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     

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.     

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.     

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     

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.     

Anterior-medial thalamic lesions in dementia: frequent, and volume dependently associated with sudden cognitive decline

Background

The anterior‐medial thalamus (AMT), which is associated with memory processing, is severely affected by Alzheimer''s disease pathology and, when damaged, can be the sole cause of dementia.

Objective

To assess the frequency of magnetic resonance imaging (MRI) hyperintensities affecting the AMT, and their relationship with sudden cognitive decline.

Methods

205 consecutive participants from a university cognitive neurology clinic underwent clinical evaluation, neuropsychological testing and quantitative MRI.

Results

AMT hyperintensities >5 mm³ occurred in 0 of 34 normal controls but were found in 5 of 30 (17%) participants with cognitive impairment with no dementia (CIND), 9 of 109 (8%) patients with probable Alzheimer''s disease, 7 of 17 (41%) with mixed disease and 8 of 15 (53%) with probable vascular dementia (VaD). AMT hyperintensities occurred more often in participants with stepwise decline than in those with slow progression (χ² = 31.7; p<0.001). Of the 29 people with AMT hyperintensities, those with slow progression had smaller medial temporal width (p<0.001) and smaller anterior‐medial thalamic hyperintensities (p<0.001). In a logistic regression model, both variables were significant, and the pattern of decline was correctly classified in 86% of the sample (Cox and Snell R² = 0.56; p<0.001). Those with AMT hyperintensities >55 mm³ were likely to have stepwise decline in cognitive function regardless of medial temporal lobe width; in contrast, those with smaller AMT hyperintensities showed a stepwise decline only in the absence of medial temporal lobe atrophy. All patients with VaD had left‐sided AMT hyperintensities, whereas those with CIND had right‐sided AMT hyperintensities.

Conclusions

AMT hyperintensities >55 mm³ probably result in symptomatic decline, whereas smaller lesions may go unrecognised by clinicians and radiologists. Only half of those with AMT hyperintensities had diagnoses of VaD or mixed disease; the other AMT hyperintensities occurred in patients diagnosed with Alzheimer''s disease or CIND. These silent hyperintensities may nevertheless contribute to cognitive dysfunction. AMT hyperintensities may represent a major and under‐recognised contributor to cognitive impairment.Dementia caused solely by cerebrovascular disease is rare. In a large memory clinic autopsy series of over 1900 people with dementia, only six had infarcts without any Alzheimer''s disease neuropathology,¹ and all six people had infarctions affecting at least one of three key areas: the thalamus, the medial temporal lobe and the frontal cortex.¹ Although the medial temporal lobe has long been appreciated as a site of strategic importance for dementia, the involvement of the thalamus is less frequently assessed. The anterior nucleus of the thalamus is part of a cortical network, including the hippocampus, anterior cingulate and mamillary bodies, which mediates memory processing.^2,3,4,5 Infarcts to the anterior and dorsomedial thalamus are associated with memory impairment in animal studies,⁶ human case reports^7,8,9,10 or series.^{1,11,12,13,14} One indication that thalamic infarcts may be important in dementia populations comes from the Nun Study, which found that people with infarcts to the basal ganglia, thalamus and deep white matter exhibited dementia with less Alzheimer''s disease neuropathology than in those without infarcts.¹⁵Despite this finding, and despite the appreciated role of anterior‐medial thalamic (AMT) infarcts in causing isolated cases of amnesia or dementia in stroke populations,^11,12,13,16 the frequency and consequences of thalamic lesions in a large sample of people with cognitive impairment have not been evaluated. In this study, we quantified hyperintensities on magnetic resonance images (MRI) in the anterior‐medial thalamus in a cognitive neurology clinic sample. We determined the frequency and volumes of thalamic hyperintensities and whether these hyperintensities were associated with sudden changes in cognitive status defined by clinical history.     

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.     

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.     

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.     

Long term follow-up of the first 70 operated adults in the Goteborg Epilepsy Surgery Series with respect to seizures, psychosocial outcome and use of antiepileptic drugs

Objective

To compare long term (10 years) seizure outcome, psychosocial outcome and use of antiepileptic drugs (AED) with the 2 year follow‐up in adults after resective epilepsy surgery.

