The use of wide-scale mental agility testing to identify people at risk of dementia: crucial or harmful?

The prevalence of dementia in the UK is rising rapidly and is predicted to double over the next 30 years. The NHS in England has been told to push for a rapid rise in dementia diagnosis rates, so that by 2015, two out of three cases are identified. The Prime Minister has raised the 'dementia challenge' as a priority for the NHS. While there is agreement on the need for action, debate arises over the nature of that intervention. Some, including Professor Alessi, argue that tools exist to support the diagnosis of mild cognitive impairment and they should be used because the disease is amenable to interventions. He believes that we need a shift in knowledge and attitude from thresholds to a continuum of cognitive impairment, from late to early stages and from effects to causes. The Montreal Cognitive Assessment (MoCa) should become part of the routine NHS Health Check after people reach age 40. Dr Fox argues on the other hand that widespread testing could lead to unnecessary anxiety and panic among those at risk and that funding should be focused on learning more about the early stages of dementia. While the concept of early testing is appealing, there is a large knowledge gap; instruments in use have not been tested in pre-dementia patients and have limited validity. While there is debate over the approach, we can agree that the economic and social impacts of this condition need to be addressed sooner rather than later.

Acute stroke with hyperdense middle cerebral artery sign benefits from IV rtPA.

OBJECTIVES: The current management of acute ischemic stroke is intravenous (IV) recombinant tissue plasminogen activator (rtPA). The presence of a hyperdense middle cerebral artery sign (HMCAS) on pre-treatment head computed tomogram (CT) is considered a poor prognostic sign. We compared the clinical outcome in IV rtPA-treated patients with and without a HMCAS. DESIGN: Retrospective analysis of prospectively collected cases treated with IV rtPA within three hours. Inclusion criteria were the presence of: i) an anterior circulation stroke; ii) a pre-treatment CT available; iii) a pre-treatment National Institutes of Health (NIH) stroke scale (NIHSS) score; and iv) a modified Rankin Score (mRS) at three months. RESULTS: One hundred and thirty patients were eligible for the analysis, 64 (49%) had a HMCAS. The HMCAS group had a trend toward a higher mean (+/-SD) pre-treatment NIHSS score compared to the non-HMCAS group (13.9+/-6 vs. 12.2+/-6; p=0.12). Accordingly, there were more patients with severe strokes (NIHSS>10) in the HMCAS group compared to the non-HMCAS one (48/64=75% vs. 35/66=53%; p=0.009). The mean (+/-SD) NIHSS score 24 hours after treatment was 10.6 (+/-8) in the HMCAS group and 8.3 (+/-7) in the non-HMCAS group (p=0.08). In a multiple logistic regression analysis, the only independent predictor of poor outcome (mRS 3-6) was pre-treatment NIHSS score (p<0.001). CONCLUSION: Patients with a HMCAS receiving IV rtPA did not fare worse at three months despite a greater proportion of patients with more severe strokes. Based on the current knowledge, IV rtPA remains a good treatment for patients with a HMCAS within three hours of symptom onset.

Joint effect of stroke and APOE 4 on dementia risk: the Canadian Study of Health and Aging.

BACKGROUND: Although stroke and APOE 4 are independent risk factors for dementia, their combined effect remains uncertain. We assessed their joint effect on dementia risk. METHODS: Subjects participated in Phases 1 and 2 of the Canadian Study of Health and Aging (CSHA). Dementia was diagnosed by consensus, and stroke was diagnosed by history or clinical examination. Analyses were first conducted among clinical participants only, and then rerun with the screening sample included as well. RESULTS: Analyses included 949 participants from CSHA-1 and 1,413 from CSHA-2. During a median 4.6-year follow-up, 740 were included in the CSHA-1 to -2 incidence study. Among clinical participants, the highest prevalence (40.6% for CSHA-1 and 57.6% for CSHA-2) and incidence (8.4 per 100 person-years) of dementia occurred in elderly having both stroke and APOE 4; the lowest prevalence (19.8% for CSHA-1 and 23.3% for CSHA-2) and incidence (4.3 per 100 person-years) were among persons having neither. These findings held true when the screening sample was included. The adjusted hazard ratios of incident dementia, relative to elderly with neither stroke nor APOE 4, were 1.33 (95% CI 0.73 to 2.43) for stroke alone, 2.06 (95% CI 1.42 to 2.99) for APOE 4 alone, and 2.57 (95% CI 1.11 to 5.94) for both. No interaction on additive or multiplicative scales was suggested. CONCLUSIONS: The joint presence of stroke and APOE 4 was associated with a greater risk of dementia compared with absence of these two factors. The effect of stroke on dementia does not seem to be modified by APOE 4.

