Reduction of brain stem pathology and transient amelioration of early cognitive symptoms in transgenic mice treated with a monoclonal antibody against α-synuclein oligomers/protofibrils.

Immunotherapy against alpha-synuclein (α-syn) is a promising novel treatment strategy for Parkinson's disease (PD) and related α-synucleinopathies. We have previously shown that systemic treatment with the monoclonal oligomer/protofibril-selective antibody mAb47 targeting cytotoxic α-syn leads to reduced central nervous system levels of such species as well as an indication of reduced late-stage symptoms in aged (Thy-1)-h[A30P] α-syn transgenic mice. Here, we performed an early-onset long-term treatment study with this antibody to evaluate effects on brain pathology and behavioral outcomes in the same mouse model. Compared to the placebo group, the treatment strongly reduced phosphorylated α-syn (pS129 α-syn) pathology in the upper brain stem. Moreover, a preserved recognition memory and risk assessment behavior could be seen in antibody-treated mice at six months of age, even although these effects were no longer significant at eleven months of age. Importantly, no evidence of inflammatory responses or other potential toxic effects was seen with the treatment. Taken together, this study supports the strategy to target α-syn oligomers/protofibrils with monoclonal antibodies to counteract early symptoms and slow down the progression of PD and other α-synucleinopathies.

Cognitive function in very old men does not correlate to biomarkers of Alzheimer's disease.

BACKGROUND: The Alzheimer's disease (AD) brain displays atrophy with amyloid-ß (Aß) and tau deposition, whereas decreased Aß42 and increased tau are measured in cerebrospinal fluid (CSF). The aim of this study was to relate cognitive performance to the degree of brain atrophy, CSF biomarker levels and neuropathology in a cohort of aged men. METHODS: Fifty-eight 86-92-year-old men from the Uppsala Longitudinal Study of Adult Men (ULSAM) cohort underwent cognitive testing, brain computed tomography and lumbar puncture. Atrophy was graded with established scales. Concentrations of CSF Aß42, t-tau and p-tau were measured by ELISA. Thirteen brains were examined post mortem. RESULTS: Forty-six of the individuals were considered non-demented, whereas twelve were diagnosed with dementia, either at baseline (n = 4) or during follow-up (n = 8). When comparing subjects with and without dementia, there were no differences in the degree of atrophy, although the mini mental state examination (MMSE) scoring correlated weakly with the degree of medial temporal atrophy (MTA) (p = 0.04). Moreover, the CSF biomarker levels did not differ significantly between healthy (n = 27) and demented (n = 8) subjects (median values 715 vs 472 pg/ml for Aß42, 414 vs 427 pg/ml for t-tau and 63 vs 60 pg/ml for p-tau). Similarly, there were no differences in the biomarker levels between individuals with mild (n = 24) and severe (n = 11) MTA (median values 643 vs 715 pg/ml for Aß42, 441 vs 401 pg/ml for t-tau and 64 vs 53 pg/ml for p-tau). Finally, the neuropathological changes did not correlate with any of the other measures. CONCLUSION: In this cohort of aged men only a weak correlation could be seen between cognitive performance and MTA, whereas the various neuroradiological, biochemical and neuropathological measures did not correlate with each other. Thus, AD biomarkers seem to be less informative in subjects of an advanced age.

High tau levels in cerebrospinal fluid predict rapid decline and increased dementia mortality in Alzheimer's disease.

OBJECTIVE: Cerebrospinal fluid (CSF) amyloid ß42 (Aß42), total tau (t-tau) and phosphorylated tau (p-tau) are useful as predictors of conversion from mild cognitive impairment (MCI) to Alzheimer's disease (AD) dementia. However, results are contradictory as to whether these biomarkers reflect the future rate of clinical decline. METHODS: This is a retrospective study on 196 patients with AD [mild/moderate AD (n = 72) or AD-MCI (n = 124) at baseline] with a follow-up period of 2-9 years' duration (median 6 years). Lumbar punctures were performed at baseline as a part of the diagnostic procedure. RESULTS: We found an increased risk of rapid cognitive decline defined as a drop in the Mini-Mental State Examination score of ≥ 4 points/year in patients with CSF t-tau concentrations above the median (OR 3.31, 95% CI 1.53-7.16) and CSF p-tau above the median (OR 2.53, 95% CI 1.21-5.26). Patients with CSF t-tau in the highest quartile had a higher risk of dying in severe dementia (HR 4.67, 95% CI 1.16-18.82). CONCLUSIONS: In this large AD cohort, we found an association between high levels of CSF t-tau and p-tau and a more aggressive course of the disease, measured as a rapid cognitive decline and a higher risk of dying in severe dementia.