Methods

All adults (n = 70) who underwent resective epilepsy surgery from 1987 to 1995 in the Göteborg Epilepsy Surgery Series were included. Fifty‐four had undergone temporal lobe resections and 16 extratemporal resections (12 frontal). A cross‐sectional follow‐up in the form of a semistructured interview was performed in late 2003.

Results

Mean follow‐up was 12.4 years (range 8.6–16.2). Of the 70 patients (51% males), five (7%) were dead (three as a result of non‐epilepsy related causes). Of the 65 patients interviewed, 38 (58%) were seizure‐free at the long term follow‐up: 65% of the patients with temporal lobe resections and 36% of the patients with extratemporal resections. Of the 35 patients who were seizure‐free at the 2 year follow‐up, 3 (9%) had seizures at the long term follow‐up. Of the 30 patients who had seizures at the 2 year follow‐up, 6 (20%) were seizure‐free at the long term follow‐up. Of all 65 patients, 45 (69%) had the same seizure status as the 2 year follow‐up. Sixteen (25%) had an improved seizure status and 4 (6%) had a worsened status. Of the seizure‐free patients, 11 (29%) had ceased taking AED, 28 (74%) were working and 25 (66%) had a driving license.

Conclusions

Adult patients who are seizure‐free 2 years after resective epilepsy surgery are most likely to still be seizure‐free 10 years later. Most are working and have obtained a driving license.Epilepsy surgery is a well established treatment for medically intractable epilepsy.^1,2 The ultimate aims of epilepsy surgery are to reduce the frequency and intensity of seizures and thereby to improve quality of life. Most studies of the effectiveness of epilepsy surgery have focused on seizure outcome of anterior temporal lobe resections 1–2 years after surgery. One randomised controlled study² and multiple clinical series have shown that approximately two thirds of patients become free of seizures with impairment of awareness. It has also been shown that quality of life scores improve after temporal lobe resection, especially in seizure‐free patients who also have a trend towards better social function (see Engel et al,³ Jones et al⁴ and Malmgren et al⁵).Concern has been raised about the long term seizure outcome of epilepsy surgery. Several studies have described late seizure recurrences after initial success, sometimes but not always related to discontinuation of antiepileptic drugs (AED).^6,7,8 On the other hand, it has been suggested that seizure outcome at 2 years after surgery in patients subjected to temporal lobectomy predicts the long term outcome.^6,9,10,11,12However, there are only a few studies concerning long term outcome beyond 5 years (ie, presenting data with 10 years of follow‐up).¹³ Most have only included patients subjected to temporal lobectomy and very little is known about the long term seizure outcome for patients who have undergone other resection types.Patients'' aims for epilepsy surgery are, however, not limited to seizure relief. The five commonest aims for patients during presurgical evaluation cited in the study by Taylor et al¹⁴ were: desire for work, driving of motor vehicles, independence, socialising and freedom from drugs (see also Gilliam et al¹⁵). Psychosocial outcomes (eg, employment status, educational status and driving a vehicle) are seldom reported in long term studies. Of the few studies reporting psychosocial aspects, the average follow‐up time is no more than 5 years and most of them have only included patients subjected to temporal lobectomy^4,16,17,18 (see Guldvog et al¹⁹).The Göteborg Epilepsy Surgery Series is a multidisciplinary prospective follow‐up of all patients subjected to epilepsy surgery in Göteborg since its start in 1987. We have previously described the 2 year outcome regarding alterations in seizure frequency,²⁰ general cognitive function, and memory²¹ and psychiatric morbidity²² in the first 70 consecutive operated adults. The aim of this study was to compare the long term (>10 years) outcome concerning seizure status, psychosocial issues and use of AED with the 2 year follow‐up in these well characterised 70 adults.     

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).     

Deep-brain stimulation: long-term analysis of complications caused by hardware and surgery--experiences from a single centre

Objective

To determine the surgery‐related and hardware‐related complications of deep‐brain stimulation (DBS) at a single centre.

Methods

262 consecutive patients (472 electrodes) operated for DBS in our department from February 1996 to March 2003 were retrospectively analysed to document acute adverse events (30 days postoperatively). The data of 180 of these patients were additionally revised to assess long‐term complications (352 electrodes, mean follow‐up 36.3 (SD 20.8) months).

