Intake of polyunsaturated fatty acids and vitamin E reduces the risk of developing amyotrophic lateral sclerosis

Background

To assess whether the premorbid dietary intake of fatty acids, cholesterol, glutamate or antioxidants was associated with the risk of developing amyotrophic lateral sclerosis (ALS).

Methods

Patients referred to our clinic during 2001–2002, who had definite, probable or possible ALS according to El Escorial criteria, without a familial history of ALS, were asked to participate in a case–control study (132 patients and 220 healthy controls). A food‐frequency questionnaire was used to assess dietary intake for the nutrients of interest. Multivariate logistic regression analysis was performed with adjustment for confounding factors (sex, age, level of education, energy intake, body mass index and smoking).

Results

A high intake of polyunsaturated fatty acid (PUFA) and vitamin E was significantly associated with a reduced risk of developing ALS (PUFA: odds ratio (OR) = 0.4, 95% confidence interval (CI) = 0.2 to 0.7, p = 0.001; vitamin E: OR = 0.4, 95% CI = 0.2 to 0.7, p = 0.001). PUFA and vitamin E appeared to act synergistically, because in a combined analysis the trend OR for vitamin E was further reduced from 0.67 to 0.37 (p = 0.02), and that for PUFA from 0.60 to 0.26 (p = 0.005), with a significant interaction term (p = 0.03). The intake of flavonols, lycopene, vitamin C, vitamin B₂, glutamate, calcium or phytoestrogens was not associated with the risk of developing ALS.

Conclusion

A high intake of PUFAs and vitamin E is associated with a 50–60% decreased risk of developing ALS, and these nutrients appear to act synergistically.Sporadic amyotrophic lateral sclerosis (ALS) probably develops through the combined effects of several modifying genes and environmental factors.¹ Despite several studies that investigated environmental exposures in relation to ALS, age, gender and smoking are the only established risk factors.² Several, not mutually exclusive, pathological processes may contribute to motor neurone death in ALS in a so‐called convergence model,³ including oxidative stress, mitochondrial dysfunction, protein misfolding, axonal strangulation, apoptosis, inflammation, glutamate excitotoxicity and defects in neurotrophin biology. Nutrients are factors that could influence these processes and thereby the risk of developing ALS or its clinical expression.ALS was previously found to be positively associated with intake of glutamate,⁴ fat,⁴ fish⁵ and milk,^6,7 and inversely associated with intake of lycopene,⁸ dietary fibre,⁴ bread and pasta.⁹ Two other studies, however, failed to establish the relationship with milk.^10,11 Several of these studies included only small samples of patients (<25),^5,6,9 or investigated nutrition as one of many environmental factors, thus increasing the likelihood of chance findings.^{5,6,7,9,10,11} Furthermore, most studies did not account for the possible influence of clinical onset preceding the diagnosis^{5,6,7,8,9,10,11} or adjust for possible confounders including total energy intake, body mass index (BMI), sex, smoking and education.^{5,6,7,9,10,11}One study found an association between intake of total fat and ALS, although this was not hypothesised beforehand.⁴ This finding is of interest considering the observed associations of intake of saturated and unsaturated fatty acids and cholesterol with other neurodegenerative diseases.¹² In this case–control study, therefore, we examined the possible association between premorbid dietary intake of fatty acids, cholesterol, glutamate, phytoestrogens, calcium and anti‐oxidants and the risk of developing ALS, adjusting for confounding factors.     

Carotid body autotransplantation in Parkinson disease: a clinical and positron emission tomography study

Background

Carotid body (CB) glomus cells are highly dopaminergic and express the glial cell line derived neurotrophic factor. The intrastriatal grafting of CB cell aggregates exerts neurotrophic actions on nigrostriatal neurons in animal models of Parkinson disease (PD).

Objective

We conducted a phase I–II clinical study to assess the feasibility, long term safety, clinical and neurochemical effects of intrastriatal CB autotransplantation in patients with PD.

Methods

Thirteen patients with advanced PD underwent bilateral stereotactic implantation of CB cell aggregates into the striatum. They were assessed before surgery and up to 1–3 years after surgery according to CAPIT (Core Assessment Programme for Intracerebral Transplantation) and CAPSIT‐PD (Core Assessment Programme for Surgical Interventional Therapies in Parkinson''s Disease) protocols. The primary outcome measure was the change in video blinded Unified Parkinson''s Disease Rating Scale III score in the off‐medication state. Seven patients had ¹⁸F‐dopa positron emission tomography scans before and 1 year after transplantation.

Results

Clinical amelioration in the primary outcome measure was observed in 10 of 12 blindly analysed patients, which was maximal at 6–12 months after transplantation (5–74%). Overall, mean improvement at 6 months was 23%. In the long term (3 years), 3 of 6 patients still maintained improvement (15–48%). None of the patients developed off‐period dyskinesias. The main predictive factors for motor improvement were the histological integrity of the CB and a milder disease severity. We observed a non‐significant 5% increase in mean putaminal ¹⁸F‐dopa uptake but there was an inverse relationship between clinical amelioration and annual decline in putaminal ¹⁸F‐dopa uptake (r = −0.829; p = 0.042).

Conclusions

CB autotransplantation may induce clinical effects in patients with advanced PD which seem partly related to the biological properties of the implanted glomus cells.Parkinson disease (PD) is a progressive neurodegenerative disorder of unknown aetiology. Its main pathological hallmark is the degeneration of midbrain dopaminergic neurons projecting to the striatum, although other neuronal systems are also affected.¹ Current pharmacological and surgical therapies are symptomatically effective but their long term utility is limited because of disease progression.^2,3 Therefore, there is a need for neuroprotective and/or neurorestorative therapies capable of arresting or reversing the neurodegenerative process.Over the past two decades, cell replacement therapies have been tested in PD patients with the objective of restoring the striatal dopaminergic deficit.⁴ Transplantation of fetal mesencephalic neurons, the most frequently used technique, can increase the striatal dopamine storage, but does not always produce the expected clinical benefit and may induce disabling off‐medication dyskinesias.^5,6 Thus it appears that the ectopic placement of dopamine secreting cells in the striatum is not the ideal approach to compensate for progressive nigrostriatal neuronal loss.⁷ Given this scenario, the clinical applicability of other transplantation procedures based on a similar rationale (eg, intrastriatal grafting of porcine mesencephalic neurons, retinal pigment epithelial cells or stem cell derived dopaminergic neurons) is, for the moment, uncertain.More recently, other strategies aiming to protect or restore the nigrostriatal pathway have emerged. Glial cell line derived neurotrophic factor (GDNF) has been shown to exert neuroprotective and neurorestorative actions in animal models of PD.^8,9,10 The clinical efficacy of GDNF has been assayed in clinical trials, but the method of delivery is a critical issue. Whereas intraventricular administration failed to induce clinical benefit,¹¹ intraputaminal infusion showed promising results,^12,13 although a placebo controlled trial using this route has been halted because of lack of efficacy and safety concerns about recombinant human GDNF administration.¹⁴ Other alternative methods being tested experimentally in parkinsonian animals include in vivo gene therapy using GDNF encoding viral vectors^15,16,17 and the intrastriatal grafting of recombinant GDNF producing cell lines.^18,19,20,21 Carotid body (CB) glomus cells are neural crest derived dopaminergic cells that express high levels of GDNF. Glomus cell GDNF production is resistant to 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine administration, and maintained in aged rodents or after intrastriatal grafting.^22,23 The survival rate of these cells after transplantation (>70%) is particularly high as hypoxia stimulates their growth and function. Moreover, CB grafts performed in young rats remain active for the entire animal lifespan.^22,23 Transplantation of CB cell aggregates has been shown to induce a neurotrophic mediated recovery in animal models of PD^{22,23,24,25,26,27} and stroke.^28,29We conducted a phase I–II video blinded clinical study to assess the long term safety, clinical and neurochemical effects of intrastriatal CB autotransplantation in patients with advanced PD. In a pilot report of our first six patients, we showed this procedure to be feasible.³⁰ Here we report the clinical outcomes and prognostic factors in the whole study (n = 13), as well as ¹⁸F‐dopa positron emission tomography (PET) outcomes in a subgroup of patients (n = 7).     

