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.     

Hippocampal activation in patients with mild cognitive impairment is necessary for successful memory encoding

Background

Episodic memory enables us to consciously recollect personally experienced past events. Memory performance is reduced in patients with mild cognitive impairment (MCI), an at‐risk condition for Alzheimer''s disease (AD).

Patients and methods

We used functional MRI (fMRI) to compare brain activity during memory encoding in 29 healthy elderly subjects (mean age 67.7 (SD 5.4) years) and 21 patients with MCI (mean age 69.7 (SD 7.0) years). Subjects remembered a list of words while fMRI data were acquired. Later, they had to recognise these words among a list of distractor words. The use of an event related paradigm made it possible to selectively analyse successfully encoded items in each individual. We compared activation for successfully encoded words between healthy elderly subjects and patients with MCI.

Results

The main intergroup difference was found in the left hippocampus and surrounding medial temporal lobe (MTL) regions for the patients with MCI compared with healthy subjects during successful encoding.

Conclusion

These results suggest that in patients with MCI, an increase in MTL activation is necessary for successful memory encoding. Hippocampal activation may help to link newly learned information to items already stored in memory. Increased activation in MTL regions in MCI may reflect a compensatory response to the beginning of AD pathology.Episodic memory, which enables humans to consciously recollect personally experienced past events, is based on at least two fundamental mnemonic operations: memory formation and retrieval. Event related functional MRI (fMRI) provides a unique opportunity to study the neural correlates of these processes and their subcomponents, such as successful and failed encoding.¹Studies in young healthy subjects have shown that successful declarative memory formation, measured as the difference in brain activity during encoding between subsequently remembered and forgotten items, is accompanied by increases in activity in medial temporal and inferior prefrontal areas.^{2,3,4,5,6,7,8,9,10} Structures within the medial temporal lobe (MTL) region, especially hippocampal formation,^7,11 are believed to be essential in establishing new memories.Patients with mild cognitive impairment (MCI)¹² are characterised by significant memory impairment, which is not severe enough to interfere with usual activities of daily living.¹³ The majority of patients with MCI go on to develop Alzheimer''s disease (AD).Patients with AD, in comparison with older controls, show consistently decreased MTL activation during encoding of new materials.^14,15,16,17 Fewer fMRI studies have investigated MTL encoding activation in patients with MCI,^15,16,18 showing inconsistent results. A recent fMRI study showed decreased MTL activation during a memory encoding task.¹⁵ However, another study¹⁶ found that only a subgroup of subjects with “isolated memory decline” demonstrated decreased hippocampal activation during encoding, whereas still another study¹⁹ reported increased MTL activation in cognitively intact individuals genetically at risk for AD. The variability in these fMRI results may be because the groups differed in the degree of impairment and underlying neural pathology.The degree of activation detected by fMRI within MTL regions during encoding strongly correlates with subjects'' subsequent ability to remember the items encoded.^2,8 Decreased MTL activation in patients with MCI and AD has been associated with relatively poor performance on post scan memory testing.^14,15,17 In contrast, subjects who were genetically at risk for AD, but could successfully perform the fMRI encoding task, showed increased MTL activation. It has been hypothesised that increased MTL activation during successful encoding may represent a compensatory response that allows for relatively normal memory function in the face of developing pathological change¹⁹ There is first evidence that elderly subjects with MCI and with a relatively preserved performance in the fMRI memory task show such a compensatory increased hippocampal response in comparison with healthy subjects, while patients with AD who exhibited poorer performance in the task had lower hippocampal activation.²⁰To further examine this question, it is not sufficient to compare general encoding related activation between patients with MCI and healthy subjects as this comparison would be confounded by task performance. Therefore, we used an event related fMRI paradigm, where subjects are instructed to remember visually presented words. According to task performance in subsequent recognition memory tests, all learned items can then be separated into those that are later remembered (subsequent hits) and those that are later forgotten (subsequent misses), individually for each subject. By comparing brain activation between healthy subjects and patients with MCI only for subsequent hits, brain regions can be identified that differ between groups during successful encoding into episodic memory. It has been shown previously that the degree of neural activity increases with the demands of the cognitive task and that the magnitude and spatial extent of brain activation increases with cognitive effort.^21,22,23 We hypothesise that successful memory encoding, which should be more demanding for patients with MCI than for healthy elderly subjects, would result in increased MTL activation in patients with MCI.     

Voxel based analyses of diffusion tensor imaging in Fabry disease

Background

Fabry disease (FD) is a lysosomal storage disorder associated with marked cerebrovascular disease. Conventional MRI shows an extensive load of white matter lesions (WMLs) which may already be present at an early stage in the disease.

Objective

Investigator independent and sensitive quantification of structural changes in the brain in clinically affected men and women with FD.

Methods

We performed a voxel based analysis of diffusion tensor images (DTI) in 25 patients with FD and 20 age matched normal controls.

Results

DTI revealed significant increases in cerebral white matter mean diffusivity (MD) in patients with FD, which were pronounced in the periventricular white matter. Even the subgroup of patients without significant WMLs load (n = 18) showed increased diffusivity in the cerebral white matter. In gray matter areas, MD elevation was detected only in the posterior part of the thalamus, independent of the visible pulvinar alterations on T1 weighted images. Voxel based fractional anisotropy measurements did not differ significantly between patients and controls.

Conclusions

The present study demonstrates the clinical feasibility of voxel based analysis of DTI as a sensitive tool to quantify brain tissue alterations in FD. The pattern of increased brain tissue diffusivity is probably due to microangiopathic alterations, mainly affecting the long perforating arteries.Fabry disease (FD) is a rare X‐linked hereditary lysosomal storage disease.¹ Deficiency of α‐galactosidase A activity leads to accumulation of neutral glycosphingolipids, particularly in vascular endothelial and smooth muscle cells of various organs.² Together with progressive renal and cardiac dysfunction, clinical CNS involvement mainly due to cerebral vasculopathy leading to serious complications such as stroke at an early age has been confirmed in clinical studies^3,4 and by neuroimaging.^5,6,7,8,9,10 The most prominent brain structural findings in FD are severe progressive white matter lesions (WMLs) that are detectable by T2 and FLAIR weighted images using conventional MRI.^5,7,10,11,12Focusing on WMLs and quantifying structural cerebrovascular involvement by visual rating scales on conventional MRI is compromised by limited accuracy.^13,14Investigation of the structure of the brain, in particular the detection of typical patterns of brain structural involvement as well as assessment of the natural course of these affections, is important for a better understanding of the pathophysiology of the brain and to study the potential effects of new treatment options, such as enzyme replacement therapy (ERT) in FD.There is evidence that diffusion tensor imaging (DTI) is more accurate and more sensitive in quantifying structural brain alterations than other assessments in conventional magnetic resonance techniques.^6,15,16,17 The principal parameters derived from diffusion tensor analysis are fractional anisotropy (FA) and mean diffusivity (MD). Reduced water diffusion parallel to axonal tracts represented by FA is indicative of axonal degeneration.¹⁸ Furthermore, MD, which measures randomised mean water diffusion, is a representative DTI parameter for ultrastructural brain tissue alterations.¹⁹ Thus DTI provides a promising tool for detection of early ultrastructural cerebral changes in FD.The use of diffusivity measurements in patients with FD has been demonstrated previously. One study showed global elevation of the average diffusion constant in cerebral tissue from men with FD.²⁰ Moreover, analysing DTI with regions of interest (ROI), we previously showed significant elevations in white matter diffusivity (MD), even in those FD patients without significant WMLs.⁶ However, ROI based analysis is time consuming, investigator dependent and usually does not cover the whole brain.To investigate the feasibility of investigator independent structural data processing procedures which cover the whole brain, we analysed DTI data from patients with FD using a voxel based approach. In this way, structural differences in the brain can be detected by voxel wise comparison of normalised DTI maps between patient and control groups.     

