Medial temporal lobe atrophy relates more strongly to sleep-wake rhythm fragmentation than to age or any other known risk.

Atrophy of the medial temporal lobe of the brain is key to memory function and memory complaints in old age. While age and some morbidities are major risk factors for medial temporal lobe atrophy, individual differences remain, and mechanisms are insufficiently known. The largest combined neuroimaging and whole genome study to date indicates that medial temporal lobe volume is most associated with common polymorphisms in the GRIN2B gene that encodes for the 2B subunit (NR2B) of the NMDA receptor. Because sleep disruption induces a selective loss of NR2B from hippocampal synaptic membranes in rodents, and because of several other reports on medial temporal lobe sensitivity to sleep disruption, we hypothesized a contribution of the typical age-related increase in sleep-wake rhythm fragmentation to medial temporal lobe atrophy. Magnetic resonance imaging and actigraphy in 138 aged individuals showed that individual differences in sleep-wake rhythm fragmentation accounted for more (19%) of the variance in medial temporal lobe atrophy than age did (15%), or any of a list of health and brain structural indicators. The findings suggest a role of sleep-wake rhythm fragmentation in age-related medial temporal lobe atrophy, that might in part be prevented or reversible.

Is type 2 diabetes related to leukoaraiosis? an updated review.

A significantly increased interest has been dedicated to the study of the effects of diabetes mellitus (DM) on the brain. DM is associated with an increased risk of stroke and cognitive decline. In patients with DM, neuroimaging discloses with high-frequency structural changes, such as cerebral atrophy, infarcts and white matter lesions, also called leukoaraiosis (LA), an expression of small vessel disease. A previous review showed a relation between DM and both cerebral atrophy and lacunar infarcts, while the question about the relation between DM and LA remained unanswered. In this review, we provide an update on data on this last association. In the reviewed studies, we examined the presence of DM, other disease characteristics, such as duration and complications, and laboratory markers of the disease such as blood glycated hemoglobin (HbA1c), insulin resistance, insulin concentrations and their association with LA. About 40% of the reviewed studies reported a statistically significant association between DM and LA. Long-standing DM and a poor glycemic control were associated with severe LA. Studies using innovative MRI techniques, such as diffusion tensor imaging (DTI), reported a significant association between microstructural white matter alterations and DM. This review highlights more firmly than previously reported the existence of a relation between DM and both presence and severity of LA. These results are possibly due to more sensitive and advanced imaging techniques recently used to study the extent of LA. However, because of the heterogeneous methodology used in the reviewed studies, a definitive conclusion cannot be drawn.

Mild cognitive impairment etiologic subtyping using pragmatic and conventional criteria: preliminary experience in the Florence VAS-COG clinic.

BACKGROUND: Mild cognitive impairment (MCI) is an abnormal condition defined by the presence of cognitive decline not severe enough to fit dementia criteria. According to Winblad et al.'s criteria, the clinical distinction of MCI subtypes (amnestic/non-amnestic, single/multiple domain) is based on the cognitive profiling (conventional diagnosis) and infers possible different MCI etiologies. MCI prodromic of vascular dementia (Vasc-MCI) is thought to be characterized by a multiple domain profile. In our outpatient clinic (the "Florence VAS-COG clinic"), the diagnosis of MCI and of its different subtypes (vascular, degenerative, mixed) is based on a comprehensive evaluation of clinical and neuroimaging features (pragmatic diagnosis). AIMS: To compare the pragmatic and conventional diagnoses in terms of etiologic subtyping of MCI. METHODS: We retrospectively assessed the agreement between the two diagnoses in 30 MCI patients. Agreement was considered present when degenerative MCI was of the amnestic type (single or multiple domain) and Vasc-MCI was of the multiple domain type (amnestic or non-amnestic MCI). RESULTS: In 15/30 (50 %) patients, the diagnoses were in disagreement: 5/9 (56 %) patients diagnosed with a degenerative MCI type presented a non-amnestic cognitive profile (4 single domain and 1 multiple domain); 10/21 (48 %) Vasc-MCI were classified as non-amnestic single domain. CONCLUSIONS: The application of MCI etiologic subtyping using pragmatic or conventional diagnoses leads to different results. In our setting, not all the Vasc-MCI patients have a multiple domain profile. Our preliminary study suggests that the cognitive profile of Vasc-MCI is more heterogeneous than previously suggested.