Co-occurrence of affective and schizophrenia spectrum disorders with PINK1 mutations

Objective

To investigate a possible association of mutations in the PTEN‐induced putative kinase 1 (PINK1) gene with psychiatric disorders in a large family with monogenic parkinsonism.

Method

20 members of a family (4 homozygous, 11 heterozygous and 5 non‐mutation carriers) were investigated for the presence of psychiatric disorders using the structured clinical interview for Diagnostic and Statistical Manual of Mental Disorders, 4^th edition (DSM‐IV); information on three additional heterozygous mutation carriers was obtained according to the family history research diagnostic criteria.

Results

We found predominantly affective and schizophrenia spectrum disorders in 11 (61%) of the 18 mutation carriers and in 1 (20%) of the 5 mutation‐negative cases.

Conclusions

First, affective and psychotic symptoms may be part of the phenotypic spectrum or even the sole manifestation of PINK1 mutations. Second, patients with familial movement disorders associated with psychiatric conditions may serve as a valuable study population to explore (genetic) causes of neuropsychiatric disease.In patients with Parkinson''s disease (PD), a wide range of psychiatric disorders has been described including depression (20–50%),¹ psychosis (15–40%),^2,3 anxiety disorder (20–40%) and cognitive impairment (20%).² Psychiatric disorders may be the first or even the only manifestation in carriers of Parkin gene mutations, the most‐frequent known cause of early‐onset parkinsonism (EOP).⁴ Likewise, psychiatric problems have been reported in patients and their motor‐asymptomatic relatives with mutations in the recently detected PTEN‐induced kinase 1 (PINK1) gene, the second‐commonest cause of EOP.^5,6,7,8,9Two homozygous mutations in the PINK1 gene were initially described in three consanguineous families with EOP.⁶ The frequency of PINK1 mutations ranges from 1% to 8% in patients with PD of different ethnicities who are often selected for young age of onset and for family history (for review see Klein and Schlossmacher¹⁰). Most of the currently described mutations are localised near or within the functional serine/threonine kinase domain of PINK1 and are expected to result in a loss‐of‐function effect in vivo. Wild‐type PINK1 functions as a protein kinase that is mainly located within the mitochondria.Although PINK1‐associated parkinsonism is generally considered an autosomal recessive condition, a growing body of evidence has been accumulating that supports the notion of a single heterozygous mutation conferring disease susceptibility in at least a subset of patients.^6,8,9,10,11Currently, no studies have systematically assessed psychiatric symptoms in monogenic EOP. To investigate this possible association, we evaluated a large family with EOP with PINK1 mutations for the presence of psychiatric disorders.     

Influence of cognitive impairment on the institutionalisation rate 3 years after a stroke

Background and purpose

Pre‐existing cognitive decline and new‐onset dementia are common in patients with stroke, but their influence on institutionalisation rates is unknown.

Objective

To evaluate the influence of cognitive impairment on the institutionalisation rate 3 years after a stroke.

Design

(1) The previous cognitive state of 192 consecutive patients with stroke living at home before the stroke (with the Informant Questionnaire on COgnitive Decline in the Elderly (IQCODE)), (2) new‐onset dementia occurring within 3 years and (3) institutionalisation rates within 3 years in the 165 patients who were discharged alive after the acute stage were prospectively evaluated.

Results

Independent predictors of institutionalisation over a 3‐year period that were available at admission were age (adjusted odds ratio (adjOR) for 1‐year increase  = 1.08; 95% confidence interval (CI) 1.03 to 1.15), severity of the neurological deficit (adjOR for 1‐point increase in Orgogozo score = 0.97; 95% CI 0.96 to 0.99) and severity of cognitive impairment (adjOR for 1‐point increase in IQCODE score = 1.03; 95% CI 1 to 1.06). Factors associated with institutionalisation at 3 years that were present at admission or occurred during the follow‐up were age (adjOR for 1‐year increase = 1.17; 95% CI 1.07 to 1.27) and any (pre‐existing or new) dementia (adjOR = 5.85; 95% CI 1.59 to 21.59), but not the severity of the deficit of the neurological deficit.

Conclusion

Age and cognitive impairment are more important predictors of institutionalisation 3 years after a stroke than the severity of the physical disability.Institutionalisation after a stroke increases with the severity of the neurological deficit, increasing age, female gender, low socioeconomic level, marital status and poor social environment.^1,2,3,4,5,6Dementia is common after a stroke,⁷ leading to autonomy loss.⁸ Pre‐existing dementia is present in up to 16% of patients with stroke,^9,10,11,12 and post‐stroke de mentia (PSD) occurs in up to one third.⁷ Several studies have found a link between cognitive impairment and institutionalisation after a stroke,^1,2,3,4,5 but they had several methodological limitations: (1) cross‐sectional studies were performed in long‐term stroke survivors and did not take into account patients who had been institutionalised but died before the study⁶; (2) there was no systematic cognitive assessment¹³ or only a Mini Mental State Examination,¹⁴ which is not appropriate for patients with stroke; and (3) most studies included only patients recruited in rehabilitation centres, leading to selection bias.^1,2,3,4,5 To our knowledge, no study has prospectively evaluated the influence of pre‐existing cognitive impairment and PSD on the institutionalisation rate after a stroke.The aim of this study was to evaluate the influence of the previous cognitive state and new‐onset dementia on the institutionalisation rate 3 years after a stroke.     

Changes in optic nerve head blood flow in children with cerebral malaria and acute papilloedema

Objective

To investigate capillary blood flow in the optic nerve head (ONH) of children with cerebral malaria.

Methods

Malawian children with cerebral malaria admitted to a paediatric research ward were examined by direct and indirect ophthalmoscopy. ONH blood flow was measured using laser Doppler flowmetry (LDF) in suitable patients. Mean blood volume and velocity were obtained from 30 to 60 s recordings from the temporal ONH and used to calculate blood flow. These were compared with admission variables, funduscopic findings and disease outcomes.

Results

45 children with cerebral malaria had LDF recordings; 6 subsequently died and 5 survivors had neurological sequelae. 12 (27%) had papilloedema. The mean microvascular blood volume was higher in patients with papilloedema (3.28 v 2.54 arbitrary units, p = 0.002). The blood velocity correlated directly with haematocrit (r = 0.46, p = 0.001) and inversely with blood glucose (r = −0.49, p = 0.001).

