Incidence of young-onset dementia in Italy: The Brescia register study.

INTRODUCTION: The goal of the present work was to assess the incidence of dementia with onset before the age of 65 years (i.e., young-onset dementia [YOD]) and define the frequencies of young-onset Alzheimer's disease (AD), frontotemporal lobar degeneration (FTLD), and dementia with Lewy bodies (DLB) in the general population. METHODS: The study was conducted from January 1, 2019 to December 31, 2019 in Brescia province (population: 1,268,455). During the study period, all new YOD cases (incident YOD) were counted, and all patients' records reviewed. The incidence was standardized to the Italian general population in 2019. RESULTS: A total of 29 YOD patients were diagnosed. The age-sex standardized incidence rate was 4.58 (95% confidence interval, 3.07-6.58) per 100,000 person-years. No difference in incidence rate between YOD due to AD or FTLD (P = 0.83) and between sexes (P = 0.81) was observed. YOD incidence increased with age, reaching its peak after 60 years. DISCUSSION: Presenting neurodegenerative YOD phenotypes encompasses both AD and FTLD. Improved knowledge on YOD epidemiology is essential to adequately plan and organize health services.

Cyclic alternating pattern (CAP) alterations in narcolepsy.

BACKGROUND AND PURPOSE: Narcolepsy is a sleep disorder with clinical symptoms attributed to a reduced activation of the arousal system. Cyclic alternating pattern (CAP) is the expression of rhythmic arousability during non-rapid eye movement (NREM) sleep. CAP parameters, arousals and conventional sleep measures were studied in narcoleptic patients with cataplexy. PATIENTS AND METHODS: Data were collected from all-night polysomnographic (PSG) recordings and the multiple sleep latency test (MSLT) on the intervening day of 25 drug-naive patients (10 males and 15 females; mean age: 34+/-16 years) after adaptation and exclusion of other sleep disorders. A group of 25 age- and gender-matched normal sleepers were selected as controls. Each PSG recording was subdivided into sleep cycles. Analysis of CAP included classification of A phases into subtypes A1, A2, and A3. RESULTS: There was an increase in sleep period time mainly due to an increased wake time after sleep onset. REM latency was sharply reduced. The percentage of NREM sleep was slightly reduced and the balance between light sleep (S1+S2) and deep sleep (S3+S4) showed a curtailment of the former, while deep sleep was slightly increased. Excluding sleep cycles with sleep onset REM periods (SOREMPs), the duration of ordered sleep cycles was not different between narcoleptics and controls. The two groups showed similar values of arousal index, while CAP time, CAP rate, number of CAP cycles and of phase A subtypes (in particular subtypes A1) were significantly reduced in narcoleptic patients. CONCLUSIONS: The reduced periods of CAP in narcoleptic NREM sleep could be the electroencephalographic (EEG) expression of a generally reduced arousability or an increased strength of sleep-promoting forces in the balance between sleep and arousal systems. This can explain some of the clinical correlates of the disorder, i.e. excessive sleepiness, short sleep latency and impaired attentive performances, even without any sign of arousal-induced sleep fragmentation.

Is insomnia a neurophysiological disorder? The role of sleep EEG microstructure.

Unlike other sleep disorders, such as sleep-related breathing disorders and periodic limb movement (PLM), the nature and severity of which are quantified by specific respiratory and motor indexes, no apparent organ dysfunction underlies several cases of insomnia (in particular primary insomnia), which can be objectively diagnosed only through the structural alterations of sleep. Polysomnography (PSG) investigation indicates that insomnia is the outcome of a neurophysiological disturbance that impairs the regulatory mechanisms of sleep control, including sleep duration, intensity, continuity and stability. In particular, analysis of sleep microstructure has permitted to establish that etiologic factors of different nature (including depressive disorders) exert a common destabilizing action on sleep, which is reflected in an increase of cyclic alternating pattern (CAP) rate. These premises allow us to attribute a more objective identity to insomnia, which risks otherwise to be considered as an unexplainable mental complaint. In conclusion, PSG remains the "gold standard" for measuring sleep, and especially insomnia.

CAP variables and arousals as sleep electroencephalogram markers for primary insomnia.