A randomised pilot study to assess the efficacy of an interactive, multimedia tool of cognitive stimulation in Alzheimer's disease

Objective

To determine the usefulness of an interactive multimedia internet‐based system (IMIS) for the cognitive stimulation of Alzheimer''s disease.

Methods

This is a 24‐week, single‐blind, randomised pilot study conducted on 46 mildly impaired patients suspected of having Alzheimer''s disease receiving stable treatment with cholinesterase inhibitors (ChEIs). The patients were divided into three groups: (1) those who received 3 weekly, 20‐min sessions of IMIS in addition to 8 h/day of an integrated psychostimulation program (IPP); (2) those who received only IPP sessions; and (3) those who received only ChEI treatment. The primary outcome measure was the Alzheimer''s Disease Assessment Scale‐Cognitive (ADAS‐Cog). Secondary outcome measures were: Mini‐Mental State Examination (MMSE), Syndrom Kurztest, Boston Naming Test, Verbal Fluency, and the Rivermead Behavioral Memory Test story recall subtest.

Results

After 12 weeks, the patients treated with both IMIS and IPP had improved outcome scores on the ADAS‐Cog and MMSE, which was maintained through 24 weeks of follow‐up. The patients treated with IPP alone had better outcome than those treated with ChEIs alone, but the effects were attenuated after 24 weeks. All patients had improved scores in all of the IMIS individual tasks, attaining higher levels of difficulty in all cases.

Conclusion

Although both the IPP and IMIS improved cognition in patients with Alzheimer''s disease, the IMIS program provided an improvement above and beyond that seen with IPP alone, which lasted for 24 weeks.Alzheimer''s disease is the most frequent form of dementia in elderly people,^1,2 and its current treatment includes cholinesterase inhibitors (ChEIs),^3,4,5 and n‐methyl‐d‐aspartate receptor blockers (eg, memantine).⁶ However, symptomatic treatment often entails non‐pharmacological treatments as well, and adequate dementia management requires a wide range of intervention to help maximise the patient''s independence, increase their self‐confidence and relieve burden to the care giver.Current symptomatic treatment of Alzheimer''s disease can improve cognition and functionality.^3,4,5,6 However, before the emergence of these drugs, non‐pharmacological treatments had already been evaluated and cognitive stimulation had been found to be potentially beneficial for patients with dementia.^7,8,9 Although these non‐pharmacological treatments do not always seem efficacious, methodological problems may limit the validity of some studies.¹⁰ A recent Cochrane review¹¹ emphasised caution when interpreting the results of non‐pharmacological treatments, but suggested that certain cognitive domains could, in fact, benefit from these types of interventions.Clinical and laboratory studies have shown that mental and physical activity can positively influence cognition in normal elderly people and people with dementia. Education¹² and lifestyle choices (eg, occupation and leisure activities)^13,14,15 can modulate the risk of developing dementia, and psychomotor stimulation improves cognition in patients with Alzheimer''s disease.^16,17 Environmental enrichment can improve cognition in transgenic mice.^18,19 Despite the continued deposition of β‐amyloid, exercise can increase the levels of brain‐derived neurotrophic factor²⁰ and may reduce amyloid burden.²¹Despite the progressive nature of the degenerative process, patients with Alzheimer''s disease also seem to retain the physiological capacity to alter brain structure and function. Recent studies have shown cognitive plasticity and learning potential not only in patients with Alzheimer''s disease but also in healthy elders.^22,23 Positron emission tomography studies that used activation paradigms^24,25 have found that people with Alzheimer''s disease have a greater activation than those without dementia in the brain regions usually associated with memory tasks, as well as in the frontal lobes that were activated only with increasing difficulty of tasks. Pathological studies conducted on biopsy specimens of patients with Alzheimer''s disease with mild or moderate dementia have shown increased synaptic contact size.²⁶ Thus, the brain may be able to compensate during the early stages of Alzheimer''s disease, suggesting that there may be some utility to non‐pharmacological adjunctive interventions.Although studies on cognitive stimulation show that it is possible to stimulate the memory of patients with Alzheimer''s disease, the results are often modest. Because of methodological limitations, there is a need to conduct more randomised‐controlled trials with larger samples to validate this therapeutic approach. Computerised systems²⁷ and internet‐based distance programs offer one potential mechanism by which non‐pharmacological cognitive stimulation can be conducted in patients with dementia. In this study, we evaluated an interactive multimedia internet‐based system (IMIS) as an adjunct to ChEI treatment and classic psychostimulation treatment.     

A prospective study of secondary degeneration following subcortical infarction using diffusion tensor imaging

Background

Secondary degeneration of the pyramidal tract distal to the primary lesion after a stroke has been detected by some studies using diffusion tensor imaging (DTI) but its potential clinical significance and the degeneration of the fibre tract proximal to the primary lesion have received little attention.

Methods

Twelve patients underwent DTI on the 1st, 4th and 12th week following a subcortical infarct involving the posterior limb of the internal capsule, and 12 age and sex matched controls underwent DTI once. The DTI parameters mean diffusivity and fractional anisotropy (FA), and the clinical scores before DTI examination, including the National Institutes of Health Stroke Scale (NIHSS), the Fugl–Meyer (FM) scale and the Barthel index (BI), were assessed. The relations between the per cent changes in DTI parameters and clinical scores were analysed.

Results

From the 1st to the 12th week after stroke onset, FA values decreased (p<0.01, respectively) in the fibre tract above and below the internal capsule, and the NIHSS decreased (p<0.01) but the FM scale and BI increased (p<0.01, respectively) progressively. The per cent reductions in FA value in the fibre tract above and below the internal capsule were negatively correlated with the per cent changes in NIHSS and FM scale (p<0.05, respectively).

