Daniel Alcolea

TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis

Loss of TREM2 function impairs phagocytosis and correlates with decreased soluble TREM2 in biological fluids of patients with neurodegenerative disorders. TREM2 and Neurodegeneration Little is known about how risk factors facilitate initiation and propagation of neurodegenerative disorders. Rare mutations in TREM2 increase the risk for several neurodegenerative disorders including Alzheimer’s disease (AD), Parkinson’s disease, and frontotemporal dementia (FTD). Kleinberger et al. now show that mutations associated with neurodegenerative diseases interfere with TREM2 function by preventing its maturation, transport to the cell surface, and shedding. Expression of mutant TREM2 led to reduced phagocytic activity by different cell types, suggesting that removal of cellular debris by, for example, microglia in the brain might be affected in patients with TREM2 mutations. In a patient with FTD-like syndrome carrying a homozygous TREM2 mutation, no soluble TREM2 was detected in the cerebrospinal fluid (CSF) and plasma. Patients with sporadic FTD and AD showed slightly reduced concentrations of soluble TREM2 in their CSF. Although much further testing and validation are needed, soluble TREM2 might be useful as a marker of neurodegeneration. Genetic variants in the triggering receptor expressed on myeloid cells 2 (TREM2) have been linked to Nasu-Hakola disease, Alzheimer’s disease (AD), Parkinson’s disease, amyotrophic lateral sclerosis, frontotemporal dementia (FTD), and FTD-like syndrome without bone involvement. TREM2 is an innate immune receptor preferentially expressed by microglia and is involved in inflammation and phagocytosis. Whether and how TREM2 missense mutations affect TREM2 function is unclear. We report that missense mutations associated with FTD and FTD-like syndrome reduce TREM2 maturation, abolish shedding by ADAM proteases, and impair the phagocytic activity of TREM2-expressing cells. As a consequence of reduced shedding, TREM2 is virtually absent in the cerebrospinal fluid (CSF) and plasma of a patient with FTD-like syndrome. A decrease in soluble TREM2 was also observed in the CSF of patients with AD and FTD, further suggesting that reduced TREM2 function may contribute to increased risk for two neurodegenerative disorders.

Low cerebrospinal fluid concentration of mitochondrial DNA in preclinical Alzheimer disease

To identify a novel biochemical marker that precedes clinical symptoms in Alzheimer disease (AD).

Dementia risk in Parkinson disease: disentangling the role of MAPT haplotypes.

BACKGROUND Dementia in Parkinson disease (PD) causes nursing home placement, caregiver distress, higher health care burden, and increased mortality. OBJECTIVE To determine whether the microtubule-associated protein tau (MAPT) H1 haplotype and MAPT subhaplotypes play a role in the risk of PD and Parkinson disease-dementia (PDD) complex. DESIGN Case-control genetic analysis. SETTING Movement Disorders and Memory Units, Hospital de Sant Pau, Barcelona, Spain. PARTICIPANTS Two hundred two patients with PD (48 of whom developed dementia>2 years after disease onset), 41 patients with Lewy body dementia (LBD, pathologically confirmed in 17), 164 patients with Alzheimer disease (AD), and 374 controls. METHODS The MAPT haplotype was determined by testing for a 238-base pair deletion between exons 9 and 10, which is characteristic of the H2 haplotype. Haploview was used to visualize linkage disequilibrium relationships between all genetic variants (5 single-nucleotide polymorphisms and the del-In9 variant) within and surrounding the MAPT region. RESULTS The H1 haplotype was significantly overrepresented in PD patients compared with controls (P=.001). Stratifying the PD sample by the presence of dementia revealed a stronger association in PDD patients (sex- and age-adjusted odds ratio, 3.73; P=.002) than in PD patients without dementia (sex- and age-adjusted odds ratio, 1.89; P=.04). Examination of specific subhaplotypes showed that a rare version of the H1 haplotype (named H1p) was overrepresented in PDD patients compared with controls (2.3% vs 0.1%; P=.003). No positive signals for any of the MAPT variants or H1 subhaplotypes were found in AD or LBD. CONCLUSIONS Our data confirm that MAPT H1 is associated with PD and has a strong influence on the risk of dementia in PD patients. Our results also suggest that none of the MAPT subhaplotypes play a significant role in other neurodegenerative diseases, such as LBD or AD.

sTREM2 cerebrospinal fluid levels are a potential biomarker for microglia activity in early‐stage Alzheimer's disease and associate with neuronal injury markers

TREM2 is an innate immune receptor expressed on the surface of microglia. Loss‐of‐function mutations of TREM2 are associated with increased risk of Alzheimers disease (AD). TREM2 is a type‐1 protein with an ectodomain that is proteolytically cleaved and released into the extracellular space as a soluble variant (sTREM2), which can be measured in the cerebrospinal fluid (CSF). In this cross‐sectional multicenter study, we investigated whether CSF levels of sTREM2 are changed during the clinical course of AD, and in cognitively normal individuals with suspected non‐AD pathology (SNAP). CSF sTREM2 levels were higher in mild cognitive impairment due to AD than in all other AD groups and controls. SNAP individuals also had significantly increased CSF sTREM2 compared to controls. Moreover, increased CSF sTREM2 levels were associated with higher CSF total tau and phospho‐tau181P, which are markers of neuronal degeneration and tau pathology. Our data demonstrate that CSF sTREM2 levels are increased in the early symptomatic phase of AD, probably reflecting a corresponding change of the microglia activation status in response to neuronal degeneration.