Influence of vascular risk factors and neuropsychological profile on functional performances in CADASIL: results from the MIcrovascular LEukoencephalopathy Study (MILES).

BACKGROUND AND PURPOSE: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited cerebral small vessel disease that may lead to disability and whose phenotype modulators are still unknown. METHODS: In the MIcrovascular LEukoencephalopathy Study (MILES), we assessed the influence of vascular risk factors and the effect of different cognitive domains (memory, psychomotor speed and executive functions) performances on functional abilities in CADASIL in comparison with age-related leukoencephalopathy (ARL). RESULTS: We evaluated 51 CADASIL patients (mean age 50.3 ± 13.8 years, 47.1% males) and 68 ARL patients (70.6 ± 7.4 years, 58.8% males). Considering vascular risk factors, after adjustment for age, CADASIL patients had higher mean BMI values than ARL patients. Stroke history frequency was similar in the two groups. After adjustment for age, more CADASIL patients were disabled (impaired on ≥ 2 items of the Instrumental Activities of Daily Living scale) in comparison with ARL patients, and CADASIL patients had worse functional performances evaluated with the Disability Assessment for Dementia (DAD) scale. In CADASIL patients, hypertension was related to both DAD score and disability. The cognitive profile of CADASIL and ARL patients was similar, but on a stepwise linear regression analysis functional performances were mainly associated with the memory index (ß = -0.418, P < 0.003) in CADASIL patients and the executive function index (ß = -0.321, P = 0.028) in ARL. CONCLUSIONS: This study suggests that hypertension may contribute to functional impairment in CADASIL and that memory impairment has a large influence on functional decline in contrast with that observed in a sample of subjects with ARL.

Corpus callosum atrophy as a predictor of age-related cognitive and motor impairment: a 3-year follow-up of the LADIS study cohort.

The aim of this 3-year follow-up study was to investigate whether corpus callosum (CC) atrophy may predict future motor and cognitive impairment in an elderly population. On baseline MRI from 563 subjects with age-related white matter changes (ARWMC) from the Leukoaraiosis And DISability (LADIS) study, the CC was segmented and subdivided into five anterior-posterior regions (CC1-CC5). Associations between the CC areas and decline in motor performance and cognitive functions over a 3-year period were analyzed. CC atrophy at baseline was significantly associated with impaired cognitive performance (p<0.01 for CC1, p<0.05 for CC5), motor function (p<0.05 for CC2 and CC5), and walking speed (p<0.01 for CC2 and CC5, p<0.05 for CC3 and total CC), and with development of dementia at 3 years (p<0.05 for CC1) after correction for appropriate confounders (ARWMC volume, atrophy, age, gender and handedness). In conclusion, CC atrophy, an indicator of reduced functional connectivity between cortical areas, seems to contribute, independently of ARWMC load, to future cognitive and motor decline in the elderly.

Major depression and bipolar disorders in CADASIL: a study using the DSM-IV semi-structured interview.

