Agnita J.W. Boon

Frontal presentation in progressive supranuclear palsy

Background: Progressive supranuclear palsy (PSP) is a progressive hypokinetic rigid disorder with supranuclear gaze palsy and frequent falls. Although clinical consensus criteria are available, an atypical presentation may lead to clinical misdiagnosis in the initial phase. In the present study we investigated the clinical presentation of PSP and its relationship to initial clinical diagnosis and survival. Methods: We ascertained patients with PSP in a prospective cohort by nationwide referral from neurologists and nursing home physicians. All patients underwent a structural interview and clinical examination before entering the study. Medical records were reviewed for the presence of symptoms during the first 2 years. Results: A total of 152 patients ascertained between 2002 and 2005 fulfilled the international consensus criteria for PSP. Categorical principal component analysis of clinical symptoms within the first 2 years showed apart from a cluster of typical PSP symptoms, the clustering of cognitive dysfunction and behavioral changes. Further analysis showed that 20% of patients had a predominant frontal presentation with less than two other PSP symptoms. Survival analysis showed that this subgroup had a similar prognosis to that of the total group of patients with PSP. Conclusions: There exists a subgroup of patients with progressive supranuclear palsy (PSP) with a predominant frontal presentation, who progressed into typical PSP over the course of the disease.

Survival in progressive supranuclear palsy and frontotemporal dementia

Objective To compare survival and to identify prognostic predictors for progressive supranuclear palsy and frontotemporal dementia. Background Progressive supranuclear palsy (PSP) and frontotemporal dementia (FTD) are related disorders. Homozygosity for H1 haplotype is associated with PSP, whereas several MAPT mutations have been identified in FTLD-τ. Survival duration probably reflects underlying pathophysiology or disease. Methods Patients with PSP and FTD were recruited by nationwide referral. Survival of 354 FTD patients was compared with that of 197 PSP patients. Cox regression analysis was performed to identify prognostic predictors. FTLD-τ was defined as Pick disease and FTDP-17 with MAPT mutations. Semiquantitative evaluation of τ-positive pathology was performed on all pathologically proven cases. Results The median survival of PSP patients (8.0 years; 95% CI 7.3 to 8.7) was significantly shorter than that of FTD patients (9.9 years; 95% CI 9.2 to 10.6). Corrected for demographic differences, PSP patients were still significantly more at risk of dying than FTD patients. In PSP, male gender, older onset-age and higher PSP Rating Scale score were identified as independent predictors for shorter survival, whereas in FTD a positive family history and an older onset-age were associated with a poor prognosis. The difference in hazard rate was even more pronounced when comparing pathologically proven cases of PSP with FTLD-τ. Conclusion Survival of PSP patients is shorter than that of FTD patients, and probably reflects a more aggressive disease process in PSP. Independent predictors of shorter survival in PSP were male gender, older onset-age and higher PSP rating scale score, whereas in FTD a positive family history and higher onset-age were predictors for worse prognosis.

Familial aggregation of parkinsonism in progressive supranuclear palsy

Background: Progressive supranuclear palsy (PSP) is a progressive neurodegenerative disorder characterized by aggregates of the microtubule-associated protein tau (MAPT). A nonsignificant trend for positive family history has been observed in two case-control studies and several pedigrees with familial clustering of parkinsonism have been described. Occasionally, mutations in MAPT are found in patients with a clinical phenotype similar to PSP. In this case-control study, we compared the occurrence of dementia and parkinsonism among first-degree relatives of patients with PSP with an age- and sex-matched control group. Methods: Family history of dementia and parkinsonism was collected from all first-degree relatives of patients with PSP who fulfilled the international National Institute of Neurological Disorders and Stroke criteria for PSP. Age- and sex-matched controls were selected from the Rotterdam Study. Genetic testing and pathologic examination was performed in a subset of familial PSP cases. Results: Fifty-seven (33%) of the 172 patients with PSP had at least one first-degree relative who had dementia or parkinsonism compared to 131 (25%) of the control subjects (odds ratio [OR] 1.5, 95% confidence interval [CI] 1.01–2.13). In patients with PSP, more first-degree relatives with parkinsonism were observed compared to controls, with an OR 3.9 (95% CI 1.99–7.61). Twelve patients with PSP (7%) fulfilled the criteria for an autosomal dominant mode of transmission. The intrafamilial phenotype within these pedigrees varied among PSP, dementia, tremor, and parkinsonism. Genetic studies revealed one patient with a P301L mutation in MAPT. Pathologic examination of five familial cases confirmed the clinical diagnosis of PSP, with predominant four repeat tau pathology in affected brain areas. Conclusion: This study demonstrates familial aggregation of parkinsonism in progressive supranuclear palsy.

