Cerebrospinal fluid biomarkers that reflect clinical symptoms in idiopathic normal pressure hydrocephalus patients.

BACKGROUND: The relationship between cerebrospinal fluid (CSF) biomarkers and the clinical features of idiopathic normal pressure hydrocephalus (iNPH) has been inconclusive. We aimed to evaluate CSF biomarkers reflecting Alzheimer's disease (AD)-related amyloid ß (Aß) aggregation, tau pathology, neuroinflammation and axonal degeneration in relation to the clinical features of pre- and post-shunt surgery in iNPH patients. METHODS: Mini Mental State Examination (MMSE) scores and gait velocity were evaluated pre- and postoperatively in cohorts of 65 Finnish (FIN) and 82 Swedish (SWE) iNPH patients. Lumbar CSF samples were obtained prior to shunt surgery and analysed for soluble amyloid precursor protein alpha (sAPPα) and beta (sAPPß); amyloid-ß isoforms of 42, 40 and 38 (Aß42, Aß40, Aß38); total tau (T-tau); phosphorylated tau (P-tau181); neurofilament light (NfL) and monocyte chemoattractant protein 1 (MCP1). RESULTS: Preoperative patient characteristics showed no significant differences between patients in the FIN and SWE cohorts. Patients in both cohorts had significantly improved gait velocity after shunt surgery (p < 0.0001). Low CSF T-tau and absence of apolipoprotein E ε4 predicted over 20% gait improvement postoperatively (p = 0.043 and p = 0.008). Preoperative CSF T-tau, P-tau181 and NfL correlated negatively with MMSE scores both pre- (p < 0.01) and post-surgery (p < 0.01). Furthermore, T-tau, NfL and Aß42 correlated with MMSE outcomes (p < 0.05). Low preoperative CSF P-tau181 (p = 0.001) and T-tau with NfL (p < 0.001 and p = 0.049) best predicted pre- and postoperative MMSE scores greater than or equal to 26. CONCLUSIONS: CSF biomarkers of neurodegeneration appeared to correlate with pre- and postoperative cognition, providing a window into neuropathological processes. In addition, preoperative CSF neurodegeneration biomarkers may have potential in the prediction of gait and cognitive outcomes after shunt surgery.

Apolipoprotein E ε4 genotype and risk of freezing of gait in Parkinson's disease.

OBJECTIVE: To investigate the association between Apolipoprotein E (APOE) genotype and freezing of gait (FOG) in Parkinson's disease (PD). METHODS: This cohort study included 339 early PD patients who were divided into APOE ε4-positive (n = 88) and ε4-negative (n = 251) groups. They were followed-up for up to 6 years to identify the development of FOG. To investigate the influence of CSF ß-amyloid 1-42 (Aß42) on the association between APOE ε4 and FOG, the patients were additionally dichotomized into "high-level" and "low-level" groups using three different cutoff values for the CSF Aß42 levels. RESULTS: At baseline, the APOE ε4-positive group had lower CSF Aß42 levels than the APOE ε4-negative group. During a median follow-up of 5.0 years, the APOE ε4-positive group had a higher incidence of FOG than the APOE ε4-negative group. In the multivariable Cox model excluding CSF Aß42, APOE ε4 was a significant predictor of FOG. However, after adding CSF Aß42 in the model, APOE ε4 did not survive, whereas lower CSF Aß42 levels were associated with FOG. In the subgroup analyses, the effect of the APOE ε4 allele was not found in the "low-level" group. However, in the "high-level" group, the APOE ε4 allele independently increased the risk of FOG, and this association was stronger than the association with CSF Aß42. CONCLUSION: The APOE ε4 allele may be a novel genetic risk factor for FOG in PD. This association seemed to be mainly mediated by Aß-dependent pathways, but its Aß-independent effects might also contribute to the development of FOG.

Are gait changes linked to CSF flow changes in the sagittal sinus?