Genome-wide haplotype association study identifies the FRMD4A gene as a risk locus for Alzheimer's disease.

Recently, several genome-wide association studies (GWASs) have led to the discovery of nine new loci of genetic susceptibility in Alzheimer's disease (AD). However, the landscape of the AD genetic susceptibility is far away to be complete and in addition to single-SNP (single-nucleotide polymorphism) analyses as performed in conventional GWAS, complementary strategies need to be applied to overcome limitations inherent to this type of approaches. We performed a genome-wide haplotype association (GWHA) study in the EADI1 study (n=2025 AD cases and 5328 controls) by applying a sliding-windows approach. After exclusion of loci already known to be involved in AD (APOE, BIN1 and CR1), 91 regions with suggestive haplotype effects were identified. In a second step, we attempted to replicate the best suggestive haplotype associations in the GERAD1 consortium (2820 AD cases and 6356 controls) and observed that 9 of them showed nominal association. In a third step, we tested relevant haplotype associations in a combined analysis of five additional case-control studies (5093 AD cases and 4061 controls). We consistently replicated the association of a haplotype within FRMD4A on Chr.10p13 in all the data set analyzed (OR: 1.68; 95% CI: (1.43-1.96); P=1.1 × 10(-10)). We finally searched for association between SNPs within the FRMD4A locus and Aß plasma concentrations in three independent non-demented populations (n=2579). We reported that polymorphisms were associated with plasma Aß42/Aß40 ratio (best signal, P=5.4 × 10(-7)). In conclusion, combining both GWHA study and a conservative three-stage replication approach, we characterised FRMD4A as a new genetic risk factor of AD.

The tau S305S mutation causes frontotemporal dementia with parkinsonism.

Members of families with mutations in the tau gene are known to be heterogeneous in their clinical presentation, ranging from frontotemporal dementia to a clinical picture more resembling corticobasal degeneration or progressive supranuclear palsy. In this report, we describe a new phenotype for the tau S305S mutation, previously described as progressive supranuclear palsy. Clinically, the three affected family members showed alterations in personality and behaviour as well as cognitive decline and late levodopa-resistant parkinsonian symptoms, consistent with the diagnosis of frontotemporal dementia with parkinsonism linked to chromosome 17. One autopsied case displayed degeneration of the frontal and temporal lobes together with extensive tau pathology in both neurones and glial cells. Sarkosyl-soluble and -insoluble tau extracted from frontal cortex revealed a ratio shift with decreased levels of tau with three microtubule-binding repeats and increased levels of tau with four microtubule-binding repeats (4R tau). These findings provide further evidence for the clinical and pathological variation both within and between families with mutations in the tau gene. In addition, they support previous studies which demonstrate that the S305S mutation influences the splicing of tau exon 10 and results in an overproduction of 4R tau.

Clinical and biochemical correlates of insoluble alpha-synuclein in dementia with Lewy bodies.

Alpha-synuclein is a major constituent of Lewy bodies, the fibrillar aggregates that form within neurons in Parkinson's disease and dementia with Lewy bodies (DLB). Recent biochemical data show that alpha-synuclein accumulates in Parkinson's disease in a detergent insoluble form. We now examine the relationship between detergent insoluble alpha-synuclein and the presence of Lewy bodies, clinical measures of dementia and biochemical parameters in a series of individuals with DLB. We found that Triton X-100 insoluble alpha-synuclein enriched nearly twofold in the temporal cortex of patients with DLB compared to age-matched controls. By contrast the total amount of alpha-synuclein protein was unchanged. Surprisingly, the degree of Triton X-100 insoluble alpha-synuclein did not correlate with either the duration of illness or the number of Lewy bodies counted using stereological methods from an adjacent block of tissue. However, the Triton X-100 soluble fraction of alpha-synuclein did correlate strongly with the expression of several heat shock proteins (HSPs) in DLB but not control cases, suggesting a coordinated HSP response in DLB neocortex.

