Neuroinflammation in Preclinical Alzheimer's Disease: A Review of Current Evidence

The pathology of sporadic Alzheimer’s disease (AD) may be present at mid-life and precede the prodromal and clinical dementia syndromes associated with the disorder by decades. Few successful therapeutic treatments exist and, as a result, attention is turning to the preclinical stages of the disease for the development of future intervention strategies. The success of such strategies will rely on well-defined biomarkers of preclinical disease to identify and monitor changes earlier in the disease course. Here, we consider whether immune function changes are potentially useful markers of preclinical disease. We have selected studies spanning epidemiological, animal, clinical and imaging research pertaining to the earliest stages of AD pathogenesis, as well as studies of non-demented adults at high AD risk. We examine changes in inflammatory markers, alongside changes in established biomarkers, to highlight their suitability as disease indicators across preclinical and prodromal stages. We conclude that further work surrounding this topic is required, calling for larger prospective epidemiological studies of preclinical disease that incorporate serial assessment designs with a wider range of inflammatory mediators. We anticipate that future benefits of work in this area include improved disease detection and modification, as well as diagnostic accuracy of trial participants, leading to more cost-effective observation and intervention studies

Alwyn Lishman’s contribution to the neuropsychiatry of head injury (traumatic brain injury); two key papers

Introduction Alwyn Lishman appreciated that if we are to understand the psychological consequences of cerebral disorder we must study the interaction between organic disease and psychological processes. Methods We have reviewed Lishman’s two major publications on the neuropsychiatry of head injury, published in 1968 and 1988, and considered their conclusions in the light of current knowledge. Results In his 1968 paper on the psychiatric sequelae of open head injuries sustained in World War II Lishman demonstrated associations between the type of psychiatric sequelae and the location of the injury. He also found that those with “somatic complaints”, such as fatigue or sensitivity to light, showed less evidence of organic injury. In his 1988 paper, he attempted to explain why a mild head injury may be followed by long-lasting symptoms. He suggested that in the absence of complications early, organic, symptoms (physiogenesis) should recover quickly. However, this healthy recovery could be jeopardised by psychological factors (psychogenesis), resulting in long-lasting symptoms. This model of physiogenesis and psychogenesis remains relevant today. Conclusions The ideas Lishman developed in these two papers were the basis for his huge contribution to the field of neuropsychiatry, and remain relevant today

Alzheimer's disease research: past approaches and future directions

Background: Three decades after the amyloid cascade hypothesis was first proposed, research into discovery of effective treatments for Alzheimer's disease has not yet produced any disease-modifying treatments.  Aims: This review outlines the progress made by dementia research thus far, and provides a brief overview of the therapeutic approaches resulting from the amyloid cascade hypothesis. It then describes the shift in research focus to the early stages of the condition, the challenges it presents and potential consequences for care.  Methods: A literature overview was undertaken by reviewing research papers, published protocols and policy guidelines.  Findings: Past research has failed to produce effective treatments for dementia, yet the causes of this failure remain debated. Discovery of affordable, early biomarkers has emerged as a key target of investigation as the focus has shifted from treatment to prevention of the condition.  Conclusions: Failures in identifying effective treatments for dementia have highlighted the importance of earlyidentification and intervention in patients as a way to prevent neurodegeneration and progression to dementia. Discovery of biomarkers is a key focus of current research. In the future, regular screening for dementia may be recommended for all older people in an effort to assess individual risk. Care may reflect a combination of early pharmacological interventions and lifestyle modification programmesbased on risk

Education is power: preserving cognition in the UK Biobank

Introduction: Dementia is a debilitating syndrome characterized by the gradual loss of memory and cognitive function. Although there are currently limited, largely symptomatic treatments for the diseases that can lead to dementia, its onset may be prevented by identifying and modifying relevant life style risk factors. Commonly described modifiable risk factors include diet, physical inactivity, and educational attainment. Importantly, however, to maximize the utility of our understanding of these risk factors, tangible and meaningful changes to policy must also be addressed. Objectives: Here, we aim to identify the mechanism(s) by which educational attainment influences cognition. Methods: We investigated data from 502,357 individuals (Mage = 56.53, SDage = 8.09, 54.40% female) from the UK Biobank cohort via Structural Equation Modelling to illustrate links between predictor variables (i.e., Townsend Deprivation Index, coastal distance, greenspace, years of education), covariates (i.e., participant age) and cognitive function as outcome variables (i.e., pairs-matching, trail-making task B, fluid intelligence). Results: Our model demonstrated that higher education was associated with better cognitive performance (ps  Conclusion: Accordingly, our model evinces the mediating effect of socioeconomic and environmental factors on the relationship between years of education and cognitive function. These results further demonstrate the utility and necessity of adapting public policy to encourage equitable access to education and other supports in deprived areas