Dutch normal pressure hydrocephalus study: baseline characteristics with emphasis on clinical findings

We present the baseline characteristics of 101 patients with normal pressure hydrocephalus (NPH), entering a study that evaluates the diagnostic reliability of CSF outflow resistance. Patients were assessed by a gait scale consisting of 10 features of walking and the number of steps and seconds necessary for 10 m, a dementia scale comprising the 10 word test, trail making, digit span and finger tapping, the modified Mini Mental State Examination (3MSE) and the modified Rankin scale (MRS). Inclusion criteria were a gait and dementia scale ≥ 12 (range 2–40), a MRS ≥ 2 and a communicating hydrocephalus on CT. Gait disorder and dementia varied from mild to severe leading to MRS 2 in 17%, MRS 3 in 34%, MRS 4 in 21%, MRS 5 in 16% and MRS 6, including akinetic mutism, in 12%. Only one patient showed both normal tandem walking and turning. Small steps, reduced foot floor clearance and wide base were also frequently seen in the 67 patients walking independently; 34 needed assistance or could not walk at all. Applying the 3MSE, 64% were demented; the remaining 36% exhibited a milder cognitive deficit. The 10 word test and trail making decreased with increasing dementia. Digit span and finger tapping declined in the most demented patients. This group of elderly patients with NPH, mostly of the idiopathic type, proved to be vulnerable because of considerable disability and comorbidity.

DNAJC6 Mutations Associated with Early-Onset Parkinson's Disease

DNAJC6 mutations were recently described in two families with autosomal recessive juvenile parkinsonism (onset age < 11), prominent atypical signs, poor or absent response to levodopa, and rapid progression (wheelchair‐bound within ∼10 years from onset). Here, for the first time, we report DNAJC6 mutations in early‐onset Parkinsons disease (PD).

Does CSF Outflow Resistance Predict the Response to Shunting in Patients with Normal Pressure Hydrocephalus

The value of the measurements of CSF outflow resistance (Rcsf) relative to predicting outcome after shunting was studied. In a group of 101 patients with mainly idiopathic normal pressure hydrocephalus (NPH) Rcsf was obtained by lumbar constant flow infusion. Gait disturbance and dementia were quantified using an NPH scale (NPHS) and disability by the Modified Rankin scale (MRS). Patients were assessed before and at 1, 3, 6, 9 and 12 months after surgery. Outcome measures were differences between the preoperative and last NPHS and MRS scores. Improvement was defined as a change of > or = 15% in NPHS and > or = 1 grade in MRS. Intention-to-treat analysis of all patients at one year yielded improvement of 57% in NPHS and 59% in MRS. Efficacy analysis, excluding comorbidity unrelated to NPH, revealed positive predictive values of around 80% at Rcsf < 18, and between 90% and 100% at Rcsf > or = 18 mm Hg/ml/min. For Rcsf > or = 18, the likelihood ratios were also higher. We conclude that the best predictor of the response to shunting is an Rcsf > or = 18 mm Hg/ml/min. Since two-thirds of the patients with Rcsf < 18 showed improvement as well, these patients should not be denied shunting.

Cerebral hemodynamics before and after shunting in normal pressure hydrocephalus

Objective– To study the relationship between cerebral hemodynamics and clinical performance in normal pressure hydrocephalus (NPH), before and after surgery. Material and methods – Ten patients were studied prospectively before and 3 months after shunt surgery by means of transcranial Doppler (TCD). Clinical performance was scored by means of an NPH scale and the modified Rankin scale. Results– Peak systolic and mean cerebral blood flow velocity (MCV) were lower and cerebrovascular CO2 reactivity was higher after shunt surgery. The three patients with clinical improvement had higher preoperative end diastolic cerebral blood flow velocity and MCV. All postoperative cerebral blood flow velocities were higher in patients with clinical improvement. Conclusion– Our data suggest that higher cerebral blood flow velocity before surgery in patients with NPH is related to clinical improvement after shunt surgery. Cerebral hemodynamic parameters may develop into predictors of successful shunt surgery in patients with normal pressure hydrocephalus.

