Anastasios Bonakis

Diagnostic value of CSF biomarker profile in frontotemporal lobar degeneration.

BackgroundCerebrospinal fluid (CSF) biomarkers have been increasingly studied in dementia clinical and differential diagnosis. MethodsWe assessed levels of total tau protein (τT), tau phosphorylated at threonine 181 (τP-181), and β-amyloid1-42 (Aβ42) in 34 patients with frontotemporal lobar degeneration (FTLD), 76 Alzheimer disease (AD) cases, and 93 controls (CTRL). Double sandwich enzyme-linked immunosorbent assays (Innogenetics) were used for measurements. ResultsTotal τ was significantly increased and Aβ42 decreased in FTLD and AD patients as compared with CTRL. CSF τP-181 levels were significantly increased only in AD. The τT/Aβ42 ratio successfully discriminated FTLD from CTRL with a 86.7% specificity and 80.6% sensitivity, whereas the τT alone was more specific (95.7%) but less sensitive (64.75%). For the discrimination of FTLD from AD, τT/Aβ42 ratio was better (90.3% sensitivity and 64.5% specificity) compared with the other biomarkers alone or in combination, whereas τP-181 was less sensitive but more specific (68.4% and 85.7%, respectively). Subtype analysis revealed that the most AD-like profile of biomarkers were observed in FTLD with motor neuron signs, whereas the most non-AD profile were observed in patients with primary progressive aphasia. ConclusionsCombined analysis of CSF biomarkers may be useful for the best possible antemortem discrimination of FTLD from AD.

The Stroop Effect in Greek Healthy Population: Normative Data for the Stroop Neuropsychological Screening Test

The Stroop Test is a quick and frequently used measure in screening for brain damage, dysfunction of selective attention, and cognitive flexibility. The purpose of the present study is to provide normative data for Trenerrys Stroop Neuropsychological Screening Test (SNST) in a sample of 605 healthy Greek participants (age range: 18-84 years, education range: 6-18 years). Results revealed that age and education significantly contributed to SNST scores, accounting for a significant proportion of variance in time needed to complete the color task and in the interference Color-Word score. Performance on most of the measures decreases with increasing age and lower levels of education. Normative data stratified by age and education for the Greek adult population are provided as a useful set of norms for clinical practice.

Time-frequency analysis methods to quantify the time-varying microstructure of sleep EEG spindles: Possibility for dementia biomarkers?

The time-varying microstructure of sleep EEG spindles may have clinical significance in dementia studies and can be quantified with a number of techniques. In this paper, real and simulated sleep spindles were regarded as AM/FM signals modeled by six parameters that define the instantaneous envelope (IE) and instantaneous frequency (IF) waveforms for a sleep spindle. These parameters were estimated using four different methods, namely the Hilbert transform (HT), complex demodulation (CD), matching pursuit (MP) and wavelet transform (WT). The average error in estimating these parameters was lowest for HT, higher but still less than 10% for CD and MP, and highest (greater than 10%) for WT. The signal distortion induced by the use of a given method was greatest in the case of HT and MP. These two techniques would necessitate the removal of about 0.4s from the spindle data, which is an important limitation for the case of spindles with duration less than 1s. Although the CD method may lead to a higher error than HT and MP, it requires a removal of only about 0.23s of data. An application of this sleep spindle parameterization via the CD method is proposed, in search of efficient EEG-based biomarkers in dementia. Preliminary results indicate that the proposed parameterization may be promising, since it can quantify specific differences in IE and IF characteristics between sleep spindles from dementia subjects and those from aged controls.

Frequency and causes of early-onset dementia in a tertiary referral center in Athens.

