Detection of early Alzheimer's disease in MCI patients by the combination of MMSE and an episodic memory test.

BACKGROUND: Mild cognitive impairment (MCI) is a heterogeneous clinical entity that comprises the prodromal phase of Alzheimer's disease (Pr-AD). New biomarkers are useful in detecting Pr-AD, but they are not universally available. We aimed to investigate baseline clinical and neuropsychological variables that might predict progression from MCI to AD dementia. METHODS: All patients underwent a complete clinical and neuropsychological evaluation at baseline and every 6 months during a two-year follow-up period, with 54 out of 109 MCI patients progressing to dementia (50 of them progressed to AD dementia), and 55 remaining as stable MCI (S-MCI). RESULTS: A combination of MMSE and California Verbal Learning Test Long Delayed Total Recall (CVLT-LDTR) constituted the best predictive model: subjects scoring above 26/30 on MMSE and 4/16 on CVLT-LDTR had a negative predictive value of 93.93% at 2 years, whereas those subjects scoring below both of these cut-off scores had a positive predictive value of 80.95%. CONCLUSIONS: Pr-AD might be distinguished from S-MCI at baseline using the combination of MMSE and CVLT-LDTR. These two neuropsychological predictors are relatively brief and may be readily completed in non-specialist clinical settings.

Caspase-1 genetic variation is not associated with Alzheimer's disease risk.

BACKGROUND: Interleukin (IL)-1beta is a potent proinflammatory cytokine markedly overexpressed in the brains of patients with Alzheimer's disease (AD), and also involved in development of atherosclerosis and coronary artery disease. Caspase-1 (CASP1), formerly called IL-1beta converting enzyme (ICE), mediates the cleavage of the inactive precursor of IL-1beta into the biologically active form. CASP1 genetic variation (G+7/in6A, rs501192) has been associated with susceptibility to myocardial infarction and cardiovascular death risk. We examined the contribution of this gene to the susceptibility for AD. METHODS: We examined genetic variations of CASP1 by genotyping haplotype tagging SNPs (htSNPs) (rs501192, rs556205 and rs530537) in a group of 628 Spanish AD cases and 722 controls. RESULTS: There were no differences in the genotypic, allelic or haplotypic distributions between cases and controls in the overall analysis or after stratification by age, gender or APOE epsilon4 allele. CONCLUSION: Our negative findings in the Spanish population argue against the hypothesis that CASP1 genetic variations are causally related to AD risk.

A snake that bites its own tail. Acquisition and loss of concepts in children and semantic dementia patients through the analysis of drawings.

OBJECTIVE: The structure of the semantic network is constructed and organized during childhood development. Previous publications have hypothesized that neurodegenerative diseases would lead to a disruption of this network reversing the steps acquired in childhood. Semantic Dementia (SD) is a subtype of frontotemporal lobe degeneration in which the main symptom is a specific loss of semantic memory. We aimed to describe the sequential acquisition of concepts in 3-8 years old children evaluated through the production of drawings and, in parallel, their progressive loss in SD patients. METHODS: 104 children between 40 and 96 months categorized into tertiles according to their age, 21 SD patients categorized into tertiles according to their score on a category fluency task and 34 healthy volunteers were asked to draw 12 items with, a priori, different age of acquisition and familiarity, belonging to four different semantic categories. We employed the drawings of the healthy volunteers to build a scoring scheme. We considered that a concept was acquired in children when 50% or more of its features were present in their drawings, and it was lost in patients when more than 50% were missing. RESULTS: Those concepts which the children were able to acquire earlier, according to our scoring scheme, tended to remain in patients with more advanced SD. While the items that children acquired later, were, in general, those that the SD patients lost at earlier disease stages. CONCLUSION: The patterns of concept acquisition in children were the mirror image of the loss in patients with SD. Our study supports the hypothesis that the sequence of concept acquisition in childhood is reversed in SD patients.

No association of CDK5 genetic variants with Alzheimer's disease risk.

