Suzanne Timmons

Defects in IGF-1 receptor, insulin receptor and IRS-1/2 in Alzheimer's disease indicate possible resistance to IGF-1 and insulin signalling

Insulin like growth factor-1 receptor (IGF-1R) and insulin receptor (IR) signalling control vital growth, survival and metabolic functions in the brain. Here we describe specific and significant alterations in IGF-1R, IR, and their key substrate adaptor proteins IRS-1 and IRS-2 in Alzheimers disease (AD). Western immunoblot analysis detected increased IGF-1R levels, and decreased levels of IGF-1-binding protein-2 (IGFBP-2), a major IGF-1-binding protein, in AD temporal cortex. Increased IGF-1R was observed surrounding and within amyloid-beta (Abeta)-containing plaques, also evident in an animal model of AD, and in astrocytes in AD. However, despite the overall increase in IGF-1R levels, a significantly lower number of neurons expressed IGF-1R in AD, and IGF-1R was aberrantly distributed in AD neurons especially evident in those with neurofibrillary tangles (NFTs). IR protein levels were similar in AD and control cases, however, the IR was concentrated intracellularly in AD neurons, unlike its distribution throughout the neuronal cell soma and in dendrites in control brain. Significant decreases in IRS-1 and IRS-2 levels were identified in AD neurons, in association with increased levels of inactivated phospho(Ser312)IRS-1 and phospho(Ser616)IRS-1, where increased levels of these phosphoserine epitopes colocalised strongly with NFTs. Our results show that IGF-1R and IR signalling is compromised in AD neurons and suggest that neurons that degenerate in AD may be resistant to IGF-1R/IR signalling.

Delirium in an adult acute hospital population: predictors, prevalence and detection

Background To date, delirium prevalence and incidence in acute hospitals has been estimated from pooled findings of studies performed in distinct patient populations. Objective To determine delirium prevalence across an acute care facility. Design A point prevalence study. Setting A large tertiary care, teaching hospital. Patients 311 general hospital adult inpatients were assessed over a single day. Of those, 280 had full data collected within the studys time frame (90%). Measurements Initial screening for inattention was performed using the spatial span forwards and months backwards tests by junior medical staff, followed by two independent formal delirium assessments: first the Confusion Assessment Method (CAM) by trained geriatric medicine consultants and registrars, and, subsequently, the Delirium Rating Scale-Revised-98 (DRS-R98) by experienced psychiatrists. The diagnosis of delirium was ultimately made using DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) criteria. Results Using DSM-IV criteria, 55 of 280 patients (19.6%) had delirium versus 17.6% using the CAM. Using the DRS-R98 total score for independent diagnosis, 20.7% had full delirium, and 8.6% had subsyndromal delirium. Prevalence was higher in older patients (4.7% if <50 years and 34.8% if >80 years) and particularly in those with prior dementia (OR=15.33, p<0.001), even when adjusted for potential confounders. Although 50.9% of delirious patients had pre-existing dementia, it was poorly documented in the medical notes. Delirium symptoms detected by medical notes, nurse interview and patient reports did not overlap much, with inattention noted by professional staff, and acute change and sleep-wake disturbance noted by patients. Conclusions Our point prevalence study confirms that delirium occurs in about 1/5 of general hospital inpatients and particularly in those with prior cognitive impairment. Recognition strategies may need to be tailored to the symptoms most noticed by the detector (patient, nurse or primary physician) if formal assessments are not available.

Akt signal transduction dysfunction in Parkinson's disease.

Significant attention has been drawn to the potential role of defective PI3-kinase-Akt (PKB) signalling in Parkinsons disease (PD) neurodegeneration and to the possibility that activation of Akt may provide neuroprotection in PD. However, little knowledge exists on the integrity of the Akt system in PD. Results of the present study show diminished levels of both total and active phospho(Ser473)-Akt in the brain in PD. This was evident by western blot analysis of midbrain fractions from PD compared to non-PD control brain, but more specifically by immunofluorescence microscopy of the substantia nigra pars compacta (SNpc). Here, double immunofluorescence microscopy found Akt and phospho(Ser473)-Akt to be expressed at high levels in tyrosine hydroxylase (TH) immunopositive dopaminergic neurons in control human brain. Selective loss of these neurons was accompanied by a marked decrease of Akt and phospho(Ser473)-Akt expression in the PD brain, however Akt and active phospho(Ser473)-Akt are still evident in degenerating dopaminergic neurons in the disease. This suggests that it may be possible to target neuronal Akt in advanced PD. Converse to the marked loss of neuronal Akt in PD, increased Akt and phospho(Ser473)-Akt levels were observed in small non-TH positive cells in PD SNpc, whose increased number and small nuclear size indicate they are glia. These findings implicate defective Akt as a putative signalling pathway linked to loss of dopaminergic neurons in PD.