How to Select Patients with Normal Pressure Hydrocephalus for Shunting

The objective was to compare predictive values of clinical and CT findings, co-existing cerebrovascular disease (CVD) and CSF outflow resistance (Rcsf) for outcome of shunting in NPH. A group of 95 NPH patients was shunted and followed for one year. Gait disturbance and dementia were quantified by an NPH scale (NPHS) and handicap by the modified Rankin scale (MRS). Improvement was defined as a change of at least 15% in NPHS and one grade in MRS at last follow-up. Clinical and CT findings at entry were classified as typical or not typical for NPH. CVD was defined as a history of stroke or CT-scans showing infarcts or moderate to severe white matter hypodense lesions. Clinical and CT findings typical for NPH, absence of CVD and Rcsf > 18 mmHg/ml/min were positive tests and the reciprocal outcomes negative tests. Typical clinical and CT findings were found in 69% and 68%, CVD (history of stroke n = 14, infarcts on CT n = 13, leucoaraiosis n = 32) in 47% and Rcsf > 18 in 38% of patients. The ratio of patients classified as improved in both scales was significantly greater for those with positive than negative tests. Mean improvement differed the most between patients with and without CVD. Using logistic regression analysis Rcsf > 18 was the only significant predictor of improvement in NPHS (OR 4.4, 95% CI 1.3-16.7) and typical CT findings in MRS (OR 5.6, 95% CI 1.8-17.9). We conclude that CVD is an important predictor of poor outcome. The best strategy is to shunt NPH patients if Rcsf is > 18 mmHg/ml/min or, when Rcsf is lower, if CT findings are typical for NPH and there is no or limited CVD.

Midcingulate involvement in progressive supranuclear palsy and tau positive frontotemporal dementia

Background Progressive supranuclear palsy (PSP) patients often exhibit cognitive decline and behavioural changes during the disease course. In a subset, these symptoms may be the presenting manifestation and can be similar to those in frontotemporal dementia (FTD). However, correlation studies between quantitative imaging measures and detailed neuropsychological assessment are scarce. The aim of this study was to investigate the functional role of affected brain regions in cognition in PSP compared with controls and subsequently examine these regions in FTD patients with known tau pathology (FTD tau). Methods 21 PSP patients, 27 healthy controls and 11 FTD tau patients were enrolled. All participants underwent neuropsychological testing and technetium-99m-hexamethyl-propylenamine-oxime single photon emission CT. Regression slope analyses were performed in statistical parametric mapping to find significant associations between neuropsychological test results and brain perfusion. Results PSP patients showed hypoperfusion in the midcingulate cortex (MCC) of which the posterior part correlated with Stroop III and Weigl. In FTD tau patients, MCC involvement was located more anterior and correlated with Stroop III and Wisconsin Card Sorting Test concepts. The degree of hypoperfusion in the anterior cortex and MCC in the disorders differed in the subgenual anterior cingulate cortex only. Conclusions The posterior part of the MCC is prominently involved in the neurodegenerative process of PSP, and the severity of its hypoperfusion correlated with the extent of executive dysfunction. In FTD tau, this cognitive domain was associated with anterior MCC involvement. The degree of hypoperfusion in these regions did not differ between PSP and FTD tau. These observations provide insight into the role of the cingulate cortex in cognitive dysfunction in these neurodegenerative disorders and warrant further investigations.

Phenotypes and genetic architecture of focal primary torsion dystonia

Background The focal primary torsion dystonias (FPTDs) form a group of clinical heterogeneous syndromes and can be considered a genetic complex disease; it is thought to be primed by genetic variants with variable impact and triggered by non-genetic factors. Thorough clinical description of FPTDs cohorts is sparse but essential for further progress in genetic research. Objective To establish suggested relations between age at onset (AaO), site and family history in a large focal dystonias cohort and gain more insight into familial clustering for genetic research. Patients and methods A prospective cohort study between March 2008 and March 2011, including 676 FPTD patients attending the botulinum toxin outpatient clinics of six Dutch movement disorder centres. Results and conclusions Of all of the FPTD patients, 25% had a familial predisposition; in 2.4% a Mendelian inheritance pattern was noted. With a stronger family history, a significantly lower AaO was seen in all focal dystonias. In both the sporadic and familial focal dystonia groups, AaO had an effect on the distribution of dystonia, with a caudal to cranial tendency. In all focal dystonia forms, women were more frequently affected, except for writers cramp. Careful clinical characterisation will allow the formation of phenotype subgroups. We suggest that genetic research into FPTDs will benefit from this approach and discuss genetic research strategies to decipher the complex background of focal dystonias.