ObjectiveTo investigate the frequency and causes of early-onset dementia (EOD) in consecutive patients in a highly specialized dementia referral center, focusing on unusual cases, particularly with early and/or rapid onset, in Athens, Greece. MethodsPatients referred for dementia diagnosis according to specific referral criteria during a 3 years period. We examined the distribution of patients diagnosis and differences in sex, education, dementia severity, cognitive function, and the duration of disease (from onset to referral) between the EOD (<65 y) and the late-onset dementia (LOD) groups. ResultsFrom a total of 260 consecutive demented patients, there were 114 EOD patients or 44% of all demented patients. No significant differences were observed between the EOD and LOD groups in cognitive or behavioral measures. However, the duration from onset to consultation was significantly longer in the EOD group. Also, in the EOD group, the rates of patients with Alzheimer disease and Parkinson disease dementia were relatively low and the rate of patients with frontotemporal lobar degeneration was relatively high and the proportion of secondary dementias was high. ConclusionsWe conclude that EOD patients are more likely to be seen in specialized settings. The underlying diseases are considerably different in EOD compared with LOD. Secondary causes are often found in patients with EOD. Patients with EOD had an unexpectedly longer time-to-diagnosis than patients with LOD. This argues for a need of better education about the clinical presentation of dementia in the young and middle aged.

Rapidly progressive dementia: causes found in a Greek tertiary referral center in Athens.

Dementia is generally considered as rapidly progressive [rapidly progressive dementia (RPD)], in cases with overt cognitive impairment, established within months. Data about the relative frequency of underlying diseases in cases of RPD are few and extremely variable, depending on the clinical setting. We examined the relative frequency of the underlying causes of RPD, in a university tertiary referral center, in Athens. A series of consecutive patients presenting with RPD in a 3-year period was included. All patients received a comprehensive clinical, imaging, and laboratory evaluation. Of a total of 279 patients hospitalized for dementia diagnosis, 68 patients had RPD (37 males and 31 females). Mean age at onset ±SD was 65.5±10.0. The most common cause of RPD was secondary dementias, accounting for 18 cases (26.5%). Alzheimer disease and frontotemporal dementia were almost equally represented, accounting for 12 (17.6%) and 11 (16.2%) cases, respectively. Vascular dementia, Creutzfeldt-Jakob disease, and various neurodegenerative diseases accounted for 9 cases each (13.2%). In a tertiary referral center, secondary dementias represented the most frequent cause of cases presenting with RPD. As a substantial number of these cases are potentially treatable, our finding reconfirms and underscores the importance of an exhaustive evaluation in any case presenting with RPD.

Narcolepsy presenting as REM sleep behaviour disorder

REM sleep behaviour disorder (RBD) is a neurological condition well known to be associated with the synucleinopathies in middle-aged patients. However, there is much less data concerning its development, evolution, and association with other disorders in younger patients. We report two patients aged less than 33 years who presented with clinical and polysomnographical features of RBD, both of whom proved to have previously undiagnosed narcolepsy. Whilst the association of narcolepsy with RBD has been previously recognised, this is the first report of narcoleptic patients presenting with RBD. Narcolepsy should be included in the differential diagnosis of young patients presenting with abnormal behaviour during sleep compatible with RBD.

Sleep in frontotemporal dementia is equally or possibly more disrupted, and at an earlier stage, when compared to sleep in Alzheimer's disease.

BACKGROUND Conversely to other neurodegenerative diseases (i.e., Alzheimers disease, AD), sleep in frontotemporal dementia (FTD) has not been studied adequately. Although some evidence exists that sleep-wake disturbances occur in FTD, very little is known regarding sleep macrostructure and/or primary sleep disorders. OBJECTIVE To investigate these issues in this population and compare them to similar issues in AD and in healthy elderly (HE). METHODS Twelve drug-naïve behavioral-variant FTD (bvFTD) patients (7 men/5 women) of mean age 62.5 ± 8.6 years were compared to seventeen drug-naïve AD patients (8 men/9 women) of mean age 69.0 ± 9.9 years and twenty drug-naïve HE (12 men/8 women) of mean age 70.2 ± 12.5 years. All participants were fully assessed clinically, through a sleep questionnaire, an interview, and video-polysomnography recordings. RESULTS The two patient groups were comparably cognitively impaired. However, compared to FTD patients, the AD patients had a statistically significant longer disease duration. Overall, the sleep profile was better preserved in HE. Sleep complaints did not differ considerably between the two patient groups. Sleep parameters and sleep macrostructure were better preserved in AD compared to FTD patients, regardless of primary sleep disorders, which occurred equally in the two groups. CONCLUSIONS With respect to AD, FTD patients had several sleep parameters similarly or even more affected by neurodegeneration, but in a much shorter time span. The findings probably indicate a centrally originating sleep deregulation. Since in FTD patients sleep disturbances may be obvious from an early stage of their disease, and possibly earlier than in AD patients, physicians and caregivers should be alert for the early detection and treatment of these symptoms.