Characterization of the repeat expansion size in C9orf72 in amyotrophic lateral sclerosis and frontotemporal dementia

Hexanucleotide repeat expansions within the C9orf72 gene are the most important genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The difficulty of developing a precise method to determine the expansion size has hampered the study of possible correlations between the hexanucleotide repeat number and clinical phenotype. Here we characterize, through a new non-radioactive Southern blot protocol, the expansion size range in a series of 38 ALS and 22 FTD heterozygous carriers of >30 copies of the repeat. Maximum, median and modal hexanucleotide repeat number were higher in ALS patients than in FTD patients (P< 0.05 in all comparisons). A higher median number of repeats correlated with a bigger range of repeat sizes (Spearmans ρ = 0.743, P = 1.05 × 10(-11)). We did not find any correlation between age of onset or disease duration with the repeat size in neither ALS nor FTD mutation carriers. Clinical presentation (bulbar or spinal) in ALS patients did not correlate either with the repeat length. We finally analyzed two families with affected and unaffected repeat expansion carriers, compared the size of the repeat expansion between two monozygotic (MZ) twins (one affected of ALS and the other unaffected), and examined the expansion size in two different tissues (cerebellum and peripheral blood) belonging to the same FTD patient. The results suggested that the length of the C9orf72 repeat varies between family members, including MZ twins, and among different tissues from the same individual.

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 (Aβ42, sAPPβ, β-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–Alzheimers 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 sAPPβ than participants in stage 0 and 1. No differences were found between stages 0, 1, and 2–3 in sAPPβ and β-secretase activity in CSF. Age correlated with t-tau, p-tau, and YKL-40. It also correlated with Aβ42, but only in APOE ε4 carriers. Aβ42 correlated positively with t-tau, sAPPβ, and YKL-40 in participants with normal Aβ42. 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. sAPPβ and β-secretase activity are not useful diagnostic or staging markers in preclinical AD.

Performance and complications of lumbar puncture in memory clinics : Results of the multicenter lumbar puncture feasibility study

Lumbar puncture (LP) is increasingly performed in memory clinics. We investigated patient‐acceptance of LP, incidence of and risk factors for post‐LP complications in memory clinic populations.

Cerebrospinal fluid β‐amyloid and phospho‐tau biomarker interactions affecting brain structure in preclinical Alzheimer disease

To assess the relationships between core cerebrospinal fluid (CSF) biomarkers and cortical thickness (CTh) in preclinical Alzheimer disease (AD).

Relationship Between β-Secretase, Inflammation and Core Cerebrospinal Fluid Biomarkers for Alzheimer's Disease

BACKGROUND Biomarkers in the cerebrospinal fluid (CSF) can track specific pathophysiological pathways underlying Alzheimers disease (AD). The connection between these biomarkers remains unclear. OBJECTIVE To study six CSF biomarkers in a clinical cohort of patients with different neurodegenerative conditions. METHODS We measured markers of amyloid-β protein precursor (AβPP) processing (Aβ42, sAβPPβ, β-secretase activity), neuronal damage (total tau, p-tau), and inflammation (YKL-40) in CSF from 194 participants with the following diagnoses: subjective cognitive impairment or non-amnestic mild cognitive impairment (na-SCI, n = 44), amnestic mild cognitive impairment (aMCI, n = 45), dementia of the Alzheimer type (DAT, n = 59), frontotemporal dementia (FTD, n = 22), and 24 cognitively normal controls. We compared biomarkers between clinical groups and CSF-profile groups, and we analyzed the correlation between biomarkers. RESULTS CSF levels of sAβPPβ were decreased in FTD patients compared to the other groups. YKL-40 was elevated in DAT and FTD, and also in aMCI patients. CSF Aβ42 correlated positively with β-secretase activity (RS = 0.262) and sAβPPβ (RS = 0.341). CSF YKL-40 correlated positively with total tau (RS = 0.467) and p-tau (RS = 0.429). CSF p-tau and sAβPPβ contributed significantly to distinguish DAT from FTD. CONCLUSIONS CSF biomarkers of AβPP processing correlate with each other and are decreased in FTD. The inflammatory marker YKL-40 is increased in different neurodegenerative diseases, even in early stages, and it correlates with biomarkers of neurodegeneration. This suggests that inflammation is a common feature in AD and FTD. A combination of CSF biomarkers tracking distinct pathophysiological processes may be useful to classify subjects with neurodegenerative conditions.

Relationship between cortical thickness and cerebrospinal fluid YKL-40 in predementia stages of Alzheimer's disease

Cerebrospinal fluid YKL-40 has been described as a marker of glial inflammation. We aimed to study the relationship between YKL-40 and brain structure and its interactions with core Alzheimers disease (AD) biomarkers. We measured cortical thickness (CTh) and cerebrospinal fluid biomarkers (amyloid-β 1-42 [Aβ42], total tau, p-tau, and YKL-40) of 80 cognitively normal controls and 27 patients with amnestic mild cognitive impairment. Subjects were classified as Aβ42+ (<550 pg/mL) or Aβ42- (>550 pg/mL). CTh difference maps were derived from the interaction and correlation analyses in the whole sample and within clinical groups. There was a strong correlation between YKL-40 and markers of neurodegeneration (total tau and p-tau). In the whole sample, we found a negative correlation between YKL-40 and CTh in AD vulnerable areas in Aβ42+ subjects but not in Aβ42 participants. Our results suggest that YKL-40 could track the inflammatory processes associated to tau-related neurodegeneration in the presence of the AD pathophysiological process.