Conclusion

The increase in ONH microvascular blood volume in papilloedema measured by LDF is consistent with current theories of pathogenesis of papilloedema. LDF has potential as a tool to distinguish papilloedema from pseudopapilloedematous disc swellings. The relationship between blood velocity and haematocrit may relate to levels of sequestration in cerebral malaria.Cerebral malaria, caused by Plasmodium falciparum, primarily affects children in sub‐Saharan Africa with mortality ranging from 15% to 50%. The characteristic histological feature of malaria caused by P falciparum is sequestration of parasitised erythrocytes within the microvasculature by cytoadherence. This occurs in the brain^1,2,3 and other organs, including the retina.⁴ Sequestration in small vessels is implicated in the pathogenesis of coma in cerebral malaria, although the mechanism remains unclear.⁵Papilloedema occurs in 10–15% of patients with cerebral malaria, increasing the risk of death by 4.5‐fold.^6,7 Other ocular fundus features associated with cerebral malaria are retinal whitening, orange or white vessels, and retinal haemorrhage.^6,7,8,9 As in other neurological conditions, papilloedema is associated with raised intracranial pressure.⁵ The pathogenesis of papilloedema is associated with increased pressure within the optic nerve sheath, a compartment in contact with the subarachnoid space. This leads to interruption of axoplasmic flow in the optic nerve fibres, resulting in swelling of their prelaminar portion.^10,11 The exact mechanism of this restriction and the importance of vascular changes remain unclear.¹²The optic nerve head (ONH) is an accessible element of the central nervous system (CNS), and measuring blood flow in the ONH could illuminate the pathogenic mechanisms in cerebral malaria. Laser Doppler flowmetry (LDF) is a non‐invasive method of measuring blood flow in the ONH using the Doppler shift in laser light scattered by moving erythrocytes. By directing the laser away from visible blood vessels the microcirculation can be sampled. The mean relative blood velocity and volume are computed from the spectrum of Doppler frequency shifts. The volume is derived from the width of the Doppler shift spectrum, and the velocity from the magnitude of Doppler shifts. LDF has proved useful in physiological studies of ONH blood flow^13,14,15,16 and of glaucoma.¹⁷ A feasibility study of LDF in cerebral malaria produced promising results.¹⁸We report a study of ONH microcirculation in children with cerebral malaria in relation to clinical parameters, particularly papilloedema.     

Levodopa raises objective pain threshold in Parkinson's disease: a RIII reflex study

Background

Patients suffering from Parkinson''s disease (PD) describe painful sensations that could be related to neuropathic pain. Experimental data have indicated the involvement of basal ganglia and dopaminergic pathways in central nociceptive processing.

Aim

The objective of this study was to assess and compare the effect of levodopa on the objective pain threshold in patients with PD and healthy subjects.

Methods

The objective pain threshold was assessed by the nociceptive flexion reflex (RIII) in 13 PD patients and 10 healthy subjects. Patients and healthy subjects were evaluated under two randomised conditions: with levodopa (ON) and without (OFF).

Results

Levodopa significantly increased the RIII threshold of PD patients (6.9 (1.2) mA in the OFF condition vs 8 (1.1) mA in the ON position; p = 0.02). RIII threshold was significantly lower in PD patients than in healthy subjects in the OFF condition (6.9 (1.2) mA vs 9.7 (3.4) mA; p = 0.02). RIII threshold did not change after levodopa administration in healthy subjects.

Conclusion

These results provide evidence of a dopaminergic modulation of objective pain threshold in PD patients. In addition, the decrease in RIII threshold in PD patients, in the OFF condition, compared with controls, confirms the existence of an objective pain perception disturbance in PD.Pain is recognised as a feature of Parkinson''s disease (PD) and is reported by 40–75% of patients with PD.¹ Painful sensations are various (musculoskeletal, neuropathic pain) and may be present at any stage of the disease.^2,3Several anatomical, electrophysiological and pharmacological arguments are in favour of the involvement of the basal ganglia and dopaminergic pathways in central nociceptive processing.⁴There are only a few controversial studies on pain perception in PD. The pain threshold of patients with PD has been found to be lower than, higher than or equal to that of healthy subjects.^5,6,7 Recently, Djaldetti et al have shown that patients with PD have a lower subjective heat pain threshold than healthy subjects.⁸ To our knowledge, the effect of levodopa has only been assessed on the subjective pain threshold. Using two different experimental thermal stimulations (cold pressor test and thermotest with Peltier effect), we have previously shown that acute administration of levodopa significantly raised the subjective pain threshold of patients with PD.^9,10The nociceptive flexion reflex (RIII), a polysynaptic reflex, has been described as a useful tool for objectively investigating the pain threshold and its pharmacological modulation by analgesic drugs in normal subjects.^11,12The primary aim of the present study was to compare the effects of levodopa on objective pain threshold (RIII reflex) in pain free patients with PD and in healthy subjects. A secondary objective was to compare such parameters between these two groups.     

Cerebral venous thrombosis and plasma concentrations of factor VIII and von Willebrand factor: a case control study

Background

High plasma concentrations of factor VIII (FVIII) and von Willebrand factor (VWF) have been recently associated with a moderately increased risk of venous thrombosis, but their roles in cerebral sinus and venous thrombosis (CSVT) have not been addressed. To determine whether elevation of FVIII and VWF is more frequent in CSVT, we analysed plasma levels of FVIII and VWF in a case control study.

Methods

The study population consisted of 25 consecutive patients (of whom nine were excluded) admitted for CSVT to the Department of Neurology, Amiens University Hospital, France, from January 1997 to December 2002, for a general screening for thrombophilia. Sixty‐four healthy subjects matched for age and sex formed the group control.

Results

Mean FVIII (CSVT: 167.3 (SD 48.8) IU/dl; control group: 117.9 (39.8) IU/dl; p = 0.001) and VWF levels (CSVT: 165.4 (76.5)%; control group: 108.5 (27.8)%; p = 0.01) were significantly higher in the CSVT group. Using the 95th percentile of the control group as the cut off value, elevated FVIII (>190 IU/dl) occurred in 25% (4/16) (p = 0.005) and elevated VWF (>168%) in 37.5% (6/16) of patients with CSVT (p<0.001). Using previously reported cut off values (>150 IU/dl or >150%) showed the same results (FVIII: p = 0.005; VWF: p = 0.009).

Conclusion

Our study suggests that elevation of plasma factor VIII levels is the most common prothrombotic risk factor for CSVT. Elevation of VWF is also associated with an increased risk of CSVT but its effect seems to be partly mediated through FVIII.Cerebral sinus and vein thrombosis (CSVT) is a rare localisation of venous thromboembolic disease. It generally occurs in young or middle‐aged adults and accounts for approximately 1% of strokes.¹ Many coagulation disorders have been associated with CSVT.^2,3,4Several prospective studies showed that high concentrations of factor VIII (FVIII) are associated with a moderately increased risk of venous thromboembolism (VTE).^5,6 The role of increased levels of von Willebrand Factor (VWF) in VTE remains unclear.^5,7 Recent studies suggest that the effect of VWF is fully explained by FVIII concentrations.⁵ Indeed, the ABO blood group, which regulates plasma concentrations of both FVIII and VWF, may also play a role in susceptibility to thrombosis.^8,9,10The increased risk of VTE with elevated levels of FVIII or VWF has been observed in previous studies.^5,6,7,11 However, they did not specifically include patients with CSVT^7,9 or they were incomplete.¹²The aim of our study was to assess plasma levels of FVIII, VWF and other thrombophilic factors in patients with CSVT in a case control study.     

Diffusion anisotropy of the cervical cord is strictly associated with disability in amyotrophic lateral sclerosis

Background

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with severe cervical cord damage due to degeneration of the corticospinal tracts and loss of lower motor neurones. Diffusion tensor magnetic resonance imaging (DT MRI) allows the measurement of quantities reflecting the size (such as mean diffusivity) and orientation (such as fractional anisotropy) of water‐filled spaces in biological tissues.