Results

The frequency of minor intraoperative complications was 4.2% (11/262 patients). Transient (0.2%) or permanent (0.4%) neurological deficits, and in one case asymptomatic intracranial haemorrhage (0.2%), were registered as acute severe adverse events caused by surgery. Among minor acute complications were subcutaneous bleeding along the extension wire (1.2%) and haematoma at the pulse generator implantation site (1.2%). Skin infection caused by the implanted material was registered in 15 of 262 patients (5.7%). The infection rate during the first observation period was 1.5% (4/262 patients) and the late infection rate was 6.1% (11/180 patients). Partial or complete removal of the stimulation system was necessitated in 12 of 262 (4.6%) patients because of skin infection. During the long‐term observation period, hardware‐related problems were registered in 25 of 180 (13.9%) patients.

Conclusions

Stereotactic implantation of electrodes for DBS, if performed with multiplanar three‐dimensional imaging and advanced treatment planning software, is a safe procedure with no mortality and low morbidity. The main causes for the patients'' prolonged hospital stay and repeated surgery were wound infections and hardware‐related complications.During the past 10 years, worldwide, a growing number of patients with movement disorders have been treated with deep‐brain stimulation (DBS). The most frequent indications were Parkinson''s disease, tremor and dystonia. At present, new indications such as obsessive–compulsive disorders (OCD), Gilles‐de‐la‐Tourette syndrome, severe depression or epilepsy are under investigation.^1,2,3,4,5DBS is now considered to modulate the functional units of the CNS, serving as a permanent and lifelong treatment. Therefore, a realistic analysis of complications should not be restricted to acute hardware‐related and surgery‐related adverse events, but should also document problems occurring in the long term. In the literature, a reasonably high number of publications have already dealt with the adverse events associated with DBS. Only a few studies, however, analysed a larger number of patients (n>50),^{6,7,8,9,10,11} and some of this work considered only one possible source for complications, either surgery^6,10 or the implanted hardware.^8,9 In this article, we present a comprehensive analysis of 262 patients of a single centre (Department of Stereotaxy and Functional Neurosurgery, University of Cologne, Cologne, Germany).     

Idiopathic normal-pressure hydrocephalus: clinical comorbidity correlated with cerebral biopsy findings and outcome of cerebrospinal fluid shunting

Objectives

To elucidate the importance of clinically diagnosed cerebral comorbidity in idiopathic normal‐pressure hydrocephalus (INPH) and its effect on improvement after shunt surgery as well as concordance with parenchymal pathological changes described in frontal cerebral biopsy specimens.

Methods

In 28 consecutive patients diagnosed with INPH and shunted according to clinical, radiological and cerebrospinal fluid dynamic criteria, concomitant disorders were carefully registered, with special emphasis on cerebrovascular disease (CVD) and possible Alzheimer''s disease. During shunt surgery, a frontal cerebral biopsy specimen was obtained and subsequently analysed for pathological changes.

Results

One or several concurrent disorders were present in 89% of the patients, most often CVD (n = 17) and possible Alzheimer''s disease (n = 12), of which eight patients presented both, diagnosed according to the criteria of the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer''s Disease and Related Disorders Association. The shunt success rate was 33%. A clear tendency towards increasing prevalence of CVD or Alzheimer''s disease was found in the subgroups with no improvement or clinical deterioration compared with the patients improving after shunt surgery. The presence of CVD tended towards an unfavourable shunt outcome. The pathological parenchymal changes reflected the clinical diagnoses of comorbidity, and were described in about half of the biopsy specimens, with Alzheimer''s disease (n = 7) and vascular changes (n = 7) being the most common findings. However, no significant correlation was found with the clinical diagnoses of Alzheimer''s disease and CVD. The presence of cerebral comorbidity, whether diagnosed clinically or by brain biopsy, did not preclude clinical improvement after shunt operation.