Tau suppression in a neurodegenerative mouse model improves memory function.

Neurofibrillary tangles (NFTs) are the most common intraneuronal inclusion in the brains of patients with neurodegenerative diseases and have been implicated in mediating neuronal death and cognitive deficits. Here, we found that mice expressing a repressible human tau variant developed progressive age-related NFTs, neuronal loss, and behavioral impairments. After the suppression of transgenic tau, memory function recovered, and neuron numbers stabilized, but to our surprise, NFTs continued to accumulate. Thus, NFTs are not sufficient to cause cognitive decline or neuronal death in this model of tauopathy.

Early Abeta accumulation and progressive synaptic loss, gliosis, and tangle formation in AD brain.

BACKGROUND: Pathologic changes in the Alzheimer disease (AD) brain occur in a hierarchical neuroanatomical pattern affecting cortical, subcortical, and limbic regions. OBJECTIVE: To define the time course of pathologic and biochemical changes-amyloid deposition, amyloid beta-peptide (Abeta) accumulation, neurofibrillary tangle (NFT) formation, synaptic loss, and gliosis-within the temporal association cortex of AD cases of varying disease duration, relative to control brains. METHODS: Stereologic assessments of amyloid burden and tangle density as well as ELISA-based measurements of Abeta, synaptophysin, and glial fibrillary acidic protein (GFAP) were performed in the superior temporal sulcus from a cohort of 83 AD and 26 nondemented control brains. RESULTS: Relative to control cases, AD brains were characterized by accumulation of NFT and amyloid plaques, increase of tris- and formic acid-extractable Abeta species, reduced levels of synaptophysin, and elevated levels of GFAP. In AD cases, the duration of dementia correlated with the degree of tangle formation, gliosis, and synaptic loss but not with any Abeta measures. Accumulation of Abeta, measured both neuropathologically and biochemically, was markedly increased in AD brains independent of disease duration, even in cases of short duration. CONCLUSIONS: These data support distinct processes in the initiation and progression of AD pathology within the temporal cortex: Deposition of Abeta reaches a "ceiling" early in the disease process, whereas NFT formation, synaptic loss, and gliosis continue throughout the course of the illness.

Neuritic alterations and neural system dysfunction in Alzheimer's disease and dementia with Lewy bodies.

Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) are neurodegenerative disorders that share progressive dementia as the common major clinical symptom. Damages to memory-related brain structures are the likely pathological correlate, and in both illnesses deposition of amyloidogenic proteins are present mainly within these limbic structures. Amyloid-beta-positive plaques and phospho-tau-positive neurofibrillary tangles are the main feature of AD and alpha-synuclein-positive Lewy bodies and Lewy neurites are found in DLB. Interestingly the associated proteins also interfere with synaptic function and synaptic plasticity. Here, we propose that the same neuronal circuits are disturbed within the hippocampal formation in AD and DLB and that in both diseases the associated proteins might lead to changes in synaptic plasticity and function. Thus both classic neuropathological changes and cellular dysfunctions might contribute to the cognitive impairments in AD and DLB.

Treatment co-operation in orthodontic patients.

The aim of the present investigation was to determine the reasons for lack of patient co-operation and premature termination of orthodontic treatment. Over a period of 10 years files at the School of Dentistry, Huddinge, Sweden, showed that 80 patients (4 per cent) terminated treatment prematurely. These patients were interviewed regarding their reasons for not completing treatment. Lack of motivation was the most common reason given. Insufficient information about orthodontic treatment and lack of communication between the orthodontist and patient were the basis for the reasons given. Orthodontists require more knowledge of psychology and should have some training in information communication in order to further reduce the level of discontinued treatments.