Direct oral anticoagulant– vs vitamin K antagonist–related nontraumatic intracerebral hemorrhage

Objective: To compare the neuroimaging profile and clinical outcomes among patients with intracerebral hemorrhage (ICH) related to use of vitamin K antagonists (VKAs) or direct oral anticoagulants (DOACs) for nonvalvular atrial fibrillation (NVAF). Methods: We evaluated consecutive patients with NVAF with nontraumatic, anticoagulant-related ICH admitted at 13 tertiary stroke care centers over a 12-month period. We also performed a systematic review and meta-analysis of eligible observational studies reporting baseline characteristics and outcomes among patients with VKA- or DOAC-related ICH. Results: We prospectively evaluated 161 patients with anticoagulation-related ICH (mean age 75.6 ± 9.8 years, 57.8% men, median admission NIH Stroke Scale [NIHSSadm] score 13 points, interquartile range 6–21). DOAC-related (n = 47) and VKA-related (n = 114) ICH did not differ in demographics, vascular risk factors, HAS-BLED and CHA2DS2-VASc scores, and antiplatelet pretreatment except for a higher prevalence of chronic kidney disease in VKA-related ICH. Patients with DOAC-related ICH had lower median NIHSSadm scores (8 [3–14] vs 15 [7–25] points, p = 0.003), median baseline hematoma volume (12.8 [4–40] vs 24.3 [11–58.8] cm3, p = 0.007), and median ICH score (1 [0–2] vs 2 [1–3] points, p = 0.049). Severe ICH (>2 points) was less prevalent in DOAC-related ICH (17.0% vs 36.8%, p = 0.013). In multivariable analyses, DOAC-related ICH was independently associated with lower baseline hematoma volume (p = 0.006), lower NIHSSadm scores (p = 0.022), and lower likelihood of severe ICH (odds ratio [OR] 0.34, 95% confidence interval [CI] 0.13–0.87, p = 0.025). In meta-analysis of eligible studies, DOAC-related ICH was associated with lower baseline hematoma volumes on admission CT (standardized mean difference = −0.57, 95% CI −1.02 to −0.12, p = 0.010) and lower in-hospital mortality rates (OR = 0.44, 95% CI 0.21–0.91, p = 0.030). Conclusions: DOAC-related ICH is associated with smaller baseline hematoma volume and lesser neurologic deficit at hospital admission compared to VKA-related ICH.

Toward Understanding Cognitive Impairment in Patients with Myotonic Dystrophy Type 1

Cognitive dysfunction and sleep disruption are two frequent but underestimated features of adult onset myotonic dystrophy type 1 (MD1). In order to investigate the MD1 cognitive profile and its relationship with sleep disruption, 23 patients with genetically proved MD1 (mild-moderate in severity) underwent neuropsychological (nps) and polysomnography assessment. Patients scored lower than controls on almost all nps tests but cognitive impairments were mostly observed in executive functions (z-score = -2.14), with complex attention (z-score = -1.04), memory (z-score = -0.65), constructions (z-score = -1.29), and reasoning (z-score = -0.75) being slightly affected. Moderate-severe sleep apnea (apnea-hypopnea index [AHI] > or =15) was very frequent with most of the apneas being of the obstructive type. However, we found hardly any evidence of association between subjective, objective sleep parameters, and nps performance (p > .001). Thus, in our cohort of 23 adult MD1 patients, mild cognitive dysfunction, which is mostly related to the dysfunction of frontal association cortex and its underlying neural networks, does not seem to be significantly influenced by sleep disruption, which is mainly caused by obstructive apnea events.

