We propose that cerebrovascular disease may predispose, precipitate, or perpetuate some geriatric depressive syndromes. The "vascular depression" hypothesis is supported by the comorbidity of depression, vascular disease, and vascular risk factors and the association of ischemic lesions to distinctive behavioral symptoms. Disruption of prefrontal systems or their modulating pathways by single lesions or by an accumulation of lesions exceeding a threshold are hypothesized to be central mechanisms in vascular depression. The vascular depression concept can generate studies of clinical and heuristic value. Drugs used for the prevention and treatment of cerebrovascular disease may be shown to reduce the risk for vascular depression or improve its outcomes. The choice of antidepressants in vascular depression may depend on their effect on neurologic recovery from ischemic lesions. Research can clarify the pathways to vascular depression by focusing on the site of the lesion, the resultant brain dysfunction, the presentation of depression and time of onset, and the contribution of nonbiological factors.

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ARTICLESBiological circadian clocks oscillate with an approximately 24-hour period, are ubiquitous, and presumably confer a selective advantage by anticipating the transitions between day and night. The circadian rhythms of sleep, melatonin secretion and body core temperature are thought to be generated by the suprachiasmatic nucleus of the hypothalamus, the anatomic locus of the mammalian circadian clock 1,2 . Autosomal semi-dominant mutations in rodents with fast or slow biological clocks (that is, short or long endogenous period lengths; τ) are associated with phase-advanced or delayed sleep-wake rhythms, respectively. These models predict the existence of familial human circadian rhythm variants 3,4 but none of the human circadian rhythm disorders are known to have a familial tendency 5 . Although a slight 'morning lark' tendency is common, individuals with a large and disabling sleep phase-advance are rare. This disorder, advanced sleep-phase syndrome, is characterized by very early sleep onset and offset; only two cases are reported in young adults 6,7 . Here we describe three kindreds with a profound phase advance of the sleep-wake, melatonin and temperature rhythms associated with a very short τ. The trait segregates as an autosomal dominant with high penetrance. These kindreds represent a well-characterized familial circadian rhythm variant in humans and provide a unique opportunity for genetic analysis of human circadian physiology.The first advanced sleep-phase syndrome (ASPS) patient in this study presented to our sleep center with disabling early evening sleepiness and early morning awakening. Because she recognized a similar trait in some family members, we evaluated consenting relatives from her extended family and from two additional families that were subsequently identified. A structured interview with each participant focused on the underlying preferred sleep schedule in the absence of psychosocial factors that would delay or advance sleep phase. Individuals were considered 'affected' if they described a life-long, stable pattern of early sleep onset and offset and met strict classification criteria. Individuals were considered 'unaffected' if they described an anambiguously normal or delayed sleep-wake schedule and 'unknown' if they did not meet either affected or unaffected criteria. We administered the Horne-Östberg questionnaire 8 (a validated measure of 'morning lark' or 'night owl' tendency).Using our strict classification criteria, we identified 29 people with familial ASPS (FASPS) and 46 unaffected people. ASPS segregates as a highly penetrant autosomal dominant trait in these families (Fig. 1). All three families are of Northern European descent (ancestors of kindreds 2174 and 3840 were from the British Isles). The youngest affected subject was 8 years old. Most FASPS subjects knew they were obligate 'morning larks' by 30 years of age. The Horne-Östberg scores were consistent with our classification scheme: FASPS patients, 76.2 ± 5.6 (n = 14); unaffected relatives, 60.5 ± 6.8 (n = 12) ...

SUMMARY Patterns of daily human activity are controlled by an intrinsic circadian clock that promotes ~24 hour rhythms in many behavioral and physiological processes. This system is altered in Delayed Sleep Phase Disorder (DSPD), a common form of insomnia where sleep episodes are shifted to later times misaligned with the societal norm. Here, we report a hereditary form of DSPD associated with a dominant coding variation in the core circadian clock gene CRY1, which creates a transcriptional inhibitor with enhanced affinity for circadian activator proteins Clock and Bmal1. This gain-of-function CRY1 variant causes reduced expression of key transcriptional targets and lengthens the period of circadian molecular rhythms, providing a mechanistic link to DSPD symptoms. The allele has a frequency of up to 0.6% and reverse phenotyping of unrelated families corroborates late and/or fragmented sleep patterns in carriers, suggesting that it affects sleep behavior in a sizeable portion of the human population.

The findings demonstrate the effectiveness of timed exposure to bright light in the treatment of age-related sleep maintenance insomnia. With further refinement of treatment regimens, this non-drug intervention may prove useful in a large proportion of sleep disturbed elderly.

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Physiological and behavioral rhythms are governed by an endogenous circadian clock. The response of the human circadian clock to extraocular light exposure was monitored by measurement of body temperature and melatonin concentrations throughout the circadian cycle before and after light pulses presented to the popliteal region (behind the knee). A systematic relation was found between the timing of the light pulse and the magnitude and direction of phase shifts, resulting in the generation of a phase response curve. These findings challenge the belief that mammals are incapable of extraretinal circadian phototransduction and have implications for the development of more effective treatments for sleep and circadian rhythm disorders.

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