Alpha- and gamma-synuclein proteins are present in cerebrospinal fluid and are increased in aged subjects with neurodegenerative and vascular changes.

BACKGROUND: Disease-specific biomarkers should reflect a fundamental feature of neuropathology and be validated in neuropathologically confirmed cases. Several synaptic proteins have been described in cerebrospinal fluid (CSF) of patients with dementia. In Lewy body disease alpha-synuclein is incorporated within Lewy bodies and alpha-, beta- and gamma-synucleins in dystrophic neuritis. These pathological changes are expected to be seen in CSF. METHODS: A total of 25 CSF post-mortem samples (8 control and 17 subjects with dementia) were used to quantify alpha- and gamma-synucleins and IgG. RESULTS: We describe for the first time the presence of gamma-synuclein in CSF. There is an elevation of both alpha- and gamma-synucleins in CSF from elderly individuals with Alzheimer's disease, Lewy body disease (LBD) and vascular dementia (CVD), compared to normal controls. gamma-Synuclein showed a greater elevation in LBD, IgG in CVD. The elevation of alpha- and gamma-synucleins was seen from Braak stage III onwards and remained stable until Braak stage VI. These results were not influenced by age at death or post-mortem delay. CONCLUSIONS: The reported increases in alpha- and gamma-synucleins and IgG in the ventricular CSF of individuals with dementia are novel findings. They now need to be explored further using a greater number of cases in each subgroup, using lumbar CSF samples to determine their applicability and relevance to a clinical diagnostic setting. It needs to be established whether using these markers may help to discriminate LBD from other types of neurodegenerative and vascular dementias.

Loss of synaptophysin and synaptosomal-associated protein 25-kDa (SNAP-25) in elderly Down syndrome individuals.

AIMS: This study quantified the density of the synaptic proteins synaptophysin and synaptosomal-associated protein 25-kDa (SNAP-25) in brains from elderly Down's syndrome individuals. METHODS: Six areas (frontal, occipital, parietal and temporal lobes, cerebellum and hippocampus) of post mortem brains from elderly Down's syndrome (DS) individuals (with reported functional memory problems and pathologically established Alzheimer's disease) and elderly controls were studied. RESULTS: Collectively in the six brain areas studied, there were significantly lower levels of both synaptophysin and SNAP-25 immunostaining in the DS group compared with controls. The elderly control group displayed a significant decrease in the densities of synaptophysin and SNAP-25 as a function of age at death (AAD; P < or = 0.001), whereas the DS group only showed a significant decrease as a function of AAD for synaptophysin. Assessing synaptic density as a function of Braak stage (BST) revealed a significant decrease in synaptophysin density for both groups. SNAP-25 was only significantly decreased as a function of BST in the DS group. Synaptic protein density was also shown to vary according to gender. Thus, both DS and control female subjects had a higher synaptic density of SNAP-25 than their male counterparts. In contrast, male DS and control individuals had a significantly greater density of synaptophysin than females. CONCLUSIONS: These results indicate that elderly DS individuals have lower synaptic densities of both analysed proteins than cognitively intact elderly individuals. Although AAD and BST show varying significance to decreases in protein density for both DS and control groups, results suggest that gender differences also play a role in the type of synaptic protein lost in elderly DS individuals.

Molecular neuropathology of MELAS: level of heteroplasmy in individual neurones and evidence of extensive vascular involvement.

Mitochondrial DNA (mtDNA) disease is an important genetic cause of neurological disability. A variety of different clinical features are observed and one of the most common phenotypes is MELAS (Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis and Stroke-like episodes). The majority of patients with MELAS have the 3243A>G mtDNA mutation. The neuropathology is dominated by multifocal infarct-like lesions in the posterior cortex, thought to underlie the stroke-like episodes seen in patients. To investigate the relationship between mtDNA mutation load, mitochondrial dysfunction and neuropathological features in MELAS, we studied individual neurones from several brain regions of two individuals with the 3243A>G mutation using dual cytochrome c oxidase (COX) and succinate dehydrogenase (SDH) histochemistry, and Polymerase Chain Reaction Restriction Fragment Lenght Polymorphism (PCR-RFLP) analysis. We found a low number of COX-deficient neurones in all brain regions. There appeared to be no correlation between the threshold level for the 3243A>G mutation to cause COX deficiency within single neurones and the degree of pathology in affected brain regions. The most severe COX deficiency associated with the highest proportion of mutated mtDNA was present in the walls of the leptomeningeal and cortical blood vessels in all brain regions. We conclude that vascular mitochondrial dysfunction is important in the pathogenesis of the stroke-like episodes in MELAS patients. As migraine is a commonly encountered feature in MELAS, we propose that coupling of the vascular mitochondrial dysfunction with cortical spreading depression (CSD) might underlie the selective distribution of ischaemic lesions in the posterior cortex in these patients.