Association of genetically proven Huntington's disease and sporadic amyotrophic lateral sclerosis in a 72-year-old woman.

Sirs: The association of chorea and motor neuron disease is extremely rare in clinical practice [1] and was initially reported by Fotopoulos in 1966 [2]. Here we report a case of late onset, genetically confirmed Huntington’s disease (HD) and sporadic amyotrophic lateral sclerosis (ALS) that appeared concomitantly. A 72-year-old woman presented with involuntary movements of the head and extremities. In the following 18 months, frequent falls and, later, dysarthria and dysphagia were added to the clinical picture while the choreic movements became more prominent. Her past history was unremarkable. She had no family history of ALS or HD, with the exception of involuntary movements of late onset (at the age of 70 years) and benign course that were reported in her brother. At the time of hospitalization, 20 months after her first symptoms, the neurological examination revealed jerky tendon reflexes on the upper and lower limbs, bilateral Babinski’s sign and a brisk masticatory reflex. There was a mild proximal weakness, with no amyotrophy or fasciculations. Speech was dysarthric with pseudo-bulbar features. Atrophy and fasciculations of the tongue were noted. Frequent choreoathetotic movements of the head and the four extremities were seen. There was no sensory, cerebellar, sphincter or autonomic dysfunction. Her relatives reported no signs of cognitive impairment. Her MMSE score was 27. However, detailed cognitive testing revealed a frontal-dysexecutive syndrome with moderate verbal and visuo-spatial memory impairment. Electrophysiological assessment confirmed the diagnosis of ALS, revealing fibrillation potentials in the first dorsal interossei bilaterally and right tibialis anterior muscles. Motor and sensory conduction velocities were normal. Genetic testing revealed 20 and 40 repeats of CAG for each of the two alleles of the IT15 huntingtin gene, confirming the diagnosis of HD. Laboratory and imaging investigations excluded the possibility of other ALS-like syndromes (neoplasia, lymphoma, monoclonal gammopathy, HIV infection, hyperparathyroidism). Tests for GM1, GM2 gangliosidosis and metachromatic leukodystrophy were negative. Serum uric acid, serum ceruloplasmine and copper, and urine copper levels were within normal range. Erythrocyte blood testing for neuroacanthocytosis was negative. The brain MRI showed a mild diffuse cerebral atrophy and periventricular T2 signal hyperintensities linked to aging. Brain SPECT imaging with HMPAO showed a mild bifrontal and right temporal hypoperfusion. After her first evaluation, the patient’s neurological state deteriorated rather rapidly and on follow up, one year later fasciculations, amyotrophy, muscle weakness at four extremities and severe cognitive deterioration with anarthria were prominent. The association of chorea and ALS is extremely rare. However, this association is heterogeneous and has been reported in different clinical settings. In his initial description, Fotopoulos [2] referred to the association of Huntington’s chorea and chronic spinal muscular atrophy of the shoulder girdle. However, as genetic tests were not available at that time, the diagnosis of HD is uncertain. Chorea, not due to HD (excluded by genetic testing) and appearing after a prolonged clinical course of ALS has been related to the extension of ALS in the extrapyramidal system [3]. Some rare neurological syndromes are also characterized by various combinations of acanthocytosis, chorea, amyotrophy and parkinsonism. In the few reports where HD was confirmed by genetic testing, chorea was associated with familial ALS [4], putting into question a genetic linkage between the two entities. Our case is different from Fotopoulos’ syndrome and raises the question of a possible co-existence of HD with sporadic ALS. To the best of our knowledge this is the first case with genetic confirmation. Similar cases have been referred in the S.G. Papageorgiou (&) A. Antelli Æ A. Bonakis Æ E. Vassos I. Zalonis Æ N. Kalfakis Æ M. Panas Dept. of Neurology Eginition Hospital Athens Medical School Vas Sophias 72-74 11528 Athens, Greece E-Mail: sokpapa@med.uoa.gr LETTER TO THE EDITORS J Neurol (2006) 253: 1649–1650 DOI 10.1007/s00415-006-0267-z