OBJECTIVE: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited cerebral microangiopathy characterized by migraine, cerebrovascular events, and cognitive impairment. Although recognized as a cardinal feature of the disease, psychiatric disturbances have rarely been the object of focused studies. We performed a structured evaluation of mood disorders in CADASIL. MATERIALS AND METHODS: Twenty-three patients with CADASIL (five men and 18 women) were assessed by psychiatrists using the Structured Clinical Interview for the DSM-IV, clinician version. For the quantitative assessment of current mood disorder symptoms, the Hamilton Rating Scale for Depression (HRSD) and the Young Mania Rating Scale (YMRS) were used. RESULTS: A lifetime depressive episode was recorded in 17/23 (73.9%) patients with CADASIL. Six (26.1%) patients with CADASIL reported a current depressive episode. A diagnosis of manic lifetime episode was made in 6 (26.1%) patients with CADASIL. The HRSD mean score in patients with current depression was 9.1 ± SD 8.1. The YMRS mean score was 14.2 ± SD 4.1 for manic CADASIL. CONCLUSION: This study confirms that mood disorders are frequent in CADASIL. The use of a structured psychiatric interview outlines a frequency of depression higher than that previously reported but also reveals a considerable frequency of bipolar disorders. If confirmed in larger series, these data suggest that a greater attention should be paid to the psychiatric aspects in CADASIL.

Stroke unit care in clinical practice: an observational study in the Florence center of the European Registers of Stroke (EROS) Project.

BACKGROUND: Randomized trials and meta-analyses indicate positive effects of stroke unit (SU) care on survival and dependency of patients with stroke. However, data on the advantages of SU in 'real-world' settings are limited. We prospectively assessed, in a large University Hospital, the effect of SU versus other conventional wards (OCW) care on all-cause mortality, death or dependency, death or institutionalization. METHODS: In a prospective observational study in the European Registers of Stroke Project, patients hospitalized for first-in-a-lifetime stroke were evaluated for demographics, risk factors, clinical presentation, resource use, 3-month and 1-year survival, and functional outcome. RESULTS: Overall, 355 patients (54.1% men, mean age 73.4 ± 14.5 years) were registered, 140 (39.4%) admitted to the SU, and 215 (60.6%) to OCW. OCW patients were older, whilst SU patients had more severe strokes according to NIHSS (P for trend = 0.025). SU patients were significantly more often treated by specialists in stroke medicine, stroke nurses, physiotherapists and speech therapists (all P < 0.001), psychologists (P = 0.025), dietitians (P < 0.001), and social workers (P = 0.003). MRI, carotid, and transcranial Doppler were significantly more often performed in SU patients (all P < 0.001). Intravenous fluids (P = 0.003) and intravenous anticoagulation (P < 0.001) were more often prescribed in SU. Controlling for case-mix, SU significantly reduced 1-year mortality (P = 0.020), death or dependency at 3 months (P = 0.006) and 1 year (P = 0.043), and death or institutionalization at 3 months (P = 0.001) and 1 year (P = 0.009). CONCLUSIONS: We confirmed the benefits of SU care in a clinical setting. Further analyses should define the contribution of individual components of care to stroke outcome.

Relationship between baseline white-matter changes and development of late-life depressive symptoms: 3-year results from the LADIS study.

BACKGROUND: Growing evidence suggests that cerebral white-matter changes and depressive symptoms are linked directly along the causal pathway. We investigated whether baseline severity of cerebral white-matter changes predict longer-term future depressive outcomes in a community sample of non-disabled older adults. METHOD: In the Leukoaraiosis and Disability in the Elderly (LADIS) study, a longitudinal multi-centre pan-European study, 639 older subjects underwent baseline structural magnetic resonance imaging (MRI) and clinical assessments. Baseline severity of white-matter changes was quantified volumetrically. Depressive outcomes were assessed in terms of depressive episodes and depressive symptoms, as measured by the Geriatric Depression Scale (GDS). Subjects were clinically reassessed annually for up to 3 years. Regression models were constructed to determine whether baseline severity of white-matter changes predicted future depressive outcomes, after controlling for confounding factors. RESULTS: Baseline severity of white-matter changes independently predicted depressive symptoms at both 2 (p<0.001) and 3 years (p=0.015). Similarly, white-matter changes predicted incident depression (p=0.02). Over the study period the population became significantly more disabled (p<0.001). When regression models were adjusted to account for the influence of the prospective variable transition to disability, baseline severity of white-matter changes no longer predicted depressive symptoms at 3 years (p=0.09) or incident depression (p=0.08). CONCLUSIONS: Our results support the vascular depression hypothesis and strongly implicate white-matter changes in the pathogenesis of late-life depression. Furthermore, the findings indicate that, over time, part of the relationship between white-matter changes and depression may be mediated by loss of functional activity.