Conclusions

Secondary degeneration of the fibre tract proximal and distal to a primary lesion can be detected by DTI clearly and quantitatively and deteriorates with time progressively, which may hamper functional recovery after a subcortical cerebral infarct.Animal experiments and post‐mortem examinations have demonstrated that a focal cerebral infarct can cause secondary degeneration in fibre pathways remote from the primary lesion. Delayed disintegration of such a fibre tract is considered to be Wallerian degeneration (WD), defined as anterograde degeneration of a nerve tract distal to an injury.^1,2,3,4,5 Conventional MRI can detect the ipsilateral cerebral peduncle atrophy during the chronic stage of a focal cortical infarct^6,7,8 but cannot reveal the delayed degeneration in the pyramidal tract on other regions clearly or quantitatively. Diffusion tensor imaging (DTI), which uses diffusion sensitive gradients applied in at least six non‐collinear directions, can determine the diffusivity of every voxel and fully depict tissue diffusion characteristics. DTI has been used to detect and quantify the secondary degeneration in the fibre tract in vivo.^9,10Thomalla et al¹¹ reported that secondary degeneration revealed by DTI occurred in the pyramidal tract distal to the primary lesion from the acute (5 days from onset) to the chronic (288 days) stage in two patients with ischaemic stroke. In some cross sectional studies, fractional anisotropy (FA) values were found to be generally reduced along the pyramidal tract on the infarct side distal to the primary lesion.^9,12,13 After middle cerebral artery territory infarction, lower FA values in the cerebral peduncle were associated with a greater neurological deficit acutely, with worse outcomes 3 months later.¹³ However, to date, no prospective, controlled, contrast enhanced studies have monitored secondary degeneration, and the potential clinical significance of the degeneration distal to the primary lesion has not been confirmed. In addition, only one case report revealed that a pontine infarct can cause retrograde degeneration in the fibre pathway proximal to the primary lesion.¹⁴ However, there has been little research on the retrograde degeneration of the fibre tract after subcortical infarction, and its impact on the patient''s outcome is not well understood.In this study, DTI was used to prospectively quantify and monitor changes in diffusivity in the fibre pathway both proximal and distal to a recent subcortical infarct in 12 patients. The relation between the per cent changes in DTI parameters and clinical scores were analysed.     

Botulinum toxin for writer's cramp: a randomised, placebo-controlled trial and 1-year follow-up

Background

Botulinum toxin type A (BoNT‐A) has become the treatment of choice for most types of focal dystonia.

Objective

To investigate the efficacy of BoNT‐A injections in patients with writer''s cramp in a double‐blind, randomised, placebo‐controlled trial and to evaluate the follow‐up results.

Methods

Forty participants were randomised to treatment with either BoNT‐A or placebo injections in two sessions. Trial duration was 12 weeks. The primary outcome measure was the patients'' choice to continue with the treatment, despite its possible disadvantages. Secondary outcome measures included several clinical rating scales on the levels of impairment and disability. Assessments were made at baseline and 2 months (secondary outcomes) and 3 months (primary outcome). Duration of follow‐up was 1 year.

Results

39 patients completed the trial. Fourteen of 20 patients (70%) receiving BoNT‐A reported a beneficial effect and chose to continue treatment, versus 6 of 19 patients (31.6%) in the placebo group (p = 0.03). The changes on most of the clinical rating scales were significantly in favour of BoNT‐A. Side effects reported were hand weakness, which was mostly mild and always transient, and pain at the injection site. After 1 year, 20 of 39 patients were still under treatment with a positive effect.

Conclusion

Treatment with BoNT‐A injections led to a significantly greater improvement compared with placebo, according to patients'' opinion and clinical assessment scales. Weakness in the hand is an important side effect of BoNT‐A injections, but despite this disadvantage, most patients preferred to continue treatment. About 50% of our patients were still under treatment after 1 year.Writer''s cramp is a task‐specific, focal hand dystonia. It is characterised by involuntary, repetitive or sustained contractions of finger, hand or arm muscles that occur during writing and produce abnormal postures or movements that interfere with normal handwriting.^1,2,3,4 Two categories are recognised: simple writer''s cramp, in which dystonic posturing of the hand and arm occurs only during writing, and complex or dystonic writer''s cramp, in which the condition manifests also during other manual tasks and sometimes with spontaneous abnormal posturing.^1,2,5 In most patients, no specific cause can be identified. Although the prevalence is relatively low, varying from 3 to 7/100 000,^6,7,8 writer''s cramp may be responsible for considerable morbidity in terms of working impairment, pain, embarrassment, low self‐esteem and poor social interaction.Therapeutic recommendations have included physical treatment, postural and writing re‐education exercises, relaxation techniques, hypnosis, biofeedback, use of special writing devices, acupuncture and transcranial magnetic stimulation, but most of the patients do not obtain satisfactory and sustained benefit.^9,10,11,12 Some patients learn to write with their non‐dominant hand, but there is a 25% chance that this hand will become afflicted with the same problem.¹³ Drug treatment has been disappointing so far.^3,9,14 The use of splints or braces and constraint‐induced movement treatment may occasionally be helpful, but it is not clear if they produce sustained relief.^15,16,17 There is presently only limited experience with stereotactic neurosurgical procedures for focal hand dystonia.^18,19 The treatment of dystonic syndromes such as blepharospasm and cervical dystonia has been much improved by the introduction of botulinum toxin as a therapeutic agent.^20,21 When botulinum toxin is injected into muscles, the toxin produces local chemodenervation by interfering with the release of acetylcholine from the presynaptic nerve terminal.⁴ However, there are also several drawbacks. Firstly, the effects of botulinum toxin type A (BoNT‐A) are not permanent, lasting for only approximately 3 months; thus, regular injections are required. Secondly, inconvenient muscle weakness interfering with other non‐writing activities may occur.²² Regarding the treatment of writer''s cramp, three randomised, double‐blind, placebo‐controlled studies have been undertaken, however, with small numbers of patients, different methods and inconclusive results.^23,24,25We performed a randomised, double blind, placebo‐controlled trial in 40 patients with writer''s cramp, to assess whether the benefits of BoNT‐A treatment outweigh its disadvantages. The trial duration was 12 weeks and thereafter patients were followed for 1 year.     

Evidence for white matter disruption in traumatic brain injury without macroscopic lesions

Background

Non‐missile traumatic brain injury (nmTBI) without macroscopically detectable lesions often results in cognitive impairments that negatively affect daily life.

Aim

To identify abnormal white matter projections in patients with nmTBI with cognitive impairments using diffusion tensor magnetic resonance imaging (DTI).

Methods

DTI scans of healthy controls were compared with those of 23 patients with nmTBI who manifested cognitive impairments but no obvious neuroradiological lesions. DTI was comprised of fractional anisotropy analysis, which included voxel‐based analysis and confirmatory study using regions of interest (ROI) techniques, and magnetic resonance tractography of the corpus callosum and fornix.

