B. Borroni

Tau forms in CSF as a reliable biomarker for progressive supranuclear palsy

Objective: In CSF, extended (55 kDa) and truncated (33 kDa) tau forms have been previously recognized, and the tau 33 kDa/55 kDa ratio has been found significantly reduced in progressive supranuclear palsy (PSP) vs in other neurodegenerative disorders. The aim of this study was to evaluate the diagnostic value of the CSF tau form ratio as a biomarker of PSP and to correlate the structural anatomic changes as measured by means of voxel-based morphometry (VBM) to CSF tau form ratio decrease. Methods: A total of 166 subjects were included in the study (21 PSP, 20 corticobasal degeneration syndrome, 44 frontotemporal dementia, 29 Alzheimer disease, 10 Parkinson disease, 15 dementia with Lewy bodies, and 27 individuals without any neurodegenerative disorder). Each patient underwent a standardized clinical and neuropsychological evaluation. In CSF, a semiquantitative immunoprecipitation was developed to evaluate CSF tau 33 kDa/55 kDa ratio. MRI assessment and VBM analysis was carried out. Results: Tau form ratio was significantly reduced in patients with PSP (0.504 ± 0.284) when compared to age-matched controls (0.989 ± 0.343), and to patients with other neurodegenerative conditions (range = 0.899–1.215). The area under the curve (AUC) of the receiver operating characteristic analysis in PSP vs other subgroups ranged from 0.863 to 0.937 (PSP vs others, AUC = 0.897, p < 0.0001). VBM study showed that CSF tau form ratio decrease correlated significantly with brainstem atrophy. Conclusions: Truncated tau production, which selectively affects brainstem neuron susceptibility, can be considered a specific and reliable marker for PSP. Tau form ratio was the lowest in progressive supranuclear palsy with no overlap with any other neurodegenerative illness. GLOSSARY: AD = Alzheimer disease; AUC = area under the curve; BADL = Basic Activity of Daily Living; CBDS = corticobasal degeneration; CON = controls; DLB = dementia with Lewy bodies; DSM-IV = Diagnostic and Statistical Manual of Mental Disorders, 4th edition; FTD = frontotemporal dementia; IADL = Instrumental Activities of Daily Living; MMSE = Mini-Mental State Examination; MSA = multiple system atrophy; PD = Parkinson disease; PSP = progressive supranuclear palsy; ROC = receiver operating characteristic; UPDRS = Unified Parkinson’s Disease Rating Scale; VBM = voxel-based morphometry.

Brain Magnetic Resonance Imaging Structural Changes in a Pedigree of Asymptomatic Progranulin Mutation Carriers

Mutations in the progranulin (PGRN) gene have been recently demonstrated as a cause of frontotemporal lobar degeneration (FTLD) with ubiquitin-immunoreactive neuronal inclusion (FTD-U). Neuropathologic, clinical, and neuroimaging features associated with PGRN mutations have been carefully described. No studies on asymptomatic subjects carrying pathogenetic PGRN mutations are available yet. These would be crucial for establishing the timing of brain changes and bringing new insight into disease pathogenesis and disease course. The aim of this study was to evaluate structural brain morphology using diffusion tensor imaging (DTI) and voxel-based morphometry (VBM) in asymptomatic carriers of PGRN delCACT mutation belonging to a four-generation FTLD pedigree (mean age, 37.0 +/- 12.0). The evaluation of the family proband presenting with progressive nonfluent aphasia at 53 years of age, revealed left frontotemporal hypoperfusion and atrophy. VBM analysis of gray and white matter reductions revealed no differences between asymptomatic carriers (n = 7) and controls (n = 15), and between no-carriers (n = 10) and controls (p < 0.001). DTI analysis revealed a reduction in fractional anisotropy in healthy PGRN mutation carriers in the left uncinate fasciculus, connecting the orbito-frontal regions to the temporal pole, and in the left inferior occipitofrontal fasciculus, connecting the parieto-occipital cortex to the dorsolateral frontal cortex (p < 0.001). No significant difference in fractional anisotropy between no-carriers and controls was found. Our data indicate loss of white matter integrity as an early preclinical feature in familial FTD that might antedate the onset of specific neurologic features. Alteration of fiber tracts within the perisylvian language network might represent the early hallmark of subsequent aphasia onset. The study of other pedigrees of asymptomatic PGRN mutation carriers is warranted.

Early stages of probable Alzheimer disease are associated with changes in platelet amyloid precursor protein forms.