PURPOSE: To identify if specific findings on magnetic resonance imaging (MRI) cerebrospinal fluid (CSF) flow studies can be utilised to identify which patients with idiopathic normal pressure hydrocephalus (iNPH) will have improved gait following a CSF tap test (TT). METHODS: Prospective study of patients undergoing a CSF TT for iNPH. Functional gait was assessed using the timed up and go (TUG) test before and after the CSF TT. MRI CSF flow studies accompanied the CSF TT. The minimum clinically important difference for the TUG (3.63 s) was used as a cutoff value to categorise patients as responders to the CSF TT. RESULTS: Fifty-three patients underwent CSF TT and MRI CSF flow studies. Significant differences were identified between groups for (non-responder vs responder) superior sagittal sinus flow (47.10% vs 40.41%), sagittal sinus stroke volume (274 vs 176.5 µl), sagittal sinus to arterial stroke volume ratio (0.203 vs 0.164), sagittal sinus area (42.2 mm2 vs 36.2 mm2) and circumference (27.7 mm vs 24.95 mm). No differences were present for aqueduct stroke volume, arterial stroke volume or aqueduct net flow. CONCLUSION: A link between gait improvement resulting from CSF drainage and sagittal sinus measurements indicates that the sagittal sinus may play a role in the manifestation of symptoms in iNPH. This may have implications for the diagnosis of iNPH and potentially inform clinical decision making regarding surgical intervention.

Aß42/Aß40 and Aß42/Aß38 Ratios Are Associated with Measures of Gait Variability and Activities of Daily Living in Mild Alzheimer's Disease: A Pilot Study.

Gait disturbances are some of the earliest changes in dementia and their monitoring presents an opportunity for early diagnosis. The exact relationship between gait and well-established biomarkers of Alzheimer's disease (AD) remains to be clarified. In this study we compared gait-related measures with cerebrospinal fluid (CSF) markers of AD pathology. We recruited seventeen participants with mild AD in a multi-site study and performed gait assessment as well as lumbar punctures to obtain CSF. CSF Aß42/Aß40 and Aß42/Aß38 correlated positively with measures of variability (step time and step length) in the clinic-based assessments. This was driven by a negative relationship between gait variability and Aß40 and Aß38 but not Aß42.The amyloid ratios and gait variability measures were also associated with more severe functional impairment. We interpret these data as an indication that increasing amyloid production (i.e., increasing Aß40 and Aß38) is associated with diminishing cognitive-motor control of gait. These preliminary results suggest that the two amyloid ratios may be a marker of the earliest disturbances in the interplay between cognitive and motor control which characterize dementia.

Parkinsonism is a Phenotypical Signature of Amyloidopathy in Patients with Gait Disorders.

BACKGROUND: Central neurological gait abnormalities (CNGA) are frequently associated with parkinsonism in older adults. However, the neuropathological substrates and the clinical impact of parkinsonism have been not described in CNGA. OBJECTIVE: This cross-sectional study aims to compare the CSF total tau, Aß1-42, and phosphorylated tau levels in non-Parkinson's disease (PD) patients with CNGA with and without parkinsonism and to study the clinical impact of parkinsonism on gait and cognition. METHODS: CSF biomarkers were measured by ELISA in 49 non-PD patients with CNGA (77.7±6.6 years; 32.7% women). Gait was quantified with an optoelectronic system and cognition with a comprehensive neuropsychological assessment. Parkinsonism was defined by presence of bradykinesia and at least one of the following signs among muscular rigidity, rest tremor, or postural instability. RESULTS: Parkinsonism was identified in 14 CNGA patients (28.6% ). CSF Aß1-42 level was decreased in CNGA patients with parkinsonism (ß: - 189.4; 95% CI [- 352.3; - 26.6]; p = 0.024) even after adjusting for age, gender, comorbidities, and total white matter burden; while CSF total tau and phosphorylated tau levels were similar between CNGA patients with and without parkinsonism. CNGA patients with parkinsonism presented decreased attentional and executive performances but similar gait parameters than those without parkinsonism. CONCLUSION: Parkinsonism represents a phenotype related with amyloidopathy-decreased CSF Aß1-42 level-in non-PD patients with CNGA. This phenotype is clinically associated with impaired cognition, but similar quantitative gait parameters in comparison to CNGA patients without parkinsonism.

