Alberto Villarejo-Galende

Long sleep duration in elders without dementia increases risk of dementia mortality (NEDICES).

Objective: To determine in a population-based study whether long sleep duration was associated with increased risk of dementia mortality. Methods: In this prospective, population-based study of 3,857 people without dementia aged 65 years and older (NEDICES [Neurological Disorders in Central Spain]), participants reported their daily sleep duration. The average daily total sleep duration was grouped into 3 categories: ≤5 hours (short sleepers), 6–8 hours (reference category), and ≥9 hours (long sleepers). Community-dwelling elders were followed for a median of 12.5 years, after which the death certificates of those who died were examined. Results: A total of 1,822 (47.2%) of 3,857 participants died, including 201 (11.0%) deaths among short sleepers, 832 (45.7%) among long sleepers, and 789 (43.3%) among those participants in the reference category. Of 1,822 deceased participants, 92 (5.1%) had a dementia condition reported on the death certificate (49 [53.3%] were long sleepers, 36 [39.1%] reported sleeping between 6 and 8 hours, and 7 [7.6%] were short sleepers). In an unadjusted Cox model, risk of dementia-specific mortality was increased in long sleepers (hazard ratio for dementia mortality in long sleepers = 1.58, p = 0.04) when compared with the reference group. In a Cox model that adjusted for numerous demographic factors and comorbidities, the hazard ratio for dementia mortality in long sleepers was 1.63 (p = 0.03). Conclusions: Self-reported long sleep duration was associated with 58% increased risk of dementia-specific mortality in this cohort of elders without dementia. Future studies are required to confirm these findings.

Eculizumab-related progressive multifocal leukoencephalopathy

Progressive multifocal leukoencephalopathy (PML) is an opportunistic infection of the CNS caused by reactivation of the polyomavirus JC (JCV). In the context of immunosuppression, JCV can reactivate and spread to brain infecting oligodendrocytes.1

Under-reporting of Parkinson's disease on death certificates: A population-based study (NEDICES)

BACKGROUND Parkinsons disease is frequently omitted as a cause of death from death certificates. A limitation of previous studies that attempted to assess the validity of death certificates is that population-dwelling cases, with milder, undiagnosed Parkinsons disease were likely excluded. As a result, those studies likely overestimated the validity of death certificates because they did not include these milder cases. We assessed the validity of death certificates in a prospective population-based study (NEDICES), which includes previously undiagnosed Parkinsons disease cases detected during the assessment. METHODS 3926 community-dwelling elderly subjects with and without Parkinsons disease were followed during a median of 12.6 years, after which the death certificates of those who died were examined. We calculated the proportion of cases of clinically diagnosed Parkinsons disease for whom a diagnosis of Parkinsons disease was certified as the basic cause of death on death certificates. RESULTS 1791 (45.6%) of the 3926 participants died over a median follow-up of 7.1 years, including 82 (73.9%) deaths among 111 participants with Parkinsons disease. Parkinsons disease was rarely certified as the basic cause of death (14.6%). Gender, disease stage and the period during which the study was conducted (i.e., 1994 to 2007) did not influence the likelihood that Parkinsons disease would be reported. CONCLUSIONS Our findings reinforce the notion that the reporting of Parkinsons disease on death certificates remains poor. This suggests a lack of awareness of the importance of Parkinsons disease as a cause of death.

Hypercholesterolemia in elders is associated with slower cognitive decline: A prospective, population-based study (NEDICES)

BACKGROUND Studies investigating the association between hypercholesterolemia in the elderly and cognitive decline report discrepant outcomes. We determined in a prospective population-based cohort (NEDICES) in elders whether hypercholesterolemia was associated with slower cognitive decline. METHODS Participants were evaluated at baseline and 3 years later. Baseline demographic variables were recorded. Hypercholesterolemia was defined by total cholesterol of >200mg/dl or current use of lipid-lowering drugs. At baseline and at follow-up, a 37-item version of the Mini-Mental State Examination (37-MMSE) was administered. RESULTS The final sample, 2015 participants (72.9 ± 6.1 years), comprised 1166 (57.9%) hypercholesterolemic and 849 (42.1%) non-hypercholesterolemic participants (reference category). The mean follow-up was 3.4 ± 0.5 years. During the three year follow-up period, the 37-MMSE declined by 0.7 ± 4.3 points (median=0 point) in non-hypercholesterolemic participants vs. 0.3 ± 3.9 points in hypercholesterolemic participants (median=0 points) (Mann-Whitney test, p=0.007). In analyses adjusted for baseline age and other potential confounders, this difference remained robust. We also assessed the cognitive decline per unit time (i.e., the rate of cognitive decline). The rate of cognitive decline was 0.2 ± 1.3 (median=0.0) points/year for non-hypercholesterolemic participants and 0.1 ± 1.2 (median=0.0) points/year for hypercholesterolemic participants (Mann-Whitney test, p=0.028). CONCLUSIONS In this prospective population-based cohort study, cognitive test scores among hypercholesterolemic elders declined more slowly than observed in their non-hypercholesterolemic counterparts. Additional studies are needed to confirm these results.

