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2.  Clinical and neuropathologic variation in neuronal intermediate filament inclusion disease 
Neurology  2004;63(8):1376-1384.
Background
Recently described neuronal intermediate filament inclusion disease (NIFID) shows considerable clinical heterogeneity.
Objective
To assess the spectrum of the clinical and neuropathological features in 10 NIFID cases.
Methods
Retrospective chart and comprehensive neuropathological review of these NIFID cases was conducted.
Results
The mean age at onset was 40.8 (range 23 to 56) years, mean disease duration was 4.5 (range 2.7 to 13) years, and mean age at death was 45.3 (range 28 to 61) years. The most common presenting symptoms were behavioral and personality changes in 7 of 10 cases and, less often, memory loss, cognitive impairment, language deficits, and motor weakness. Extrapyramidal features were present in 8 of 10 patients. Language impairment, perseveration, executive dysfunction, hyperreflexia, and primitive reflexes were frequent signs, whereas a minority had buccofacial apraxia, supranuclear ophthalmoplegia, upper motor neuron disease (MND), and limb dystonia. Frontotemporal and caudate atrophy were common. Histologic changes were extensive in many cortical areas, deep gray matter, cerebellum, and spinal cord. The hallmark lesions of NIFID were unique neuronal IF inclusions detected most robustly by antibodies to neurofilament triplet proteins and α-internexin.
Conclusion
NIFID is a neuropathologically distinct, clinically heterogeneous variant of frontotemporal dementia (FTD) that may include parkinsonism or MND. Neuronal IF inclusions are the neuropathological signatures of NIFID that distinguish it from all other FTD variants including FTD with MND and FTD tauopathies.
PMCID: PMC3516854  PMID: 15505152
3.  Mild cognitive impairment in Parkinson disease 
Neurology  2010;75(12):1062-1069.
Background:
In studies of mild cognitive impairment (MCI) in Parkinson disease (PD), patients without dementia have reported variable prevalences and profiles of MCI, likely to be due to methodologic differences between the studies.
Objective:
The objective of this study was to determine frequency and the profile of MCI in a large, multicenter cohort of well-defined patients with PD using a standardized analytic method and a common definition of MCI.
Methods:
A total of 1,346 patients with PD from 8 different cohorts were included. Standardized analysis of verbal memory, visuospatial, and attentional/executive abilities was performed. Subjects were classified as having MCI if their age- and education-corrected z score on one or more cognitive domains was at least 1.5 standard deviations below the mean of either control subjects or normative data.
Results:
A total of 25.8% of subjects (95% confidence interval [CI] 23.5–28.2) were classified as having MCI. Memory impairment was most common (13.3%; 11.6–15.3), followed by visuospatial (11.0%; 9.4–13.0) and attention/executive ability impairment (10.1%; 8.6–11.9). Regarding cognitive profiles, 11.3% (9.7–13.1) were classified as nonamnestic single-domain MCI, 8.9% (7.0–9.9) as amnestic single-domain, 4.8% (3.8–6.1) as amnestic multiple-domain, and 1.3% (0.9–2.1) as nonamnestic multiple-domain MCI. Having MCI was associated with older age at assessment and at disease onset, male gender, depression, more severe motor symptoms, and advanced disease stage.
Conclusions:
MCI is common in patients with PD without dementia, affecting a range of cognitive domains, including memory, visual-spatial, and attention/executive abilities. Future studies of patients with PD with MCI need to determine risk factors for ongoing cognitive decline and assess interventions at a predementia stage.
GLOSSARY
= amnestic multiple-domain MCI;
= amnestic single-domain MCI;
= confidence interval;
= Diagnostic and Statistical Manual of Mental Disorders, 4th edition;
= mild cognitive impairment;
= Mini-Mental State Examination;
= nonamnestic multiple-domain MCI;
= nonamnestic single-domain MCI;
= Parkinson disease;
= Parkinson's Disease Cognitive Rating Scale;
= Unified Parkinson's Disease Rating Scale.
doi:10.1212/WNL.0b013e3181f39d0e
PMCID: PMC2942065  PMID: 20855849
4.  The basal ganglia cholinergic neurochemistry of progressive supranuclear palsy and other neurodegenerative diseases 
Background
Progressive supranuclear palsy (PSP) is a progressive neurodegenerative disorder involving motor and cognitive dysfunction. Currently, there is no effective treatment either for symptomatic relief or disease modification. This relates, in part, to a lack of knowledge of the underlying neurochemical abnormalities, including cholinergic receptor status in the basal ganglia.
