Comparison of CSF biomarkers in Down syndrome and autosomal dominant Alzheimer's disease: a cross-sectional study.

BACKGROUND: Due to trisomy of chromosome 21 and the resultant extra copy of the amyloid precursor protein gene, nearly all adults with Down syndrome develop Alzheimer's disease pathology by the age of 40 years and are at high risk for dementia given their increased life expectancy compared with adults with Down syndrome in the past. We aimed to compare CSF biomarker patterns in Down syndrome with those of carriers of autosomal dominant Alzheimer's disease mutations to enhance our understanding of disease mechanisms in these two genetic groups at high risk for Alzheimer's disease. METHODS: We did a cross-sectional study using data from adults enrolled in the Alzheimer's Biomarker Consortium-Down Syndrome (ABC-DS) study, a multisite longitudinal study of Alzheimer's disease in Down syndrome, as well as a cohort of carriers of autosomal dominant Alzheimer's disease mutations and non-carrier sibling controls enrolled in the Dominantly Inherited Alzheimer Network (DIAN) study. For ABC-DS, participants with baseline CSF, available clinical diagnosis, and apolipoprotein E genotype as of Jan 31, 2019, were included in the analysis. DIAN participants with baseline CSF, available clinical diagnosis, and apolipoprotein E genotype as of June 30, 2018, were evaluated as comparator groups. CSF samples obtained from adults with Down syndrome, similarly aged carriers of autosomal dominant Alzheimer's disease mutations, and non-carrier siblings (aged 30-61 years) were analysed for markers of amyloid ß (Aß1-40, Aß1-42); tau phosphorylated at threonine 181-related processes; neuronal, axonal, or synaptic injury (total tau, visinin-like protein 1, neurofilament light chain [NfL], synaptosomal-associated protein 25); and astrogliosis and neuroinflammation (chitinase-3-like protein 1 [YKL-40]) via immunoassay. Biomarker concentrations were compared as a function of dementia status (asymptomatic or symptomatic), and linear regression was used to evaluate and compare the relationship between biomarker concentrations and age among groups. FINDINGS: We assessed CSF samples from 341 individuals (178 [52%] women, 163 [48%] men, aged 30-61 years). Participants were adults with Down syndrome (n=41), similarly aged carriers of autosomal dominant Alzheimer's disease mutations (n=192), and non-carrier siblings (n=108). Individuals with Down syndrome had patterns of Alzheimer's disease-related CSF biomarkers remarkably similar to carriers of autosomal dominant Alzheimer's disease mutations, including reductions (all p<0·0080) in Aß1-42 to Aß1-40 ratio and increases in markers of phosphorylated tau-related processes; neuronal, axonal, and synaptic injury (p<0·080); and astrogliosis and neuroinflammation, with greater degrees of abnormality in individuals with dementia. Differences included overall higher concentrations of Aß and YKL-40 (both p<0·0008) in Down syndrome and potential elevations in CSF tau (p<0·010) and NfL (p<0·0001) in the asymptomatic stage (ie, no dementia symptoms). FUNDING: National Institute on Aging, Eunice Kennedy Shriver National Institute of Child Health and Human Development, German Center for Neurodegenerative Diseases, and Japan Agency for Medical Research and Development.

A multicentre validation study of the diagnostic value of plasma neurofilament light.

Increased cerebrospinal fluid neurofilament light (NfL) is a recognized biomarker for neurodegeneration that can also be assessed in blood. Here, we investigate plasma NfL as a marker of neurodegeneration in 13 neurodegenerative disorders, Down syndrome, depression and cognitively unimpaired controls from two multicenter cohorts: King's College London (n = 805) and the Swedish BioFINDER study (n = 1,464). Plasma NfL was significantly increased in all cortical neurodegenerative disorders, amyotrophic lateral sclerosis and atypical parkinsonian disorders. We demonstrate that plasma NfL is clinically useful in identifying atypical parkinsonian disorders in patients with parkinsonism, dementia in individuals with Down syndrome, dementia among psychiatric disorders, and frontotemporal dementia in patients with cognitive impairment. Data-driven cut-offs highlighted the fundamental importance of age-related clinical cut-offs for disorders with a younger age of onset. Finally, plasma NfL performs best when applied to indicate no underlying neurodegeneration, with low false positives, in all age-related cut-offs.

