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Concept: Dementia

431

In retired professional association football (soccer) players with a past history of repetitive head impacts, chronic traumatic encephalopathy (CTE) is a potential neurodegenerative cause of dementia and motor impairments. From 1980 to 2010, 14 retired footballers with dementia were followed up regularly until death. Their clinical data, playing career, and concussion history were prospectively collected. Next-of-kin provided consent for six to have post-mortem brain examination. Of the 14 male participants, 13 were professional and 1 was a committed amateur. All were skilled headers of the ball and had played football for an average of 26 years. Concussion rate was limited in six cases to one episode each during their careers. All cases developed progressive cognitive impairment with an average age at onset of 63.6 years and disease duration of 10 years. Neuropathological examination revealed septal abnormalities in all six post-mortem cases, supportive of a history of chronic repetitive head impacts. Four cases had pathologically confirmed CTE; concomitant pathologies included Alzheimer’s disease (N = 6), TDP-43 (N = 6), cerebral amyloid angiopathy (N = 5), hippocampal sclerosis (N = 2), corticobasal degeneration (N = 1), dementia with Lewy bodies (N = 1), and vascular pathology (N = 1); and all would have contributed synergistically to the clinical manifestations. The pathological diagnosis of CTE was established in four individuals according to the latest consensus diagnostic criteria. This finding is probably related to their past prolonged exposure to repetitive head impacts from head-to-player collisions and heading the ball thousands of time throughout their careers. Alzheimer’s disease and TDP-43 pathologies are common concomitant findings in CTE, both of which are increasingly considered as part of the CTE pathological entity in older individuals. Association football is the most popular sport in the world and the potential link between repetitive head impacts from playing football and CTE as indicated from our findings is of considerable public health interest. Clearly, a definitive link cannot be established in this clinico-pathological series, but our findings support the need for further systematic investigation, including large-scale case-control studies to identify at risk groups of footballers which will justify for the implementation of protective strategies.

Concepts: Alzheimer's disease, Pathology, Parkinson's disease, Dementia, Lewy body, Autopsy, Cerebral amyloid angiopathy, Football

302

The genetic predispositions which describe a diagnosis of familial Alzheimer’s disease can be considered as cornerstones of the amyloid cascade hypothesis. Essentially they place the expression and metabolism of the amyloid precursor protein as the main tenet of disease aetiology. However, we do not know the cause of Alzheimer’s disease and environmental factors may yet be shown to contribute towards its onset and progression. One such environmental factor is human exposure to aluminium and aluminium has been shown to be present in brain tissue in sporadic Alzheimer’s disease. We have made the first ever measurements of aluminium in brain tissue from 12 donors diagnosed with familial Alzheimer’s disease. The concentrations of aluminium were extremely high, for example, there were values in excess of 10μg/g tissue dry wt. in 5 of the 12 individuals. Overall, the concentrations were higher than all previous measurements of brain aluminium except cases of known aluminium-induced encephalopathy. We have supported our quantitative analyses using a novel method of aluminium-selective fluorescence microscopy to visualise aluminium in all lobes of every brain investigated. The unique quantitative data and the stunning images of aluminium in familial Alzheimer’s disease brain tissue raise the spectre of aluminium’s role in this devastating disease.

Concepts: Alzheimer's disease, Scientific method, Protein, Neuron, Environment, Dementia, Beta amyloid, Amyloid precursor protein

199

Many choice situations require imagining potential outcomes, a capacity that was shown to involve memory brain regions such as the hippocampus. We reasoned that the quality of hippocampus-mediated simulation might therefore condition the subjective value assigned to imagined outcomes. We developed a novel paradigm to assess the impact of hippocampus structure and function on the propensity to favor imagined outcomes in the context of intertemporal choices. The ecological condition opposed immediate options presented as pictures (hence directly observable) to delayed options presented as texts (hence requiring mental stimulation). To avoid confounding simulation process with delay discounting, we compared this ecological condition to control conditions using the same temporal labels while keeping constant the presentation mode. Behavioral data showed that participants who imagined future options with greater details rated them as more likeable. Functional MRI data confirmed that hippocampus activity could account for subjects assigning higher values to simulated options. Structural MRI data suggested that grey matter density was a significant predictor of hippocampus activation, and therefore of the propensity to favor simulated options. Conversely, patients with hippocampus atrophy due to Alzheimer’s disease, but not patients with Fronto-Temporal Dementia, were less inclined to favor options that required mental simulation. We conclude that hippocampus-mediated simulation plays a critical role in providing the motivation to pursue goals that are not present to our senses.

