Assessing functional status using the IADL-extended scale: results from the HELIAD study.

OBJECTIVES: Instrumental activities of daily living (IADL) have been operationalized as exhibiting a greater level of complexity than basic ADL. In the same way, incorporating more advanced ADLs may increase the sensitivity of functional measures to identify cognitive changes that may precede IADL impairment. Towards this direction, the IADL-extended scale (IADL-x) consists of four IADL tasks and five advanced ADLs (leisure time activities). DESIGN: Retrospective, cross-sectional study. SETTING: Athens and Larissa, Greece. PARTICIPANTS: 1,864 community-dwelling men and women aged over 64. MEASUREMENTS: We employed both the IADL-x and IADL scales to assess functional status among all the participants. Diagnoses were assigned dividing the population of our study into three groups: cognitively normal (CN), mild cognitive impairment (MCI) and dementia patients. Neuropsychological evaluation was stratified in five cognitive domains: memory, language, attention-speed, executive functioning and visuospatial perception. Z scores for each cognitive domain as well as a composite z score were constructed. Models were controlled for age, sex, education and depression. RESULTS: In both IADL-x and IADL scales dementia patients reported the most functional difficulties and CN participants the fewest, with MCI placed in between. When we restricted the analyses to the CN population, lower IADL-x score was associated with worse cognitive performance. This association was not observed when using the original IADL scale. CONCLUSION: There is strong evidence that the endorsement of more advanced IADLs in functional scales may be useful in detecting cognitive differences within the normal spectrum.

MRI Planimetry and Magnetic Resonance Parkinsonism Index in the Differential Diagnosis of Patients with Parkinsonism.

BACKGROUND AND PURPOSE: Differential diagnosis of multiple system atrophy, progressive supranuclear palsy, and corticobasal degeneration from Parkinson disease on clinical grounds is often difficult. MR imaging biomarkers could assist in a more accurate diagnosis. We examined the utility of MR imaging surface measurements (MR imaging planimetry) in the differential diagnosis of patients with parkinsonism. MATERIALS AND METHODS: Fifty-two patients with Parkinson-plus (progressive supranuclear palsy, n = 24; corticobasal degeneration, n = 9; multiple system atrophy, n = 19), 18 patients with Parkinson disease, and 15 healthy controls were included. Corpus callosum, midbrain, and pons surfaces; relevant indices; and the Magnetic Resonance Parkinsonism Index were calculated. Corpus callosum subsection analysis was performed, and the corpus callosum posteroanterior gradient was introduced. RESULTS: A Magnetic Resonance Parkinsonism Index value of >12.6 discriminated progressive supranuclear palsy from other causes of parkinsonism with a 91% sensitivity and 95% specificity. No planimetry measurement could accurately discriminate those with multiple system atrophy with parkinsonism from patients with Parkinson disease. A corpus callosum posteroanterior gradient value of ≤191 was highly specific (97%) and moderately sensitive (75%) for the diagnosis of corticobasal degeneration versus all other groups. A midbrain-to-corpus callosum posteroanterior gradient ratio of ≤0.45 was highly indicative of progressive supranuclear palsy over corticobasal degeneration (sensitivity 86%, specificity 88%). CONCLUSIONS: MR imaging planimetry measurements are potent imaging markers of progressive supranuclear palsy and promising markers of corticobasal degeneration but do not seem to assist in the diagnosis of multiple system atrophy with parkinsonism.

Biochemical markers in vascular cognitive impairment associated with subcortical small vessel disease - A consensus report.