Results

A decline in fractional anisotropy around the genu, stem and splenium of the corpus callosum was shown by voxel‐based analysis. Fractional anisotropy values of the genu (0.47), stem (0.48), and splenium of the corpus callosum (0.52), and the column of the fornix (0.51) were lower in patients with nmTBI than in healthy controls (0.58, 0.61, 0.62 and 0.61, respectively) according to the confirmatory study of ROIs. The white matter architecture in the corpus callosum and fornix of patients with nmTBI were seen to be coarser than in the controls in the individual magnetic resonance tractography.

Conclusions

Disruption of the corpus callosum and fornix in patients with nmTBI without macroscopically detectable lesions is shown. DTI is sensitive enough to detect abnormal neural fibres related to cognitive dysfunction after nmTBI.Cognitive and vocational sequelae are common complications after non‐missile traumatic brain injury (nmTBI) without obvious neuroradiological lesions.^1,2 They may present as memory disturbance, impairments in multitask execution and loss of self‐awareness.³ These symptoms have been attributed to diffuse brain injury and the diffuse loss of white matter or neural networks in the brain.^4,5,6 Currently no accurate method is available for diagnosing and assessing the distribution and severity of diffuse axonal injury. As computed tomography and magnetic resonance imaging (MRI) findings underestimate the extent of diffuse axonal injury and correlate poorly with the final neuropsychological outcome,^7,8 this dysfunction tends to be clinically underdiagnosed or overlooked. Indirect evidence for loss of functional connectivity after nmTBI has been provided by both morphometric and functional neuroimaging studies. Morphometric analysis of nmTBI has shown the relationship between atrophy of the corpus callosum and fornix and the neuropsychological outcome.⁹ Most functional neuroimaging studies conducted after nmTBI have shown that cognitive and behavioural disorders are correlated, with some degree of secondary hypometabolism or hypoperfusion in regions of the cortex.⁵ To date, however, there has been no direct in vivo demonstration of structural disconnections without macroscopically detectable lesions in patients with nmTBI.Diffusion tensor magnetic resonance imaging (DTI), which measures diffusion anisotropy in vivo, is a promising method for the non‐invasive detection of the degree of fibre damage in various disease processes affecting the white matter.^10,11 In biological systems, the diffusional motion of water is impeded by tissue structures, such as cell membranes, myelin sheaths, intracellular microtubules and associated proteins. Motion parallel to axons or myelin sheaths is inhibited to a lesser degree than perpendicular motion, a phenomenon known as diffusion anisotropy.¹² Fractional anisotropy was applied to evaluation of post‐traumatic diffuse axonal injury¹³ and its clinical usefulness described. In a previous study,¹⁴ fractional anisotropy score in the acute stage as an index of injury to white matter showed promise in predicting outcome in patients with traumatic brain injury, by using the regions of interest (ROIs) techniques. MRI voxel‐based analysis, a statistical normalising method, has been developed to reduce interindividual variability and to evaluate the whole brain objectively.^15,16,17 We investigated the regions in the whole brain that are commonly injured in patients having nmTBI with cognitive impairments but no macroscopic lesions, using voxel‐based analysis of fractional anisotropy, referred to as diffusion anisotropy. The advent of DTI has allowed inter‐regional fibre tracking, called magnetic resonance tractography, which reconstructs the three‐dimensional trajectories of white matter tracts.^11,18,19 We also investigated whether magnetic resonance tractography sensitively recognises degeneration of the corpus callosum and fornix in individual patients with nmTBI.     

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     

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.     

Single photon emission computed tomography perfusion differences in mild cognitive impairment

Objective

To relate cerebral perfusion abnormalities to subsequent changes in clinical status among patients with mild cognitive impairment (MCI).

Methods

Perfusion single photon emission computed tomography (SPECT) images were acquired in 105 elderly patients without dementia with MCI, using 99mTc‐HMPAO. Clinical outcome after a 5‐year follow‐up period was heterogeneous.

Results

Baseline SPECT data differed in those patients with MCI who were later diagnosed with Alzheimer''s disease (the converter group) from those patients with MCI who experienced clinically evident decline but did not progress to a diagnosis of Alzheimer''s disease within the follow‐up period (the decliner group), from patients with MCI who had no clinical evidence of progression (the stable group), and from a group of 19 normal subjects (the control group). The most consistent decreases in relative perfusion in converters compared with the normal, stable and decliner groups were observed in the caudal anterior cingulate, and in the posterior cingulate. In addition, converters showed increased relative perfusion in the rostral anterior cingulate in comparison to the stable and decliner groups. A group of patients with Alzheimer''s disease were also included for purposes of comparison. The group of patients with Alzheimer''s disease at baseline differed from each of the other groups, with temporoparietal regions showing the most significant reductions in perfusion.

Conclusions

These results suggest that clinical heterogeneity in MCI is reflected in SPECT perfusion differences, and that the pattern of perfusion abnormalities evolves with increasing clinical severity.Regional abnormalities in glucose metabolism and cerebral perfusion are known to occur in patients with a diagnosis of probable Alzheimer''s disease, based on positron emission tomography (PET) and single photon emission computed tomography (SPECT). Decreased metabolism and/or perfusion has been reported primarily in temporoparietal, posterior cingulate and medial temporal regions, and such abnormalities seem to reflect the severity and progression of both clinical impairment and pathological involvement.^1,2,3,4,5Identification of Alzheimer''s disease at the earliest possible time is crucial for optimal care and treatment. Therefore, recent studies have focused on prodromal Alzheimer''s disease. This has been studied by examining baseline PET or SPECT images in patients who are at increased risk for developing Alzheimer''s disease because of mild cognitive impairment, and who then go on to be diagnosed with probable Alzheimer''s disease. Brain regions reported to show metabolism or perfusion abnormalities in those who progress to Alzheimer''s disease have included the temporoparietal neocortex, posterior cingulate, anterior cingulate and medial temporal lobe regions.^{3,6,7,8,9,10,11,12,13,14,15}Few of these studies have compared those patients with MCI who will progress over the next few years to the point where they satisfy the diagnostic criteria for probable Alzheimer''s disease with those who decline to a more limited extent and are not diagnosed with Alzheimer''s disease and with those who remain stable. Only one previous study, to our knowledge, has dealt with this issue.⁸ The authors reported that left temporoparietal reductions in glucose metabolism, in combination with performance on a neuropsychological task (ie, block design), considerably discriminated those people with memory problems who developed Alzheimer''s disease within 3 years from those who remained stable. This study targeted a small number of brain regions for examination, as sample size was limited.We dealt with this question by examining whole brain SPECT datasets using statistical parametric mapping (SPM) in a large number of subjects, some of whom were normal and some of whom had mild cognitive impairments but did not have dementia when the data were acquired. The subjects were then followed longitudinally, and we were able to identify perfusion differences at baseline between subjects who progressed to a diagnosis of Alzheimer''s disease, versus those who remained stable, and those who declined, but were not diagnosed with Alzheimer''s disease during the follow‐up interval. We also determined whether the changes were consistently decreased in cerebral perfusion, or whether increases were also observed, as reported by a recent study.¹⁴ Lastly, we examined the relationship between SPECT perfusion measures and neuropsychological test scores in the same subjects.     