Abstract. Previous findings demonstrated an altered pattern of amyloid precursor protein (APP) forms in platelets of Alzheimer disease (AD) patients, compared both with healthy control subjects or patients with non-Alzheimer-type dementia. The present study aims to evaluate whether platelet APP form ratio (APPr) is altered in patients with early stage AD. We selected 40 patients with early stage AD and 40 age-matched healthy controls. Compared with controls (mean±SD=0.91±0.3), mean APPr was decreased in AD (mean±SD=0.46±0.26, p<0.0001). Sixteen very mild AD patients (clinical dementia rating=0.5), identified among the AD group, showed a significant decrease of APPr values (mean±SD=0.50±0.3, p<0.0001). These findings indicate that alteration of APP processing in platelets is an early event and suggest that this assay might be of diagnostic value in differentiating mild AD from normal ageing.

Homocysteine, vitamin B6, and vascular disease in patients with AD

To the Editor: We read with interest the article by Miller et al. about plasma homocysteine (Hcy) levels in patients with AD.1 They found that high Hcy levels are not associated with AD, whereas, in AD and controls, they are related to vascular disease. These conclusions fit well with our on-going study carried out on a consecutive series of patients with AD and controls. One hundred and six patients with AD and 186 age- and gender-matched controls have been enrolled so far. All subjects performed a standardized clinical and laboratory workup including plasmatic levels of vitamin B12, folate, and Hcy. Patients and controls were classified into two subgroups (vascular vs nonvascular) according to the presence of hypertension, diabetes, history of stroke or TIA, cerebrovascular lesions on CT, myocardial infarction, angina, congestive heart failure, coronary artery disease, or peripheral vascular disease. No significant difference in Hcy levels was found between patients with AD and controls (16.2 ± 8.3 vs 17.1 ± 9.1; p = 0.37), whereas, within each group, vascular subgroups showed higher Hcy levels. In particular, within the AD group, there …

Tau haplotype affects CSF Tau levels in frontotemporal dementia: implication for diagnostic purposes.

Sirs: Several lines of evidence have suggested a role of cerebrospinal (CSF) total-Tau (hTau) and phospho-Tau (pTau) levels as a diagnostic biomarker of help in early recognition and differentiation of degenerative dementias including frontotemporal dementia (FTD) [1]. High hTau and pTau levels are indeed elevated in FTD compared with control subjects, though reported values appear very widespread and do not correlate with disease severity [2]. Explanations for such variability in FTD include clinical heterogeneity, different underlying pathogenetic mechanisms, and CSF sample storage conditions. In light of these findings, we analysed the effect of Tau haplotype segregation on CSF hTau and pTau levels. Epidemiological studies have demonstrated that there is no difference in Tau haplotype frequencies between FTD and normal controls, though in Progressive Supranuclear Palsy and Parkinson’s Disease there is an increased frequency of H1-carriers. Indeed, it has been reported that H1 haplotype drives Tau gene expression more efficiently compared with H2 haplotype, modulating Tau transcription [3]; notwithstanding, the association between Tau haplotype-related expression and Tau protein levels is still unknown. Accordingly, we hypothesised that Tau haplotype strictly affects CSF levels of hTau and pTau in FTD patients. In this study, 28 frontal variant FTD (fvFTD) patients diagnosed according to current clinical criteria were enrolled (age = 65.0 ± 7.4; F = 54.8 %) from 1 January 1998 to 31 December 2004 [4]. Each patient underwent an extensive standardised neuropsychological assessment, laboratory examinations, a structural (CT and/or MRI) and a functional (SPECT) neuroimaging study. A lumbar puncture for CSF analysis was performed as well as a venous blood sampling for DNA extraction and Tau haplotype and Apolipoprotein E (ApoE) genotype determinations [5]. The fvFTD patients were grouped according to Tau haplotype, and named *H1, as carrying H1/H1 (n = 17) genotype, or *H2 as carrying H1/H2 (n = 10) or H2/H2 (n = 1). *H1and *H2-carriers did not differ in demographic (*H1 vs *H2, age = 64.0 ± 6.7 vs 66.8 ± 8.7; F% = 50 % vs 63.6 %) or clinical characteristics (CDR, 1.2 ± 1.0 vs 1.0 ± 0.6; MMSE, 19.6 ± 6.0 vs 21.9 ± 4.9). *H2-carriers showed significantly higher CSF hTau levels (mean ± standard deviation [SD], 888.4 ± 461.0 pg/mL) compared with *H1-carriers (500.7 ± 402.8 pg/mL, Mann-Whitney test, p < 0.03). pTau was higher, although not significantly, in *H2 (158.1 ± 105.0 pg/mL) compared with *H1 (119.9 ± 137.1). No difference in hTau or pTau levels depending on ApoE genotype was found. It could be speculated that Tau haplotype segregation might affect CSF hTau and pTau. These preliminary findings argue for a biological heterogeneity due to genetic background in fvFTD. It may be speculated, however, that H1 and H2 haplotypes may also affect CSF tau in another neurodegenerative dementia, i. e. Alzheimer disease. Further studies are needed to evaluate whether Tau haplotype may have a role in defining clinical phenotypes, and its consequence for diagnostic and prognostic purposes.