BACKGROUND: Vascular cognitive impairment (VCI) is a heterogeneous entity with multiple aetiologies, all linked to underlying vascular disease. Among these, VCI related to subcortical small vessel disease (SSVD) is emerging as a major homogeneous subtype. Its progressive course raises the need for biomarker identification and/or development for adequate therapeutic interventions to be tested. In order to shed light in the current status on biochemical markers for VCI-SSVD, experts in field reviewed the recent evidence and literature data. METHOD: The group conducted a comprehensive search on Medline, PubMed and Embase databases for studies published until 15.01.2017. The proposal on current status of biochemical markers in VCI-SSVD was reviewed by all co-authors and the draft was repeatedly circulated and discussed before it was finalized. RESULTS: This review identifies a large number of biochemical markers derived from CSF and blood. There is a considerable overlap of VCI-SSVD clinical symptoms with those of Alzheimer's disease (AD). Although most of the published studies are small and their findings remain to be replicated in larger cohorts, several biomarkers have shown promise in separating VCI-SSVD from AD. These promising biomarkers are closely linked to underlying SSVD pathophysiology, namely disruption of blood-CSF and blood-brain barriers (BCB-BBB) and breakdown of white matter myelinated fibres and extracellular matrix, as well as blood and brain inflammation. The leading biomarker candidates are: elevated CSF/blood albumin ratio, which reflects BCB/BBB disruption; altered CSF matrix metalloproteinases, reflecting extracellular matrix breakdown; CSF neurofilment as a marker of axonal damage, and possibly blood inflammatory cytokines and adhesion molecules. The suggested SSVD biomarker deviations contrasts the characteristic CSF profile in AD, i.e. depletion of amyloid beta peptide and increased phosphorylated and total tau. CONCLUSIONS: Combining SSVD and AD biomarkers may provide a powerful tool to identify with greater precision appropriate patients for clinical trials of more homogeneous dementia populations. Thereby, biomarkers might promote therapeutic progress not only in VCI-SSVD, but also in AD.

Incidence of rotational vertigo in supratentorial stroke: a prospective analysis of 112 consecutive patients.

BACKGROUND: Single cases with hemispheric, cortical or subcortical, ischemic lesions presenting with rotational vertigo (RV), that challenge the notion of infratentorial or peripheral generation of RV have been published, but the incidence of this symptom in a larger series is unknown. The aim of this study was to investigate whether acute hemispheric cerebrovascular lesions cause vertiginous sensations with particular emphasis on RV. METHODS: A total of 112 consecutive stroke patients were assessed in a prospective single-center study over a 22-month inclusion period. Rotational or other vertiginous sensations were assessed using a structured 5-item questionnaire and patients with vertigo were further evaluated with Yardley's Vertigo Symptom Scale. All subjects underwent standard clinical neuro-ophthalmological and neuro-otological testing and data were correlated to imaging findings. RESULTS: RV was absent among our patients. Few subjects reported non-rotational vertiginous sensations with stroke onset. These were mainly right-hemispheric strokes with concomitant subcortical leukoaraiosis. CONCLUSION: In this case series we did not find any patients with spinning sensations which is supportive of the dogma that supratenotrial lesions do not cause RV. Certain hemispheric stroke patterns, however, may be related to non-rotational dizziness.

Vertical and horizontal integrator failure in a ponto-medullary infarction: A possible role for paramedian tract neurons.

Gaze-evoked nystagmus is caused by a "leaky" neural integrator, which fails to maintain eccentric gaze positions after centrifugal eye movements. It is usually observed as the result of toxic, metabolic or paraneoplastic disorders, rather than single structural lesions. We demonstrate a case of an omnidirectional gaze-evoked nystagmus due to an ischemic paramedian ponto-medullar infarction. The most probable explanation is a damage of paramedian tract neurons, which have been recently recognized as a site of neural integration.

CSF biomarker profile and diagnostic value in vascular dementia.

BACKGROUND AND PURPOSE: The differential diagnosis between vascular dementia (VD) and Alzheimer's disease (AD) or mixed dementia (MD) is not always easy in clinical practice. The purpose of the present study was to evaluate the cerebrospinal fluid (CSF) biomarkers tau protein in its total (tau(T)) or hyperphosphorylated at threonin-181(tau(P-181)) form and beta amyloid peptide 1-42 (A beta 42) alone and their combinations to investigate their diagnostic value in the discrimination between VD and AD or MD. METHODS: The above CSF biomarkers were determined in duplicate and blind to the clinical diagnosis by double sandwich, enzyme-linked immunosorbent assay (ELISA) commercial kits (Innogenetics, Gent, Belgium) in 92 AD patients, 23 VD patients, 17 patients with MD and 68 controls. RESULTS: Alzheimer's disease and MD showed increased levels of tau(T), tau(P) and reduced levels of A beta 42 as compared with the controls. The best discrimination between VD and AD or MD was achieved by the combination of all three biomarkers, correctly classifying >or=85% of patients, either in the form of a discriminant function or in the form of the tau(T) x tau(P-181)/A beta 42 formula. CONCLUSIONS: Cerebrospinal fluid biomarkers may be a useful adjunct for the discrimination between AD/ MD and VD in every day clinical practice.