BACKGROUND: As cyclin-dependent kinase 5 (CDK5) has been implicated in the abnormal hyperphosphorylation of tau in Alzheimer's disease (AD) brain, and the development of neurofibrillary tangles, we examined the contribution of this gene to the susceptibility for AD. METHODS: We examined genetic variations of CDK5 by genotyping haplotype tagging SNPs (htSNPs) (rs9278, rs2069459, rs891507, rs2069454, rs1549759 and rs2069442) in a group of 408 Spanish AD cases and 444 controls. RESULTS: There were no differences in the genotypic, allelic or haplotypic distributions between cases and controls in the overall analysis or after stratification by APOE epsilon4 allele. CONCLUSION: Our negative findings in the Spanish population argue against the hypothesis that CDK5 genetic variations are causally related to AD risk. Still, additional studies using different sets of patients and control subjects deserve further attention, since supporting evidence for association between CDK5 gene and AD risk in the Dutch population exists.

DYRK1A genetic variants are not linked to Alzheimer's disease in a Spanish case-control cohort.

BACKGROUND: As dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) has been implicated in the abnormal hyperphosphorylation of tau in Alzheimer's disease (AD) brain, and the development of neurofibrillary tangles, we examined the contribution of this gene to the susceptibility for AD. METHODS: We examined genetic variations of DYRK1A by genotyping haplotype tagging SNPs (htSNPs) (rs11701483, rs2835740, rs1137600, rs2835761, rs2835762, rs2154545 and rs8132976) in a group of 634 Spanish AD cases and 733 controls. RESULTS: There were no differences in the genotypic, allelic or haplotypic distributions between cases and controls in the overall analysis or after stratification by APOE epsilon4 allele. CONCLUSION: Our negative findings in the Spanish population argue against the hypothesis that DYRK1A genetic variations are causally related to AD risk. Still, additional studies using different sets of patients and control subjects deserve further attention, since supporting evidence for association between DYRK1A gene and AD risk in the Japanese population exists.

Genetic interaction between tau and the apolipoprotein E receptor LRP1 Increases Alzheimer's disease risk.

Abnormal tau hyperphosphorylation is one of the central events in the development of neurofibrillary tangles (NFTs) in Alzheimer's disease (AD), and phosphorylation of tau is accelerated by the increase in the level of neuronal cholesterol. Apolipoprotein E (APOE) promotes the neuronal uptake of cholesterol via APOE receptors such as the low-density lipoprotein receptor-related protein 1 (LRP1), and the APOE epsilon4 allele is associated with an increase in NFT burden in AD brain. In a case-control study in 246 AD patients and 237 healthy controls, we examined whether the combined gene effects between tau (intron 9, rs2471738) polymorphism and LRP1 (exon 3, rs1799986) polymorphism might be responsible for susceptibility to AD, independently or in concert with the APOE epsilon4 allele. Subjects carrying both the tau (intron 9, rs2471738) T allele (CT and TT genotypes) and the LRP1 (exon 3, rs1799986) T allele (CT and TT genotypes) had a 6 times higher risk of developing AD than subjects without these risk genotypes (odds ration = 6.20, 95% confidence interval = 1.74-22.05, p = 0.005), and this genetic interaction was observed in either the presence or the absence of the APOE epsilon4 allele. These data suggest that the synergistic effects (epistasis) between tau and LRP1 might modify the risk of AD in an APOE epsilon4 allele-independent fashion.

Persistent isolated mydriasis as an early sign of internal carotid artery dissection: Pourfour du petit syndrome.

BACKGROUND: The dissection of the internal carotid artery (ICA) is commonly associated with miosis in Bernard-Horner syndrome (BHS). The presence of mydriasis is exceptional but can occur in the context of Pourfour du Petit syndrome (PDPS), a rare entity opposite of BHS accompanied by eyelid retraction and hyperhidrosis and caused by hyperactivity of the sympathetic cervical chain. AIM: To report on a case of PDPS as the first manifestation of an ICA dissection. METHOD: A 54-year-old man presented with isolated left mydriasis with no other abnormalities in the examination. Six months later, he suffered an ischemic stroke in the left middle cerebral artery territory secondary to a left ICA dissection. RESULTS: The initial study with Intracranial computed tomographic angiography and brain magnetic resonance imaging ruled out compressive cause of the third cranial nerve or structural lesion in the midbrain. The absence of hypersensitivity to Pilocarpine discarded postganglionic parasympathetic involvement. CONCLUSIONS: In the presence of unilateral mydriasis and once common causes are ruled out an imaging examination of the supra-aortic trunks should be completed, since it could represent the first sign of carotid pathology in the context of PDPS.