Concepts: Alzheimer's disease, Brain, Epistemology, Memory, Dementia, Operations research, Futures contract, Semantic memory

177

Neurofibrillary tangles (NFT) and β-amyloid plaques are the neurological hallmarks of both Alzheimer’s disease and an unusual paralytic illness suffered by Chamorro villagers on the Pacific island of Guam. Many Chamorros with the disease suffer dementia, and in some villages one-quarter of the adults perished from the disease. Like Alzheimer’s, the causal factors of Guamanian amyotrophic lateral sclerosis/parkinsonism dementia complex (ALS/PDC) are poorly understood. In replicated experiments, we found that chronic dietary exposure to a cyanobacterial toxin present in the traditional Chamorro diet, β-N-methylamino-l-alanine (BMAA), triggers the formation of both NFT and β-amyloid deposits similar in structure and density to those found in brain tissues of Chamorros who died with ALS/PDC. Vervets (Chlorocebus sabaeus) fed for 140 days with BMAA-dosed fruit developed NFT and sparse β-amyloid deposits in the brain. Co-administration of the dietary amino acid l-serine with l-BMAA significantly reduced the density of NFT. These findings indicate that while chronic exposure to the environmental toxin BMAA can trigger neurodegeneration in vulnerable individuals, increasing the amount of l-serine in the diet can reduce the risk.

Concepts: Alzheimer's disease, Medicine, Neurology, Dementia, Mariana Islands, Guam, Northern Mariana Islands, Chamorro people

173

Filamentous inclusions made of hyperphosphorylated tau are characteristic of numerous human neurodegenerative diseases, including Alzheimer’s disease, tangle-only dementia, Pick disease, argyrophilic grain disease (AGD), progressive supranuclear palsy, and corticobasal degeneration. In Alzheimer’s disease and AGD, it has been shown that filamentous tau appears to spread in a stereotypic manner as the disease progresses. We previously demonstrated that the injection of brain extracts from human mutant P301S tau-expressing transgenic mice into the brains of mice transgenic for wild-type human tau (line ALZ17) resulted in the assembly of wild-type human tau into filaments and the spreading of tau inclusions from the injection sites to anatomically connected brain regions. Here we injected brain extracts from humans who had died with various tauopathies into the hippocampus and cerebral cortex of ALZ17 mice. Argyrophilic tau inclusions formed in all cases and following the injection of the corresponding brain extracts, we recapitulated the hallmark lesions of AGD, PSP and CBD. Similar inclusions also formed after intracerebral injection of brain homogenates from human tauopathies into nontransgenic mice. Moreover, the induced formation of tau aggregates could be propagated between mouse brains. These findings suggest that once tau aggregates have formed in discrete brain areas, they become self-propagating and spread in a prion-like manner.

Concepts: Alzheimer's disease, Brain, Cerebral cortex, Neurodegenerative disorders, Dementia, Progressive supranuclear palsy, Tau protein, Tauopathy

171

BACKGROUND: Although diffusion tensor imaging has been a major research focus for Alzheimer’s disease in recent years, it remains unclear whether it has sufficient stability to have biomarker potential. To date, frequently inconsistent results have been reported, though lack of standardisation in acquisition and analysis make such discrepancies difficult to interpret. There is also, at present, little knowledge of how the biometric properties of diffusion tensor imaging might evolve in the course of Alzheimer’s disease. METHODS: The biomarker question was addressed in this study by adopting a standardised protocol both for the whole brain (tract-based spatial statistics), and for a region of interest: the midline corpus callosum. In order to study the evolution of tensor changes, cross-sectional data from very mild (N = 21) and mild (N = 22) Alzheimer’s disease patients were examined as well as a longitudinal cohort (N = 16) that had been rescanned at 12 months. FINDINGS AND SIGNIFICANCE: The results revealed that increased axial and mean diffusivity are the first abnormalities to occur and that the first region to develop such significant differences was mesial parietal/splenial white matter; these metrics, however, remained relatively static with advancing disease indicating they are suitable as ‘state-specific’ markers. In contrast, increased radial diffusivity, and therefore decreased fractional anisotropy-though less detectable early-became increasingly abnormal with disease progression, and, in the splenium of the corpus callosum, correlated significantly with dementia severity; these metrics therefore appear ‘stage-specific’ and would be ideal for monitoring disease progression. In addition, the cross-sectional and longitudinal analyses showed that the progressive abnormalities in radial diffusivity and fractional anisotropy always occurred in areas that had first shown an increase in axial and mean diffusivity. Given that the former two metrics correlate with dementia severity, but the latter two did not, it would appear that increased axial diffusivity represents an upstream event that precedes neuronal loss.