VAMP-2 is a surrogate cerebrospinal fluid marker of Alzheimer-related cognitive impairment in adults with Down syndrome.

BACKGROUND: There is an urgent need for objective markers of Alzheimer's disease (AD)-related cognitive impairment in people with Down syndrome (DS) to improve diagnosis, monitor disease progression, and assess response to disease-modifying therapies. Previously, GluA4 and neuronal pentraxin 2 (NPTX2) showed limited potential as cerebrospinal fluid (CSF) markers of cognitive impairment in adults with DS. Here, we compare the CSF profile of a panel of synaptic proteins (Calsyntenin-1, Neuroligin-2, Neurexin-2A, Neurexin-3A, Syntaxin-1B, Thy-1, VAMP-2) to that of NPTX2 and GluA4 in a large cohort of subjects with DS across the preclinical and clinical AD continuum and explore their correlation with cognitive impairment. METHODS: We quantified the synaptic panel proteins by selected reaction monitoring in CSF from 20 non-trisomic cognitively normal controls (mean age 44) and 80 adults with DS grouped according to clinical AD diagnosis (asymptomatic, prodromal AD or AD dementia). We used regression analyses to determine CSF changes across the AD continuum and explored correlations with age, global cognitive performance (CAMCOG), episodic memory (modified cued-recall test; mCRT) and CSF biomarkers, CSF Aß42:40 ratio, CSF Aß1-42, CSF p-tau, and CSF NFL. P values were adjusted for multiple testing. RESULTS: In adults with DS, VAMP-2 was the only synaptic protein to correlate with episodic memory (delayed recall adj.p = .04) and age (adj.p = .0008) and was the best correlate of CSF Aß42:40 (adj.p = .0001), p-tau (adj.p < .0001), and NFL (adj.p < .0001). Compared to controls, mean VAMP-2 levels were lower in asymptomatic adults with DS only (adj.p = .02). CSF levels of Neurexin-3A, Thy-1, Neurexin-2A, Calysntenin-1, Neuroligin-2, GluA4, and Syntaxin-1B all strongly correlated with NPTX2 (p < .0001), which was the only synaptic protein to show reduced CSF levels in DS at all AD stages compared to controls (adj.p < .002). CONCLUSION: These data show proof-of-concept for CSF VAMP-2 as a potential marker of synapse degeneration that correlates with CSF AD and axonal degeneration markers and cognitive performance.

Cerebrospinal fluid profile of NPTX2 supports role of Alzheimer's disease-related inhibitory circuit dysfunction in adults with Down syndrome.

BACKGROUND: Alzheimer's disease (AD) is the major cause of death in adults with Down syndrome (DS). There is an urgent need for objective markers of AD in the DS population to improve early diagnosis and monitor disease progression. NPTX2 has recently emerged as a promising cerebrospinal fluid (CSF) biomarker of Alzheimer-related inhibitory circuit dysfunction in sporadic AD patients. The objective of this study was to evaluate NPTX2 in the CSF of adults with DS and to explore the relationship of NPTX2 to CSF levels of the PV interneuron receptor, GluA4, and existing AD biomarkers (CSF and neuroimaging). METHODS: This is a cross-sectional, retrospective study of adults with DS with asymptomatic AD (aDS, n = 49), prodromal AD (pDS, n = 18) and AD dementia (dDS, n = 27). Non-trisomic controls (n = 34) and patients with sporadic AD dementia (sAD, n = 40) were included for comparison. We compared group differences in CSF NPTX2 according to clinical diagnosis and degree of intellectual disability. We determined the relationship of CSF NPTX2 levels to age, cognitive performance (CAMCOG, free and cued selective reminding, semantic verbal fluency), CSF levels of a PV-interneuron marker (GluA4) and core AD biomarkers; CSF Aß1-42, CSF t-tau, cortical atrophy (magnetic resonance imaging) and glucose metabolism ([18F]-fluorodeoxyglucose positron emission tomography). RESULTS: Compared to controls, mean CSF NPTX2 levels were lower in DS at all AD stages; aDS (0.6-fold, adj.p < 0.0001), pDS (0.5-fold, adj.p < 0.0001) and dDS (0.3-fold, adj.p < 0.0001). This reduction was similar to that observed in sporadic AD (0.5-fold, adj.p < 0.0001). CSF NPTX2 levels were not associated with age (p = 0.6), intellectual disability (p = 0.7) or cognitive performance (all p > 0.07). Low CSF NPTX2 levels were associated with low GluA4 in all clinical groups; controls (r2 = 0.2, p = 0.003), adults with DS (r2 = 0.4, p < 0.0001) and sporadic AD (r2 = 0.4, p < 0.0001). In adults with DS, low CSF NPTX2 levels were associated with low CSF Aß1-42 (r2 > 0.3, p < 0.006), low CSF t-tau (r2 > 0.3, p < 0.001), increased cortical atrophy (p < 0.05) and reduced glucose metabolism (p < 0.05). CONCLUSIONS: Low levels of CSF NPTX2, a protein implicated in inhibitory circuit function, is common to sporadic and genetic forms of AD. CSF NPTX2 represents a promising CSF surrogate marker of early AD-related changes in adults with DS.