Aim
To measure muscarinic M2 and M4 receptors in the basal ganglia in PSP.
Methods
The muscarinic M2 (presynaptic) and M4 (postsynaptic) receptors in the striatum, pallidum and adjacent insular cortex were autoradiographically measured in pathologically confirmed cases of PSP (n = 18), and compared with cases of Lewy body dementias (LBDs; n = 45), Alzheimer's disease (AD; n = 39) and controls (n = 50).
Results
In cases of PSP, there was a reduction in M2 and M4 receptors in the posterior caudate and putamen compared to controls, but no significant changes in the pallidum. Cases with AD showed lower M2 receptors in the posterior striatum. Groups with LBD and AD showed higher M2 binding in the insular cortex compared with controls.
Conclusions
The results suggest loss of posterior striatal cholinergic interneurones in PSP, and reduction in medium spiny projection neurones bearing M4 receptors. These results should be taken in the context of more widespread pathology in PSP, but may have implications for future trials of cholinergic treatments.
doi:10.1136/jnnp.2006.099937
PMCID: PMC2077948  PMID: 17178818
5.  A multicentre longitudinal observational study of changes in self reported health status in people with Parkinson's disease left untreated at diagnosis 
Background
The issue of when to start treatment in Parkinson's disease (PD) remains controversial. Some favour treatment at diagnosis while others opt for a “wait and watch” policy. The effect of the latter policy on the self reported health status of people with PD is unknown.
Aims
To record self reported health status through longitudinal use of a validated PD specific questionnaire (PDQ‐39) in untreated PD patients in multiple centres in the UK. To compare patients who were left untreated with those who were offered treatment during follow‐up.
Methods
A multicentre, prospective, “real life” observational audit based study addressing patient reported outcomes in relation to self reported health status and other sociodemographic details.
Results
198 untreated PD were assessed over a mean period of 18 months. During two follow‐up assessments, the self reported health status scores in all eight domains of the PDQ‐39 and the overall PDQ‐39 summary index worsened significantly (p<0.01) in patients left untreated. In a comparative group in whom treatment was initiated at or soon after diagnosis, there was a trend towards improvement in self reported health status scores after treatment was started.
Conclusions
This study addresses for the first time self reported health status, an indicator of health related quality of life, in untreated PD. The findings may strengthen the call for re‐evaluation of the policy to delay treatment in newly diagnosed patients with PD.
doi:10.1136/jnnp.2006.098327
PMCID: PMC2117846  PMID: 17098846
6.  Tauopathies with parkinsonism: clinical spectrum, neuropathologic basis, biological markers, and treatment options 
Tauopathies with parkinsonism represent a spectrum of disease entities unified by the pathologic accumulation of hyperphosphorylated tau protein fragments within the central nervous system. These pathologic characteristics suggest shared pathogenetic pathways and possible molecular targets for disease-modifying therapeutic interventions. Natural history studies, for instance, in progressive supranuclear palsy, frontotemporal dementia with parkinsonism linked to chromosome 17, corticobasal degeneration, and Niemann-Pick disease type C as well as in amyotrophic lateral sclerosis/Parkinson–dementia complex permit clinical characterization of the disease phenotypes and are crucial to the development and validation of biological markers for differential diagnostics and disease monitoring, for example, by use of neuroimaging or proteomic approaches. The wide pathologic and clinical spectrum of the tauopathies with parkinsonism is reviewed in this article, and perspectives on future advances in the understanding of the pathogenesis are given, together with potential therapeutic strategies.