Conclusions

A high prevalence of CVD and Alzheimer''s disease was found in patients shunted for INPH, which was reflected, although less commonly, by similar neuropathological biopsy findings. No significant correlation was found between the presence of comorbidity and shunt outcome. The findings support the perception of INPH as a multiaetiological clinical entity, possibly overlapping pathophysiologically with CVD and Alzheimer''s disease.Patients with the idiopathic normal‐pressure hydrocephalus (INPH) syndrome are traditionally described as presenting a clinical triad of progressing gait disturbances, dementia and urinary urge incontinence, and with a radiologically defined hydrocephalus on computed tomography or magnetic resonance imaging.As opposed to secondary normal‐pressure hydrocephalus (NPH), no apparent precipitating factor is identified in INPH. The patients are generally older¹ and consequently more prone to have concomitant diseases. In concordance, the shunt success rate in patients with possible INPH is lower than in patients with secondary NPH,^2,3 varying from 25% to 80%.^4,5In patients not responding to shunt surgery, cerebrovascular disease (CVD) and Alzheimer''s Disease are the predominant disorders thought to mimic the INPH syndrome. This presumption is based on the fact that Alzheimer''s disease and CVD are the most common causes of dementia, and from autopsy and biopsy findings of CVD or Alzheimer''s disease in patients with INPH—including patients improving after a shunt operation.^{6,7,8,9,10,11} It has also been hypothesised that INPH shares common pathophysiology with Alzheimer''s disease¹² or CVD,^13,14,15 which only further confounds the clinical picture.Thus, the main question for the clinician contemplating a shunt operation is not whether the patient has INPH or a concurrent irreversible disorder, but whether the hydrocephalus or the presence of a non‐shunt responsive comorbidity—most often CVD or Alzheimer''s disease—is the major contributor to the symptomatology. The selection of patients for shunt surgery has become even more controversial after recent data suggesting shunt improvement in patients with no symptoms or signs of INPH but with a clinical diagnosis of Alzheimer''s disease.¹⁶In this prospective study of patients shunted for INPH according to clinical, radiological and cerebrospinal fluid (CSF) dynamic criteria, frontal cerebral biopsy specimens were obtained before the insertion of a shunt and examined for pathological parenchymal changes. Clinical comorbidity was carefully registered, and the clinical diagnoses of CVD and Alzheimer''s disease were established by a trained neurologist. The presence of concomitant disorders was correlated with shunt outcome and cerebral biopsy findings to elucidate the importance of clinical comorbidity in patients with INPH, and its effect on improvement after shunt surgery as well as concordance with the pathological cerebral parenchymal changes.     

Moderate therapeutic efficacy of positron emission tomography-navigated repetitive transcranial magnetic stimulation for chronic tinnitus: a randomised, controlled pilot study

Background

Tinnitus has been shown to respond to modulations of cortical activity by high‐frequency and low‐frequency repetitive transcranial magnetic stimulation (rTMS).

Objective

To determine the tinnitus‐attenuating effects of a 2‐week daily regimen of rTMS, navigated to the maximum of tinnitus‐related increase in regional cerebral blood flow.

Methods

Six patients with chronic tinnitus were enrolled in this sham‐controlled crossover study and treated with 2×2 weeks of suprathreshold 1 Hz rTMS (30 min) applied to the region with maximal tinnitus‐related increase in regional cerebral blood flow delineated by functional imaging with [¹⁵O]H₂O positron emission tomography and a control area. Tinnitus‐related distress was assessed before and after each treatment and 2 weeks after the end of the 4‐week course of stimulation using a validated tinnitus questionnaire. Additional self‐assessment scores of tinnitus change, loudness and annoyance were obtained.

Results

In five of six patients, rTMS induced greater reduction of the tinnitus questionnaire score than sham stimulation. In two patients, all parameters measured (tinnitus change score, tinnitus loudness, tinnitus annoyance) showed unequivocal improvement. At the group level, the degree of response in the tinnitus questionnaire score was correlated with tinnitus‐associated activation of the anterior cingulate cortex. Two weeks after the final stimulation, tinnitus had returned to baseline in all patients but one.