Early diagnosis of mild cognitive impairment and Alzheimer's disease based on salivary lactoferrin

The Alzheimers disease (AD) process is likely initiated many years before clinical onset. Biomarkers of preclinical disease are critical for the development of disease‐modifying or even preventative therapies. Current biomarkers for early disease, including cerebrospinal fluid tau and amyloid β (Aβ) levels, structural and functional magnetic resonance imaging, and the use of brain amyloid imaging, are limited because they are very invasive or expensive. Noninvasive biomarkers may be a more accessible alternative, but none can currently detect preclinical AD with the required sensitivity and specificity.

PET-Florbetapir findings in primary cerebral amyloidoma.

Amyloidosis is a heterogeneous group of diseases characterized by the extracellular deposition of an amorphous material, composed of insoluble fibrillar proteins. Cerebral amyloidoma is a type of localized amyloidosis that can rarely affect the brain, with around 30 cases described in the literature [1–5]. Florbetapir is an amyloid radioligand developed to support diagnosis of Alzheimeŕs disease [6, 7]. Its role in the diagnosis of other cerebral amyloidosis has to be further defined. To our knowledge, this is the first report of PET-Florbetapir findings in cerebral amyloidoma. A 51-year-old man was admitted after presenting with two complex partial seizures. His wife reported mild difficulties to carry out demanding tasks in the last year. Neurological examination demonstrated an impairment of executive funtion and ideomotor apraxia. A CT scan showed multifocal hyperdense lesions, most prominent in the cerebellum, right frontal and left parietal white matter, with contrast enhancement. On MRI, these lesions were isointense with the white matter on T1-weighted images, hyperintense on T2-weighted images, and showed intense contrast enhancement, with a pattern of irregular lines radiating from the ventricular wall (Fig. 1a). Comprehensive evaluation including CSF examination did not reveal any other abnormalities. Stereotactic brain biopsy of the left parietal white matter showed nodular, confluent amyloid masses. With hematoxilin-eosin they consisted of homogeneneous eosinofilic material, showed apple-green birefringence upon polarization with Congo-red staining (Fig. 1b) and intense

Slowly progressive behavioral frontotemporal dementia with C9orf72 mutation. Case report and review of the literature

ABSTRACT We present a 86-year-old woman without relevant medical history and two brothers who died by dementia, who started at 55 years with depression and personality changes with ongoing worsening (>30 years) and functional decline. Screening dementia blood test and brain magnetic resonance imaging did not show results that pointed to a secondary cause. The patient met the diagnostic criteria for possible behavioral frontotemporal dementia with a slow progression (bvFTD-SP), suggesting a benign variant. A genetic study confirmed a C9ORF72 hexanucleotide expansion, making this the sixth case mentioned in the literature. We review and discuss the other cases described previously.

Delayed tacrolimus leukoencephalopathy, a rare and reversible cause of dementia

The immunosuppressant tacrolimus (FK506) is widely used in transplantation medicine. An acute leukoencephalopathy with clinical and radiologic features similar to posterior reversible encephalopathy syndrome (PRES) is a common side effect of tacrolimus, and usually develops within the first year of commencing treatment,1 but a delayed and chronic leukoencephalopathy has been reported rarely in the literature. We describe a patient who developed extensive chronic leukoencephalopathy with contrast enhancement, reversible after tacrolimus withdrawal.