A Brief Drawing Task for the Differential Diagnosis of Semantic Dementia.

BACKGROUND: Semantic dementia (SD) is a subtype of frontotemporal lobe degeneration characterized by semantic loss, with other cognitive functions initially preserved. SD requires differential diagnosis with Alzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD). Semantic knowledge can be evaluated through different tests; however, most of them depend on language. OBJECTIVE: We describe the development of a brief drawing task that may be helpful for the differential diagnosis of SD. METHODS: Seventy-two patients, including 32 AD, 19 bvFTD, and 21 SD were asked to draw 12 items with different age of acquisition and familiarity, belonging to four different semantic categories. We employed the drawings of healthy volunteers to build a scoring scheme. RESULTS: Turtle, strawberry, train, and envelope were the items of each category that best discriminated between groups and were selected for the Brief drawing task. The discriminatory power of the Brief drawing task between SD versus AD and bvFTD patients, estimated through the area under the curve was 0.84 (95% CI = 0.72-0.96, p = 0.000007). In a logistic model, the Brief drawing task (p = 0.003) and VOSP "number location" subtest (p = 0.016) were significant predictors of the diagnosis of SD versus AD and bvFTD after adjustment by the main covariates. The Brief drawing task provided clinically useful qualitative information. SD drawings were characterized by loss of the distinctive features, intrusions, tendency to prototype, and answers like "I don't know what this is". CONCLUSION: The Brief drawing task appears to reveal deficits in semantic knowledge among patients with SD that may assist in the differential diagnosis with other neurodegenerative diseases.

Cognitive and Behavioral Profiles of Left and Right Semantic Dementia: Differential Diagnosis with Behavioral Variant Frontotemporal Dementia and Alzheimer's Disease.

BACKGROUND: Semantic dementia (SD) is a subtype of frontotemporal dementia (FTD) characterized by semantic memory loss and preserved abilities of other cognitive functions. The clinical manifestations of SD require a differential diagnosis with Alzheimer's disease (AD), especially those with early onset, and behavioral variant FTD (bvFTD). OBJECTIVE: The present study aimed to compare cognitive performances and neuropsychiatric symptoms in a population of AD, bvFTD, and left and right SD defined with the support of molecular imaging (amyloid and 2-[18F] fluoro-2-deoxy-D-glucose positron emission tomography) and assessed the accuracy of different neuropsychological markers in distinguishing these neurodegenerative diseases. METHODS: Eighty-seven participants (32 AD, 20 bvFTD, and 35 SD (17 Left-SD and 18 Right-SD) completed a comprehensive neuropsychological battery that included memory, language, attention and executive functions, visuospatial function, visuoconstructional skills, and tasks designed specifically to evaluate prosopagnosia and facial emotions recognition. The Neuropsychiatric Inventory was administered to assess neuropsychiatric symptoms. RESULTS: An episodic memory test that included semantic cues, a visuospatial test (both impaired in AD), a naming test and a prosopagnosia task (both impaired in SD) were the four most valuable cognitive metrics for the differential diagnosis between groups. Several behavioral abnormalities were differentially present, of which aggression, self-care (both more frequent in bvFTD), and eating habits, specifically overeating and altered dietary preference (more frequent in SD), were the most valuable in group discrimination. CONCLUSION: Our study highlights the value of a comprehensive neuropsychological and neuropsychiatric evaluation for the differential diagnosis between FTD syndromes and AD.

Synergistic effect of heme oxygenase-1 and tau genetic variants on Alzheimer's disease risk.

Oxidative stress plays a role in tau hyperphosphorylation and the development of neurofibrillary tangles (NFT). In Alzheimer's disease (AD) brain, accumulation of hyperphosphorylated tau in NFT is associated with the induction of heme oxygenase-1 (HO-1), a potent antioxidant that downregulates the production of tau. In a case-control study of 300 AD patients and 360 healthy controls, we examined whether the combined gene effects between HO-1 (-413, rs2071746) and tau (5' of exon 1, rs242557) polymorphisms might be responsible for susceptibility to AD. Subjects carrying both the HO-1 (-413) TT and the tau (5' of exon 1) AA genotypes had a more than 6.5-time higher risk of developing AD than subjects without these risk genotypes (OR = 6.65, 95% CI 1.12-39.29; p = 0.037). These data support a role for tau-related genes in the risk of AD.