Conclusion

Tinnitus can be attenuated by low‐frequency rTMS navigated to each person''s maximum tinnitus‐related cortical hyperactivity. The effects are only moderate; interindividual responsiveness varies and the attenuation seems to wear off within 2 weeks after the last stimulation session. Notably, tinnitus‐related anterior cingulate cortex activation seems to predict the response to rTMS treatment.Tinnitus is the phantom perception of sound or noise in the absence of an auditory stimulus and is a common symptom of disorders of the auditory system.¹ Its chronic form affects between 5% and 15% of the general population.² In 1–3% of the population, it causes severe impairment of the quality of life.^3,4 In most cases, tinnitus is associated with hearing loss that is often induced by noise exposure or is age related.¹ Nevertheless, currently no specific pharmacological treatments are available that provide a replicable, long‐term effect on tinnitus superior to placebo. The use of antidepressants, anticonvulsants and benzodiazepines may offer relief to some patients, but these treatments are largely considered palliative rather than curative. Hearing aids or electronic devices, producing a white noise that covers up the annoying perception, can be of help.^5,6 The combination of noise generators and counselling is called “tinnitus retraining therapy” and is often used in the management of chronic tinnitus.⁷ Although psychology‐based strategies effectively support the habituation and adaptation to tinnitus,⁸ the development of treatments is constrained by the limited pathophysiological knowledge.In recent years, it has become widely accepted that maladaptive changes of central information processing are critically involved in tinnitus perception and generation. Particularly, studies on positron emission tomography (PET) have provided evidence for an association between tinnitus and activation of areas involved in the perception and processing of sounds and speech.^9,10 In these studies, regional cerebral blood flow (rCBF) during tinnitus perception was contrasted with rCBF when tinnitus was transiently reduced by lidocaine injection,^9,11,12 oral facial movements¹³ or gaze.^10,14 These data indicate that tinnitus corresponds to abnormally high levels of regional cortical activity, which would increase and decrease with tinnitus loudness. This is in line with animal studies indicating a reduction of intracortical inhibition due to deafferentation.^15,16 Nevertheless, imaging studies alone cannot warrant the behavioural relevance of the associated activation.In the initial studies on transcranial magnetic stimulation (TMS), these areas were subjected to short trains of repetitive transcranial magnetic stimulation (rTMS), interfering with the neuronal activity in underlying areas.^17,18 Indeed, a short‐lasting decrease in tinnitus was observed, providing evidence for the critical role of cortical auditory and association areas in tinnitus perception. In contrast with short trains of high‐frequency rTMS, low‐frequency rTMS is suited to induce a longer‐lasting decrease in cortical activity in the stimulated area, as shown in the motor cortex.¹⁹ We have previously shown that this kind of stimulation can reduce tinnitus in a dose‐dependent manner for up to 30 min.¹² However, the clinical use of rTMS in tinnitus would require a persistent reduction in tinnitus loudness and its associated distress. A prior series of experiments has provided initial evidence for the efficacy and practicability of this treatment strategy. Repeated sessions of rTMS directed towards the auditory cortex were applied over 1 week in a placebo‐controlled, crossover design.^20,21 After real rTMS, Kleinjung et al²¹ reported a reduction of the mean tinnitus score by 7.5% (compared with baseline). Interestingly, after 6 months the reduction was even more pronounced (12%).The aim of this study was to test whether a 2‐week series of low‐frequency rTMS, guided to each patient''s maximum of tinnitus‐related cortical activity as assessed by [¹⁵O]H₂O PET, can induce a lasting suppression of tinnitus compared with the control stimulation of a non‐cortical site eliciting equivalent noise and sensations.     

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.     

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.     

Diffusion indices on magnetic resonance imaging and neuropsychological performance in amnestic mild cognitive impairment

Background

Magnetic resonance diffusion tensor imaging (DTI) shows promise in the early detection of microstructural pathophysiological changes in the brain.

Objectives

To measure microstructural differences in the brains of participants with amnestic mild cognitive impairment (MCI) compared with an age‐matched control group using an optimised DTI technique with fully automated image analysis tools and to investigate the correlation between diffusivity measurements and neuropsychological performance scores across groups.

Methods

34 participants (17 participants with MCI, 17 healthy elderly adults) underwent magnetic resonance imaging (MRI)‐based DTI. To control for the effects of anatomical variation, diffusion images of all participants were registered to standard anatomical space. Significant statistical differences in diffusivity measurements between the two groups were determined on a pixel‐by‐pixel basis using gaussian random field theory.

Results

Significantly raised mean diffusivity measurements (p<0.001) were observed in the left and right entorhinal cortices (BA28), posterior occipital–parietal cortex (BA18 and BA19), right parietal supramarginal gyrus (BA40) and right frontal precentral gyri (BA4 and BA6) in participants with MCI. With respect to fractional anisotropy, participants with MCI had significantly reduced measurements (p<0.001) in the limbic parahippocampal subgyral white matter, right thalamus and left posterior cingulate. Pearson''s correlation coefficients calculated across all participants showed significant correlations between neuropsychological assessment scores and regional measurements of mean diffusivity and fractional anisotropy.