Cerebrospinal fluid and blood Aß levels in Down syndrome patients with and without dementia: a meta-analysis study.

Abnormal ß-amyloid (Aß) levels were found in patients with Down syndrome (DS). However, Aß levels in patients with DS and DS with dementia (DSD) vary considerably across studies. Therefore, we performed a systematic literature review and quantitatively summarized the clinical Aß data on the cerebrospinal fluid (CSF) and blood of patients with DS and those with DSD using a meta-analytical technique. We performed a systematic search of the PubMed and Web of Science and identified 27 studies for inclusion in the meta-analysis. Random-effects meta-analysis indicated that the levels of blood Aß1-40 and Aß1-42 were significantly elevated in patients with DS compared with those in healthy control (HC) subjects. In contrast, there were no significant differences between patients with DS and those with DSD in the blood Aß1-40 and Aß1-42 levels. The CSF Aß1-42 levels were significantly decreased in patients with DS compared to those in HC subjects. Further, CSF Aß1-42 levels were significantly decreased in patients with DSD compared to those with DS, with a large effect size. Taken together, our results demonstrated that blood Aß1-40 and Aß1-42 levels were significantly increased in patients with DS while CSF Aß1-42, but not Aß1-40 levels were significantly decreased in patients with DS.

Plasma and CSF biomarkers for the diagnosis of Alzheimer's disease in adults with Down syndrome: a cross-sectional study.

BACKGROUND: Diagnosis of Alzheimer's disease in Down syndrome is challenging because of the absence of validated diagnostic biomarkers. We investigated the diagnostic performance of plasma and CSF biomarkers in this population. METHODS: We did a cross-sectional study of adults aged 18 years and older with Down syndrome enrolled in a population-based health plan in Catalonia, Spain. Every person with Down syndrome assessed in the health plan was eligible to enter the Down Alzheimer Barcelona Neuroimaging Initiative, and those with a plasma or CSF sample available were included in this study. Participants underwent neurological and neuropsychological examination and blood sampling, and a subset underwent a lumbar puncture. Adults with Down syndrome were classified into asymptomatic, prodromal Alzheimer's disease, or Alzheimer's disease dementia groups by investigators masked to biomarker data. Non-trisomic controls were a convenience sample of young (23-58 years) healthy people from the Sant Pau Initiative on Neurodegeneration. Amyloid-ß (Aß)1-40, Aß1-42, total tau (t-tau), 181-phosphorylated tau (p-tau; only in CSF), and neurofilament light protein (NfL) concentrations were measured in plasma with a single molecule array assay and in CSF with ELISA. Plasma and CSF biomarker concentrations were compared between controls and the Down syndrome clinical groups. Diagnostic performance was assessed with receiver operating characteristic curve analyses between asymptomatic participants and those with prodromal Alzheimer's disease and between asymptomatic participants and those with Alzheimer's disease dementia. FINDINGS: Between Feb 1, 2013, and Nov 30, 2017, we collected plasma from 282 participants with Down syndrome (194 asymptomatic, 39 prodromal Alzheimer's disease, 49 Alzheimer's disease dementia) and 67 controls; CSF data were available from 94 participants (54, 18, and 22, respectively) and all 67 controls. The diagnostic performance of plasma biomarkers was poor (area under the curve [AUC] between 0·53 [95% CI 0·44-0·62] and 0·74 [0·66-0·82]) except for plasma NfL concentrations, which had an AUC of 0·88 (0·82-0·93) for the differentiation of the asymptomatic group versus the prodromal Alzheimer's disease group and 0·95 (0·92-0·98) for the asymptomatic group versus the Alzheimer's disease dementia group. In CSF, except for Aß1-40 concentrations (AUC 0·60, 95% CI 0·45-0·75), all biomarkers had a good performance in the asymptomatic versus prodromal Alzheimer's disease comparison: AUC 0·92 (95% CI 0·85-0·99) for Aß1-42, 0·81 (0·69-0·94) for t-tau, 0·80 (0·67-0·93) for p-tau, and 0·88 (0·79-0·96) for NfL. Performance of the CSF biomarkers was optimal in the asymptomatic versus Alzheimer's disease dementia comparison (AUC ≥0·90 for all except Aß1-40 [0·59, 0·45-0·72]). Only NfL concentrations showed a strong correlation between plasma and CSF biomarker concentrations in participants with Down syndrome (rho=0·80; p<0·0001). INTERPRETATION: Plasma NfL and CSF biomarkers have good diagnostic performance to detect Alzheimer's disease in adults with Down syndrome. Our findings support the utility of plasma NfL for the early detection of Alzheimer's disease in Down syndrome in clinical practice and clinical trials. FUNDING: Institute of Health Carlos III, Fundació La Marató de TV3, Fundació Bancaria Obra Social La Caixa, Fundació Catalana Síndrome de Down, and Fundació Víctor Grífols i Lucas.