Brain comorbidities in normal pressure hydrocephalus.

BACKGROUND AND PURPOSE: This cross-sectional study aims to compare gait changes after the cerebrospinal fluid (CSF) tap test between normal pressure hydrocephalus patients with and without brain comorbidities (NPH+ and NPH- respectively) and then to identify significant contributors to a poor CSF tap test amongst individuals with NPH+. METHODS: Gait changes (during the single task and the dual task of backward counting) were quantified before and 24 h after the CSF tap test with an optoelectronic system in 52 NPH patients (77.4 ± 6.0 years; 34.6% women). Changes after the CSF tap test in stride time variability (STV, %) were our main outcome. CSF Alzheimer's disease biomarkers, cerebrovascular white matter changes assessed with brain imaging and neurodegenerative diseases with parkinsonian syndrome represented the three individual brain comorbidities. RESULTS: Brain comorbidities were frequently identified, NPH+ patients representing 40 patients of our sample (76.9%). NPH- patients improved their STV better in the single task (delta of STV = -58.6% ± 54.3% vs. -14.1% ± 62.0%; P = 0.031) and in the dual task (delta of STV =-32.2% ± 33.7% vs. 6.3% ± 58.4%; P = 0.028) after the CSF tap test than NPH+ patients. Amongst NPH+ individuals, only comorbid Alzheimer's disease was associated with STV increase (i.e. deterioration of gait) in the dual task [ß 38.4; 95% confidence interval (5.64; 71.24); P = 0.023] after the CSF tap test, whilst it was borderline in the single task [ß 35.0; 95% confidence interval (-1.97; 71.90); P = 0.063]. CONCLUSIONS: Brain comorbidities affect gait improvement after the CSF tap test in NPH patients; this influence is driven by Alzheimer's disease-related pathology.

A combined cognitive and gait quantification to identify normal pressure hydrocephalus from its mimics: The Geneva's protocol.

OBJECTIVES: Idiopathic normal pressure hydrocephalus (iNPH) is very prevalent in aging, underdiagnosed, and represents a rare cause of reversible neurological condition. The clinical triad of iNPH - gait, cognitive and urinary symptoms - and its neuroradiological features (i.e. ventriculomegaly) are not specific and found a various neurodegenerative and/or vascular conditions. We present our iNPH standardized protocol at the Geneva University Hospitals involving a multispecialty team of behavioral neurologists, neurosurgeons, neuropsychologists, engineers, and physical therapists. Based on a pragmatic approach, the goal of this protocol is to improve the identification of older patients with iNPH from its mimics (i.e. vascular dementia or other parkinsonian syndromes). PATIENTS AND METHODS: We used a novel standardized paradigm with a simultaneous quantification of cognition and gait (dual task gait assessment and mental imagery of locomotion) before and 24h after CSF tapping. RESULTS: We assessed 125 patients with suspicion of iNPH (age: 75.9±7.4years; 34.4% female) in 5 years: 54.4% of probable/possible iNPH and 45.6% of mimics. Among the mimics, vascular dementia (24.6%) and patients with multifactorial conditions (19.9%) were the two most common diagnoses. A total of 27 patients with iNPH (39.7%) accepted the neurosurgical shunt procedure. CONCLUSION: This report shows that a quantified gait and cognitive assessment - using dual-task paradigms - before and after CSF tapping is feasible among older adults with suspicion of iNPH and that this multidisciplinary approach contributes to the identification of patients with iNPH from its mimics.

Interleukin 10 Level in the Cerebrospinal Fluid as a Possible Biomarker for Lymphomatosis Cerebri.