OBJECTIVE: Polysomnographic (PSG) measures consistently reflect poor sleep quality and effective treatment in insomniac patients. METHODS: The PSG findings of 47 patients (18 M and 29 F, 42.5+/-10 years) meeting the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for a diagnosis of primary insomnia were compared with those of 25 age- and gender-balanced healthy subjects (controls) without sleep complaints. After one adaptation night to the sleep lab, each patient underwent two randomized double-blind PSG recordings. Twenty-four patients followed a placebo-drug sequence and 23 a drug-placebo succession. Active treatment consisted of widely used hypnotic drugs, i.e. zolpidem, triazolam, zopiclone, brotizolam. Conventional PSG measures, electroencephalogram (EEG) arousals and CAP variables (including phase A subtypes) were quantified and statistically analyzed. RESULTS: Compared to controls, insomniac patients under placebo showed a significant increase of CAP rate, subtypes A1 and A2, EEG arousals, nocturnal wakefulness and stage 1, associated with reduced values of total sleep time and slow wave sleep (stages 3 and 4). In insomniac patients, sleep quality was significantly improved by hypnotic treatment. Compared to placebo, active medication significantly reduced CAP rate, subtypes A1 and A2, but had only marginal effects on subtypes A3 and on EEG arousals. Under hypnotic treatment total sleep time, nocturnal awakenings, stage 1 and slow wave sleep recuperated normal values. The most significant correlation between sleep quality and PSG variables was found for CAP rate (P<0.0001). CONCLUSIONS: PSG investigation extended to CAP variables and EEG arousals can be an important procedure for the diagnosis of primary insomnia and evaluation of treatment efficacy.

New drugs for insomnia: comparative tolerability of zopiclone, zolpidem and zaleplon.

Insomnia affects 30-35% of people living in developed countries. The impact of insomnia on daytime functioning and its relationship with medical and psychiatric illnesses necessitate early treatment to prevent insomnia becoming persistent and to avoid the development of complications. However, pharmacological strategies must achieve a balance between sedative and adverse effects. In the last 30 years, benzodiazepines have been the preferred drugs for the treatment of insomnia. Benzodiazepines act nonselectively at two central receptor sites, named omega(1) and omega(2), which are located in different areas of the CNS. The sedative action of benzodiazepines is related to omega(1) receptors, whereas omega(2) receptors are responsible for their effects on memory and cognitive functioning. According to their pharmacokinetic profile, benzodiazepines can be classified into three groups: short half-life (<3 hours), medium half-life (8-24 hours) and long half-life (>24 hours). The newer non-benzodiazepine agents zopiclone, zolpidem and zaleplon have a hypnosedative action comparable with that of benzodiazepines, but they display specific pharmacokinetic and pharmacodynamic properties. These three 'Z' agents all share a short plasma half-life and limited duration of action. In addition, these agents are selective compounds that interact preferentially with omega(1) receptors (sedative effect), whereas benzodiazepines also interact with omega(2) receptors (adverse effects on cognitive performance and memory). Zaleplon is characterised by an ultrashort half-life (approximately 1 hour). Zolpidem and zopiclone have longer half-lives (approximately 2.4 and 5 hours, respectively). These properties, together with the low risk of residual effect, may explain the limited negative influences of these agents on daytime performance. Psychomotor tasks and memory capacities appear to be better preserved by non-benzodiazepine agents than by benzodiazepines. When present, cognitive deficits almost exclusively coincide with the peak plasma concentration. In particular, impairment can emerge in the first hours after drug administration, whereas psychomotor and memory tests carried out 7-8 hours later (i.e. in the morning) generally show no relevant alterations. As with benzodiazepines, the three 'Z' non-benzodiazepine agents should be used for a limited period, even in chronic relapsing conditions. Further evaluation is needed of the safety of hypnosedative medications in the long-term management of insomnia.

CAP and arousals in the structural development of sleep: an integrative perspective.

OBJECTIVES: It is known that the number of arousals per hour of sleep increases linearly across life, while the amount of cyclic alternating pattern (CAP) undergoes a u-shaped evolution. The present study aimed at investigating the differences, overlaps and age-related distribution of arousals and CAP components, i.e. subtypes A1, A2, A3. The relationship between the phase A subtypes and the structural organization of sleep was also evaluated. METHODS: Forty healthy subjects were examined. Polysomnographic analysis was performed according to the scoring rules for sleep stages, CAP and American Sleep Disorders Association arousals. RESULTS: Arousals occurred more frequently during CAP (40 events per hour) than in total sleep time (18 events per hour), non-rapid eye movement (NREM) sleep (20 events per hour), and rapid eye movement (REM) sleep (12 events per hour). Within CAP, arousals always coincided with a subtype A2 or A3. Both arousals and subtypes A2 and A3 showed a similar evolution with relation to age (linear positive), and to the amounts of light NREM sleep (linear positive) and deep NREM sleep (linear negative). In contrast, subtypes A1 showed a u-shaped profile across the life span and appeared closely related (linear positive) to the time spent in stages 3 and 4. Almost 90% of arousals occurring in NREM sleep were preceded in the previous 3s by a K-complex or a delta burst, indicating a topical involvement of slow electroencephalographic (EEG) components in the arousal build-up. CONCLUSIONS: Arousals show only one side of the multi-faceted activation complexes, whereas the three subtypes of CAP provide a graded picture of arousal features from the strongest A3 subtypes, showing a prevalence of EEG desynchrony, to the weakest A1 phases, which are dominated by EEG synchrony and represent the prevalent components of CAP (60% of all the phase A subtypes).