C-terminal fragments of the amyloid precursor protein in cerebrospinal fluid as potential biomarkers for Alzheimer disease.

This study assesses whether C-terminal fragments (CTF) of the amyloid precursor protein (APP) are present in cerebrospinal fluid (CSF) and their potential as biomarkers for Alzheimer's disease (AD). Immunoprecipitation and simultaneous assay by Western blotting using multiplex fluorescence imaging with specific antibodies against particular domains served to characterize CTFs of APP in human CSF. We demonstrate that APP-CTFs are detectable in human CSF, being the most abundant a 25-kDa fragment, probably resulting from proteolytic processing by η-secretase. The level of the 25-kDa APP-CTF was evaluated in three independent CSF sample sets of patients and controls. The CSF level of this 25-kDa CTF is higher in subjects with autosomal dominant AD linked to PSEN1 mutations, in demented Down syndrome individuals and in sporadic AD subjects compared to age-matched controls. Our data suggest that APP-CTF could be a potential diagnostic biomarker for AD.

Cerebral amyloid angiopathy in Down syndrome and sporadic and autosomal-dominant Alzheimer's disease.

INTRODUCTION: We aimed to investigate if cerebral amyloid angiopathy (CAA) is more frequent in genetically determined than in sporadic early-onset forms of Alzheimer's disease (AD) (early-onset AD [EOAD]). METHODS: Neuroimaging features of CAA, apolipoprotein (APOE), and cerebrospinal fluid amyloid ß (Aß) 40 levels were studied in subjects with Down syndrome (DS, n = 117), autosomal-dominant AD (ADAD, n = 29), sporadic EOAD (n = 42), and healthy controls (n = 68). RESULTS: CAA was present in 31%, 38%, and 12% of cognitively impaired DS, symptomatic ADAD, and sporadic EOAD subjects and in 13% and 4% of cognitively unimpaired DS individuals and healthy controls, respectively. APOE ε4 genotype was borderline significantly associated with CAA in sporadic EOAD (P = .06) but not with DS or ADAD. There were no differences in Aß040 levels between groups or between subjects with and without CAA. DISCUSSION: CAA is more frequently found in genetically determined AD than in sporadic EOAD. Cerebrospinal fluid Aß40 levels are not a useful biomarker for CAA in AD.

Feasibility of Lumbar Puncture in the Study of Cerebrospinal Fluid Biomarkers for Alzheimer's Disease in Subjects with Down Syndrome.