Differential roles of polar orbital prefrontal cortex and parietal lobes in logical reasoning with neutral and negative emotional content

© 2018 The Authors To answer the question of how brain pathology affects reasoning about negative emotional content, we administered a disjunctive logical reasoning task involving arguments with neutral content (e.g. Either there are tigers or women in NYC, but not both; There are no tigers in NYC; There are women in NYC) and emotionally laden content (e.g. Either there are pedophiles or politicians in Texas, but not both; There are politicians in Texas; There are no pedophiles in Texas) to 92 neurological patients with focal lesions to various parts of the brain. A Voxel Lesion Symptom Mapping (VLSM) analysis identified 16 patients, all with lesions to the orbital polar prefrontal cortex (BA 10 & 11), as being selectively impaired in the emotional reasoning condition. Another 17 patients, all with lesions to the parietal cortex, were identified as being impaired in the neutral content condition. The reasoning scores of these two patient groups, along with 23 matched normal controls, underwent additional analysis to explore the effect of belief bias. This analysis revealed that the differences identified above were largely driven by trials where there was an incongruency between the believability of the conclusion and the validity of the argument (i.e. valid argument/false conclusion or invalid argument/true conclusion). Patients with lesions to polar orbital prefrontal cortex underperformed in incongruent emotional content trials and over performed in incongruent neutral content trials (compared to both normal controls and patients with parietal lobe lesions). Patients with lesions to parietal lobes underperformed normal controls (at a trend level) in neutral trials where there was a congruency between the believability of the conclusion and the validity of the argument (i.e. valid argument/true conclusion or invalid argument/false conclusion). We conclude that lesions to the polar orbital prefrontal cortex (i) prevent these patients from enjoying any emotionally induced cognitive boost, and (ii) block the belief bias processing route in the neutral condition. Lesions to parietal lobes result in a generalized impairment in logical reasoning with neutral content

Bilingualism: a global public health strategy for healthy cognitive aging

Dementia is a global public health priority which cost global societies $818 billion in 2015 and is disproportionately impacting low and middle-income countries (LMICs). With limited availability of disease modifying drugs to treat Alzheimer's disease (AD), researchers have increasingly focused on preventative strategies which may promote healthy cognitive aging and mitigate the risk of cognitive impairment in aging. Lifelong bilingualism has been presented as both a highly debated and promising cognitive reserve factor which has been associated with better cognitive outcomes in aging. A recent metanalysis has suggested that bilingual individuals present on average 4.05 years later with the clinical features of AD than monolinguals. Bilinguals are also diagnosed with AD ~2.0 years later than monolingual counterparts. In this perspective piece we critically evaluate the findings of this metanalysis and consider the specific implications of these findings to LMICs. Furthermore, we appraise the major epidemiological studies conducted globally on bilingualism and the onset of dementia. We consider how both impactful and robust studies of bilingualism and cognition in older age may be conducted in LMICs. Given the limited expenditure and resources available in LMICs and minimal successes of clinical trials of disease modifying drugs we propose that bilingualism should be positioned as an important and specific public health strategy for maintaining healthy cognitive aging in LMICs. Finally, we reflect upon the scope of implementing bilingualism within the education systems of LMICs and the promotion of bilingualism as a healthy cognitive aging initiative within government policy

Analysis of brain lesions associated with narrative discourse impairments following penetrating head injury.