Circulating interleukin-10 and interleukin-12 in Parkinson's disease.

BACKGROUND: Interleukin (IL)-12 is a heterodimeric cytokine produced by activated blood monocytes, macrophages and glial cells. It enhances differentiation and proliferation of T cells and increases production of proinflammatory cytokines. IL-10 is a pleiotropic cytokine produced by both lymphocytes and mononuclear phagocytes including microglia. Recent studies demonstrated the neuroprotective effect of IL-10. There is little information about the involvement of IL-12 or IL-10 in the pathophysiology of Parkinson's disease (PD). OBJECTIVES: The objective of our study was to assess the role of IL-12 as a potential marker of immune reactions in patients with PD and to investigate whether IL-10, an immunosuppressive cytokine, may have a neuroprotective effect in the pathogenesis of PD. PATIENTS AND METHODS: We measured using immunoassay serum IL-12 and IL-10 levels in 41 patients with PD in comparison with serum levels in 19 healthy subjects (controls) age and sex matched. IL-12 and IL-10 levels were tested for correlation with sex, age, disease duration, Hoehn and Yahr stage and the UPDRS III score. RESULTS: The PD group presented with significantly increased IL-10 levels when compared with the control group (P = 0.02). The increase observed was not affected by the treatment status. A strong and significant correlation between IL-10 and IL-12 levels was observed in patients with PD (R(S) = 0.7, P < 0.000001). CONCLUSIONS: Our findings suggest that IL-10 may be involved in the pathogenetic mechanisms of PD. The elevation of IL-10 and the significant correlation between IL-10 and IL-12, a proinflammatory cytokine, may suggest that immunological disturbances and neuroprotective mechanisms are involved in patients with PD.

Circulating interleukin-15 and RANTES chemokine in Parkinson's disease.

UNLABELLED: Interleukin-15 promotes T-cell proliferation, induction of cytolytic effector cells including natural killer (NK) and cytotoxic cells and stimulates B-cell to proliferate and secrete immunoglobulins. RANTES is a C-C beta chemokine with strong chemoattractant activity for T lymphocytes and monocytes. OBJECTIVES: The objective of our study was to find out whether IL-15 and RANTES are involved in the possible inflammatory reactions of PD. PATIENTS AND METHODS: We measured by immunoassay serum IL-15 and RANTES levels in 41 patients with PD in comparison with serum levels in 19 healthy subjects age and sex-matched. IL-15 and RANTES levels were correlated with sex, age, disease duration. H-Y stage and the UPDRS III score in all the studied groups and were also correlated with treatment status in PD patients. RESULTS: The PD group presented with significantly increased RANTES levels as compared to the control group (P = 0.0009). No difference was observed as regards IL-15 levels. A strong and significant correlation between RANTES levels and UPDRS III score was observed in PD patients (R(s) = 0.42, P = 0.007). Untreated patients had significantly higher RANTES levels as compared to the controls. CONCLUSIONS: Our findings may suggest a recruitment of activated monocytes, macrophages and T lymphocytes to sites of inflammation in the central nervous system of PD patients.

Cerebrospinal fluid tau, phospho-tau181 and beta-amyloid1-42 in idiopathic normal pressure hydrocephalus: a discrimination from Alzheimer's disease.

The aim of the present study was the quantitation of total tau protein (tau(T)), tau phosphorylated at threonine 181 (tau(P-181)) and beta-amyloid(1-42) (Abeta42) in the cerebrospinal fluid (CSF) of patients with idiopathic normal pressure hydrocephalus (iNPH), Alzheimer's disease (AD) and controls. Double sandwich ELISAs (Innogenetics) were used for the measurements. Total tau was significantly increased in iNPH and highly increased in AD as compared with the control group, whilst Abeta42 was decreased in both diseases. CSF tau(P-181) levels were significantly increased only in AD, but not in iNPH as compared with the controls. A cut-off level for tau(T) at 300 pg/ml, successfully discriminated AD from normal aging with a 95.8% specificity and 91% sensitivity; whilst the tau(P-181)/tau(T) ratio (cut-off value 0.169) was more specific (100%) but less sensitive (92.5%). For the discrimination of iNPH from AD tau(T) achieved low specificity (77.8%) but high sensitivity (92.5%), whilst tau(P-181) (cut-off value 47.4) was both sensitive and specific (88.7% and 86.7% respectively) for the discrimination of these disorders. The present study, despite being clinical, supports the notion that CSF tau(P-181) alone or in combination with tau(T) may be a useful marker in the discrimination of iNPH from AD.