A 71-year-old immunocompetent man developed cognitive decline and gait disturbance. Brain magnetic resonance imaging (MRI) revealed bilateral diffuse leukoencephalopathy without a mass lesion. An analysis of the cerebrospinal fluid (CSF) showed elevated levels of interleukin (IL)-10. The condition of the patient progressively deteriorated, and intravenous high-dose steroids proved ineffective. Detection of non-destructive, diffusely infiltrating, large B-cell lymphoma in biopsy and autopsy specimens led to a diagnosis of lymphomatosis cerebri (LC). On serial MRI, the basal ganglia and white matter lesions increased in parallel with the levels of IL-10. These findings suggest that the IL-10 level in the CSF may represent a potentially useful biomarker for the early diagnosis and monitoring of the disease progression in LC.

Idiopathic normal-pressure hydrocephalus, cerebrospinal fluid biomarkers, and the cerebrospinal fluid tap test.

Cerebrospinal fluid (CSF) biomarkers, including soluble amyloid ß-42 (Aß-42) and phosphorylated-tau (P-tau), reflect core pathophysiological features of Alzheimer's disease (AD). AD is frequently a concomitant pathology in older patients with idiopathic normal-pressure hydrocephalus (iNPH), and somewhat similar altered CSF dynamics exist in both AD and iNPH. We therefore investigated relationships between lumbar CSF biomarkers Aß-42 and P-tau and clinical parameters in iNPH patients, along with differences in these biomarkers between CSF tap test (CSFTT) responders and non-responders. Thirty-one iNPH patients (14 CSFTT responders and 17 CSFTT non-responders) were included in the final analysis. We found lower CSF Aß-42 correlated with poor cognitive performance (r=0.687, p<0.001 for Korean Mini Mental State Examination; r=0.568, p=0.001 for Frontal Assessment Battery; r=-0.439, p=0.014 for iNPH grading scale [iNPHGS] cognitive score; r=-0.588, p=0.001 for Clinical Dementia Rating Scale), and lower CSF P-tau correlated with gait dysfunction (r=-0.624, p<0.001 for Timed Up and Go Test; r=-0.652, p<0.001 for 10meter walking test; r=-0.578, p=0.001 for Gait Status Scale; r=-0.543, p=0.002 for iNPHGS gait score). In subgroup analysis, CSF P-tau/Aß-42 ratios were significantly higher in CSFTT non-responders compared to responders (p=0.027). Two conjectures are suggested. One, CSF biomarkers may play different and characteristic roles in relation to different iNPH symptoms such as cognition and gait. Two, comorbid AD pathology in iNPH patients may affect the response to the CSFTT. Larger studies using combinations of other biomarkers associated with AD would be necessary to evaluate these hypotheses.

Foot drop splints improve proximal as well as distal leg control during gait in Charcot-Marie-Tooth disease.

INTRODUCTION: During walking, people with Charcot-Marie-Tooth (CMT) disease may compensate for distal weakness by using proximal muscles. We investigated the effect of different AFOs on distal leg control and proximal compensatory actions. METHODS: Fourteen people with CMT were tested while wearing 3 types of ankle-foot orthosis (AFO) bilaterally compared with shoes alone. Walking was assessed using three-dimensional gait analysis. Stiffness of the splints was measured by applying controlled 5-degree ankle stretches using a motor. RESULTS: The results showed that each AFO significantly stiffened the ankle and increased ankle dorsiflexion at foot clearance compared with shoes alone. At push off, peak ankle power generation was reduced, but only with 1 type of AFO. A significant decrease in hip flexion amplitude during the swing phase was observed with all 3 AFOs. CONCLUSIONS: These results indicate that AFOs reduce foot drop and remove the need for some proximal compensatory action.

Cerebrospinal fluid Aß and tau level fluctuation in an older clinical cohort.