A Comparison Study of Cognitive and Neuropsychiatric Features of Essential Tremor and Parkinson’s Disease

Background Essential tremor (ET) and Parkinson’s disease (PD) are two of the most common movement disorders. Leaving aside their motor features, these two conditions share several non-motor features, including cognitive dysfunction and personality changes. However, there are few data comparing the cognitive and personality profiles of ET with PD. Here we compare the cognitive and personality profiles of the two diseases. Methods Thirty-two consecutive non-demented ET patients (13 females and 19 males) (67.7±9.8 years), 32 non-demented PD patients (13 females and 19 males) (67.7±9.5 years), and 32 healthy matched controls (14 females and 18 males) (67.9±10.1 years) underwent a neuropsychological test battery, including a global cognitive assessment and tests of attention, executive function, memory, language, and visuospatial function, as well as the Personality Assessment Inventory. Multivariable linear regression analyses were performed, adjusted for age, sex, years of education, medications that potentially affect cognitive function, number of medications, and the 17-item Hamilton Depression Rating Scale Total Score. Results Neuropsychological scores were similar in PD and ET patients, but patients with disease performed more poorly than control subjects in cognitive tasks such as attention, executive function, memory, and naming. Discussion ET and PD exhibited similar deficits in specific aspects of neuropsychological functioning, particularly those thought to rely on the integrity of the prefrontal cortex, and this suggests involvement of frontocerebellar circuits. These findings further challenge the traditional view of ET as a benign and monosymptomatic disorder.

Clinical heterogeneity and underlying pathophysiological mechanisms of lateral flexion of the trunk in Parkinson's disease.

We read with interest the article by Di Matteo et al. [1] about different EMG patterns in lateral flexion of the trunk (LFT) in Parkinson’s disease (PD). A similar view would be valuable considering the clinical presentation; we would like to emphasize the clinical heterogeneity of LFT in PD, and to make some pathophysiological considerations apropos of a case. A 74-year-old woman with a 2-year history of rightpredominant PD treated with rasagiline 1 mg/day developed a slowly progressive abnormal trunk flexion unnoticed by the patient 10 months after pramipexole addition (0.18 mg tds). Neurological examination showed a mildmoderate akinetic-rigid syndrome (motor UPDRS score: 20) without any other sign suggesting atypical parkinsonism. A continuous LFT to the right with a slight forward flexion which worsened with walking and resolved with passive mobilization or when lying back was noted (Fig. 1). The patient denied any motor complication of the disease or LFT fluctuation with dopaminergic medication. Pramipexole was withdrawn and she was progressively started on levodopa/carbidopa up to 100/25 mg tds. LFT was completely resolved 4 weeks later and parkinsonian symptoms were markedly improved (motor UPDRS score: 12). Unfortunately, an EMG study of the paravertebral muscles was not performed. Although the patient was under-treated with pramipexole, the temporal relationship between LFT and dopamine agonist initiation, the lack of fluctuations of the abnormal posture and the improvement after drug withdrawal (with a minimal dose of levodopa) point to a pramipexole-induced LFT. Heterogeneity of clinical presentation and prognosis [2–6] resulted in attempts to better define LFT in PD [7, 8], distinguishing between irreversible-chronic forms characterized by rigidity and mediated by non-dopaminergic neurotransmitters, acute-subacute dystonic forms in both, off [5] and on periods [6] as a consequence of levodopa plasma level fluctuations, and drug-induced forms (DIF) associated to dopaminergic treatment changes (mainly after dopamine agonist initiation) [1–4]. The latter may resolve after prompt drug discontinuation, therefore its early diagnosis has important clinical implications. DIF are clinically similar to LFT associated to antipsychotic treatment, known as Pisa syndrome [9, 10], however the use of this term to designate them in PD patients is a matter of controversy [7, 8]. This important distinction was not made by Di Matteo et al. [1] and different types of postural abnormalities are included under the generic term LFT. The great clinical variability of LFT in PD, even in patients presenting with DIF, points to the involvement of different pathophysiological mechanisms. Close temporal relationship between postural abnormalities and dopaminergic therapy, and its reversibility after drug withdrawal [2, 4, 6], suggest a strong dopaminergic contribution. Dopaminergic asymmetrical transmission [3] or a cholinergic-dopaminergic imbalance [11] have been proposed; nevertheless, there is no clear DIF laterality and patients can deviate to the side more affected by parkinsonian symptoms [4–6] or contralaterally [1, 3, 4] suggesting the contribution of other neurotransmitter systems in certain cases, such as serotonergic and adrenergic [2, 12]. E. de Pablo-Fernandez (&) Neurology Department, King’s College Hospital, Denmark Hill, London SE5 9RS, UK e-mail: edepablofernandez@nhs.net