Dementia in older people admitted to hospital: a regional multi-hospital observational study of prevalence, associations and case recognition

Background: previous studies have indicated a prevalence of dementia in older admissions of ∼42% in a single London teaching hospital, and 21% in four Queensland hospitals. However, there is a lack of published data from any European country on the prevalence of dementia across hospitals and between patient groups. Objective: to determine the prevalence and associations of dementia in older patients admitted to acute hospitals in Ireland. Methods: six hundred and six patients aged ≥70 years were recruited on admission to six hospitals in Cork County. Screening consisted of Standardised Mini-Mental State Examination (SMMSE); patients with scores <27/30 had further assessment with the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE). Final expert diagnosis was based on SMMSE, IQCODE and relevant medical and demographic history. Patients were screened for delirium and depression, and assessed for co-morbidity, functional ability and nutritional status. Results: of 598 older patients admitted to acute hospitals, 25% overall had dementia; with 29% in public hospitals. Prevalence varied between hospitals (P < 0.001); most common in rural hospitals and acute medical admissions. Only 35.6% of patients with dementia had a previous diagnosis. Patients with dementia were older and frailer, with higher co-morbidity, malnutrition and lower functional status (P < 0.001). Delirium was commonly superimposed on dementia (57%) on admission. Conclusion: dementia is common in older people admitted to acute hospitals, particularly in acute medical admissions, and rural hospitals, where services may be less available. Most dementia is not previously diagnosed, emphasising the necessity for cognitive assessment in older people on presentation to hospital.

Attention! A good bedside test for delirium?

Background Routine delirium screening could improve delirium detection, but it remains unclear as to which screening tool is most suitable. We tested the diagnostic accuracy of the following screening methods (either individually or in combination) in the detection of delirium: MOTYB (months of the year backwards); SSF (Spatial Span Forwards); evidence of subjective or objective ‘confusion’. Methods We performed a cross-sectional study of general hospital adult inpatients in a large tertiary referral hospital. Screening tests were performed by junior medical trainees. Subsequently, two independent formal delirium assessments were performed: first, the Confusion Assessment Method (CAM) followed by the Delirium Rating Scale-Revised 98 (DRS-R98). DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, fourth edition) criteria were used to assign delirium diagnosis. Sensitivity and specificity ratios with 95% CIs were calculated for each screening method. Results 265 patients were included. The most precise screening method overall was achieved by simultaneously performing MOTYB and assessing for subjective/objective confusion (sensitivity 93.8%, 95% CI 82.8 to 98.6; specificity 84.7%, 95% CI 79.2 to 89.2). In older patients, MOTYB alone was most accurate, whereas in younger patients, a simultaneous combination of SSF (cut-off 4) with either MOTYB or assessment of subjective/objective confusion was best. In every case, addition of the CAM as a second-line screening step to improve specificity resulted in considerable loss in sensitivity. Conclusions Our results suggest that simple attention tests may be useful in delirium screening. MOTYB used alone was the most accurate screening test in older people.

Delirium: A disturbance of circadian integrity?

Delirium is a serious neuropsychiatric syndrome of acute onset that occurs in approximately one in five general hospital patients and is associated with serious adverse outcomes that include loss of adaptive function, persistent cognitive problems and increased mortality. Recent studies indicate a three-domain model for delirium that includes generalised cognitive impairment, disturbed executive cognition, and disruption of behaviours that are under circadian control such as sleep-wake cycle and motor activity levels. As a consequence, attention has focused upon the possible role of the circadian timing system (CTS) in the pathophysiology of delirium. We explored this possibility by reviewing evidence that (1) many symptoms that occur in delirium are influenced by circadian rhythms, (2) many features of recognised circadian rhythm disorders are similar to characteristic features of delirium, (3) common risk factors for delirium are known to disrupt circadian systems, (4) physiological disturbances of circadian systems have been noted in delirious patients, and (5) positive effects in the treatment of delirium have been demonstrated for melatonin and related agents that influence the circadian timing system. A programme of future studies that can help to clarify the relevance of circadian integrity to delirium is described. Such work can provide a better understanding of the pathophysiology of delirium while also identifying opportunities for more targeted therapeutic efforts.

Comparison of the quick mild cognitive impairment (Qmci) screen and the SMMSE in screening for mild cognitive impairment.

Introduction: differentiating mild cognitive impairment (MCI) from normal cognition (NC) is difficult. The AB Cognitive Screen (ABCS) 135, sensitive in differentiating MCI from dementia, was modified to improve sensitivity and specificity, producing the quick mild cognitive impairment (Qmci) screen. Objective: this study compared the sensitivity and specificity of the Qmci with the Standardised MMSE and ABCS 135, to differentiate NC, MCI and dementia. Methods: weightings and subtests of the ABCS 135 were changed and a new section ‘logical memory’ added, creating the Qmci. From four memory clinics in Ontario, Canada, 335 subjects (154 with MCI, 181 with dementia) were recruited and underwent comprehensive assessment. Caregivers, attending with the subjects, without cognitive symptoms, were recruited as controls (n = 630). Results: the Qmci was more sensitive than the SMMSE and ABCS 135, in differentiating MCI from NC, with an area under the curve (AUC) of 0.86 compared with 0.67 and 0.83, respectively, and in differentiating MCI from mild dementia, AUC of 0.92 versus 0.91 and 0.91. The ability of the Qmci to identify MCI was better for those over 75 years. Conclusion: the Qmci is more sensitive than the SMMSE in differentiating MCI and NC, making it a useful test, for MCI in clinical practice, especially for older adults.