Conclusions

DTI‐based diffusivity measures may offer a sensitive method of detecting subtle microstructural brain changes associated with preclinical Alzheimer''s disease.Substantial effort is currently being focused towards improving the diagnosis of early Alzheimer''s disease. The term mild cognitive impairment (MCI) is often used to describe the transitional stage between normal ageing and dementia. Owing to the heterogeneity of MCI, not all participants with MCI will have predementia Alzheimer''s disease.¹ Peterson et al² suggested the criteria for a subtype of MCI, so‐called amnestic MCI, which is presumed to present a typical prodrome of dementia in Alzheimer''s disease. People with amnestic MCI have a 10–15% annual conversion rate to Alzheimer''s disease compared with 1–2% in the normal elderly population.² Neuroimaging studies conducted on participants with MCI using magnetic resonance imaging (MRI) morphological analysis have consistently reported atrophic changes primarily in the medial temporal lobe and, to a lesser extent, in the thalamus and cingulate gyrus.^3,4,5 Furthermore, the degree of atrophy in temporal lobe structures correlates with performance on memory tasks³ and with density of neurofibrillar tangles at autopsy.⁶ These findings support the concept that MRI‐based neuroimaging studies together with neuropsychological assessment may enable identification of participants with MCI which may progress to Alzheimer''s disease, and evaluation of the efficacy of novel treatments.Recent studies using diffusion tensor magnetic resonance imaging (DTI) have shown microstructural changes in the hippocampus of participants with MCI that may not be apparent using standard anatomical imaging.^7,8,9 DTI measures the random motion of bulk water in cerebral tissue. When the random motion of water is restricted preferentially in one direction when compared with the orthogonal planes, such as occurs in white matter, diffusion is referred to as anisotropic; in contradistinction, bulk water motion in the cerebrospinal fluid is equal in all directions and is thus referred to as isotropic. Fractional anisotropy, a quantitative measurement of the degree of anisotropy, can be used to probe the integrity of white matter fibre tracts.¹⁰ The mean diffusivity is a quantitative measurement of the bulk mean motion of water considered in all directions and is used to interrogate pathological changes in cerebral tissue, such as ischaemia in patients with stroke.¹⁰ DTI studies in patients with MCI have shown raised mean diffusivity in the hippocampus and other temporal lobe regions, using manually traced regions of interest (ROI).^7,8,9 Although the precise neural correlates of altered mean diffusivity measurements are uncertain, increased mean diffusivity most likely results from loss of neurones, axons and dendrites, resulting in an increase in extracellular space and raised water diffusivity in these regions.⁷ It is unknown whether such microstructural changes, detectable by DTI, are due to amyloid or neurofibrillar tangle formation or some other neuropathological process in Alzheimer''s disease. However, the finding of a negative correlation between hippocampal diffusivity and volume in people with MCI indicates that both measurements are sensitive to early Alzheimer''s disease neuropathology.⁷ Using manually defined ROI analyses, a recent study has identified marked changes in volume, mean diffusivity and fractional anisotropy indices in the hippocampus in participants with MCI compared with age‐matched controls.⁹ Specifically, compared with volume measurements, raised left hippocampal mean diffusivity was found to be a strong independent predictor of poor verbal memory performance in both controls and participants with MCI.In this study, we investigated whether mean diffusivity and fractional anisotropy measurements differed between participants with MCI and age‐matched controls, using an optimised DTI protocol¹¹ and a fully automated voxel‐by‐voxel method of data analysis. This approach assesses the entire brain, rather than just one structure, and circumvents any operator‐introduced errors in the manual selection of ROI for analysis. In addition, we investigated the relationship between measurements of water diffusivity and performance on memory and other cognitive tasks across participants.     

Improvement of gait by chronic, high doses of methylphenidate in patients with advanced Parkinson's disease

Background

Therapeutic management of gait disorders in patients with advanced Parkinson''s disease (PD) can sometimes be disappointing, since dopaminergic drug treatments and subthalamic nucleus (STN) stimulation are more effective for limb‐related parkinsonian signs than for gait disorders. Gait disorders could also be partly related to norepinephrine system impairment, and the pharmacological modulation of both dopamine and norepinephrine pathways could potentially improve the symptomatology.

