS: (i) Pick's disease may occur also in elderly patients and is characterized by a relatively uniform pathology with 3R tau inclusions particularly in the granule cells of dentate gyrus; (ii) even minor deviation from these morphological criteria suggests a different disorder; and (iii) immunohistological revision of archival cases expands the spectrum of tauopathies that require further classification.

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.

Recent advances in progressive supranuclear palsy: a review.

Progressive Supranuclear Palsy has been used over decades as a term denoting an uniform disorder with progressive parkinsonism with early falls, vertical supranulcear gaze palsy, pseudobulbar dysfunction and cognitive decline. Over the last decade, heterogeneity of the disease into different clinical subtypes has been recognized in clinicopathological studies. Although neuroimaging features and laboratory findings may support the diagnosis, true biomarkers are still lacking in the clinical setting. Neuronal and glial tau positive aggregates are predominantly found in basal ganglia and brainstem, and the significant association of PSP with the common H1 tau haplotype likely points to a pathophysiological role of the tau protein in the disease process. Future genetic studies of familial cases and an ongoing genome-wide association study of large series of pathological-proven cases may reveal additional genetic factors in the near future.

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.

Cathepsin D gene and the risk of Alzheimer's disease: a population-based study and meta-analysis.

Cathepsin D (CTSD) is a gene involved in amyloid precursor protein processing and is considered a candidate for Alzheimer's disease (AD). The aim of the current study was to examine if variation in CTSD increases the risk of AD. We performed a candidate-gene analysis in a population-based cohort study (N=7983), and estimated the effect of CTSD on the risk of AD. Additionally, a large meta-analysis was performed incorporating our data and previously published data. The T-allele of CTSD rs17571 was associated with an increased risk of AD (p-value 0.007) in the Rotterdam Study. This association was predominantly found in APOE ε4 noncarriers. A meta-analysis of previously published data showed a significantly increased risk of AD in carriers of the T-allele of rs17571 (OR 1.22, 95% CI 1.03-1.44), irrespective of APOE ε4 carrier status. This study adds to the evidence that CTSD increases the risk of AD, although the effect size is moderate.

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.

Inherited Creutzfeldt-Jakob disease in a Dutch patient with a novel five octapeptide repeat insertion and unusual cerebellar morphology.

An atypical case of inherited Creutzfeldt-Jakob disease (CJD) is described in a 35-year-old Dutch woman, homozygous for methionine at codon 129 of the prion protein gene (PRNP). The clinical phenotype was characterised by slowly progressive cognitive decline and parkinsonism. Neuropathological findings consisted of scanty spongiosis and only faint to absent immunohistochemical staining for the abnormal prion protein, PrP(Sc), with patchy deposits in the cerebellar cortex. Purkinje cells were abnormally located in the molecular layer of the cerebellum. Western blot analysis showed the co-occurrence of PrP(Sc) types 1 and 2 with an unusual distribution. Sequence analysis disclosed a novel 120 bp insertion in the octapeptide repeat region of the PRNP, encoding five additional R2 octapeptide repeats. These features define an unusual neuropathological phenotype and novel genotype, further expanding the spectrum of genotype-phenotype correlations in inherited prion diseases and emphasising the need to carry out pre-mortem PRNP sequencing in all young patients with atypical dementias.

Familial aggregation of parkinsonism in progressive supranuclear palsy.

BACKGROUND: Progressive supranuclear palsy (PSP) is a progressive neurodegenerative disorder characterized by aggregates of the microtubule-associated protein tau (MAPT). A nonsignificant trend for positive family history has been observed in two case-control studies and several pedigrees with familial clustering of parkinsonism have been described. Occasionally, mutations in MAPT are found in patients with a clinical phenotype similar to PSP. In this case-control study, we compared the occurrence of dementia and parkinsonism among first-degree relatives of patients with PSP with an age- and sex-matched control group. METHODS: Family history of dementia and parkinsonism was collected from all first-degree relatives of patients with PSP who fulfilled the international National Institute of Neurological Disorders and Stroke criteria for PSP. Age- and sex-matched controls were selected from the Rotterdam Study. Genetic testing and pathologic examination was performed in a subset of familial PSP cases. RESULTS: Fifty-seven (33%) of the 172 patients with PSP had at least one first-degree relative who had dementia or parkinsonism compared to 131 (25%) of the control subjects (odds ratio [OR] 1.5, 95% confidence interval [CI] 1.01-2.13). In patients with PSP, more first-degree relatives with parkinsonism were observed compared to controls, with an OR 3.9 (95% CI 1.99-7.61). Twelve patients with PSP (7%) fulfilled the criteria for an autosomal dominant mode of transmission. The intrafamilial phenotype within these pedigrees varied among PSP, dementia, tremor, and parkinsonism. Genetic studies revealed one patient with a P301L mutation in MAPT. Pathologic examination of five familial cases confirmed the clinical diagnosis of PSP, with predominant four repeat tau pathology in affected brain areas. CONCLUSION: This study demonstrates familial aggregation of parkinsonism in progressive supranuclear palsy.

Tauopathies with parkinsonism: clinical spectrum, neuropathologic basis, biological markers, and treatment options.

Tauopathies with parkinsonism represent a spectrum of disease entities unified by the pathologic accumulation of hyperphosphorylated tau protein fragments within the central nervous system. These pathologic characteristics suggest shared pathogenetic pathways and possible molecular targets for disease-modifying therapeutic interventions. Natural history studies, for instance, in progressive supranuclear palsy, frontotemporal dementia with parkinsonism linked to chromosome 17, corticobasal degeneration, and Niemann-Pick disease type C as well as in amyotrophic lateral sclerosis/Parkinson-dementia complex permit clinical characterization of the disease phenotypes and are crucial to the development and validation of biological markers for differential diagnostics and disease monitoring, for example, by use of neuroimaging or proteomic approaches. The wide pathologic and clinical spectrum of the tauopathies with parkinsonism is reviewed in this article, and perspectives on future advances in the understanding of the pathogenesis are given, together with potential therapeutic strategies.