Methods

Mean diffusivity and fractional anisotropy histograms from the cervical cord of patients with ALS were obtained to: (1) quantify the extent of tissue damage in this critical central nervous system region; and (2) investigate the magnitude of the correlation of cervical cord DT MRI metrics with patients'' disability and tissue damage along the brain portion of the corticospinal tracts. Cervical cord and brain DT MRI scans were obtained from 28 patients with ALS and 20 age‐matched and sex‐matched controls. Cord mean diffusivity and fractional anisotropy histograms were produced and the cord cross‐sectional area was measured. Average mean diffusivity and fractional anisotropy along the brain portion of the corticospinal tracts were also measured.

Results

Compared with controls, patients with ALS had significantly lower mean fractional anisotropy (p = 0.002) and cord cross‐sectional area (p<0.001). Mean diffusivity histogram‐derived metrics did not differ between the two groups. A strong correlation was found between mean cord fractional anisotropy and the ALS Functional Rating Score (r = 0.74, p<0.001). Mean cord and brain fractional anisotropy values correlated moderately (r = 0.37, p = 0.05).

Conclusions

Cervical cord DT MRI in patients with ALS allows the extent of cord damage to be graded. The conventional and DT MRI changes found are compatible with the presence of neuroaxonal loss and reactive gliosis, with a heterogeneous distribution of the pathological process between the brain and the cord. The correlation found between cord fractional anisotropy and disability suggests that DT MRI may be a useful adjunctive tool to monitor the evolution of ALS.Amyotrophic lateral sclerosis (ALS) is the most common adult‐onset motor neurone disease, characterised by a progressive and simultaneous degeneration of upper and lower motor neurones.^1,2 In its typical form, the disease begins either in one limb or with a combination of bulbar and corticobulbar symptoms, and continues with progressive weakness of the bulbar, limb, thoracic and abdominal musculature.^1,2 By using a variety of conventional magnetic resonance imaging (MRI) sequences, several studies^{3,4,5,6,7,8,9,10,11,12,13,14,15} have shown changes in signal intensity along the brain portion of the corticospinal tracts, particularly in the posterior limb of the internal capsule and cerebral peduncles, varying between 25% and 80%. Reduced magnetisation transfer ratios in the internal capsule^8,11 and N‐acetylaspartate levels in the motor cortex^13,16,17 of patients with ALS have also been observed. However, none of these studies has reported a correlation between such magnetic resonance abnormalities and the degree of disability.^{8,11,13,16,17}Diffusion‐tensor magnetic resonance imaging (DT MRI) enables the random diffusional motion of water molecules to be measured and thus provides quantitative indices of the structural and orientational features of the central nervous system (CNS).¹⁸ DT MRI has been used to assess quantitatively the tissue damage of the brain portion of the corticospinal tracts in ALS,^{12,19,20,21,22,23} and all studies have shown increased mean diffusivity (indicating a loss of structural barriers limiting the motion of water molecules) and decreased fractional anisotropy (indicating a loss of tissue organisation). However, brain DT MRI studies also resulted in heterogeneous clinicopathological correlations, as some authors found a moderate correlation between brain DT MRI metrics and the severity of disability,^12,21,23 but others did not.¹⁹ In the past few years, DT MRI has also been used successfully to grade the extent of cervical cord damage associated with demyelinating conditions.^24,25,26Considering that the cervical cord in ALS is one of the most affected portions of the CNS (owing to the combined presence of neuronal loss in the anterior horns of the grey matter and degeneration of the corticospinal tracts), we obtained mean diffusivity and fractional anisotropy histograms of the cervical cord from patients with ALS with the following aims: (1) to quantify the extent of tissue damage in this critical CNS region; and (2) to investigate the magnitude of the correlation of cervical cord DT MRI metrics with patients'' disability and tissue damage along the brain portion of the corticospinal tracts.     

Case control study of diffusion tensor imaging in Parkinson's disease

Background

Preliminary work has shown that diffusion tensor MRI (DTI) may contribute to the diagnosis of Parkinson''s disease (PD).

Objectives

We conducted a large, prospective, case control study to determine: (1) if fractional anisotropy (FA) and apparent diffusion coefficient (ADC) values on DTI in the basal ganglia and substantia nigra are different between patients with PD and healthy controls; and (2) the predictive value of these parameters and their clinical utility.

Methods

DTI imaging was carried out in patients with PD and controls. FA and ADC values were obtained from various brain structures on the DTI scan using the diffusion tensor taskcard. The structures studied were: caudate, putamen, globus pallidus, thalamus and substantia nigra.

Results

151 subjects (73 PD patients, 41 men, 32 women; mean age 63.6 years) and 78 age and sex matched control subjects were studied. The FA value of the substantia nigra in patients with PD was lower compared with controls (0.403 vs 0.415; p = 0.001). However, no significant differences were demonstrated for FA or ADC values of other structures. Multiple regression analysis revealed that the clinical severity of PD correlated inversely with the FA value in the substantia nigra in patients with PD (regression coefficient −0.019). No single FA value had both a high positive and negative predictive power for PD.

Conclusions

We demonstrated in a large, prospective, case control study that the FA value in the substantia nigra on DTI was lower in PD compared with healthy controls, and correlated inversely with the clinical severity of PD. Further longitudinal studies would be helpful to assess the clinical utility of serial FA measurements of the substantia nigra in objective quantification of disease progression and monitoring of the therapeutic response.The diagnosis of Parkinson''s disease (PD) is usually made clinically, based on the presence of rest tremor, bradykinesia and rigidity.^1,2 However, in select cases, the diagnosis may not be clear, especially in patients without tremor. Large community based studies have also shown that there is considerable difficulty in diagnosing parkinsonism or PD among elderly subjects in clinical practice.^3,4 Subtle signs of parkinsonism can be detected on clinical examination in approximately 30% of apparently healthy community based elderly cohorts.^4,5,6Diffusion tensor imaging (DTI) is an MRI technique that can indirectly evaluate the integrity of white matter tracts by measuring water diffusion and its directionality in three dimensions.⁷ The magnitude (diffusivity) and directionality (anisotropy) of water molecular displacement by diffusion in the brain can be quantified by the apparent diffusion coefficient (ADC) and fractional anisotropy (FA), respectively.^{8,9,10,11,12,13,14,15} Studies have revealed age related declines in white matter FA of normal healthy adults in whom volume loss may not even be evident.^12,15,16 DTI changes have also been reported in structures with relatively low inherent anisotropy, such as the thalamus and putamen.^11,12,17A small pilot study reported lower FA values in the nigrostriatal projection of patients with PD.¹⁸ Another group showed that ADC values in the basal ganglia and substantia nigra were no different between patients with PD and controls.^19,20 To our knowledge, correlation of FA and ADC values on DTI with clinical severity, and determination of positive and negative predictive values of DTI parameters have not been demonstrated for PD. Hence, we conducted a large, prospective, case control study to determine the clinical utility of FA and ADC values on DTI in distinguishing patients with PD from healthy controls.     

Prevalence and pattern of perceived intelligibility changes in Parkinson's disease

Background

Changes to spoken communication are inevitable in Parkinson''s disease (PD). It remains unclear what consequences changes have for intelligibility of speech.

Aims

To establish the prevalence of impaired speech intelligibility in people with PD and the relationship of intelligibility decline to indicators of disease progression.

Methods

125 speakers with PD and age matched unaffected controls completed a diagnostic intelligibility test and described how to carry out a common daily activity in an “off drug” state. Listeners unfamiliar with dysarthric speech evaluated responses.