Cerebral changes and disrupted gray matter cortical networks in asymptomatic older adults at risk for Alzheimer's disease.

The diagnostic value of cerebrospinal fluid (CSF) biomarkers is well established in Alzheimer's disease, but our current knowledge about how abnormal CSF levels affect cerebral integrity, at local and network levels, is incomplete in asymptomatic older adults. Here, we have collected CSF samples and performed structural magnetic resonance imaging scans in cognitively normal elderly as part of a cross-sectional multicenter study (SIGNAL project). To identify group differences in cortical thickness, white matter volume, and properties of structural networks, participants were split into controls (N = 20), positive amyloid-ß (Aß1-42+) (N = 19), and positive phosphorylated tau (N = 18). The Aß1-42+ group exhibited thickening of middle temporal regions, while positive phosphorylated tau individuals showed thinning in the superior parietal and orbitofrontal cortices. Subjects with abnormal CSF biomarkers further showed regional white matter atrophy and more segregated cortical networks, the Aß1-42+ group showing heightened isolation of cingulate and temporal cortices. Collectively, these findings highlight the relevance of combining structural brain imaging and connectomics for in vivo tracking of Alzheimer's disease lesions in asymptomatic stages.

Utility of Amyloid and FDG-PET in Clinical Practice: Differences Between Secondary and Tertiary Care Memory Units.

The clinical utility of amyloid positron emission tomography (PET) has not been fully established. Our aim was to evaluate the effect of amyloid imaging on clinical decision making in a secondary care unit and compare our results with a previous study in a tertiary center following the same methods. We reviewed retrospectively 151 cognitively impaired patients who underwent amyloid (Pittsburgh compound B [PiB]) PET and were evaluated clinically before and after the scan in a secondary care unit. One hundred and fifty concurrently underwent fluorodeoxyglucose (FDG)-PET. We assessed changes between the pre- and post-PET clinical diagnosis and Alzheimer's disease treatment plan. The association between PiB/FDG results and changes in management was evaluated using χ2 and multivariate logistic regression. Concordance between classification based on scan readings and baseline diagnosis was 66% for PiB and 47% for FDG. The primary diagnosis changed after PET in 17.2% of cases. When examined independently, discordant PiB and discordant FDG were both associated with diagnostic change (p < 0.0001). However, when examined together in a multivariate logistic regression, only discordant PiB remained significant (p = 0.0002). Changes in treatment were associated with concordant PiB (p = 0.009) while FDG had no effect on treatment decisions. Based on our regression model, patients with diagnostic dilemmas, a suspected non-amyloid syndrome, and Clinical Dementia Rating <1 were more likely to benefit from amyloid PET due to a higher likelihood of diagnostic change. We found that changes in diagnosis after PET in our secondary center almost doubled those of our previous analysis of a tertiary unit (9% versus 17.2%). Our results offer some clues about the rational use of amyloid PET in a secondary care memory unit stressing its utility in mild cognitive impairment patients.

MicroRNA Profile in Patients with Alzheimer's Disease: Analysis of miR-9-5p and miR-598 in Raw and Exosome Enriched Cerebrospinal Fluid Samples.