Location of lacunar infarcts correlates with cognition in a sample of non-disabled subjects with age-related white-matter changes: the LADIS study.

OBJECTIVES: In cerebral small vessel disease, white-matter hyperintensities (WMH) and lacunes are both related to cognition. Still, their respective contribution in older people remains unclear. The purpose of this study is to assess the topographic distribution of lacunes and determine whether it has an impact on cognitive functions in a sample of non-disabled patients with age-related white-matter changes. METHODS: Data were drawn from the baseline evaluation of the LADIS (Leucoaraioisis and Disability study) cohort of non-disabled subjects beyond 65 years of age. The neuropsychological evaluation was based on the Mini Mental Status Examination (MMSE), a modified Alzheimer Diseases Assessment Scale for global cognitive functions, and compound Z scores for memory, executive functions, speed and motor control. WMH were rated according to the Fazekas scale; the number of lacunes was assessed in the following areas: lobar white matter, putamen/pallidum, thalamus, caudate nucleus, internal/external capsule, infratentorial areas. An analysis of covariance was performed after adjustment for possible confounders. RESULTS: Among 633 subjects, 47% had at least one lacune (31% at least one within basal ganglia). The presence of lacunes in the thalamus was associated with lower scores of MMSE (beta = -0.61; p = 0.043), and worse compound scores for speed and motor control (beta = -0.25; p = 0.006), executive functions (beta = -0.19; p = 0.022) independently of the cognitive impact of WMH. There was also a significant negative association between the presence of lacunes in putamen/pallidum and the memory compound Z score (beta = -0.13; p = 0.038). By contrast, no significant negative association was found between cognitive parameters and the presence of lacunes in internal capsule, lobar white matter and caudate nucleus. CONCLUSION: In non-disabled elderly subjects with leucoaraisosis, the location of lacunes within subcortical grey matter is a determinant of cognitive impairment, independently of the extent of WMH.

Deep frontal and periventricular age related white matter changes but not basal ganglia and infratentorial hyperintensities are associated with falls: cross sectional results from the LADIS study.

BACKGROUND: Global age related white matter changes (ARWMC) are associated with progressive gait disturbances and falls, hypothesised to result from interruptions of cortico-subcortical circuits controlling balance, posture and locomotion. METHODS: The location of ARWMC in a large cohort of elderly non-disabled individuals with reported falls was analysed, using the cross sectional data of the Leukoaraiosis and Disability (LADIS) study. Detailed anatomical distributions of ARWMC assessed by MRI studies were analysed with respect to falls and balance performance. RESULTS: The severity of global ARWMC was significantly associated with a history of falls in the year prior to study inclusion (22.2% in the mild, 31.6% in the moderate and 37.3% in the severe ARWMC group according to the Fazekas scale; p = 0.002). Analysing the anatomical distribution of ARWMC, using the semiquantitative Scheltens scale, in multivariate analysis, periventricular (p = 0.006) and frontal deep (p = 0.033) ARWMC were independently associated with falls. Furthermore, logistic regression identified frontal deep (p = 0.003) ARWMC, but not basal ganglia and infratentorial hyperintensities, as significantly associated with balance disturbances. CONCLUSION: The association of frontal and periventricular ARWMC with falls supports the hypothesis that interruption of frontal subcortical motor circuits lead to balance disturbances and hence to an increased risk for falls in ARWMC.

Psychiatric disturbances in CADASIL: a brief review.