BACKGROUND: Alzheimer's disease (AD) is the main medical problem in older adults with Down syndrome (DS). Studies of cerebrospinal fluid (CSF) AD biomarkers are limited and the feasibility of lumbar puncture (LP) is controversial in this population. OBJECTIVE: To analyze the frequency of complications after a LP in DS. METHODS: We collected data from 80 adults with DS that underwent a LP within the Down Alzheimer Barcelona Neuroimaging Initiative. Demographics, cognitive status, headache history, and presence of complications after the LP were recorded in every subject. In 53 of them (active group), this information was collected following a semi-structured and validated protocol that actively looks for complications. Other variables related to the LP procedure were also recorded. A telephone interview to the caregiver was performed 5-7 days after the procedure to ask about complications. Data from 27 subjects (clinical practice group), from whom the presence of complications was obtained in a medical follow-up visit within the three months after the LP, were also included. RESULTS: There were no adverse events in 90% of our participants. The most frequent complication was headache (6.25%); only one subject reported a typical post-lumbar puncture headache with moderate severity that required analgesic treatment. Dizziness (3.75%) and back pain (1.25%) were also reported. All the participants that reported complications belonged to the active group. CONCLUSION: LP can be safely performed to study CSF biomarkers in DS. The reported complications are qualitatively similar to the general population, but are less frequently reported, even when actively searched for.

Exploring Alzheimer molecular pathology in Down's syndrome cerebrospinal fluid.

BACKGROUND: Individuals with Down's syndrome (DS) develop early Alzheimer's disease (AD) with ß-amyloid (Aß) plaque pathology. The extra amyloid precursor protein (APP) gene copy in DS is believed to result in a 50% increase in Aß production, but it is unclear how this relates to the development of other AD hallmarks, including axonal degeneration and microglia cell activation, and to other neurological problems in DS, including disturbed sleep regulation. OBJECTIVE: To evaluate if cerebrospinal fluid (CSF) biomarkers for cerebral amyloidosis, axonal degeneration, microglial activation and sleep regulation were altered in young and old patients with DS, and if these biomarkers were related to altered Aß and APP metabolism, reflected by CSF levels of different Aß and APP peptides. METHODS: CSF from DS patients (n=12) and healthy controls (n=20) were analyzed for Aß peptides (Aß1-42, AßX-38/40/42), secreted APP species (sAPPα/ß), biomarkers for AD-like axonal degeneration [total tau (T-tau), phosphorylated tau], microglial activation (YKL-40, CC chemokine ligand 2) and orexin-A, which is a peptide involved in sleep regulation. We compared biomarker levels between groups and tested for relations between biomarkers, disease stage and age. RESULTS: Several of the markers were specifically increased in DS, including AßX-40, sAPPα and sAPPß. Οrexin-A was significantly decreased in DS and correlated with Aß and sAPP. Orexin-A decreased with age in DS, while T-tau and YKL-40 increased with age. CONCLUSION: Down's patients have increased APP and Aß production and increased microglial activation with age. The orexin-A metabolism is disturbed in DS and may be linked to APP and Aß production. Biomarker studies of DS may contribute to our understanding of the amyloidogenic and neurodegenerative process in AD.

Altered cerebrospinal fluid levels of amyloid ß and amyloid precursor-like protein 1 peptides in Down's syndrome.

Down's syndrome (DS) patients develop early Alzheimer's disease pathology with abundant cortical amyloid plaques, likely due to overproduction of the amyloid precursor protein (APP), which subsequently leads to amyloid ß (Aß) aggregation. This is reflected in cerebrospinal fluid (CSF) levels of the 42-amino acid long Aß peptide (Aß1-42), which are increased in young DS patients and decreases with age. However, it is unclear whether DS also affects other aspects of Aß metabolism, including production of shorter C- and N-terminal truncated Aß peptides, and production of peptides from the amyloid precursor-like protein 1 (APLP1), which is related to APP, and cleaved by the same enzymatic processing machinery. APLP1-derived peptides may be surrogate markers for Aß1-42 production in the brain. Here, we used hybrid immunoaffinity-mass spectrometry and enzyme-linked immunosorbent assays to monitor several Aß and APLP1 peptides in CSF from DS patients (n = 12) and healthy controls (n = 20). CSF levels of Aß1-42 and three endogenous peptides derived from APLP1 (APL1ß25, APL1ß27 and APL1ß28) were decreased in DS compared with controls, while a specific Aß peptide, Aß1-28, was increased in a majority of the DS individuals. This study indicates that DS causes previously unknown specific alterations of APP and APLP1 metabolism.

Whole-brain voxel-based morphometry study of children and adolescents with Down syndrome.