OBJECTIVE: To determine whether cerebrospinal fluid (CSF) biomarkers for Alzheimer disease fluctuate significantly over time in a cohort of older, mildly symptomatic individuals. DESIGN: Biomarker validation in a clinical cohort. SETTING: University hospital inpatient unit. PARTICIPANTS: Ten patients admitted for CSF drainage for diagnostic purposes. MAIN OUTCOME MEASURES: The CSF levels of Aß1-40, Aß1-42, tau, and phosphorylated tau on threonine 181 (p-tau(181)) were measured every 6 hours for 24 or 36 hours. RESULTS: The mean coefficient of variation values for each biomarker assessed in our 10 patients were 5.5% (95% CI, 3.8%-10.0%) for Aß1-42, 12.2% (9.0%-24.2%) for Aß1-40, 8.2% (5.7%-15.1%) for total tau, and 11.9% (8.5%-23.0%) for p-tau(181). These values are only slightly higher than the variability in the assay. In addition, no significant circadian fluctuation in any Alzheimer disease biomarker was observed given the limitations of our sampling frequency. CONCLUSION: In a cohort of elderly patients, little fluctuation in the levels of important Alzheimer disease biomarkers in lumbar CSF is seen as a function of time.

A case of progressive ataxia followed by cognitive and behavioral changes.

The patient is a 60-year-old man who initially presented to his local hospital with complaints of gait difficulties that started suddenly after waking. Results of brain magnetic resonance imaging performed 1 week later were normal. Three weeks after that he developed blurred vision and he complained of a severe headache in the posterior head and neck regions at the onset of symptoms, which necessitated several visits to his local emergency room. The patient presented to our institution 1 month later, with progressive gait difficulty and truncal instability over a 2-week period.

Features of gait most responsive to tap test in normal pressure hydrocephalus.

OBJECTIVE: To identify components of gait associated with a positive tap test (TT) in patients with idiopathic normal pressure hydrocephalus (iNPH). PATIENTS AND METHODS: Thirty-three patients with iNPH underwent clinical evaluation pre- and post-TT and were classified as responders (Rs) or non-responders (NRs). Elements of gait were assessed with a formal standardized Gait Scale and compared between groups. RESULTS: Analysis of pre/post-TT group differences revealed an interaction for Total Gait Score and Walking Score, with improvements in responders only. Total Gait Scores improved by 29% in the Rs and 4.85% in the NRs. Rs showed significant post-TT improvements on a timed 10m walk, turning, and balance. Tandem walking, turning, truck balance and start stop hesitation showed trends toward improvement. CONCLUSIONS: The classic features of gait often used in determining diagnosis of NPH (wide based stride, reduced foot-floor clearance, and small steps) were not helpful in identifying responders to the TT. Walking speed, steps for turning, and tendency towards falling were most likely to improve post-TT. These straightforward measures can readily be adapted into clinical practice to assist in determination of shunt candidacy.

Lumbar infusion test in normal pressure hydrocephalus.

OBJECTIVE: To compare potential clinical value of plateau pressure (P(pl)), resistance to outflow (R(out)), pulse-pressure amplitude (P(plA)) and rate of pressure increase (v(P)), taken from the constant rate lumbar infusion test (LIT), as predictors for the outcome of shunt surgery. METHODS: Recordings from preoperative LIT in 55 patients were scrutinized for the values of P(pl), P(plA), v(P) and R(out). Gait, memory, spatial capacity and reaction ability were tested before and 6 months after shunt surgery. RESULTS: Forty-three (78%) of the patients improved. There were no statistically significant differences in P(pl), R(out), P(plA) or v(P) between improved and not improved patients. Five patients with P(pl) below 22 mmHg (the cut off level) improved after shunting, while 16 and eight patients with R(out) below the cut off levels of 18 and 14 mmHg/ml/min improved. P(plA) correlated with P(pl) and R(out) (r = 0.74 and 0.63, respectively). In the group of patients with high P(plA) (>/=20 mmHg) as many as 93% improved but a high P(plA) did not recruit more improved patients than P(pl) or R(out) alone. CONCLUSION: v(P) or P(plA) does not add useful information to P(pl) for selecting patients with suspected NPH for surgery. R(out) calculations from LIT does not provide advantage over using the steady-state plateau pressure for selecting patients for surgery and may increase the risk of missing patients who should benefit from surgery.