BACKGROUND: MicroRNAs have been postulated as potential biomarkers for Alzheimer's disease (AD). Exosomes are nanovesicles which transport microRNAs, proteins, and other cargos. It has been hypothesized that the exosome traffic might be increased in neurodegenerative disorders. OBJECTIVE: i) To assess the cerebrospinal fluid (CSF) microRNA profile in a group of AD patients and control subjects and to validate a group of microRNAs previously reported by other authors. ii) To compare microRNA levels in whole CSF and in the exosome-enriched fraction in AD patients. METHODS: A panel of 760 microRNAs was analyzed in the CSF of 10 AD patients and 10 healthy subjects. Among microRNAs differently expressed, we selected those that had been previously reported by other authors. Candidates were validated in a larger group by individual qPCR assays. MicroRNA expression was also evaluated in exosome-enriched CSF samples of patients with AD and controls. RESULTS: Fifteen microRNAs were differently expressed in AD. MiR-9-5p, miR-134, and miR-598 were selected as candidates for further analysis. MiR-9-5p and miR-598 were detected in 50 and 75% of control CSF samples, respectively, while they were not detected in any AD CSF samples. We observed an opposite pattern when we evaluated the microRNA expression in the exosome-enriched CSF AD samples. No pattern variations were noted among healthy subjects. CONCLUSION: These data propose miR-9-5p and miR-598 as potential biomarkers for AD. Further studies in plasma and other body fluids will confirm their potential role as easily accessible biomarkers. In addition, our data suggest that exosome trafficking is different between AD and control subjects raising the need to take this phenomenon into consideration in future studies of AD biomarkers.

MAPT H1 Haplotype is Associated with Late-Onset Alzheimer's Disease Risk in APOEɛ4 Noncarriers: Results from the Dementia Genetics Spanish Consortium.

The MAPT H1 haplotype has been linked to several disorders, but its relationship with Alzheimer's disease (AD) remains controversial. A rare variant in MAPT (p.A152T) has been linked with frontotemporal dementia (FTD) and AD. We genotyped H1/H2 and p.A152T MAPT in 11,572 subjects from Spain (4,327 AD, 563 FTD, 648 Parkinson's disease (PD), 84 progressive supranuclear palsy (PSP), and 5,950 healthy controls). Additionally, we included 101 individuals from 21 families with genetic FTD. MAPT p.A152T was borderline significantly associated with FTD [odds ratio (OR) = 2.03; p = 0.063], but not with AD. MAPT H1 haplotype was associated with AD risk (OR = 1.12; p = 0.0005). Stratification analysis showed that this association was mainly driven by APOE ɛ4 noncarriers (OR = 1.14; p = 0.0025). MAPT H1 was also associated with risk for PD (OR = 1.30; p = 0.0003) and PSP (OR = 3.18; p = 8.59 × 10-8) but not FTD. Our results suggest that the MAPT H1 haplotype increases the risk of PD, PSP, and non-APOE ɛ4 AD.

Amyloid precursor protein metabolism and inflammation markers in preclinical Alzheimer disease.

OBJECTIVE: To investigate CSF markers involved in amyloid precursor protein processing, neuronal damage, and neuroinflammation in the preclinical stages of Alzheimer disease (AD) and participants with suspected non-Alzheimer pathology (SNAP). METHODS: We collected CSF from 266 cognitively normal volunteers participating in a cross-sectional multicenter study (the SIGNAL study) to investigate markers involved in amyloid precursor protein processing (Aß42, sAPPß, ß-secretase activity), neuronal damage (total-tau [t-tau], phospho-tau [p-tau]), and neuroinflammation (YKL-40). We analyzed the relationship among biomarkers, clinical variables, and the APOE genotype, and compared biomarker levels across the preclinical stages of the National Institute on Aging-Alzheimer's Association classification: stage 0, 1, 2, 3, and SNAP. RESULTS: The median age in the whole cohort was 58.8 years (range 39.8-81.6). Participants in stages 2-3 and SNAP had higher levels of YKL-40 than those in stages 0 and 1. Participants with SNAP had higher levels of sAPPß than participants in stage 0 and 1. No differences were found between stages 0, 1, and 2-3 in sAPPß and ß-secretase activity in CSF. Age correlated with t-tau, p-tau, and YKL-40. It also correlated with Aß42, but only in APOE ε4 carriers. Aß42 correlated positively with t-tau, sAPPß, and YKL-40 in participants with normal Aß42. CONCLUSIONS: Our findings suggest that inflammation in the CNS increases in normal aging and is intimately related to markers of neurodegeneration in the preclinical stages of AD and SNAP. sAPPß and ß-secretase activity are not useful diagnostic or staging markers in preclinical AD.

APOE dependent-association of PPAR-γ genetic variants with Alzheimer's disease risk.