The effect of the apolipoprotein E gene polymorphisms and haplotypes on behavioural and psychological symptoms in probable Alzheimer's disease

Background

Patients with Alzheimer''s disease and dementia commonly suffer from behavioural and psychological symptoms of dementia (BPSD). A genetic component to BPSD development in Alzheimer''s disease has been demonstrated. Several studies have investigated whether the exon 4 ε2/ε3/ε4 haplotype of the apolipoprotein E (APOE) gene is associated with BPSD, with variable results.

Objective

We investigated the exon 4 polymorphisms and extended this study to include promoter polymorphisms and the resultant haplotypes across the gene.

Methods

Our large independent cohort of 388 patients with longitudinal measures of BPSD assessed by the Neuropsychiatric Inventory was used to analyse whether any of these variants were associated with the presence of BPSD.

Results

We revealed several significant relationships before correction for multiple testing. The exon 4 haplotype was associated with hallucinations and anxiety, A‐491T with irritability, T‐427C with agitation/aggression and appetite disturbances, and T‐219C with depression. Haplotype analyses of all variants did not reveal any statistically significant findings.

Conclusions

Our data and a review of previous studies showed a diversity of relationships, suggesting that these findings might be due to chance and so collectively do not support a role for the APOE gene in BPSD.Many patients with dementia display behavioural and psychological symptoms of dementia (BPSD). Unlike cognitive decline, BPSD do not continuously exist in a patient once they have occurred. Genetic determinants of BPSD in Alzheimer''s disease have been proposed from studies on families.^1,2,3 It has been hypothesised that the genes that increase the risk for Alzheimer''s disease may also determine the presence of BPSD.⁴ The ε4 allele of the apolipoprotein E (APOE) gene is the only risk factor robustly associated with Alzheimer''s disease. However, previous investigations on APOE have produced inconsistent findings on BPSD, with some researchers reporting associations with a variety of different symptoms and alleles^{4,5,6,7,8,9,10,11,12,13,14,15,16} (summarised in the table provided online at http://jnnp.bmjjournals.com/supplemental), whereas others find no relevant relationships.^{17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33} We used a large independent clinical cohort of patients with Alzheimer''s disease, with longitudinal data on BPSD to further extend these studies, and additionally investigated promoter polymorphisms of APOE, which have been shown to independently incur risk of Alzheimer''s disease in some studies.³⁴     

Psychiatric disorders in preclinical Huntington's disease

Background

Psychiatric symptoms are a common feature of Huntington''s disease (HD) and often precede the onset of motor and cognitive impairments. However, it remains unclear whether psychiatric changes in the preclinical period result from structural change, are a reaction to being at risk or simply a coincidental occurrence. Few studies have investigated the temporal course of psychiatric disorder across the preclinical period.

Objectives

To compare lifetime and current prevalence of psychiatric disorder in presymptomatic gene carriers and non‐carriers and to examine the relationship of psychiatric prevalence in gene carriers to temporal proximity of clinical onset.

Methods

Lifetime and current psychiatric histories of 204 at risk individuals (89 gene carriers and 115 non‐carriers) were obtained using a structured clinical interview, the Composite International Diagnostic Interview. Psychiatric disorders were classified using both standardised diagnostic criteria and a more subtle symptom based approach. Follow‐up of gene carriers (n = 51) enabled analysis of the role of temporal proximity to clinical onset.

Results

Gene carriers and non‐carriers did not differ in terms of the lifetime frequency of clinical psychiatric disorders or subclinical symptoms. However, gene carriers reported a significantly higher rate of current depressive symptoms. Moreover, the rate of depression increased as a function of proximity to clinical onset.

Conclusions

Affective disorder is an important feature of the prodromal stages of HD. The findings indicate that depression cannot be accounted for by natural concerns of being at risk. There is evidence of a window of several years in which preclinical symptoms are apparent.Huntington''s disease (HD) is an inherited neurodegenerative disorder, characterised by motor dysfunction, cognitive impairment and psychiatric disturbance. HD is associated with a wide range of psychiatric disturbances, including affective disorders,^1,2,3 irritability,^4,5,6 apathy^1,3,6 and psychosis.^4,7,8 Both major depression^1,2,4,9 and more subtle mood disturbances¹⁰ have been reported to predate clinical onset, conventionally defined by onset of motor symptoms. However, the basis for psychiatric symptoms remains unclear. Depression has been observed to occur up to 20 years before the onset of motor symptoms,^9,11 raising the possibility that psychiatric symptoms are an early indicator of HD and result from incipient neurodegenerative changes. However, the finding that psychiatric symptoms tend to cluster in certain HD families might indicate that psychiatric changes have a genetic basis and reflect a “switching on” of the HD gene early in life.^2,8 High rates of psychiatric disturbance have also been observed in HD family members who do not carry the genetic mutation,^9,10 raising the alternative possibility that affective changes arise in response to emotional stressors, such as being at risk, or the burden of growing up in a family with affected members. A more thorough understanding of the underlying basis of psychiatric changes in preclinical gene carriers is crucial, as future therapeutic strategies are most likely to target such individuals.Previous psychiatric studies of at risk individuals have yielded inconsistent results. Earlier studies reported high lifetime rates of psychiatric disorder in preclinical gene carriers (eg, 18% major affective disorder),² whereas more recent studies indicate little difference between rates for gene carrier and non‐carrier groups.^10,12,13,14 A number of factors may account for these discrepancies. The majority of earlier reports were limited to retrospective observation of affected individuals and therefore lacked appropriate controls.^4,5 The advent of predictive testing has enabled direct comparison of at risk individuals who have the HD mutation and those who do not, thereby controlling for social and environmental factors.^10,12,13,14 Whereas the majority of earlier studies lacked standardised assessment criteria,^4,7 more recent studies have utilised operational diagnostic criteria, although these have in turn been criticised for failing to detect the more subtle psychiatric disturbances that can occur in HD.^3,15Few studies have taken account of the temporal distance to onset of motor symptoms. It is now well established that the clinical onset of HD is typically preceded by a prodromal period of several months or years during which non‐specific mild neurological signs arise intermittently.¹⁶ The difficulty in establishing exact dates of onset for retrospective cases may have led to the inclusion in earlier studies of individuals who were already in the early stages of HD. Studies of presymptomatic individuals have typically recruited participants without motor signs, who may have been further from clinical onset.The present study is a double blind comparison of lifetime and current prevalence of psychiatric disorders in preclinical gene carriers and non‐carriers, using a combination of standardised psychiatric diagnostic criteria and a more subtle symptom based approach. Follow‐up of gene carriers has enabled analysis of the role of temporal proximity to clinical onset.     