doi:10.1111/j.1468-1331.2008.02513.x
PMCID: PMC2847416  PMID: 19364361
corticobasal degeneration; frontotemporal dementia with parkinsonism linked to chromosome 17; microtubule-associated protein tau, multiple system atrophy; Parkinson disease; parkinsonism; progressive supranuclear palsy; tauopathies
7.  Effect of levodopa on cognitive function in Parkinson's disease with and without dementia and dementia with Lewy bodies 
Background
Levodopa (L‐dopa) is the gold standard treatment for Parkinson's disease, but a lack of clear efficacy combined with a perceived liability to neuropsychiatric side effects has limited L‐dopa use in patients with parkinsonism and dementia. Therefore, the effect of L‐dopa on the cognitive profile of dementia with Lewy bodies (DLB) and Parkinson's disease with dementia (PDD) is unclear.
Aim
To ascertain the acute and long‐term effects of L‐dopa on aspects of attention and cognition in patients with DLB and PDD, and to compare these with the effects in Parkinson's disease.
Method
Baseline cognitive and motor function was assessed off L‐dopa in patients with Parkinson's disease (n = 22), PDD (n = 27) and DLB (n = 11) using standard “bedside” measures and a computerised programme detecting reaction times and accuracy. All patients then underwent an acute L‐dopa challenge with subsequent subjective and objective analysis of alertness, verbal recall, reaction times and accuracy. The same parameters were measured after 3 months on L‐dopa to assess the prolonged effect.
Results
Acute L‐dopa challenge considerably improved motor function and subjective alertness in all patients without compromising either reaction times or accuracy, but increased fluctuations were noted in both groups with dementia. Neuropsychiatric scores improved in patients with Parkinson's disease both with and without dementia on L‐dopa at 3 months. Although patients with Parkinson's disease also had better mean global cognitive function at this time, mean verbal attention and memory deteriorated, and patients with PDD had slower reaction times in some tests. No patient had a marked deterioration over this time. Patients with DLB did not experience any adverse cognitive or neuropsychiatric effects after 3 months of L‐dopa treatment.
Conclusion
The use of L‐dopa in patients with parkinsonism with dementia does not adversely affect cognitive function.
doi:10.1136/jnnp.2006.098079
PMCID: PMC2077405  PMID: 16952917
8.  Ten steps to identify atypical parkinsonism 
Credibility of the 10‐step test in atypical parkinsonism
doi:10.1136/jnnp.2006.102087
PMCID: PMC2077402  PMID: 17110742
9.  Haplotypes and gene expression implicate the MAPT region for Parkinson disease 
Neurology  2008;71(1):28-34.
Background
Microtubule-associated protein tau (MAPT) has been associated with several neurodegenerative disorders including forms of parkinsonism and Parkinson disease (PD). We evaluated the association of the MAPT region with PD in a large cohort of familial PD cases recruited by the GenePD Study. In addition, postmortem brain samples from patients with PD and neurologically normal controls were used to evaluate whether the expression of the 3-repeat and 4-repeat isoforms of MAPT, and neighboring genes Saitohin (STH) and KIAA1267, are altered in PD cerebellum.
Methods
Twenty-one single-nucleotide polymorphisms (SNPs) in the region of MAPT on chromosome 17q21 were genotyped in the GenePD Study. Single SNPs and haplotypes, including the H1 haplotype, were evaluated for association to PD. Relative quantification of gene expression was performed using real-time RT-PCR.
Results
After adjusting for multiple comparisons, SNP rs1800547 was significantly associated with PD affection. While the H1 haplotype was associated with a significantly increased risk for PD, a novel H1 subhaplotype was identified that predicted a greater increased risk for PD. The expression of 4-repeat MAPT, STH, and KIAA1267 was significantly increased in PD brains relative to controls. No difference in expression was observed for 3-repeat MAPT.
Conclusions
This study supports a role for MAPT in the pathogenesis of familial and idiopathic Parkinson disease (PD). Interestingly, the results of the gene expression studies suggest that other genes in the vicinity of MAPT, specifically STH and KIAA1267, may also have a role in PD and suggest complex effects for the genes in this region on PD risk.
doi:10.1212/01.wnl.0000304051.01650.23
PMCID: PMC2654275  PMID: 18509094
10.  Motor subtype and cognitive decline in Parkinson's disease, Parkinson's disease with dementia, and dementia with Lewy bodies 
Background
A previous cross sectional study found over‐representation of a postural instability gait difficulty (PIGD) motor subtype in Parkinson's disease patients with dementia (PDD) and dementia with Lewy bodies (DLB), compared with Parkinson's disease (PD).