Narrative discourse performance of two groups with penetrating head injuries, left- and right-hemisphere damaged, was examined and compared to that of a non-injured control group. Discourse deficits were then associated with lesion size and brain regions (Brodmann areas) included within lesion boundaries. Findings indicated that discourse impairments involving the organization of language and maintenance of a narrative theme result from large or relatively small lesions to either hemisphere. Although specific frontal and temporal regions within both hemispheres were most commonly implicated, parietal and limbic areas also appear to play a role in the production of narrative discourse

Lesions to Polar/Orbital Prefrontal Cortex Selectively Impair Reasoning about Emotional Material

While it is widely accepted that lesions to orbital prefrontal cortex lead to emotion related disruptions and poor decision-making, there is very little patient data on this issue involving actual logical reasoning tasks. We tested patients with circumscribed, focal lesions largely confined to polar/orbital prefrontal cortex (BA 10 and 11) (N=17) on logical reasoning tasks involving neutral and emotional content, and compared their performance to that of an age and education-matched normal control group (N=22) and a posterior lesion control group (N=24). Our results revealed a significant group by content interaction driven by a selective impairment in the polar/orbital prefrontal cortex group compared to healthy normal controls and to the parietal patient group, in the emotional content reasoning trials. Subsequent analyses of congruent and incongruent reasoning trials indicated that this impairment was driven by the poor performance of patients with polar/orbital lesions in the incongruent trials. We conclude that the polar/orbital prefrontal cortex plays a critical role in filtering emotionally charged content from the material before it is passed on to the reasoning system in lateral/dorsal regions of prefrontal cortex. Where unfiltered content is passed to the reasoning engine, either as a result of pathology (as in the case of our patients) or as a result of individual differences, reasoning performance suffers

Decision-making capacity for treatment in psychiatric and medical in-patients: Cross-sectional, comparative study

BackgroundIs the nature of decision-making capacity (DMC) for treatment significantly different in medical and psychiatric patients?AimsTo compare the abilities relevant to DMC for treatment in medical and psychiatric patients who are able to communicate a treatment choice.MethodA secondary analysis of two cross-sectional studies of consecutive admissions: 125 to a psychiatric hospital and 164 to a medical hospital. The MacArthur Competence Assessment Tool – Treatment and a clinical interview were used to assess decision-making abilities (understanding, appreciating and reasoning) and judgements of DMC. We limited analysis to patients able to express a choice about treatment and stratified the analysis by low and high understanding ability.ResultsMost people scoring low on understanding were judged to lack DMC and there was no difference by hospital (P=0.14). In both hospitals there were patients who were able to understand yet lacked DMC (39% psychiatric v. 13% medical in-patients, P&lt;0.001). Appreciation was a better ‘test’ of DMC in the psychiatric hospital (where psychotic and severe affective disorders predominated) (P&lt;0.001), whereas reasoning was a better test of DMC in the medical hospital (where cognitive impairment was common) (P=0.02).ConclusionsAmong those with good understanding, the appreciation ability had more salience to DMC for treatment in a psychiatric setting and the reasoning ability had more salience in a medical setting.</jats:sec

BDNF Polymorphism Predicts General Intelligence after Penetrating Traumatic Brain Injury

Neuronal plasticity is a fundamental factor in cognitive outcome following traumatic brain injury. Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, plays an important role in this process. While there are many ways to measure cognitive outcome, general cognitive intelligence is a strong predictor of everyday decision-making, occupational attainment, social mobility and job performance. Thus it is an excellent measure of cognitive outcome following traumatic brain injury (TBI). Although the importance of the single-nucleotide polymorphisms polymorphism on cognitive function has been previously addressed, its role in recovery of general intelligence following TBI is unknown. We genotyped male Caucasian Vietnam combat veterans with focal penetrating TBI (pTBI) (n = 109) and non-head injured controls (n = 38) for 7 BDNF single-nucleotide polymorphisms. Subjects were administrated the Armed Forces Qualification Test (AFQT) at three different time periods: pre-injury on induction into the military, Phase II (10–15 years post-injury, and Phase III (30–35 years post-injury). Two single-nucleotide polymorphisms, rs7124442 and rs1519480, were significantly associated with post-injury recovery of general cognitive intelligence with the most pronounced effect at the Phase II time point, indicating lesion-induced plasticity. The genotypes accounted for 5% of the variance of the AFQT scores, independently of other significant predictors such as pre-injury intelligence and percentage of brain volume loss. These data indicate that genetic variations in BDNF play a significant role in lesion-induced recovery following pTBI. Identifying the underlying mechanism of this brain-derived neurotrophic factor effect could provide insight into an important aspect of post-traumatic cognitive recovery