Cognitive outcome 5 years after bilateral chronic stimulation of subthalamic nucleus in patients with Parkinson's disease

Aim

To assess the long‐term cognitive and behavioural outcome after bilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN) in patients affected by Parkinson''s disease, with a 5‐year follow‐up after surgery.

Methods

11 patients with Parkinson''s disease treated by bilateral DBS of STN underwent cognitive and behavioural assessments before implantation, and 1 and 5 years after surgery. Postoperative cognitive assessments were carried out with stimulators turned on.

Results

A year after surgery, there was a marginally significant decline on a letter verbal fluency task (p = 0.045) and a significant improvement on Mini‐Mental State Examination (p = 0.009). 5 years after surgery, a significant decline was observed on a letter verbal fluency task (p = 0.007) and an abstract reasoning task (p = 0.009), namely Raven''s Progressive Matrices 1947. No significant postoperative change was observed on other cognitive variables. No patient developed dementia 5 years after surgery. A few days after the implantation, two patients developed transient manic symptoms with hypersexuality and one patient developed persistent apathy.

Conclusion

The decline of verbal fluency observed 5 years after implantation for DBS in STN did not have a clinically meaningful effect on daily living activities in our patients with Parkinson''s disease. As no patient developed global cognitive deterioration in our sample, these findings suggest that DBS of STN is associated with a low cognitive and behavioural morbidity over a 5‐year follow‐up, when selection criteria for neurosurgery are strict.Chronic bilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective neurosurgical procedure for treatment of motor symptoms in patients with advanced Parkinson''s disease, who cannot be satisfactorily treated with pharmacological treatments. The safety of this procedure has been investigated by several studies, which have assessed the effects of STN DBS on cognition and behaviour.^1,2,3 Some investigations have also attempted to distinguish between the cognitive effects of surgical intervention and those of DBS of STN in itself.^4,5,6,7All neuropsychological investigations in patients treated by STN DBS showed a postoperative decline of verbal fluency, whereas less consistent effects have been reported on other cognitive tasks in different studies. A postoperative decline of episodic verbal memory, which was detectable 3 months after surgery, has been reported in some investigations.^6,8Different effects of STN DBS on various frontal cognitive functions have been described. STN stimulation may impair response‐inhibition performance on the interference task of the Stroop test, as compared with the off‐stimulation condition.^5,7,9 A positron emission tomography study showed that such impaired performance on the Stroop test in the on‐stimulation condition is associated with decreased activation in both the right anterior cingulate cortex and the right ventral striatum.⁹ Conversely, short‐term STN stimulation may improve performance on cognitive flexibility tasks, including random number generation⁷ and the Modified Wisconsin Card Sorting Test (MWCST).⁵Various behavioural effects have been described in patients with Parkinson''s disease treated by STN DBS. Some studies reported cases of depression¹⁰ or increased apathy,¹¹ whereas cases of mania were described in other studies^12,13,14 and an improvement of depression¹ or apathy¹⁵ was also found.The long‐term cognitive and behavioural effects of bilateral STN DBS were investigated in 70 patients with Parkinson''s disease followed up for 3 years.¹¹ In this study, a decline of verbal fluency, an improvement of depression and an increased apathy were observed 3 years after surgery. Some patients showed behavioural changes (aggressive behaviour, hypomania, depression and psychosis), which were mostly transient. Recently, the long‐term outcome of bilateral DBS of STN was investigated in a multicentre study conducted in 49 patients with Parkinson''s disease followed up for 3 or 4 years.¹⁶ This study showed that stimulation of the STN induced a significant improvement in Parkinsonian motor symptoms and activities of daily living 3–4 years after surgery. Among the adverse events, the authors reported memory decline or psychiatric disturbances (including hallucinations, delirium, depression, apathy and anxiety), which occurred in about 30% of the patients.In two recent investigations, the long‐term outcome of bilateral DBS of STN was investigated in patients with a 5‐year follow‐up.^17,18 In one study conducted on 49 patients with Parkinson''s disease,¹⁷ cognitive performance was assessed by means of the Mattis Dementia Rating Scale (MDRS)¹⁹ and a frontal‐lobe score.⁴ Five years after surgery, there was a marked improvement of both motor function, while off drugs, and activities of daily living, a statistical trend towards a decline on the MDRS (reflecting the appearance of progressive dementia in three patients between the third and the fifth postoperative years) and a significant decline in the average frontal‐lobe score. Another study carried out on 37 patients with Parkinson''s disease¹⁸ also assessed cognitive performance by means of MDRS¹⁹ and a frontal score.²⁰ Five years after the implantation, there was an improvement in Parkinsonian motor symptoms and activities of daily living and a reduction of levodopa‐related motor complications and levodopa daily doses. However, a significant decline in cognitive performance was detected on the MDRS and the frontal score.To our knowledge, no extensive neuropsychological data have been reported so far in patients with a follow‐up >3 years. The aim of the present study was to assess the long‐term cognitive and behavioural outcome after bilateral DBS of the STN in a series of patients followed up for 5 years after surgery.     

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.     

A population-based study of depressive symptoms in multiple sclerosis in Stockholm county: association with functioning and sense of coherence

Objectives

To explore and analyse the prevalence of depressive symptoms in people with multiple sclerosis (PwMS), taking into account disease‐related and sociodemographic factors, and also to analyse the association between depressive symptoms and functioning (tested and self‐reported) and sense of coherence (SOC), respectively.

Methods

Home visits were made to a population‐based sample of 166 PwMS. Data were obtained from structured, face‐to‐face interviews using the Beck Depression Inventory (BDI), the Sickness Impact Profile (SIP) and the SOC scale. A range of tests were also carried out for analyses of different aspects of functioning such as cognitive function, walking capacity and manual dexterity, and structured interviews examined activities of daily living and frequency of social/lifestyle activities.

Results

19% (28/149) of the people were depressed (BDI ⩾13). Depressive symptoms were associated with worse self‐reported functioning on the SIP and with poor memory function, but not with any of the other tests of functioning. Depressive symptoms were associated with weak SOC, but not with any of the disease‐related or sociodemographic factors studied.