Concepts: Alzheimer's disease, Neuron, Medical imaging, Neuroimaging, Dementia, Diffusion MRI, Corpus callosum, Imaging

171

Small molecules with antioxidative properties have been implicated in amyloid disorders. Curcumin is the active ingredient present in turmeric and known for several biological and medicinal effects. Adequate evidence substantiates the importance of curcumin in Alzheimer’s disease and recent evidence suggests its role in Prion and Parkinson’s disease. However, contradictory effects have been suggested for Huntington’s disease. This difference provided a compelling reason to investigate the effect of curcumin on glutamine-rich (Q-rich) and non-glutamine-rich (non Q-rich) amyloid aggregates in the well established yeast model system. Curcumin significantly inhibited the formation of htt72Q-GFP (a Q-rich) and Het-s-GFP (a non Q-rich) aggregates in yeast. We show that curcumin prevents htt72Q-GFP aggregation by down regulating Vps36, a component of the ESCRT-II (Endosomal sorting complex required for transport). Moreover, curcumin disrupted the htt72Q-GFP aggregates that were pre-formed in yeast and cured the yeast prion, [PSI(+)].

Concepts: Alzheimer's disease, Model organism, Prion, Neurodegenerative disorders, Parkinson's disease, Dementia, Turmeric, Curcumin

169

Alzheimer’s disease (AD) is characterized by deposition of amyloid-β (Aβ) plaques and neurofibrillary tangles in the brain, accompanied by synaptic dysfunction and neurodegeneration. Antibody-based immunotherapy against Aβ to trigger its clearance or mitigate its neurotoxicity has so far been unsuccessful. Here we report the generation of aducanumab, a human monoclonal antibody that selectively targets aggregated Aβ. In a transgenic mouse model of AD, aducanumab is shown to enter the brain, bind parenchymal Aβ, and reduce soluble and insoluble Aβ in a dose-dependent manner. In patients with prodromal or mild AD, one year of monthly intravenous infusions of aducanumab reduces brain Aβ in a dose- and time-dependent manner. This is accompanied by a slowing of clinical decline measured by Clinical Dementia Rating-Sum of Boxes and Mini Mental State Examination scores. The main safety and tolerability findings are amyloid-related imaging abnormalities. These results justify further development of aducanumab for the treatment of AD. Should the slowing of clinical decline be confirmed in ongoing phase 3 clinical trials, it would provide compelling support for the amyloid hypothesis.

Concepts: Alzheimer's disease, Neuron, Clinical trial, Monoclonal antibodies, Neurology, Dementia, Mental status examination, Neurofibrillary tangle

168

Alzheimer’s dementia (AD) is increasingly being recognized as one of the most important medical and social problems in older people in industrialized and non-industrialized nations. To date, only symptomatic treatments exist for this disease, all trying to counterbalance the neurotransmitter disturbance. Three cholinesterase inhibitors (CIs) are currently available and have been approved for the treatment of mild to moderate AD. A further therapeutic option available for moderate to severe AD is memantine, an N-methyl-D-aspartate receptor noncompetitive antagonist. Treatments capable of stopping or at least effectively modifying the course of AD, referred to as ‘disease-modifying’ drugs, are still under extensive research. To block the progression of the disease they have to interfere with the pathogenic steps responsible for the clinical symptoms, including the deposition of extracellular amyloid β plaques and intracellular neurofibrillary tangle formation, inflammation, oxidative damage, iron deregulation and cholesterol metabolism. In this review we discuss current symptomatic treatments and new potential disease-modifying therapies for AD that are currently being studied in phase I-III trials.

Concepts: Alzheimer's disease, Medicine, Neurology, Dementia, Acetylcholine, Acetylcholinesterase inhibitor, Memantine, Donepezil

167

OBJECTIVE: The evaluation of visual acuity (VA) in cognitively impaired older individuals may be limited by a reduced ability to cooperate or communicate. The objective of this research was to assess VA in older institutionalized individuals with cognitive impairment, including severe dementia, using various acuity charts. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: Three groups of 30 participants each were recruited: (1) young participants; (2) older participants with no history of cognitive or communication disorders; and (3) older participants with cognitive impairment, including severe dementia, residing in long term care facilities. The Mini-Mental State Examination was performed for each institutionalized subject. VA was measured using 6 validated charts [Snellen, Teller cards, Early Treatment Diabetic Retinopathy Study (ETDRS)-letters, -numbers, -Patty Pics, -Tumbling Es] presented in random order. Nonparametric tests were used to compare VA scores between charts, after Bonferroni-Holm corrections for multiple comparisons. RESULTS: Participants in groups 1 and 2 responded to all charts. A large proportion of participants with dementia responded to all charts (n = 19), whereas only one did not respond to any chart. In group 3, VA charts with the lowest scores were the Teller cards (20/65) and Patty Pics (20/62), regardless of the level of dementia, whereas the highest VA scores were obtained with the Snellen (20/35) and ETDRS-letter (20/36) charts. Across all groups, the ETDRS-letter chart was the only one whose scores did not differ from those obtained with the standard Snellen chart. CONCLUSIONS: Visual acuity can be measured, and should at least be attempted, in older cognitively impaired individuals having a reduced ability to communicate.

Concepts: Dementia, Visual acuity, Ophthalmology, Diabetic retinopathy, Psychiatry, Snellen chart, Abbreviated mental test score, Charts