Hospital volume and stroke outcome: does it matter?

BACKGROUND: Although hospital-outcome relationships have been explored for a variety of procedures and interventions, little is known about the association between annual stroke admission volumes and stroke mortality. Our aim was to determine whether facility type and hospital volume was associated with stroke mortality. METHODS: All hospital admissions for ischemic stroke were identified from the Hospital Morbidity database (HMDB) from April 2003 to March 2004. The HMDB is a national database that contains patient-level sociodemographic, diagnostic, procedural, and administrative information across Canada. Ischemic stroke was identified through patient's principal diagnosis recorded using the International Classification of Diseases (9 and 10). Multivariable analysis was performed with generalized estimating equations with adjustment for demographic characteristics, provider specialty, facility type, hospital volume, and clustering of observations at institutions. RESULTS: Overall, 26,676 patients with ischemic stroke were admitted to 606 hospitals. Seven-day stroke mortality was 7.6% and mortality at discharge was 15.6%. Adverse outcomes were more frequent in patients treated in low-volume facilities (<50 strokes/year) than in those treated in high volume facilities (100 to 199 and >200 strokes patients/year) (for 7-day mortality: 9.5 vs 7.3%, p < 0.001; 9.5 vs 6.0%, p < 0.001; for discharge mortality: 18.2 vs 15.2%, p < 0.001; 18.2 vs 12.8%, p < 0.001). The difference persisted after multivariable adjustment or when hospital volume was divided into quartiles. CONCLUSIONS: High annual hospital volume was consistently associated with lower stroke mortality. Our study encourages further research to determine whether this is due to differences in case mix, more organized care in high-volume facilities, or differences in the performance or in the processes of care among facilities.

Identification of penumbra and infarct in acute ischemic stroke using computed tomography perfusion-derived blood flow and blood volume measurements.

BACKGROUND AND PURPOSE: We investigated whether computed tomography (CT) perfusion-derived cerebral blood flow (CBF) and cerebral blood volume (CBV) could be used to differentiate between penumbra and infarcted gray matter in a limited, exploratory sample of acute stroke patients. METHODS: Thirty patients underwent a noncontrast CT (NCCT), CT angiography (CTA), and CT perfusion (CTP) scan within 7 hours of stroke onset, NCCT and CTA at 24 hours, and NCCT at 5 to 7 days. Twenty-five patients met the criteria for inclusion and were subsequently divided into 2 groups: those with recanalization at 24 hours (n=16) and those without (n=9). Penumbra was operationally defined as tissue with an admission CBF <25 mL x 100 g(-1) x min(-1) that was not infarcted on the 5- to 7-day NCCT. Logistic regression was applied to differentiate between infarct and penumbra data points. RESULTS: For recanalized patients, CBF was significantly lower (P<0.05) for infarct (13.3+/-3.75 mL x 100 g(-1) x min(-1)) than penumbra (25.0+/-3.82 mL x 100 g(-1) x min(-1)). CBV in the penumbra (2.15+/-0.43 mL x 100 g(-1)) was significantly higher than contralateral (1.78+/-0.30 mL x 100 g(-1)) and infarcted tissue (1.12+/-0.37 mL x 100 g(-1)). Logistic regression using an interaction term (CBFxCBV) resulted in sensitivity, specificity, and accuracy of 97.0%, 97.2%, and 97.1%, respectively. The interaction term resulted in a significantly better (P<0.05) fit than CBF or CBV alone, suggesting that the CBV threshold for infarction varies with CBF. For patients without recanalization, CBF and CBV for infarcted regions were 15.1+/-5.67 mL x 100 g(-1) x min(-1) and 1.17+/-0.41 mL x 100 g(-1), respectively. CONCLUSIONS: We have shown in a limited sample of patients that CBF and CBV obtained from CTP can be sensitive and specific for infarction and should be investigated further in a prospective trial to assess their utility for differentiating between infarct and penumbra.