Aims
(1) To examine rates of cognitive and motor decline over two years in PD (n = 40), PDD (n = 42) and DLB (n = 41) subjects, compared with age matched controls (n = 41), (2) to record whether motor phenotypes of PD, PDD, and DLB subjects changed during the study, (3) to find out if cognitive and motor decline in PD was associated with baseline motor subtype, and (4) to report the incidence of dementia in PD patients in relation to baseline motor subtype.
Results
Most of PDD and DLB participants were PIGD subtype at baseline assessment. In the non‐demented PD group, tremor dominant (TD) and PIGD subtypes were more evenly represented. Cognitive decline over two years was greater in PDD and DLB groups (mean decline in MMSE −4.5 and −3.9, respectively), compared with PD (−0.2) and controls (−0.3). There was an association between PIGD subtype and increased rate of cognitive decline within the PD group. Of 40 PD patients, 25% of the 16 PIGD subtype developed dementia over two years, compared with none of the 18 TD or six indeterminate phenotype cases (χ2 = 6.7, Fisher's exact test p<0.05).
Conclusion
A PIGD motor subtype is associated with a faster rate of cognitive decline in PD and may be considered a risk factor for incident dementia in PD.
doi:10.1136/jnnp.2005.081711
PMCID: PMC2117449  PMID: 16614017
Lewy body disease; dementia; parkinsonism; motor subtype; progression
11.  Longitudinal change in 99mTcHMPAO cerebral perfusion SPECT in Parkinson's disease over one year 
Objective: To carry out a longitudinal study of perfusion in patients with Parkinson's disease and controls to find areas showing a reduction in perfusion over one year.
Methods: Two HMPAO cerebral perfusion scans were acquired one year apart in 30 subjects with Parkinson's disease (mean (SD) age, 76 (5) years) and 34 healthy comparison subjects (76 (7) years). Scans were normalised to the mean intensity in the cerebellum.
Results: Using SPM99 within groups to investigate regions that showed a decrease in perfusion between scans, it was found that in Parkinson's disease subjects but not controls there was a significant cluster in the frontal lobe (Brodmann area 10) where perfusion decreased over the year.
Conclusions: The progressive frontal perfusion deficits in Parkinson's disease are consistent with results from previous structural and neuropsychological studies suggesting frontal lobe involvement and executive dysfunction even in early Parkinson's disease.
doi:10.1136/jnnp.2004.058685
PMCID: PMC1739344  PMID: 16170094
12.  The role of levodopa in the management of dementia with Lewy bodies 
Background: One of the core clinical features of dementia with Lewy bodies (DLB) is extrapyramidal syndrome (EPS). Levodopa is currently the gold standard oral therapy for Parkinson's disease (PD), but its use in DLB has been tempered by concerns of exacerbating neuropsychiatric symptoms.
Aim: To assess the efficacy and tolerability of L-dopa in managing EPS in DLB and to compare the motor response with that seen in PD and PD with dementia (PDD).
Method: EPS assessment consisted of the Unified Parkinson's Disease Rating Scale, motor subsection (UPDRS III), and finger tapping and walking tests. Patients with DLB were commenced on L-dopa. After 6 months, patients were examined in the "off" state, given L-dopa and assessed for motor responses. Identical assessments were performed in patients with PD and PDD also receiving L-dopa.
Results: Acute L-dopa challenge in 14 DLB patients yielded a mean 13.8% (p = 0.02) improvement in UPDRS III score, compared with 20.5% in PD (n = 28, p<0.0001) and 23% in PDD (n = 30, p<0.0001) respectively. Finger tapping scores increased (12.3% v 20% and 23%), while walking test scores decreased (32% v 41% and 67%). Of the DLB patients, 36% were classified as "responders" on L-dopa challenge, compared with 70% of the PDD and 57% of the PD patients. Nineteen DLB patients were treated for 6 months with L-dopa (mean daily dose 323 mg). Two withdrew prematurely with gastrointestinal symptoms and two with worsening confusion.