In order to investigate alterations in brain morphology and a possible temporal pattern of neuroanatomical abnormalities in the gray matter (GM), white matter (WM) and cerebrospinal fluid (CSF) of young patients with Down syndrome (DS), high-resolution magnetic resonance imaging (MRI) voxel-based morphometry (VBM) was performed on 21 children and adolescents with this chromosomal aberration and 27 age-matched participants as controls. In comparison with control subjects, children and adolescents with DS showed not only an overall smaller whole-brain volume, but also volume reductions of the GM in the cerebellum, frontal lobes, frontal region of the limbic lobe, parahippocampal gyri and hippocampi and of the WM in the cerebellum, frontal and parietal lobes, sub-lobar regions and brainstem. By contrast, volume preservation was observed in the GM of the parietal lobes, temporal lobe and sub-lobar regions and in the WM of the temporal lobe and temporal regions of the limbic lobe. A lower volume of CSF was also detected in the frontal lobes. This study is the first to use the high-resolution MRI VBM method to describe a whole-brain pattern of abnormalities in young DS patients falling within such a narrow age range and it provides new information on the neuroanatomically specific regional changes that occur during development in these patients.

Increase in beta-amyloid levels in cerebrospinal fluid of children with Down syndrome.

BACKGROUND: Individuals with Down syndrome (DS) invariably develop Alzheimer's disease (AD) during their life span. It is therefore of importance to study young DS patients when trying to elucidate early events in AD pathogenesis. AIM: To investigate how levels of different amyloid-beta (Abeta) peptides, as well as tau and phosphorylated tau, in cerebrospinal fluid (CSF) from children with DS change over time. The first CSF sample was taken at 8 months and the following two samples at 20-40 and 54 months of age. RESULTS: Individual levels of the Abeta peptides, as well as total Abeta levels in CSF increased over time when measured with Western blot. Tau in CSF decreased whereas there was no change in levels of phosphorylated tau over time. CONCLUSION: The increasing levels of Abeta in CSF during early childhood of DS patients observed in this study are probably due to the trisomy of the Abeta precursor APP, which leads to an overproduction of Abeta. Despite the increased CSF concentrations of Abeta, there were no signs of an AD-indicating tau pattern in CSF, since the levels of total tau decreased and phosphorylated tau remained unchanged. This observation further strengthens the theory of Abeta pathology preceding tau pathology in AD.

Increased cytokine levels in a cerebral mycotic aneurysm in a child with Down's syndrome.

Cerebral mycotic aneurysms are one of the most serious complications of bacterial endocarditis but the mechanism underlying cerebral aneurysms is unclear. We reported the cytokine levels in a cerebral mycotic aneurysm in a child with Down's syndrome. The patient was a 12-year-old female. She was diagnosed as having Down's syndrome and congenital heart disease consisting of an endocardial cushion defect at birth. She underwent a radical operation at 9 years but mitral valve regurgitation remained. She was hospitalized with high fever, vomiting, loss of activity and gait disturbance. Neurological examination revealed facial palsy and hemiparesis on the left side. Cytokines such as IL-6, TNF-alpha, sTNFR1 and sE-selectin were elevated in blood, and IL-6, TNF-alpha and sTNFR1 in cerebrospinal fluid. T2-weighted MRI disclosed a low intensity area in the right Sylvian sulcus. MR angiography showed an aneurysm of the right middle cerebral artery. We think that cytokines and the formation abnormality of collagen fibers are related to the production of aneurysms.

A voxel-based morphometric study of nondemented adults with Down Syndrome.

Previous structural brain imaging studies of Down Syndrome (DS) have offered important insights into the underlying morphometric aberrations associated with the condition. These previous studies have relied almost exclusively on classic region-of-interest (ROI)-based morphometry, a method in which a finite number of anatomical structures must be defined and delineated a priori. Here we use the fully automated voxel-based morphometry (VBM) approach on 19 nondemented individuals with DS and 11 age-matched controls in order to provide a full-brain assessment of DS morphology. Foci of statistically significant (P < 0.05, corrected for multiple comparisons) reductions in gray matter (GM) tissue were observed in the cerebellum, cingulate gyrus, left medial frontal lobe, right middle/superior temporal gyrus, and the left CA2/CA3 region of the hippocampus. Significant decreases in white matter (WM) tissue were noted throughout the inferior brainstem. Foci of statistically significant (P < 0.05, corrected for multiple comparisons) increases in GM tissue were observed in a superior/caudal portion of the brainstem and left parahippocampal gyrus. Significant increases in WM tissue were noted bilaterally in the parahippocampal gyrus. We also noted significant increases in cerebral spinal fluid in regions suggesting enlarged lateral ventricles in the DS group. While these results are generally consistent with prior ROI-based imaging studies of nondemented DS individuals, the present findings provide additional understanding of the three-dimensional topography of DS morphology throughout the brain. The consistency of these findings with prior imaging reports demonstrates the utility of the VBM technique for investigating the neuroanatomy of DS.