Conclusion

The prevalence of depressive symptoms in a population‐based sample of PwMS is high. Given the serious nature of depression and its association with worse self‐reported functioning and weak SOC, attention to, and treatment of, mental‐health problems and depression are strongly indicated in the clinical management of multiple sclerosis.Few population‐based studies of depression have been conducted on multiple sclerosis,^1,2,3,4,5 although many reports of depression and its correlation with numerous variables in clinical samples of people with multiple sclerosis (PwMS) have been published. The population‐based studies have all reported a high prevalence of depression^1,2,3,4,5 despite using different methods of data collection.Depressive symptoms are reported to be associated with decreases in functioning.⁶ In multiple sclerosis, it has been reported that depressed PwMS perform worse than the non‐depressed in evaluations of cognitive function,⁷ but there are conflicting reports.⁵ Depressive symptoms in PwMS are also associated with worse self‐reported functioning and health‐related quality of life scores,⁸ and depressed PwMS have been shown to be more likely to perceive their disability as being greater than their doctors'' perception.⁹ It is therefore important to consider different aspects of functioning when evaluating the presence of depression in PwMS.In the salutogenic model, proposed by Antonovsky,¹⁰ health is described as a continuum between ease and disease rather than as the binary opposite of disease; the model is thus appropriate for studying people afflicted with chronic disorders. Sense of coherence (SOC) refers to “general resistance resources”—capacities that facilitate coping with stressors and thereby improve health.¹⁰ The SOC describes the degree to which a person views the world as meaningful, comprehensible and manageable.¹⁰ SOC has been studied in several patient groups^11,12 including those with multiple sclerosis.^13,14 Weak SOC has been found to be associated with a higher prevalence of depression in studies of people with chronic diseases, such as rheumatoid arthritis,¹⁵ but this has not been explored in PwMS.Certain inconsistencies were observed in previously presented results on depression and its association with disease‐related and sociodemographic factors.^1,2,3,4,5 On account of differences in healthcare systems and policies, the results from population‐based studies of depression and functioning in other countries may not easily be extrapolated to Swedish conditions.We have conducted a cross‐sectional, population‐based study of PwMS in Stockholm county, to comprehensively describe and analyse their functioning and health (the Stockholm MS Study). In this report from the Stockholm MS Study, the aim was to explore the prevalence of depressive symptoms, taking into account disease‐related and sociodemographic factors, and also to analyse the association between depressive symptoms and functioning (tested and self‐reported) and SOC, respectively.     

Post-surgical changes in brain metabolism detected by magnetic resonance spectroscopy in normal pressure hydrocephalus: results of a pilot study

Background

Adult normal pressure hydrocephalus (NPH) is one of the few potentially treatable causes of dementia. Some morphological and functional abnormalities attributed to hydrocephalus improve following treatment.

Objectives

We focused on analysis of changes in cerebral metabolites using proton magnetic resonance spectroscopy (¹H‐MRS) after NPH treatment, and its clinical and cognitive correlation.

Methods

¹H‐MRS, neuropsychological and clinical status examinations were performed before and 6 months after shunting in 12 adults with idiopathic NPH. We obtained N‐acetyl‐aspartate (NAA), choline (Cho), myoinositol (MI) and creatine (Cr) values.

Results

After surgery, NAA/Cr was significantly increased. Moreover, NAA/Cr values were related to cognitive deterioration.

Conclusion

MRS could be a marker of neuronal dysfunction in NPH.Normal pressure hydrocephalus (NPH) is a potentially treatable cause of dementia,^1,2 characterised by progressive cognitive dysfunction, gait disturbance and urinary incontinence associated with ventricular enlargement and abnormalities in CSF dynamics. In these patients, some morphological and functional abnormalities attributed to hydrocephalus improve after treatment.^3,4,5 Proton magnetic resonance spectroscopy (¹H‐MRS) allows non‐invasive in vivo measurement of brain metabolites. Findings from MRS studies reveal that ¹H‐MRS is a potentially non‐invasive technique with sufficient sensitivity to detect subtle changes in neuronal function in neurodegenerative diseases, allowing investigation of neuronal injury or dysfunction^6,7 and the assessment of treatment efficacy.^8,9,101H‐MRS studies in patients with hydrocephalus are scarce.^{6,7,11,12,13,14,15} Changes in cerebral metabolites after treatment with hydrocephalus using this technique have been analysed in only two studies, which concentrated exclusively on the results of lactate metabolites.^11,12The aim of our study was to describe changes in other major metabolites, using ¹H‐MRS, before and after treatment in idiopathic NPH patients, and to obtain preliminary data on their clinical and cognitive correlation, which could serve as the basis for larger studies with control subjects.     

Course and outcome of acute limbic encephalitis with negative voltage-gated potassium channel antibodies

Background

Limbic encephalitis is a potentially treatable immunological condition. The presence of voltage‐gated potassium channel antibodies (VGKC‐Ab) in the cerebrospinal fluid (CSF) and serum of patients with the condition is a marker of the disease associated with a non‐paraneoplastic form and good response to treatment. Recent work has highlighted absent serum VGKC‐Ab and distinct immunology in patients with the paraneoplastic form of limbic encephalitis.

Methods

The cases of four patients with the typical clinical presentation, neuropsychological features and brain imaging of acute limbic encephalitis, in the absence of any evidence for associated cancer during a follow‐up of at least 18 months are described here.

Results

All patients had negative testing for VGKC‐Ab measured during their acute presentation. All patients made some recovery, although they were left with marked cognitive deficits and persistent seizures.

Conclusion

These cases demonstrate that the absence of VGKC‐Ab in limbic encephalitis does not necessarily imply a paraneoplastic form. Further work is required to establish the immunological basis for the disorder in these patients, and the optimal treatment regimen.Limbic encephalitis is characterised by three features: a core amnesic syndrome, complex‐partial and secondary‐generalised seizures, and a variable affective prodrome.^1,2 The core memory syndrome includes profound anterograde amnesia with variable recovery.^1,3 The syndrome is associated with an isolated high signal in the mesial temporal lobes on MRI scan⁴ and histological inflammatory change in these areas.^5,6Limbic encephalitis was initially identified as a paraneoplastic phenomenon, occurring more commonly with occult small‐cell bronchial carcinoma (in association with autoantibodies to Hu), testicular carcinoma and thymoma (in association with antibodies to CRMP5/CV2).⁷ In recent years, a non‐paraneoplastic variant has been characterised.^2,8 Patients with this form have been shown to express increased levels of voltage‐gated potassium channel antibodies (VGKC‐Ab) in their serum. This antibody is also expressed in Morvan''s syndrome,⁹ also with affective and memory components. The detection of such antibodies in serum was established by radioimmunoprecipitation asssays using α‐dendrotoxin, which binds to the Kv1.1, Kv1.2 and Kv1.6 ion channel subunits.^10,11More recently, a second antibody has been identified in patients with a paraneoplastic form of the disorder, a subacute course (where the syndrome can evolve over weeks rather than days) and negative VGKC‐Ab.¹² This antibody in the serum and cerebrospinal fluid (CSF) reacts to the neuropil of the hippocampus and cerebellum. This is in contrast with other paraneoplastic syndromes where the antibody reacts either to oligodendrocytes or to the neuronal cytoplasm. The work suggests the existence of immune‐mediated bases for both paraneoplastic and non‐paraneoplastic forms of the disorder, where these bases are distinct. Consistent with an underlying immunological cause, non‐paraneoplastic^2,13 and paraneoplastic^6,14,15 types of the condition have both been shown to respond to immunotherapies including intravenous steroids, immunoglobulins and plasma exchange. Moreover, the antibody titre in non‐paraneoplastic^2,12,13 and paraneoplastic types¹² has been shown to reflect clinical response to treatment.The above studies suggest characteristic antibody “profiles” for neoplastic and non‐paraneoplastic forms of the disorder, where the non‐paraneoplastic form of the disorder is associated with VGKC‐Ab. Here, we provide evidence for a broader immunological spectrum of non‐paraneoplastic limbic encephalitis. We describe four patients with the typical features of acute limbic encephalitis with no evidence of associated cancer in the absence of serum VGKC‐Ab.     