Results

69.6% (n = 87) of people with PD fell below the control mean of unaffected speakers (n = 40), 51.2% (n = 64) by more than −1 SD below. 48% (n = 60) were perceived as worse than the lowest unaffected speaker for how disordered speech sounded. 38% (n = 47) placed speech changes among their top four concerns regarding their PD. Intelligibility level did not correlate significantly with age or disease duration and only weakly with stage and severity of PD. There were no significant differences between participants with tremor dominant versus postural instability/gait disorder motor phenotypes of PD.

Conclusions

Speech intelligibility is significantly reduced in PD; it can be among the main concerns of people with PD, but it is not dependent on disease severity, duration or motor phenotype. Patients'' own perceptions of the extent of change do not necessarily reflect objective measures.Voice and speech changes are inevitable in Parkinson''s disease (PD) as the condition progresses.^1,2 The consequences of these changes for intelligibility and acceptability of spoken communication are unclear.Previous surveys^3,4,5,6 estimate 70–90% of patients with PD present with voice changes, 45–55% with speech changes. Only Coates and Bakheit⁶ focused directly on intelligibility, determining 65% of 48 participants had problems. This study had several drawbacks, including lack of control recordings, grading of intelligibility by a single speech language therapist and failure to match word lists presented to different speakers.We assessed a large sample of people with PD using a diagnostic intelligibility test^7,8 with evaluation of responses by listeners with no professional or personal experience of listening to disordered speech or association with PD. We compared results of PD subjects to an age matched control group and in relation to a variety of indicators of disease progression.     

Symptomatic intracranial haemorrhage after intra-arterial thrombolysis in acute ischaemic stroke: assessment of 294 patients treated with urokinase

Background

The PROACT II trial showed that intra‐arterial thrombolysis (IAT) is effective for treatment of acute ischaemic stroke attributable to M1 and M2 segment occlusions. Incidence of symptomatic intracranial haemorrhage (sICH) was 10%.

Objective

: To evaluate the risk and predictors of sICH after IAT by using urokinase in a large number of patients presenting with the whole spectrum of cerebral vessel occlusions.

Methods

294 patients with stroke treated with intra‐arterial urokinase were retrospectively analysed. The risk of sICH as well as bleeding characteristics were assessed. Demographic and radiological data, time to treatment, urokinase dose, recanalisation rates, stroke aetiology and severity were analysed for predictors.

Results

sICH occurred in 14 of 294 (4.8%) patients. The median National Institute of Health Stroke Scale score of all patients was 15. All but one sICH were located in the infarcted brain tissue, and no sICH occurred in patients with peripheral vessel occlusions (M3 or M4 segments of the middle cerebral artery). Poor collaterals (p = 0.001), early signs of ischaemia on computed tomography (p = 0.003), higher urokinase dose (p = 0.019), lower recanalisation rate (p = 0.02) and higher diastolic blood pressure on admission (p = 0.04) were found to be correlated with sICH on univariate analysis. On multivariate analysis, poor collaterals (p = 0.004), urokinase dose (p = 0.021) and early signs on computed tomography (p = 0.026) remained predictors of sICH.

Conclusions

With regard to the whole spectrum of cerebral vessel occlusions, an incidence of <5% sICH after IAT is distinctly low. This result underlines the important role of IAT in the treatment of acute stroke.The aim of treatment in acute ischaemic stroke is revascularisation as fast as possible. For this purpose, both intravenous thrombolysis (IVT) and intra‐arterial thrombolysis (IAT) have proved to be effective.^1,2,3,4,5 The most devastating complication of both treatments is intracranial haemorrhage (ICH). ICH is categorised into haemorrhagic transformation, which is usually petechial and asymptomatic, and parenchymal haematomas without deterioration and those with clinical deterioration. Those with clinical deterioration are referred to as symptomatic ICH (sICH), which is associated with an increased mortality and occurs spontaneously in 0.6–4% of patients with ischaemic strokes. Thrombolysis increases the risk of sICH. Current literature reports wide ranges of incidence—for example, 3.3–21.2% for IVT and 0–14.3% for IAT.^{1,3,6,7,8,9,10,11,12,13,14}The largest IAT series was the PROACT II trial reporting on a defined subgroup of patients with stroke (n = 180) exclusively with M1 and M2 segment occlusions of the middle cerebral artery (MCA).³This study was conducted to evaluate the risk of sICH in the whole spectrum of patients with large cerebral artery occlusions treated with IAT. Characteristics of patients with sICH were assessed and predictors analysed.     

Cognitive outcome in adults after bacterial meningitis

Objective

To evaluate cognitive outcome in adult survivors of bacterial meningitis.

Methods

Data from three prospective multicentre studies were pooled and reanalysed, involving 155 adults surviving bacterial meningitis (79 after pneumococcal and 76 after meningococcal meningitis) and 72 healthy controls.

Results

Cognitive impairment was found in 32% of patients and this proportion was similar for survivors of pneumococcal and meningococcal meningitis. Survivors of pneumococcal meningitis performed worse on memory tasks (p<0.001) and tended to be cognitively slower than survivors of meningococcal meningitis (p = 0.08). We found a diffuse pattern of cognitive impairment in which cognitive speed played the most important role. Cognitive performance was not related to time since meningitis; however, there was a positive association between time since meningitis and self‐reported physical impairment (p<0.01). The frequency of cognitive impairment and the numbers of abnormal test results for patients with and without adjunctive dexamethasone were similar.

Conclusions

Adult survivors of bacterial meningitis are at risk of cognitive impairment, which consists mainly of cognitive slowness. The loss of cognitive speed is stable over time after bacterial meningitis; however, there is a significant improvement in subjective physical impairment in the years after bacterial meningitis. The use of dexamethasone was not associated with cognitive impairment.The estimated annual incidence of bacterial meningitis is 4–6 per 100 000 adults and Streptococcus pneumoniae (pneumococcus) and Neisseria meningitidis (meningococcus) are the causative bacteria in 80% of cases.^1,2 Fatality rates in patients with pneumococcal meningitis (26%) and meningococcal meningitis (7%) are significant.^1,2,3 Even in patients with apparent good recovery, cognitive impairment occurs frequently,⁴ especially after pneumococcal meningitis.^4,5,6 The cognitive functions affected by bacterial meningitis differ between studies, most likely because of the limited numbers of patients examined, and the lack of uniformity across studies in assessment methods and in the definition of cognitive impairment.^{4,5,6,7,8,9,10} We therefore pooled data on cognitive outcome after bacterial meningitis from three of our previous studies to more clearly determine which cognitive functions are affected by bacterial meningitis and to identify which patients are at risk of developing cognitive impairment.     

Trunk performance after stroke: an eye catching predictor of functional outcome

Background and aim

Trunk performance is an important predictor of functional outcome after stroke. However, the percentage of explained variance varies considerably between studies. This may be explained by the stroke population examined, the different scales used to assess trunk performance and the time points used to measure outcome. The aim of this multicentre study was to examine the predictive validity of the Trunk Impairment Scale (TIS) and its subscales when predicting the Barthel Index score at 6 months after stroke.

Methods

A total of 102 subjects were recruited in three European rehabilitation centres. Participants were assessed on admission (median time since stroke onset 20 days) and 6 months after stroke. Correlation analysis and forward stepwise multiple regression analysis were used to model outcome.

Results

The best predictors of the Barthel Index scores at 6 months after stroke were total TIS score (partial R² = 0.52, p<.0001) and static sitting balance subscale score (partial R² = 0.50, p<.0001) on admission. The TIS score on admission and its static sitting balance subscale were stronger predictors of the Barthel Index score at 6 months than the Barthel Index score itself on admission.