Conclusion: L-dopa was generally well tolerated in DLB but produced a significant motor response in only about one third of patients. Younger DLB cases were more likely to respond to dopaminergic treatment.
doi:10.1136/jnnp.2004.052332
PMCID: PMC1739807  PMID: 16107351
13.  Population based mortality and quality of death certification in progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome) 
Objective: To estimate the mortality of progressive supranuclear palsy (PSP) and to assess the quality of death certification in patients with PSP who died in England and Wales.
Methods: An analysis was conducted of ICD-9 (International Classification of Diseases, version 9) coded deaths obtained through the Office of National Statistics over an eight year period.
Results: The crude annual mortality rate was 1.77 (95% confidence interval, 1.64 to 1.90) cases per million, using the mid-1996 population estimate for England and Wales. Annual mortality increased over time, possibly as a result of increased incidence or increased awareness of the disorder. Forty nine death certificates from deceased patients previously diagnosed clinically showed that the commonest proximate cause of death was pneumonia, occurring in 45% of cases (22/49). The underlying cause of death was cited as pneumonia in 14% of cases (7/49). PSP was mentioned in only 65% of death certificates (32/49). Eight of the 49 cases (16%) underwent necropsy and results were available for five of these cases. PSP was confirmed pathologically in four; the remaining case was diagnosed as Parkinson's disease.
Conclusions: Further research is needed to establish the reasons for the observed increase in mortality. Determining the population mortality rate for PSP using the ICD-9 coding system is problematic but is likely to improve following the introduction of ICD-10 updated codes and coding rules.
doi:10.1136/jnnp.2004.039370
PMCID: PMC1739606  PMID: 15774434
15.  Frequency of orthostatic hypotension in a community based cohort of patients with Parkinson's disease 
Forty two (47%) of patients met the criteria for OH. Subjects with OH were older than those without OH, but there was no difference in PD disease duration or severity, MMSE or depression rating between the groups.
doi:10.1136/jnnp.2003.029413
PMCID: PMC1738761  PMID: 15377699
16.  Cortical Lewy body disease 
doi:10.1136/jnnp.2003.025569
PMCID: PMC1738936  PMID: 14742580
19.  Neurological emergencies, 3rd edition 
doi:10.1136/jnnp.70.6.821h
PMCID: PMC1737380
20.  Extrinsic cerebral venous sinus obstruction resulting in intracranial hypertension 
Postgraduate Medical Journal  1999;75(887):550-552.
We report the case of a 70-year-old man reporting with headache and visual disturbances who was being treated for prostate cancer. Investigations showed him to have intracranial hypertension caused by venous sinus obstruction. Patients with metastatic disease and raised intracranial pressure in the absence of focal signs should be considered as possible cases of venous outflow obstruction.


Keywords: intracranial hypertension; venous sinus thrombosis; malignancy
PMCID: PMC1741355  PMID: 10616691
21.  Multiple system atrophy: cellular and molecular pathology 
Molecular Pathology  2001;54(6):419-426.
Multiple system atrophy is an adult onset neurodegenerative disease, featuring parkinsonism, ataxia, and autonomic failure, in any combination. The condition is relentlessly progressive and responds poorly to treatment. Death occurs on average six to seven years after the onset of symptoms. No familial cases of multiple system atrophy have been reported, and no environmental factors have been robustly implicated as aetiological factors. However, analytical epidemiological studies are hampered because the condition is relatively rare. The discovery of the glial cytoplasmic inclusion (GCI) in 1989 helped to define multiple system atrophy as a clinicopathological entity, and drew attention to the prominent, if not primary, role played by the oligodendrocyte in the pathogenesis of the condition. Subsequently, GCIs were shown to be positive for α-synuclein, with immunostaining for this protein indicating that white matter pathology was more widespread than had previously been recognised. The presence of α-synuclein in GCIs provides a link with Parkinson's disease, dementia with Lewy bodies, and neurodegeneration with brain iron accumulation, type 1 (or Hallervorden-Spatz syndrome), in which α-synuclein is also found within Lewy bodies. This has led to the term “synucleinopathy” to embrace this group of conditions. The GCIs of multiple system atrophy contain a range of other cytoskeletal proteins. It is unknown how fibrillogenesis occurs, and whether there is primary oligodendrocytic dysfunction, which then disrupts the neurone/axon as a consequence of the glial pathology, or whether the oligodendrocytic changes merely represent an epiphenomenon. Further research into this devastating condition is urgently needed to improve our understanding of the pathogenesis, and also to produce new treatment approaches.