The peroxisome proliferator-activated receptor-γ (PPAR-γ) is a ligand-inducible transcription factor that suppresses microglial inflammatory responses and inhibits amyloid beta (Aß) production through promoting cholesterol efflux from glial cells. PPAR-γ agonists have been advanced as a new disease altering approach to Alzheimer's disease (AD), with rosiglitazone therapy having improved cognition in those AD patients that did not possess an Apolipoprotein E (APOE) ε4 allele. The current study was designed to explore the effect of interactions between PPAR-γ and APOE gene polymorphisms on the AD risk. We examined genetic variations of PPAR-γ by genotyping 7 haplotype tagging SNPs (htSNPs) (rs10510412, rs17793951, rs1801282, rs4135263, rs1151999, rs709149, and rs709154) in a group of 352 Spanish late-onset AD cases and 438 controls. The PPAR-γ TCCA haplotype derived from SNPs in introns 4 (rs4135263), 5 (rs1151999), and 6 (rs709149 and rs709154) showed a strong protective effect against AD in APOE ε4 allele noncarriers (p=0.001, permutation p=0.006, Bonferroni corrected p=0.021), with a frequency of 39% in cases and 50% in controls. Our data suggest that PPAR-γ genetic variants may modify the risk of AD in an APOE ε4 allele-dependent fashion.

Genetic variations in tau-tubulin kinase-1 are linked to Alzheimer's disease in a Spanish case-control cohort.

Neurofibrillary tangles, one of the characteristic neuropathological lesions found in Alzheimer's disease (AD) brains, are composed of abnormally hyperphosphorylated tau protein. Tau-tubulin kinase-1 (TTBK1) is a brain-specific protein kinase involved in tau phosphorylation at AD-related sites. We examined genetic variations of TTBK1 by genotyping nine haplotype tagging SNPs (htSNPs) (rs2104142, rs2651206, rs10807287, rs7764257, rs3800294, rs1995300, rs2756173, rs6936397, and rs6458330) in a group of 645 Spanish late-onset AD patients and 738 healthy controls. Using a recessive genetic model, minor allele homozygotes for rs2651206 in intron 1 (OR=0.50, p=0.0003), rs10807287 in intron 5 (OR=0.49, p=0.0002), and rs7764257 in intron 9 (OR=0.57, p=0.023), which are in strong linkage disequilibrium, had a lower risk of developing AD than subjects homozygotes and heterozygotes for the major allele. TTBK1 is a promising new candidate tau phosphorylation-related gene for AD risk.

Genetic variation in the tau kinases pathway may modify the risk and age at onset of Alzheimer's disease.

Tau abnormal hyperphosphorylation and the formation of neurofibrillary tangles in the Alzheimer's disease (AD) brain is the result of upregulation of tau kinases. In a group of 729 Spanish late-onset AD patients and 670 healthy controls, we examined variations into a set of 20 candidate genes of kinases involved in tau phosphorylation at AD-related sites (PRKACB; CAMK2A; MARK1, 2, 3 and 4; CSNK1D; CDC2; RPS6KB1 and 2; p38α and ß; IB1; JNK1, 2 and 3; MEK1 and 2; ERK1 and 2), to address hypotheses of genetic variation that might influence both AD risk and age at disease onset. There was an increased frequency of RPS6KB2 (intron 2, rs917570) minor allele in patients (50%) versus controls (39%) (OR = 1.52; 95% CI 1.30-1.77; p = 1.24 × 10-5 Bonferroni corrected), and the presence of this minor allele was significantly (p = 4.2 × 10-5) associated with a 3-years later onset of AD (mean age 74.1 years) when compared to age at onset of non-minor allele carriers (mean age 71.1 years). In APOE non-ε4 allele carriers, the combined effect of AD-associated risk alleles from the genes of CDC2, RPS6KB1 and 2, p38α, JNK (1, 2 and 3), MEK2, and ERK2 was significantly (p = 0.002) associated with a late-onset (>76 years) of AD. The CDC2 AGC haplotype derived from SNPs in introns 3 (rs2448347), 5 (rs2456772), and 7 (rs1871447) showed a protective effect against AD in APOE non-ε4 allele carriers (permutation p = 1.0 × 10-4) with a frequency of 9% in cases and 15% in controls. Common genetic variation in the tau kinases pathway does underlie individual differences not only in susceptibility to AD but also in disease phenotype (age at disease onset).