[Dementia and stroke: the importance of coexisting brain pathologies]. / Demencia e ictus: la importancia de la patologia cerebral coexistente.

AIM: In this paper we present evidence to support the idea that vascular and degenerative pathological processes interact synergically in the genesis of post stroke dementia. METHOD: Characteristics of vascular lesions have been identified that are linked to the development of a clinical picture of dementia. Yet, the characteristics of the brain in which infarction or brain haemorrhage occur are equally important. Recent (clinical, epidemiological and neuropathological) studies highlight the high frequency with which neurodegenerative and vascular processes coexist in the same brain, and the fact that both processes share environmental and genetic risk factors. The diagnostic criteria currently in use consider the existence of a vascular pathology as being an exclusion criterion for the diagnosis of an Alzheimer type dementia, and thus rule out the possibility of studying the interaction between the two processes. Instead of restrictive criteria, pragmatic instruments must be used to classify the possible aetiology in these patients. CONCLUSIONS: It is important to study the coexistence of vascular and degenerative pathologies in the brains of patients with a post stroke deterioration. Proving the existence of a synergic relation between the two processes would open up the possibility of performing an operation to prevent and treat the dementia displayed by these patients.

Profiles of cognitive decline in Alzheimer disease.

Most recent studies have used only two observations to estimate the rate of cognitive decline in patients with Alzheimer disease (AD); few have data taken from more than a 2-year period; and none report on autopsy-verified cases. Repeated observations over the complete course of the disease are necessary to quantitatively evaluate hypotheses such as the triphasic linear model of Brooks et al. (1993). The goal of this study is to compare the triphasic linear and quadratic models of decline in a group of 12 AD patients confirmed at autopsy with a group of age- and sex-matched normal control subjects. Both groups were taken from the University of Western Ontario Dementia Study, and the Extended Scale for Dementia was used as the outcome measure. The squared multiple correlation as a measure of goodness of fit suggested the superiority of the more parsimonious quadratic model over the triphasic linear model. Quantitative models more accurately reflect the profiles of change in AD and may prove more sensitive in measuring the effects of drugs on these patterns.

Reporting clinical trials: full access to all the data.

Authors' right to access to all data obtained in their study

Connexin43 null mutation increases infarct size after stroke.

Glial-neuronal interactions have been implicated in both normal information processing and neuroprotection. One pathway of cellular interactions involves gap junctional intercellular communication (GJIC). In astrocytes, gap junctions are composed primarily of the channel protein connexin43 (Cx43) and provide a substrate for formation of a functional syncytium implicated in the spatial buffering capacity of astrocytes. To study the function of gap junctions in the brain, we used heterozygous Cx43 null mice, which exhibit reduced Cx43 expression. Western blot analysis showed a reduction in the level of Cx43 protein and GJIC in astrocytes cultured from heterozygote mice. The level of Cx43 is reduced in the adult heterozygote cerebrum to 40% of that present in the wild-type. To assess the effect of reduced Cx43 and GJIC on neuroprotection, we examined brain infarct volume in wild-type and heterozygote mice after focal ischemia. In our model of focal stroke, the middle cerebral artery was occluded at two points, above and below the rhinal fissure. Four days after surgery, mice were killed, the brains were sectioned and analyzed. Cx43 heterozygous null mice exhibited a significantly larger infarct volume compared with wild-type (14.4 +/- 1.4 mm(3) vs. 7.7 +/- 0.82 mm(3), P < 0.002). These results suggest that augmentation of GJIC in astrocytes may contribute to neuroprotection after ischemic injury.

Progression of impairment in patients with vascular cognitive impairment without dementia.

Little is known about progression, short of dementia, in vascular cognitive impairment. In the Canadian Study of Health and Aging, 149 participants (79.3 +/- 6.7 years; 61% women) were found to have vascular cognitive impairment, no dementia (CIND). After 5 years, 77 participants (52%) had died and 58 (46%) had developed dementia. Women were at greater risk of dementia (OR 2.1, 1.0 to 4.5). Of 32 participants alive without dementia, cognition had deteriorated in seven and improved in four. Half of those with vascular CIND developed dementia within 5 years, suggesting a target for preventive interventions.