Aim

To assess the clinical value of chronic, high doses of methylphenidate (MPD) in patients with PD having gait disorders, despite their use of optimal dopaminergic doses and STN stimulation parameters.

Methods

Efficacy was blindly assessed on video for 17 patients in the absence of l‐dopa and again after acute administration of the drug, both before and after a 3‐month course of MPD, using a Stand–Walk–Sit (SWS) Test, the Tinetti Scale, the Unified Parkinson''s Disease Rating Scale (UPDRS) part III score and the Dyskinesia Rating Scale.

Results

An improvement was observed in the number of steps and time in the SWS Test, the number of freezing episodes, the Tinetti Scale score and the UPDRS part III score in the absence of l‐dopa after 3 months of taking MPD. The l‐dopa‐induced improvement in these various scores was also stronger after the 3‐month course of MPD than before. The Epworth Sleepiness Scale score fell dramatically in all patients. No significant induction of adverse effects was found.

Interpretation

Chronic, high doses of MPD improved gait and motor symptoms in the absence of l‐dopa and increased the intensity of response of these symptoms to l‐dopa in a population with advanced PD.The significant, long‐term benefits of dopaminergic treatment¹ and bilateral stimulation of the subthalamic nucleus (STN)² have been well documented for limb‐related syndromes in patients with advanced Parkinson''s disease (PD). However, after several years of disease progression (and regardless of the ongoing treatment), axial signs in general and gait disorders in particular (including reduced step length, freezing and postural instability) become more prominent and lead to falls and even institutionalisation. Therapeutic management of the condition is disappointing, since dopaminergic treatments and STN stimulation are more effective for other limb‐related parkinsonian signs than for gait disorders as such.^2,3 However, an interesting therapeutic approach could involve the combined modulation of l‐dopa bioavailability (to potentiate the partial dopa‐sensitivity of gait disorders) and the non‐dopaminergic system, particularly the norepinephrine system, which has been previously suspected to be involved in gait disorders.^4,5 This “norepinephrine hypothesis” could explain the positive results on freezing of gait observed in some open‐label studies on small populations of patients with advanced PD using the synthetic norepinephrine precursor l‐threo‐dihydroxyphenylserine^6,7 or tinazidine, an α‐2 adrenergic agonist.⁴ However, these results have never been confirmed—probably because l‐threo‐dihydroxyphenylserine is a weak precursor of norepinephrine and only slightly influences striatal, extracellular dopamine levels.⁸Methylphenidate (MPD, Ritalin) is an amphetamine‐like psychomotor stimulant, which influences both the dopaminergic and norepinephrine systems. Indeed, MPD inhibits the dopamine transporter (DAT), particularly in the striatum.⁹ The DAT is one of the most important determinants of extracellular dopamine concentrations, as demonstrated in DAT knock‐out mice.¹⁰ Through inhibition of the DAT, MPD blocks presynaptic dopamine re‐uptake.¹¹ To a lesser extent, MPD also influences the norepinephrine system through presynaptic norepinephrine transporter inhibition.^11,12,13 Hence, by targeting the DAT and the norepinephrine transporter, MPD might disperse dopamine widely and consign dopamine storage and release to regulation by norepinephrine neurones as well as by dopaminergic neurones.¹³ Effects of MPD may be mediated by restoration of the dopaminergic/norepinephrine neurotransmitter balance.^13,14A pilot study on five patients with PD with motor fluctuations showed that low doses of MPD (0.2 mg/kg) combined with l‐dopa led to greater peak right‐hand tapping speed.¹⁵ The effects of doses of up to 0.4 mg/kg of MPD were also assessed in a double‐blind, placebo‐controlled procedure; MPD seemed to lack an effect when given alone but did potentiate the effects of l‐dopa on walking speeds and dyskinesia.⁹ Recently, positive effects on gait speed, fall risk and attention were demonstrated in an open‐label study using an acute, low dose (20 mg) of MPD.¹⁶ It therefore seemed interesting to determine whether higher doses and longer‐term treatment could improve the MPD‐induced partial response for gait disorders. Indeed, up to 70% of the dopamine nerve terminals (and consequently 70% of DAT activity) are lost in severe PD.¹⁷ An oral dose of 0.25 mg/kg MPD may only occupy half of the striatal DATs in humans,¹² whereas oral doses of 0.5–0.8 mg/kg allow a higher occupancy and lead to high extracellular dopamine concentrations.^13,18,19 Moreover, high doses of MPD could also increase the norepinephrine properties of MPD.Our research hypothesis was the improvement of gait by MPD. The aim of this study was to assess the clinical value of a high‐dose, 3‐month course of MPD (1 mg/kg) in STN‐stimulated patients with advanced PD (free of motor fluctuations) having gait disorders despite their use of optimal dopaminergic doses and STN stimulation parameters. The primary outcome measure was the completion time in the Stand–Walk–Sit (SWS) Test.²⁰ Efficacy was blindly assessed on video in the absence of l‐dopa and then again after acute administration of the latter drug, to assess the potential norepinephrine and/or dopaminergic effects of MPD on gait speed and step length.     