The 39 item Parkinson's disease questionnaire (PDQ-39) revisited: implications for evidence based medicine

Background

The 39 item Parkinson''s disease questionnaire (PDQ‐39) is the most widely used patient reported rating scale in Parkinson''s disease. However, several fundamental measurement assumptions necessary for confident use and interpretation of the eight PDQ‐39 scales have not been fully addressed.

Methods

Postal survey PDQ‐39 data from 202 people with Parkinson''s disease (54% men; mean age 70 years) were analysed regarding psychometric properties using traditional and Rasch measurement methods.

Results

Data quality was good (mean missing item responses, 2%) and there was general support for the legitimacy of summing items within scales without weighting or standardisation. Score reliabilities were adequate (Cronbach''s alpha 0.72–0.95; test–retest 0.76–0.93). The validity of the current grouping of items into scales was not supported by scaling success rates (mean 56.2%), or factor and Rasch analyses. All scales represented more health problems than that experienced by the sample (mean floor effect 15%) and showed compromised score precision towards the less severe end.

Conclusions

Our results provide general support for the acceptability and reliability of the PDQ‐39. However, they also demonstrate limitations that have implications for the use of the PDQ‐39 in clinical research. The grouping of items into scales appears overly complex and the meaning of scale scores is unclear, which hampers their interpretation. Suboptimal targeting limits measurement precision and, therefore, probably also responsiveness. These observations have implications for the role of the PDQ‐39 in clinical trials and evidence based medicine. PDQ‐39 derived endpoints should be interpreted and selected cautiously, particularly regarding small but clinically important effects among people with less severe problems.The past decade has seen two major developments in clinical Parkinson''s disease (PD) research: an increasing focus on evidence based medicine and a growing emphasis on the importance of patient reported outcomes.^1,2 It is therefore reasonable to expect the effectiveness of therapy to increasingly be judged on the basis of patient completed rating scales. A prerequisite for valid interpretation of clinical findings, and hence evidence based medicine, is that rating scales can be interpreted with confidence.^3,4,5,6 The need for high quality patient reported rating scales in PD and the fundamental role of evidence based measurement in clinical research is thus apparent.The 39 item PD questionnaire (PDQ‐39)⁷ is the most widely used disease specific patient completed rating scale in PD.⁸ However, several important measurement properties of the PDQ‐39 have not been fully addressed. For example, basic requirements (scaling assumptions) that determine the legitimacy of summing PDQ‐39 item scores without weighting or standardisation have not been examined, and studies addressing the validity of grouping items into its eight scales (dimensionality) have shown inconclusive or discouraging results.^9,10,11,12 This poses limitations on the possibility to interpret study outcomes as it may be unclear what scores represent.⁴ There have also been indications that the PDQ‐39 may not target respondents adequately, which could affect its ability to detect clinically relevant changes.¹⁰ Re‐evaluation of the PDQ‐39 therefore appears warranted to help inform its use and role in clinical trials and evidence based medicine.With this in mind, we assessed the scaling assumptions, reliability, dimensionality and targeting of the eight PDQ‐39 scales. Whereas the PDQ‐39 was developed within the traditional test theory framework, modern test theory (particularly the Rasch model) is increasingly considered advantageous in scale development and evaluation.^{3,13,14,15,16} The PDQ‐39 was therefore analysed using both traditional and Rasch measurement methods.     

Head trauma in primary cranial dystonias: a multicentre case-control study

Background

The relationship between prior trauma and primary adult‐onset dystonia is not well understood. Previous uncontrolled observations and exploratory case–control studies have yielded contradictory results.

Objective

To analyse the association between cranial dystonia and prior head trauma.

Methods

An ad hoc multicentre case–control study was performed using a semistructured interview to collect detailed information on the history of head trauma before disease onset in five Italian tertiary referral centres for movement disorders. The presence of a history of head trauma and of post‐traumatic sequelae (loss of consciousness, bone fractures, scalp/facial wounds) before disease onset was recorded from 177 patients with primary adult‐onset cranial dystonia and from 217 controls with primary hemifacial spasm matched by age strata and sex. Differences between groups were assessed by Mann–Whitney U test and Fisher''s exact test, and the relationship between prior head trauma and case/control status was analysed by multivariate logistic regression models.

Results

No association was found between vault/maxillofacial trauma and cranial dystonia. Most reported traumas occurred several years before disease onset. None of the main post‐traumatic sequelae altered the chance of developing cranial dystonia compared with patients with primary hemifacial spasm, nor did head trauma modify the age at onset of cranial dystonia.

Conclusions

These results do not support prior head trauma as a possible environmental factor modifying the risk of developing late‐onset cranial dystonia. The lack of association may have pathogenetic and medical–forensic implications.Cranial dystonia is an adult‐onset dystonia most commonly affecting the orbicularis oculi and oromandibular muscles.^1,2,3 Like other forms of primary adult‐onset dystonia, cranial dystonias are thought to be multifactorial in origin, with a possible contribution of both genetic and environmental factors.⁴Head trauma leading to structural lesions in the caudate, lentiform nuclei, thalami or midbrain is one of the possible causes of secondary dystonia.^5,6,7,8 A few uncontrolled studies have also suggested an association between cranial dystonia and head trauma in the absence of overt brain lesions.^9,10 Two possible pathogenic mechanisms have been proposed to explain the link between traumatic head injury and cranial dystonia.^9,10,11 The first is discrete brain damage in “sensitive” areas such as the basal ganglia. The second mechanism is that of a peripheral maxillofacial trauma inducing topographically related dystonia^12,13 through maladaptive plastic reorganisation of cortical and subcortical circuits.^{9,10,12,13,14} Two exploratory case–control studies nevertheless found no significant association with cranial dystonia.^15,16 Because these studies assessed a large number of variables owing to multiple testing, they were more liable to a higher risk of false positive results than ad hoc hypothesis‐testing studies. In addition, prior studies^15,16 only partly explored the relationship between dystonia and clinical features of the trauma (loss of consciousness, scalp or facial wounds, cranial or maxillofacial bone fractures), the topographical distribution of the trauma (vault or maxillofacial localisation) and the time elapsed from the trauma to the development of dystonia.To discuss these shortcomings and establish the relationship between previous head trauma and primary late‐onset cranial dystonia, we conducted an ad hoc multicentre case–control study, collecting detailed information on the history of head trauma antecedent to the onset of dystonia.     

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.