Conclusions

This study emphasises the importance of trunk performance, especially static sitting balance, when predicting functional outcome after stroke. The TIS is recommended as a prediction instrument in the rehabilitation setting when considering the prognosis of stroke patients. Future studies should address the evolution of trunk performance over time and the evaluation of treatment interventions to improve trunk performance.Although the age specific incidence of major stroke has fallen over the past few years,¹ it is still the main cause of long term disability in adults, with a growing number of survivors being dependent for activities of daily living (ADL).^2,3 Frequently identified variables predicting ADL after stroke are age and initial severity of motor and functional deficits.⁴ Trunk performance has also been identified as an important independent predictor of ADL after stroke.^5,6,7,8,9 However, based on multiple regression analyses, the reported variance of functional outcome after stroke explained by trunk performance ranges from 9% to 71%.^5,6,7,8,9 Differences in reported variance could be explained by the stroke population included, the various scales used to measure trunk performance and the time points used to measure outcome.Previous studies evaluating the predictive validity of trunk performance after stroke were performed in a single rehabilitation setting, warranting caution when generalising results.^5,6,7,8,9,10 Clinical tools used to assess trunk performance are the Trunk Control Test,^5,6,10 trunk control items of the Postural Assessment Scale for Stroke patients^7,8 and trunk assessment of Fujiwara et al.⁹ A limitation of the first two tests is that they both have a ceiling effect, which makes their use less suitable in long term outcome studies.^5,11,12,13 Furthermore, the trunk control items of the Trunk Control Test and Postural Assessment Scale for Stroke patients are largely comparable with the items of the trunk measure of Fujiwara et al.⁹ All previously mentioned clinical tools include items in the supine position which involve rolling as well as only basic balance movements in sitting. Finally, with the exception of the trunk control items of the Postural Assessment Scale for Stroke patients,⁸ no study has evaluated the prognostic value of trunk performance when predicting functional outcome at 6 months after stroke.The Trunk Impairment Scale (TIS) for patients after stroke was designed to measure ADL related selective trunk movements rather than participation of the trunk in gross transfer movements.¹⁴ The TIS assesses static and dynamic sitting balance and trunk coordination. Reliability, validity, measurement error, internal consistency and discriminant ability of the TIS have been reported elsewhere.^14,15 The TIS has no ceiling effect in subacute and chronic stroke patients and already appeared to be strongly related to measures of gait, balance and functional ability in a cross sectional study.¹² To the best of our knowledge, the predictive value of the TIS and its subscales has not been evaluated. Including age and other measures of motor and functional performance could provide a useful combination of variables predicting outcome after stroke. The Barthel Index score is a widely accepted measure in stroke rehabilitation research and assesses functional milestones in stroke recovery. Predicting Barthel Index scores at 6 months after stroke based on measurements taken on admission to a rehabilitation centre would further establish the importance of trunk performance when predicting long term outcome after stroke. Experts in the field of neurological rehabilitation have addressed the trunk as the central key point of the body.¹⁶ Proximal stability of the trunk is a prerequisite for distal head and limb movement and therefore expected to be related to functional ADL.In summary, there is still a lack of clarity regarding the importance of trunk performance in functional outcome after stroke. Scales which have been used in previous studies have important statistical limitations and are likely to be a comprehensive measure of motor performance of the trunk. Therefore, the aim of this multicentre study was to examine the predictive validity of the TIS and its subcomponents, together with other known predictors, in predicting functional outcome measured as a Barthel Index score at 6 months after stroke.     

Cortical cholinergic denervation is associated with depressive symptoms in Parkinson's disease and parkinsonian dementia

Aim

To investigate the relationship between ratings of depressive symptoms and in vivo cortical acetylcholinesterase (AChE) activity in subjects with Parkinson''s disease (PD) and parkinsonian dementia (PDem).

Methods

Subjects (with PD, n = 18, including subjects with PDem, n = 6, and normal controls, n = 10) underwent [¹¹C]methyl‐4‐piperidinyl propionate AChE positron emission tomography imaging and clinical assessment including the Cornell Scale for Depression in Dementia (CSDD).

Results

Subjects with PD and PDem had higher scores on the CSDD compared with normal controls: 7.3 (5.4) and 2.8 (2.6), respectively (F = 6.9, p = 0.01). Pooled analysis demonstrated a significant inverse correlation between cortical AChE activity and CSDD scores: R = −0.5, p = 0.007. This correlation remained significant after controlling for Mini‐Mental State Examination scores.

Conclusion

Depressive symptomatology is associated with cortical cholinergic denervation in PD that tends to be more prominent when dementia is present.Depression is a frequent non‐motor manifestation of Parkinson''s disease.¹ The pathophysiology of depression in PD is complex and probably related to the dysfunction of several neurotransmitter systems, including serotonin, dopamine and norepinephrine.² However, a recent meta‐analysis of depression treatment studies in PD found less benefit from typical antidepressant treatment, particularly selective serotonin reuptake inhibitors, than seen in elderly patients without PD.³ A recent study on acute tryptophan depletion also failed to identify a specific serotonergic vulnerability for depression in PD.⁴ Dopaminergic denervation is unlikely to play a major role in depression, as antidepressant effects of levodopa treatment in PD are generally modest.⁵A relatively unique feature of depression in PD is that mood disturbance is associated with a quantitative but not qualitative worsening of cognitive deficits.⁶ This modulatory effect of depression on cognitive impairment in PD suggests that a common mechanism might underlie both types of symptoms. We recently reported in vivo findings of more severe cholinergic denervation in parkinsonian dementia (PDem) compared with Alzheimer''s disease,⁷ and cholinergic degeneration may play a significant role in the cognitive decline in PD.⁸ This raises the question of whether depression in PD is, at least in part, associated with cholinergic hypofunction.     

Axonal damage and outcome in subarachnoid haemorrhage

Background

On the basis of preliminary evidence from patients with subarachnoid haemorrhage (SAH), axonal degeneration is thought to be an underestimated pathological feature.

Methods

A longitudinal study in 17 patients with aneurysmal SAH. Ventricular CSF was collected daily for up to 14 days. The neurofilament heavy chain^SMI35 (NfH^SMI35, a biomarker for axonal damage) was quantified using a standard ELISA (upper limit of normal 0.73 ng/ml). The primary outcome measure was the Glasgow Outcome Score (GOS) at 3 months.

Results

Of 148 samples from patients with SAH, pathologically high NfH levels in the CSF were found in 78 (52.7%) samples, compared with 20 (5%) of 416 samples from the reference population (p<0.0001). A pathological increase in NfH was observed in all patients with a bad outcome (GOS 1–3) compared with 8% of those with a good outcome (GOS 4–5, p<0.0001). This increase typically became significant 7 days after the haemorrhage (p<0.01). The result was confirmed by analysing the individual mean NfH concentrations in the CSF (3.45 v 0.37 ng/ml, p<0.01), and was reinforced by the inverse correlation of NfH in the CSF with the GOS (r = −0.65, p<0.01). Severity of injury was found to be correlated to NfH^SMI35 levels in the CSF (World Federation of Neurological Surgeons, r = 0.63, p<0.01 and Glasgow Coma Score, r = −0.61, p<0.01).