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited cerebrovascular disease, clinically characterized by a variable combination of migraine, recurrent transient ischemic attack (TIA) or lacunar strokes, cognitive decline, and mood disturbances. However, the assessment of psychiatric disturbances in this disease has never been carried out systematically. METHODS: This paper presents a brief review of the literature regarding the occurrence of psychiatric disorders in CADASIL patients. RESULTS: The prevalence of psychiatric disorders in CADASIL patients is reported to range from 20% to 41%. The psychiatric disturbances reported with the highest frequency are mood disturbances (9-41%). Pooling together the studies and considering a total of 454 CADASIL patients reported in the literature, 106 of these were affected by mood disturbances (24%). The majority of studies however did not use any defined criteria to assess the presence of psychiatric disorders and diagnoses were mainly based on history or review of clinical records. CONCLUSIONS: The review of CADASIL literature suggests the need for a more structured approach to the investigation of these disturbances that are highly prevalent and may greatly impact quality of life in these patients.

Association of gait and balance disorders with age-related white matter changes: the LADIS study.

OBJECTIVE: In the Leukoaraiosis and Disability (LADIS) Study, 11 European centers are evaluating the role of age-related white matter changes (ARWMC) as an independent determinant of the transition to disability in the elderly (65 to 84 years). We aimed at determining the influence of ARWMC on different objective measures of gait and balance. METHODS: Six hundred thirty-nine nondisabled individuals were prospectively enrolled and are being followed-up for 3 years. Subjects are graded in three standardized categories of ARWMC (mild, moderate, and severe) according to central MRI reading. Quantitative tests of gait and balance include the Short Physical Performance Battery (SPPB; range: 0 [poor] to 12 [normal]), a timed 8-m walk, and a timed single leg stance test. RESULTS: In cross-sectional analysis, deficiencies in gait and balance performance were correlated with the severity of ARWMC (SPPB: 10.2 +/- 2.1 in the mild, 9.9 +/- 2.0 in the moderate, 8.9 +/- 2.6 in the severe group; p < 0.001). Walking speed correlated with the severity of ARWMC (1.24 +/- 0.28 m/second in the mild, 1.18 +/- 0.32 m/second in the moderate, and 1.09 +/- 0.31 m/second in the severe group; p < 0.001). Balance was best in individuals with mild ARWMC (single leg stance time: 18.9 +/- 10.8 seconds) compared with moderate and severe ARWMC (16.4 +/- 10.8 and 13.6 +/- 11.2 seconds) (p < 0.001). Physically inactive individuals had a higher risk of a pathologic SPPB score (moderate vs mild ARWMC: odds ratio 1.60, 95% CI 1.02 to 2.52; severe vs mild ARWMC: odds ratio 1.75, 95% CI 1.09 to 2.80). CONCLUSIONS: Our findings support a strong association between the severity of age-related white matter changes and the severity of gait and motor compromise. Physical activity might have the potential to reduce the risk of limitations in mobility.

White matter changes and late-life depressive symptoms: longitudinal study.

BACKGROUND: Evidence from cross-sectional studies suggests a link between cerebral age-related white matter changes and depressive symptoms in older people, although the temporal association remains unclear. AIMS: To investigate age-related white matter changes on magnetic resonance imaging (MRI) as an independent predictor of depressive symptoms at 1 year after controlling for known confounders. METHOD: In a pan-European multicentre study of 639 older adults without significant disability, MRI white matter changes and demographic and clinical variables, including cognitive scores, quality of life, disability and depressive symptoms, were assessed at baseline. Clinical assessments were repeated at 1 year. RESULTS: Using logistic regression analysis, severity of white matter changes was shown to independently and significantly predict depressive symptoms at 1 year after controlling for baseline depressive symptoms, quality of life and worsening disability (P<0.01). CONCLUSIONS: White matter changes pre-date and are associated with the development of depressive symptoms. This has implications for treatment and prevention of depression in later life.