Inositol monophosphatase activity in normal, Down syndrome and dementia of the Alzheimer type CSF.

Inositol monophosphatase (IMPase), a cytoplasmic enzyme that hydrolyses inositol monophosphates to produce inositol is also found in the cerebrospinal fluid (CSF). Since levels of inositol have been previously reported to be elevated in Down syndrome (DS) CSF, IMPase activity was measured in CSF of DS subjects to establish whether altered inositol levels may be related to changes in IMPase activity. In addition, and to better understand the regulation of IMPase expression in the CSF, enzyme activity was measured in normal aging, patients with Alzheimer-type or multi-infarct dementia (DAT and MID, respectively) and in CSF obtained by repeat lumbar puncture or from sequential aliquots of CSF from along the rostro-caudal axis. IMPase activity was relatively constant in CSF obtained from repeated lumbar puncture and there was no significant rostro-caudal gradient of activity in either normal or DS subjects, indicating that the enzyme originates from both brain and spinal cord. Compared to respective age-matched normal subjects, CSF IMPase activity was unaltered in DS, DAT and MID. However, in normal volunteers there was a significant positive correlation between age and CSF IMPase activity. Furthermore, there were significant correlations between CSF IMPase activity and acetylcholinesterase and butyrylcholinesterase activities and total protein, suggesting co-regulation of these parameters within the CSF.

[Transthyretin levels in serum and cerebrospinal fluid sustain the nutrio-viral hypothesis of the Cuban epidemic neuropathy]. / Niveles de transtirretina en suero y en líquido cefalorraquídeo apoyan la hipótesis nutrio-vírica de la neuropatía epidémica cubana.

INTRODUCTION: Transthyretin is considered an excellent marker for monitoring nutritional status in serum. In cerebrospinal fluid it is synthesized by chroroid plexus. Cuban epidemic neuropathy is an emergent disease with a hypothetically viral and nutritional origin. OBJECTIVE: To know the behavior of this transport molecule in serum and cerebrospinal fluid in patients with Cuban epidemic neuropathy. PATIENTS AND METHODS: Serum and cerebrospinal fluid was quantified in 11 patients with Cuban epidemic neuropathy, eight patients suffering from other neuropathies and 15 patients with Down's syndrome and 10 patients with Alzheimer's disease. RESULTS: Serum transthyretin was diminished in patients with Cuban epidemic neuropathy, other neuropathies and Alzheimer's disease. Down's syndrome patients had significantly higher transthyretin levels in comparison with Cuban epidemic neuropathy and Alzheimer's disease. Cerebrospinal fluid transthyretin was significantly increased in patients with Cuban epidemic neuropathy in comparison with the normal values and with Alzheimer's disease patients whose values were settled below the normal values. CONCLUSIONS: The decrement of serum transthyretin in Cuban epidemic neuropathy indicates malnutrition and its higher levels in cerebrospinal fluid also indicate a viral infection. These findings support the nutrio-viral hypothesis of the disease.

Tau and apo E in CSF: potential aid for discriminating Alzheimer's disease from other dementias.

To evaluate the usefulness of tau proteins as biological markers in the diagnosis of dementia of the Alzheimer type (DAT), we analyzed the concentration of tau proteins in 253 cerebrospinal fluid (CSF) samples from patients with or without neurological disorders. Our study showed a significant increase of the mean CSF tau concentration in DAT patients compared with that from non-DAT patients. Interestingly, a significative decrease of CSF tau in patients with frontotemporal dementia was found. We also observed a positive correlation between the CSF-tau concentration and the number of apoepsilon4 alleles. The CSF apolipoprotein E concentration was evaluated and revealed no variation between the groups, although we observed a significant correlation between CSF tau and apolipoprotein E in DAT patients.