Conclusion

Patients with SAH thus have secondary axonal degeneration, which may adversely affect their outcome.The presence of axonal degeneration in patients with subarachnoid haemorrhage (SAH) has recently been suggested in a longitudinal study.¹ One important finding was that damage to axons may continue after the primary injury and extend into the period of delayed cerebral ischaemia.^1,2,3,4Presence of secondary axonal degeneration in patients with SAH may be relevant to the outcome because, despite the high mortality (32–67%) during the hyperacute phase,^2,5 a considerable proportion of mostly young and otherwise healthy patients has the potential for good recovery from a limited degree of primary injury. In these patients, it is well known that secondary brain damage caused by delayed cerebral ischaemia adversely affects the potential for recovery.^2,3,4 About 50% of patients who survive do not return to their previous level of employment.^6,7,8In this longitudinal study, we monitored the development of axonal degeneration indirectly by measuring a biomarker for axonal degeneration (neurofilaments, reviewed by Petzold⁹). Firstly, we investigated whether neurofilaments would be increased early on (eg, a single peak, indicative of primary axonal injury) or rise late (eg, secondary peaks, suggestive of secondary axonal damage) in the disease course. Secondly, we tested whether the pattern of an anticipated¹ increase in neurofilament levels over time would be related to the degree of recovery.     

Influence of subjective visual vertical misperception on balance recovery after stroke

Background

Subjective visual vertical (SVV) perception can be perturbed after stroke, but its effect on balance recovery is not yet known.

Aim

To evaluate the influence of SVV perturbations on balance recovery after stroke.

Methods

28 patients (14 with a right hemisphere lesion (RHL) and 14 with a left hemisphere lesion (LHL)) were included, 5 were lost to follow‐up. SVV perception was initially tested within 3 months after stroke, then at 6 months, using a luminous line, which the patients adjusted to the vertical position in a dark room. Mean deviation (V) and uncertainty (U), defined as the standard deviation of the SVV, were calculated for eight trials. Balance was initially assessed by the Postural Assessment Scale for Stroke (PASS), and at 6 months by the PASS (PASS6), a force platform (lateral and sagittal stability limits (LSL6 and SSL6)), the Rivermead Mobility Index (RMI6) and gait velocity (v6). Functional outcome was also assessed by the Functional Independence Measure at 6 months (FIM6).

Results

The scores for balance and for FIM6 were related to the initial V value: PASS6 (p = 0.01, τ = −0.38); RMI6 (p = 0.002, τ = −0.48), LSL6 (p = 0.06, τ = −0.29), SSL6 (p = 0.004, τ = −0.43), v6 (p = 0.01, τ = −0.36) and FIM6 (p = 0.001, τ = −0.49), as well as to the initial U value: PASS6 (p = 0.03, τ = −0.32), RMI6 (p = 0.02, τ = −0.35), SSL6 (p = 0.005, τ = −0.43) and FIM6 (p = 0.01, τ = −0.38).

Conclusions

Initial misperception of verticality was related to a poor score for balance after stroke. This relationship seems to be independent of motricity and neglect. Rehabilitation programmes should take into account verticality misperceptions, which could be an important factors influencing balance recovery after stroke.Balance recovery is crucial for the acquisition of autonomy in patients with hemiplegia after stroke. In addition to weakness, increase in stiffness or sensory disorders leading to lower limb instability, recent articles have emphasised the role of space exploration disturbance, such as hemineglect in imbalance after stroke. Balance difficulties are more frequent and recovery takes a longer time after a right than after a left stroke, especially in patients with visuospatial neglect.^1,2 An additional argument supporting the crucial role of space exploration disturbance in patients with balance disorder after stroke is that sensory stimulations such as vestibular caloric stimulation¹ or neck transcutaneous electric nerve stimulation³ reduce simultaneously space disturbance and postural imbalance. Further, space exploration and balance seem to be closely linked, as the ability to perform space exploration depends on trunk orientation and vice versa in normal people as well as in patients with stroke.^4,5,6,7,8,9 The assumption for this predominance of imbalance in patients with hemineglect and more generally in patients with right stroke is that spatial cognition is processed in the right hemisphere.^1,10Nethertheless, disorders of spatial cognition after stroke are not limited to space exploration. Spatial abilities such as the sense of straight ahead,¹¹ central space representation¹² or perception of verticality can be perturbed after stroke.^13,14,15 Such abilities can be assumed to have a major role in maintaining balance. To our knowledge, no systematic study has been conducted to assess the role of these abilities on balance recovery. Regarding the perception of visual verticality, which is tested in a dark room asking patients to adjust a luminous line to a vertical position, two kinds of perturbations have been described after hemispheric stroke: a mean tilt, most of the time contralateral to the cerebral lesion,^13,14,15 and an excessive range of uncertainty between the different adjustments.^14,15 In this study, we aimed to determine whether initial SVV misperceptions (abnormal tilt or uncertainty) influence balance recovery after stroke. The results would give new insight into postural disturbance after stroke and may change clinical practice. Rehabilitation programmes of postural control for patients with hemiplegia after stroke should take into account the possible impairment of verticality perception.     

Apolipoprotein E epsilon4 and impaired episodic memory in community-dwelling elderly people: a marked sex difference. The Hordaland Health Study

Background

Among elderly people without dementia, the apolipoprotein E ε4 allele (APOE4) has been associated with cognitive deficit, particularly in episodic memory, but few reports are available on whether this association differs by sex.

Methods

In a community‐dwelling Norwegian cohort of 2181 elderly people (55% women), aged 70–74 years, episodic memory was examined in relation to sex and APOE4 zygosity, with the Kendrick Object Learning Test (KOLT).

Results

Possession of at least one APOE4 allele had a modest, detrimental effect on episodic memory in women, whereas in men, heterozygotes were unaffected and homozygotes had markedly lower scores across the distribution of KOLT scores. This sex difference was found consistently in all analyses: on comparing means and medians, examining trends across quintiles, and studying the distribution of scores and the risk of cognitive impairment. Results were broadly similar when adjusted for known determinants of cognition and also when severely impaired participants were excluded. The adjusted odds ratio (OR) of cognitive impairment in women was shown to be 1.8 (95% confidence interval (CI): 1.1 to 2.8) for heterozygotes and 1.1 (0.3 to 3.7) for homozygotes; the adjusted OR in men was observed to be 1.1 (0.6 to 2.1) for heterozygotes and 10.7 (4.7 to 24) for homozygotes.

Conclusions

Although the harmful effect of APOE4 on episodic memory was modest in women, the risk was found to occur in about 30%. APOE4 was observed to have a dramatic effect on episodic memory in men, but only in homozygotes, who comprised about 3% of men: the whole male homozygous group showed a marked shift to lower memory scores.Age and the apolipoprotein E ε4 allele (APOE4) are the most important known risk factors for sporadic Alzheimer''s disease. The disease is thought to have a long presymptomatic phase,¹ which suggests that APOE4 starts exerting its detrimental effects in the preclinical phase. Most studies on elderly people without dementia have found that the APOE4 allele is associated with various cognitive deficits,^{2,3,4,5,6,7,8,9,10,11,12,13,14} particularly in memory.^2,3,4,5,6,7 A recent meta‐analysis of more than 20 000 people concluded that this allele was associated with poorer performance on tests of global cognitive functioning, episodic memory and executive functioning.¹⁵The association of APOE4 with Alzheimer''s disease varies with sex.^{16,17,18,19,20} The meta‐analysis by Farrer et al²⁰ found that APOE4 homozygosity affords a high risk of Alzheimer''s disease for both men and women, but that a single copy of the allele confers a greater risk on women than on men. A similar sex difference related to APOE4 has been found in the degree of hippocampal atrophy in a cohort with mild cognitive impairment.²¹ We may therefore expect to find an effect related to sex of the APOE4 allele in cognitive tests in elderly people without dementia. Two studies^3,22 that have reported an influence of sex on this relationship found a stronger effect of APOE4 in women.^3,22In this study, we investigated whether sex influences the relationship between APOE alleles and episodic memory in community‐dwelling elderly people. We selected episodic memory because memory deficit is a hallmark of Alzheimer''s disease. Tests of episodic memory have been found to be particularly effective in identifying people at risk.^23,24 We compared the influence of sex in our cohort with that found on the risk of Alzheimer''s disease. We studied a relatively large group of 2181 people from western Norway.     