Screening for cognitive impairment in older general hospital patients: comparison of the six-item cognitive impairment test with the mini-mental state examination. A reply.

We read with interest the article by Tuijl et al. (Tuijl et al., 2011) and would support the use of the six-item cognitive impairment test (6CIT) screening test over the Mini-Mental State Examination (MMSE) (Folstein et al., 1975). It offers considerable advantage in its brevity and although the MMSE is one of the most widely used cognitive tests, variability in results limits its utility (Nieuwenhuis-Mark, 2010). Even though the standardised MMSE (sMMSE) was developed a decade ago to maximise inter-rater agreement by standardising the method of administration, its use is not widespread (Molloy et al., 1991). Apart from the often cited confounding effect of the patient’s education history on the MMSE score, we offer another example of a limitation of the MMSE in real-life assessment of patients with potential cognitive impairment. We recently surveyed a national sample of Irish health professionals to assess their scoring of the ‘spell WORLD backwards’ subtest in the MMSE, using eight sample responses. We distributed our survey to all consultants in geriatric medicine and psychiatry of old age in the Republic of Ireland, all specialist registrars in geriatric medicine and all occupational therapists in Ireland as well as a sample of general medicine consultants and non-consultant hospital doctors from a regional hospital. We asked the participants to indicate their age, professional grade and level of experience and training on the MMSE. We asked them to indicate what scoring method they used for the MMSE. Of 215 respondents, 32 were consultants in geriatric medicine (53% response rate), eight old age psychiatrists (40% response rate), 27 Specialist Registrars (SPRs) in geriatric medicine (64% response rate), 113 occupational therapists (56% response rate) and 19 from internal medicine (two consultants, three interns, five registrars and nine Senior House Officers (SHOs)). Median age was 34 years (Interquartile range (IQR): 29–42), 72% were female and had a median 8 years experience using MMSE (IQR: 4–12). Only 25 participants (12%) reported ever receiving training in the administration of the MMSE. One hundred and two stated they used Folstein scoring, 85 sMMSE, 12 stated they used another method (not specified) and 16 did not indicate a method. Only 55% of the responses were scored correctly according to the Folstein scoring system and 21% according to the sMMSE scoring. The percentage of correct responses in participants who stated they used the Folstein MMSE, applying the Folstein scoring system, was 55% and similarly the correct response rate using the MMSE scoring system was 23% for reported sMMSE users. The median score for all participants was four out of eight (IQR: 3–5) using the Folstein scoring and one out of eight (IQR: 1–2) using the sMMSE scoring, irrespective of what scoring method they used. There was no difference in the accuracy of scoring in those who stated they had received training for either method. Table 1 shows scores subdivided by the method used, if stated, for each occupation. Poor scoring is demonstrated across all groups especially in those who stated they used sMMSE scoring. Thus, considerable variation exists in the scoring of MMSE inattention subtest, and poor scoring is found among all groups surveyed including senior clinicians. A lack of formal training in the performing of the MMSE was identified by the responders (despite their frequent requirement to perform cognitive assessment in their everyday clinical practice) but reported training was not associated with better results. Particularly, poor results from the group who reported to use the sMMSE suggest a misunderstanding of the sMMSE scoring system. The similarity in the distributions of scores given by reported Folstein and sMMSE users also suggests some confusion among respondents regarding the appropriate scoring methods for each test. These findings highlight a further caveat in the interpretation of MMSE scores, in particular to differentiate between impaired or non-impaired patients. Thus, shorter cognitive screening tools, like

Frequency of delirium and subsyndromal delirium in an adult acute hospital population

Background The frequency of full syndromal and subsyndromal delirium is understudied. Aims We conducted a point prevalence study in a general hospital. Method Possible delirium identified by testing for inattention was evaluated regarding delirium status (full/subsyndromal delirium) using categorical (Confusion Assessment Method (CAM), DSM-IV) and dimensional (Delirium Rating Scale-Revised-98 (DRS-R98) scores) methods. Results In total 162 of 311 patients (52%) screened positive for inattention. Delirium was diagnosed in 55 patients (17.7%) using DSM-IV, 52 (16.7%) using CAM and 58 (18.6%) using DRS-R98⩾12 with concordance for 38 (12.2%) individuals. Subsyndromal delirium was identified in 24 patients (7.7%) using a DRS-R98 score of 7-11 and 41 (13.2%) using 2/4 CAM criteria. Subsyndromal delirium with inattention (v. without) had greater disturbance of multiple delirium symptoms. Conclusions The point prevalence of delirium and subsyndromal delirium was 25%. There was modest concordance between DRS-R98, DSM-IV and CAM delirium diagnoses. Inattention should be central to subsyndromal delirium definitions.

Factors influencing the successful completion of laparoscopic cholecystectomy.

This study found that advanced age, presentation with acute cholecystitis, and choledocholithiasis are independent risk factors for conversion from laparoscopic to open cholecystectomy.