IL-15 is elevated in cerebrospinal fluid of patients with Alzheimer's disease and frontotemporal dementia.

Interleukin-15 is a novel proinflammatory cytokine. It is produced by activated blood monocytes, macrophages, and glial cells. The objective of our study was to assess the role of interleukin-15 as a marker of increased proinflammatory activity in patients with Alzheimer's disease and frontotemporal dementia. We measured cerebrospinal fluid interleukin-15 levels in 17 patients with Alzheimer's disease and 7 patients with frontotemporal dementia in comparison with 17 patients with amyotrophic lateral sclerosis and 15 patients with Parkinson's disease. Patients with Alzheimer's disease and frontotemporal dementia had significantly higher cerebrospinal fluid interleukin-15 levels compared with patients with noninflammatory neurological diseases (P < .05 and P < .01, respectively). In Alzheimer's disease, a significant positive correlation was noted between interleukin-15 levels and age of onset (R = .48, P = .05). Our findings suggest that interleukin-15 may be implicated in the pathophysiology of Alzheimer's disease and frontotemporal dementia.

The cognitive effects of cholinesterase inhibitor treatment in every-day practice.

OBJECTIVE: Cholinesterase inhibitors (ChEIs) are the treatment of choice in Alzheimer's disease (AD). Their efficacy has been proven in many clinical trials. The aim of the present study was to confirm their cognitive benefit in every day practice as to whether it is similar to that expected from clinical trials. PATIENTS AND METHODS: We reviewed the files of 41 patients suffering from AD or mixed dementia and treated by ChEIs in terms of every day practice. RESULTS: During the first year MMSE scores remained better than or at baseline levels. Following that a gradual decline was noted. However, at any time point, the observed scores were significantly better than the expected ones calculated according to the pre-treatment rate of decline. The post-treatment rate of decline was significantly better than the pre-treatment one, while progression to the next stage of dementia was delayed by 8 months. CONCLUSION: The present observations from every-day practice indicate that there is a small but significant effect of ChEIs in cognition, similar to that observed in clinical trials. Furthermore, a small but significant delay in dementia progression may occur after treatment with ChEIs.

CSF tau protein and beta-amyloid (1-42) in Alzheimer's disease diagnosis: discrimination from normal ageing and other dementias in the Greek population.

Cerebrospinal fluid (CSF) levels of tau protein and amyloid beta(1-42) peptide (Abeta42) have been suggested as possible diagnostic markers of Alzheimer's disease (AD). In order to evaluate their diagnostic potential in clinical practice, we measured tau and Abeta42 levels in the CSF of 49 AD patients, 15 patients with non-AD neurodegenerative dementias (NAND), six patients with vascular dementia (VD) and 49 elderly controls. All the subjects were of Greek origin. A marked increase in tau, a decrease in Abeta42 and a marked increase in the tau/Abeta42 ratio was noted in AD. Abeta42 alone had a specificity of 80% and a sensitivity of 82% in differentiating AD from normal ageing, whilst the corresponding values for differentiating AD from NAND or VD were 80 and 71, or 67 and 82%, respectively. Tau was better in differentiating AD, from normal ageing (specificity 96%, sensitivity 88%), NAND (specificity 93%, sensitivity 71%) and VD (specificity 83%, sensitivity 94%). The tau/Abeta42 ratio achieved values comparable or even better than tau for differentiating AD from normal ageing (specificity 86%, sensitivity 96%) and VD (specificity 83%, sensitivity 90%) and definitely better than any of the candidate markers alone, for differentiating AD from NAND (specificity 100%, sensitivity 71%). Thus, the combined use of CSF tau and Abeta42 in the form of the tau/Abeta42 ratio is a simple, safe and useful adjuvant to clinical criteria for dementia diagnosis.

Highly increased CSF tau protein and decreased beta-amyloid (1-42) in sporadic CJD: a discrimination from Alzheimer's disease?