Profile of cognitive impairment in dementia associated with Parkinson's disease compared with Alzheimer's disease

Objective

To compare the profile of cognitive impairment in Alzheimer''s disease (AD) with dementia associated with Parkinson''s disease (PDD).

Methods

Neuropsychological assessment was performed in 488 patients with PDD and 488 patients with AD using the Mini‐Mental State Examination (MMSE) and the Alzheimer''s Disease Assessment Scale‐cognitive subscale (ADAS‐cog). Logistic regression analysis was used to investigate whether the diagnosis could be accurately predicted from the cognitive profile. Additionally, the cognitive profiles were compared with a normative group using standardised effect sizes (Cohen''s d).

Results

Diagnosis was predicted from the cognitive profile, with an overall accuracy of 74.7%. Poor performance of the AD patients on the orientation test in ADAS‐cog best discriminated between the groups, followed by poor performance of the PDD patients on the attentional task in MMSE. Both groups showed memory impairment, AD patients performing worse than PDD patients.

Conclusion

The cognitive profile in PDD differs significantly from that in AD. Performance on tests of orientation and attention are best in differentiating the groups.Alzheimer''s disease (AD) and Parkinson''s disease (PD) are the most common neurodegenerative diseases in the elderly. AD is primarily a dementing disease whereas PD is mainly characterised by a movement disorder. However, dementia is common among patients with PD (PDD), with an average point prevalence of 31%¹ and a cumulative prevalence close to 80%.² In PD, dementia is associated with rapid motor³ and functional decline,⁴ and increased mortality.⁵Cortical Lewy body pathology correlates best with dementia in PD^6,7,8,9; subcortical pathology¹⁰ and AD‐type pathology¹¹ have also been found to be associated with PDD. In addition to differences in morphological changes, AD and PDD also differ in the regional pattern of the pathology. In AD the first and most pronounced changes are found in the entorhinal cortex and parahippocampal region,¹² subsequently involving neocortical areas, including the posterior association cortices.¹³ In contrast, in patients with PD without dementia, brainstem nuclei and other subcortical structures are initially affected.¹⁴ In PDD, limbic areas, neocortical association cortices, and the motor cortex and primary sensory cortical areas are thought to be successively involved with disease progression.¹⁵Given the difference in the distribution and progression of pathology in AD and PDD, it is expected that their cognitive profiles would also differ.^16,17 AD is characterised by memory loss emerging in the early stages of the disease,¹⁸ primarily involving learning and encoding deficits¹⁹ which are associated with medial temporal lobe pathology.^20,21,22,23 As the disease progresses, deficits in language, praxis, visuospatial and executive functions gradually develop. In contrast, the cognitive deficits in the early stages of PDD are characterised by executive dysfunction, including impairment in attention²⁴ and working memory,^25,26,27 reflecting involvement of brainstem nuclei and frontal–subcortical circuits; deficits in visuoperceptual^28,29,30 and visuoconstructional tasks are also frequent.³¹ Memory impairment is often present^26,32,33,34 but whether it is primarily a consequence of frontally mediated executive deficits resulting in poor learning efficacy and retrieval, or whether involvement of limbic areas directly related to memory encoding (such as hippocampal atrophy) also contribute to memory impairment, is debated. Patients with PDD have difficulties in retrieving newly learned material, but perform better in recognition,³⁵ indicating that executive, rather than encoding, deficits, is the underlying mechanism. Conflicting results, however, have been reported recently^36,37 which could indicate that the type and mechanisms of memory deficits may vary within the PD group.³²Most studies investigating the cognitive profile of PDD patients included small samples which were not community based and thus not necessarily representative of the PD population at large. As there is evidence of interindividual heterogeneity,³³ such studies may not adequately reflect the cognitive profile of patients with PDD. In order to assess the profile of cognitive deficits in PDD compared with AD in larger patient populations, we analysed the baseline cognitive data from large clinical trials conducted with the cholinesterase inhibitor rivastigmine.^38,39     

A randomised controlled trial of a home based exercise programme to reduce the risk of falling among people with Parkinson's disease

Objective

To evaluate the effectiveness of a personalised home programme of exercises and strategies for repeat fallers with Parkinson''s disease (PD).

Method

Patients with a confirmed diagnosis of idiopathic PD, independently mobile, living at home in the community, experiencing more than one fall in the previous 12 months and with intact gross cognitive function were invited to participate in this randomised controlled trial. Usual care was compared with a personalised 6 week, home based exercise and strategy programme. The primary outcomes were rates of falling at 8 weeks and 6 months. Whether participants had repeat fallen, nearly fallen or experienced injurious falls were also examined. Functional Reach, the Berg Balance Test, PD Self‐assessment Scale and the Euro Quol were rated by a blinded assessor.

Results

Participants were randomised to the exercise (n = 70) and control (n = 72) groups. There was a consistent trend towards lower fall rates in the exercise group at both 8 weeks and 6 months and lower rates of injurious falls needing medical attention at 6 months. Lower rates of repeat near falling were evident for the exercise group at 8 weeks (p = 0.004) and 6 months (p = 0.007). There was a positive effect of exercises at 6 months on Functional Reach (p = 0.009) and quality of life (p = 0.033). No significant differences were found on other secondary outcomes measures.

Conclusion

There was a trend towards a reduction in fall events and injurious falls with a positive effect of exercises on near falls and quality of life.Postural instability and falls among people with Parkinson''s disease (PD) are common. In contrast with the estimated one‐third of the healthy population over 65 years who experience a fall,¹ two‐thirds of people living in the community with PD will have fallen in the previous 12 months² and those who have fallen two or more times in the previous year are likely to fall again in the next 3 months.³ As falls following PD can be injurious,⁴ prevention is important but postural instability is difficult to treat with medication. Physiotherapy may provide effective treatment for people with PD but two Cochrane reviews in 2001 on the general physical management of people with PD concluded there was insufficient evidence to support or refute the efficacy of physiotherapy or one form of physiotherapy over another for people with PD, and highlighted the need for more randomised controlled trials to test standard physiotherapy.^5,6 Most of the trials included in the systematic reviews recruited less than 20 subjects, and the use of poor research design and methodology was a common finding of the reviewers.Review of the literature on falls management among the general elderly population confirms that multidisciplinary fall prevention programmes can be beneficial for elderly people.^7,8 The most effective intervention was a multifactorial fall risk assessment and management programme. Exercise programmes, such as moderate intensity muscle strengthening and balance training, individually prescribed at home by a trained health professional, have been shown to be effective in reducing fall frequency among the elderly population living in the community.^7,8,9,10,11The purpose of this trial was to evaluate the effectiveness of a personalised home based exercise programme (activities selected from a menu of muscle strengthening, stretches, balance retraining and cognitive movement strategies for learning and compensating), administered by a physiotherapist for reducing fall events among people with PD. The research question addressed was: do repeat fallers with PD, who participate in an exercise programme of strength, balance training and strategies, experience fewer falls, near falls or injuries than those who do not?