Improved outcomes in stroke thrombolysis with pre-specified imaging criteria.

BACKGROUND: A 1995 National Institute of Neurological Disorders (NINDS) study found benefit for intravenous tissue plasminogen activator (tPA) in acute ischemic stroke (AIS). The symptomatic intracranial hemorrhage (SICH) rate in the NINDS study was 6.4%, which may be deterring some physicians from using this medication. METHODS: Starting December 1, 1998, patients with AIS in London, Ontario were treated according to NINDS criteria with one major exception; those with approximately greater than one-third involvement of the idealized middle cerebral artery (MCA) territory on neuroimaging were excluded from treatment. The method used to estimate involvement of one-third MCA territory involvement bears the acronym ICE and had a median kappa value of 0.80 among five physicians. Outcomes were compared to the NINDS study. RESULTS: Between December 1, 1998 and February 1, 2000, 30 patients were treated. Compared to the NINDS study, more London patients were treated after 90 minutes (p<0.00001) and tended to be older. No SICH was observed. Compared to the treated arm of the NINDS trial, fewer London patients were dead or severely disabled at three months (p=0.04). Compared to the placebo arm of the trial, more patients made a partial recovery at 24 hours (p=0.02), more had normal outcomes (p=0.03) and fewer were dead or severely disabled at three months (p=0.004). CONCLUSIONS: The results of the NINDS study were closely replicated and, in some instances, improved upon in this small series of Canadian patients, despite older are and later treatment. These findings suggest that imaging exclusion criteria may optimize the benefits of tPA.

Clinical and pathologic features of two groups of patients with dementia with Lewy bodies: effect of coexisting Alzheimer-type lesion load.

The objectives of this study were to examine the clinical and pathologic features of two subgroups of patients with dementia with Lewy bodies (DLB) differing in Alzheimer disease (AD)-type pathology load and to identify clinical variables useful in the differential diagnosis from AD. The records of 64 consecutive demented patients were reviewed. Pathologic diagnoses were independently established [35 AD cases, 11 cases of pure dementia with Lewy bodies (pDLB), and 18 cases of combined AD plus Lewy bodies (AD+LB)], and several neurodegenerative lesions were quantified. Clinical and pathologic data were compared between groups with univariate and multivariate analyses. Compared with the other groups, pDLB cases had more frequent acute-subacute onset of dementia [45% vs. AD (3%) and AD+LB (16%)], early parkinsonism [45% vs. AD (0%) and AD+LB (0%)], early [27% vs. AD (0%) and AD+LB (0%)] and late [73% vs. AD (11%) and AD+LB (16%)] hallucinations, fluctuating course [46% vs. AD (9%) and AD+LB (22%)], delusions [45% vs. AD (11%) and AD+LB (6%)], spontaneous parkinsonism [63% vs. AD (8%) and AD+LB (16%)], less frequent ideomotor apraxia and loss of insight, earlier urinary incontinence [3.2 +/- 1.4 years after onset vs. AD (6.3 years) and AD+LB (5.8 years)], shorter duration of dementia [7.7 +/- 2.4 years vs. AD (9.6 years) and AD+LB (11 years)], milder atrophy in computed tomography scans, greater brain weight, more transcortical spongiosis, wider cortex and subcortex, and less amyloid angiopathy. All pDLB cases but no AD cases had abnormal CA2 neurites. The clinical features of AD+LB patients were similar to those of AD patients other than more frequent acute-subacute onset and fluctuating evolution. Discriminant analyses selected four clinical variables differentiating pDLB from the other two groups as a whole: acute-subacute onset, early parkinsonism, early hallucinations, and early onset of urinary incontinence. Two or more of these features identified pDLB with a sensitivity of 81.8% and a specificity of 95.9%. Differentiation between the three groups (pDLB, AD+LB, and AD) or between both groups with LB (DLB) from AD could be only attained in 70% of cases. We conclude that early symptomatology is the main clue for the diagnosis of pDLB. We identified by discriminant analysis a set of clinical diagnostic criteria similar to those proposed by the Consortium on Dementia With Lewy Bodies. Accuracy was excellent for the diagnosis of pDLB but only mediocre for separating AD+LB as well as the entire DLB group from AD.