The aim was to quantify tau protein and beta-amyloid (Abeta42) in the CSF of patients with sporadic Creutzfeldt-Jakob disease (CJD), Alzheimer's disease (AD), and controls. Double sandwich enzyme linked immunosorbent assays (ELISAs) were used for measurements. Tau was increased 58-fold in CJD and 3.5-fold in AD compared with controls, whereas Abeta42 was decreased 0.5-fold in both CJD and AD. A cut off level for tau protein at 2131 pg/ml successfully discriminated CJD from AD (100% specificity and 93% sensitivity). Tau protein concentration in CSF is probably an additional useful marker in differentiating CJD from AD.

Increased cerebrospinal fluid tau protein in multiple sclerosis.

Axonal damage is now being recognized as a common finding in multiple sclerosis (MS) lesions and a cause of irreversible neurological damage. Attempts to identify markers of early axonal damage are of great significance. This prompted us to examine the microtubule-associated protein tau in the cerebrospinal fluid (CSF) of patients with MS vs. controls. Tau was measured by double antibody sandwich ELISA. Increased CSF tau levels were found in MS as compared to controls (medians 249.6 and 135 pg/ml respectively, p<0.001). Half of the MS patients presented with levels above the upper limit of the controls. A significant increase vs. controls was found in both relapsing-remitting and progressive subtypes. These data may indicate axonal impairment in a subpopulation of MS patients and may provide a tool for the estimation of axonal damage during life.

Correlation between denervation activity and compound muscle action potential amplitude in hereditary motor and sensory neuropathy I and II.

Studying the electrophysiological characteristics of the various types of Charcot-Marie-Tooth disease is important in the understanding of its pathophysiology. The purpose of this study was to identify the frequency of fibrillation potentials and positive sharp waves (FP/PWs) in HMSN I and II and, since they are indices of denervation, to elucidate whether they are correlated with the amplitude of compound muscle action potentials (CMAP). We reviewed the electrophysiological findings of 47 patients who have been studied in our hospital and found to suffer from Charcot-Marie-Tooth polyneuropathy. FP/PW were graded according to a 4-grade scale and the 38 m/sec criterion for motor conduction velocity (MCV) was used for distinction between HMSN I and II subgroups. Seventy percent of HMSN II patients and 81% of HMSN I patients showed fibrillation potentials in the upper or lower limbs. There was no difference in the frequency of FP/PW appearance between the two groups. In the HMSN II group the FP/PW grade correlated with CMAP amplitude in the upper limbs. In both groups there was no correlation between FP/PW grade and MCV. Our findings might indicate that in HMSN I there is a considerable axonal destruction that occurs concurrently with myelin loss.

Ascorbate in healthy subjects, amyotrophic lateral sclerosis and Alzheimer's disease.

The aim of the present study was to report the levels of ascorbic acid in amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD) and the effectiveness of ascorbic acid homeostasis in the central nervous system. Plasma and CSF ascorbic acid levels were measured by high performance liquid chromatography in 19 ALS patients, 17 AD patients and 15 controls. No statistically significant difference was found between patients and controls. However, wide fluctuations of plasma concentrations were found to result in relatively stable CSF levels, by appropriate adjustments of CSF/plasma ratio. It appears that in normal subjects and in the disease under study, this ratio reflects the activity of the choroid plexus ascorbate transporter.

Hereditary neuropathy with liability to pressure palsies: the same molecular defect can result in diverse clinical presentation.

Hereditary neuropathy with liability to pressure palsies (HNPP) is a peripheral nerve disorder characterized by autosomal dominant inheritance, recurrent pressure palsies, reduced motor and sensory conduction velocities and sausage-like swellings (tomacula) of myelin sheaths in nerve biopsy. Two young adult patients are reported as index cases of two families in which HNPP was diagnosed. The first patient presented with recurrent pressure palsies, whereas the second suffered from fasciculations and myokymias in his right hand, with difficulty in writing, and upper and lower limb paraesthesias of 3 years' duration. Electrodiagnostic studies revealed slowing of conduction primarily in common sites of compression in both patients. Sural nerve biopsy revealed the characteristic tomaculous swellings in both patients. DNA analysis showed that both patients have a deletion in chromosome 17p11.2 which is found in the majority of HNPP cases. In light of the common molecular defect, the different clinical symptomatology of the two patients is discussed.