PMCID: PMC1187133  PMID: 11724918
multiple system atrophy; glial cytoplasmic inclusion; α-synuclein; oligodendrocyte
22.  Neurology and the kidney 
Renal failure is relatively common, but except in association with spina bifida or paraplegia it is unlikely to occur as a result of disease of the CNS. Renal failure, however, commonly affects the nervous system. The effects of kidney failure on the nervous system are more pronounced when failure is acute. In addition to the important problems related to renal failure there are both acquired and genetically determined diseases which may affect the kidney and the brain. Those acquired diseases include the vasculitides, the paraproteinaemias, and various granulomatous conditions (considered in other chapters of Neurology and Medicine). In two of the most commonly encountered genetically determined diseases, Von Hippel-Lindau disease and polycystic kidney disease, location of pathogenic mutations will provide improved screening programmes and, possibly, allow therapeutic intervention. Uraemia may affect both the central and peripheral nervous systems. Whereas the clinical features of uraemia are well documented, the pathophysiology is less well understood and probably multifactorial. Uraemic encephalopathy, which classically fluctuates, is associated with problems in cognition and memory and may progress to delirium, convulsions, and coma. The encephalopathy may initially worsen with periods of dialysis and almost certainly relates to altered metabolic states in association with ionic changes and possibly impaired synaptic function. Renal failure may affect the peripheral nervous system, resulting in a neuropathy which shows a predilection for large diameter axons. This may be reversed by dialysis and transplantation. The myopathy seen in renal failure, often associated with bone pain and tenderness, is similar to that encountered in primary hyperparathyroidism and osteomalacia.
 Dialysis itself is associated with neurological syndromes including the dysequilibrium syndrome, subdural haematoma, and Wernicke's encephalopathy. Dialysis dementia, which was prevalent during the 1970s, has reduced in frequency with the use of aluminium free dialysate. With the introduction of transplantation and the concomitant use of powerful immunosuppressive drugs, the pattern of neurological problems encountered in renal replacement therapy has shifted. Five per cent of patients develop nerve injuries during renal transplantation, and up to 40% of patients experience neurological side effects from cyclosporine. Furthermore, CNS infections, often fungal in type, have been reported in up to 45% of transplant patients coming to postmortem. The nature of the involvement of neurologists with their nephrology colleagues is therefore evolving.


PMCID: PMC2170399  PMID: 9854955
23.  Familial cavernous angiomas masquerading as multiple sclerosis. 
Postgraduate Medical Journal  1998;74(874):489-491.
We report here two cases of cavernous angioma, in the proband and her father, with quite different clinical presentations. The proband presented with a brainstem syndrome, mimicking multiple sclerosis, while the father had a history of mild epilepsy. Both patients were managed conservatively. The cases also demonstrate the utility of magnetic resonance imaging in the diagnosis of cavernous angioma.
Images
PMCID: PMC2360890  PMID: 9926126
25.  Is bed rest useful after diagnostic lumbar puncture? 
Postgraduate Medical Journal  1992;68(801):581-583.
A randomized study of 110 patients undergoing their first diagnostic lumbar puncture was performed to compare the effect of immediate mobilization with 4 hours bed rest on the incidence of post lumbar puncture headache. There was no difference between the mobile (n = 54) and bed rest (n = 56) groups in the incidence of post lumbar puncture headache (32% versus 31%, respectively). We conclude that bed rest following lumbar puncture may be an unnecessary imposition on the patient, as well as on nursing staff.
PMCID: PMC2399377  PMID: 1437958

Results 1-25 (32)