Dementia with Lewy bodies: a comparison of clinical diagnosis, FP-CIT single photon emission computed tomography imaging and autopsy

Background

Dementia with Lewy bodies (DLB) is a common form of dementia. The presence of Alzheimer''s disease (AD) pathology modifies the clinical features of DLB, making it harder to distinguish DLB from AD clinically during life. Clinical diagnostic criteria for DLB applied at presentation can fail to identify up to 50% of cases. Our aim was to determine, in a series of patients with dementia in whom autopsy confirmation of diagnosis was available, whether functional imaging of the nigrostriatal pathway improves the accuracy of diagnosis compared with diagnosis by means of clinical criteria alone.

Methods

A single photon emission computed tomography (SPECT) scan was carried out with a dopaminergic presynaptic ligand [¹²³I]‐2beta‐carbometoxy‐3beta‐(4‐iodophenyl)‐N‐(3‐fluoropropyl) nortropane (FP‐CIT; ioflupane) on a group of patients with a clinical diagnosis of DLB or other dementia. An abnormal scan was defined as one in which right and left posterior putamen binding, measured semiquantitatively, was more than 2 SDs below the mean of the controls.

Results

Over a 10 year period it was possible to collect 20 patients who had been followed from the time of first assessment and time of scan through to death and subsequent detailed neuropathological autopsy. Eight patients fulfilled neuropathological diagnostic criteria for DLB. Nine patients had AD, mostly with coexisting cerebrovascular disease. Three patients had other diagnoses. The sensitivity of an initial clinical diagnosis of DLB was 75% and specificity was 42%. The sensitivity of the FP‐CIT scan for the diagnosis of DLB was 88% and specificity was 100%.

Conclusion

FP‐CIT SPECT scans substantially enhanced the accuracy of diagnosis of DLB by comparison with clinical criteria alone.Distinguishing patients with dementia with Lewy bodies (DLB) from those with Alzheimer''s disease (AD) can be challenging, in some cases even after repeated follow‐up observation. Imaging modalities which assess the integrity of the nigrostriatal pathway have detected impaired function of this pathway in patients with clinically diagnosed DLB but preserved function in patients with clinically diagnosed AD.^{1,2,3,4,5,6,7,8} Such imaging is potentially of considerable value in supporting a diagnosis of DLB. However, the accuracy of the clinical diagnosis of DLB is imperfect,^9,10 meaning that estimation of the diagnostic accuracy of the imaging investigation needs to be done against neuropathological findings.We have been following a cohort of patients with dementia whose initial dementia diagnosis was made on the basis of standard clinical criteria (for AD,¹¹ for DLB¹²). These patients underwent a single photon emission computed tomography (SPECT) scan using [¹²³I]‐2beta‐carbometoxy‐3beta‐(4‐iodophenyl)‐N‐(3‐fluoropropyl) nortropane (FP‐CIT; ioflupane), a ligand that binds to the presynaptic dopamine transporter, demonstrating the integrity of the nigrostriatal projection pathway. Scanning was undertaken at the time of presentation to our service—that is, directly after the clinical diagnosis was made. Autopsies are now available for 20 patients, enabling us to report what abnormal FP‐CIT scans actually equate to in pathological terms. Furthermore, this autopsy series allows a more robust assessment of the role of FP‐CIT SPECT scanning in the diagnosis of DLB than can be made using clinical diagnoses only.