Imaging microvascular changes and cognitive function in dementia

Abstracts / Journal of the Neurological Sciences 283 (2009) 240–320

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We included bilateral assessment of all types of microvascular lesions and used multivariate models that control for the possible confounding effect of age and Ab protein deposits. Results: Only cortical microinfarcts and periventricular demyelination were significantly associated with the CDR score. In a univariate model, the cortical microinfarcts score (CMIs) explained 9% of the variability in CDR scores and periventricular demyelination score (PVDs) 7.3%. Aß-protein deposition explained only 3.5% of the CDR variability. In a logistic regression model including CDR as a binary variable, both variables were strongly associated with the presence of dementia. Conclusions: These data reveal that cortical microinfarcts and, to a lesser degree, periventricular demyelination contribute to the cognitive decline in individuals at high risk for dementia and suggest that they should be taken into account when defining the neuropathological criteria for mixed dementia.

and the systolic/diastolic difference also decreases with age (77.5 vs 47.4 cm/ s). Young persons accelerate with apnea their resting mean MCA velocity of 71 cm/s by 44% (Breath holding index 1.4), the elderly increase their resting Vmean of 50 cm/s by only 30% (Breath holding index 0.9). Vasoconstriction after hyperventilation induces Vmean reduction in young persons by 50%, while in the elderly only by 38%. Conclusions: Aging brings about gradual reduction of cerebral arteriolar resistance and its capacity to dilate and to constrict to stimulation with different blood oxygenation levels. The diminution of systolic/diastolic flow velocity difference by approximately 40% within 30 years is accompanied by a decrease of about one third of reactive blood flow acceleration and deceleration to extreme levels of hyper/hypocapnia. The study was supported by an Educational grant of MSM CR, No VZ 0021620816.

doi:10.1016/j.jns.2009.02.094

doi:10.1016/j.jns.2009.02.096

Microvascular structure in the elderly: A new parameter to consider?

Imaging cerebral amyloid in vivo

C. Bouras Department of Psychiatry, University of Geneva School of Medicine, Geneva, Switzerland

P. Edison Imperial College London, Hammersmith Hospital, London, UK

Background and aims: The presence of microvascular changes has been documented both in brain aging and AD, although the relationship between the morphometry of brain capillaries and cognitive impairment is still unknown. Methods: We performed an analysis of capillary morphometric parameters and AD-related pathology in 19 elderly individuals with variable degrees of cognitive decline. Cognitive status was assessed prospectively using the Clinical Dementia Rating (CDR) scale. Total capillary lengths and numbers as well as mean length-weighted diameters, total NFT and neuron numbers and amyloid volume were estimated in entorhinal cortex and CA1 field. Results: Total capillary numbers and mean diameters explained almost 40% of the neuron number variability in both the CA1 and entorhinal cortex. Total capillary length and numbers in the CA1 and entorhinal cortex did not predict cognitive status. Mean capillary diameters in the CA1 and entorhinal cortex were significantly related to CDR scores, explaining 18.5% and 31.1% of the cognitive variability, respectively. This relationship persisted after controlling for NFT and neuron numbers in multivariate regression models. Conclusions: Consistent with the growing interest about microvascular pathology in brain aging, the present data indicate that changes in capillary morphometric parameters may represent independent predictors of ADrelated neuronal depletion and cognitive decline. doi:10.1016/j.jns.2009.02.095

The decay of cerebrovascular reserve capacity with aging P. Kalvach, T. Pecman, T. Peisker, K. Shubladze Department of Neurology, Charles University, 3rd Medical Faculty, Prague, Czech Republic Background and aims: The gradual loss of arterial elasticity and the diminishing cardiac driving force are counteracted during the life by decreasing peripheral arteriolar resistance. To define the extent of these changes we have compared young and elderly healthy persons in their capacity for cerebral vasodilatation and vasoconstriction. Methods: Transcranial Doppler (TCD) systolic and diastolic velocity measurements on middle cerebral artery (MCA) were carried out in 20 young persons (mean age 24 years, 21–32) and 20 elderly (mean age 56 years, 33–80) volunteers. Bilateral values at rest were compared with those after 30 s of breath holding and with measurements after 1.5 min hyperventilation. The systolic/diastolic difference and mean blood flow velocities (Vmean) under these 3 conditions were analyzed. Results: The average systolic and diastolic MCA blood flow velocities are higher in young people (115.5/38 cm/s) than in the elderly (79.4/32 cm/s)

There are now a variety of radiotracer-based techniques for assessing amyloid in dementias in vivo. 11C-PIB and 11C-SB13 are thioflavin and stilbene PET tracers which bind to fibrillar beta-amyloid with nanomolar affinity. More recently, 18F thioflavin and stilbene analogues have been developed. 18F-FDDNP is a naphthol that binds to both beta amyloid and phosphorylated tau. While the presence of amyloid plaques and neurofibrillary tangles is the pathological trademark of Alzheimer disease (AD), amyloid pathology is also associated with other dementias including dementia with Lewy bodies (DLB) and prion disease. Incidental raised amyloid can also be found in elderly normals at post-mortem. To date, PET series have reported a raised cortical amyloid load in around 90% of cases thought to have AD and 50–60% of cases diagnosed as amnestic mild cognitive impairment (MCI) based on the Petersen criteria. 80% of patients with DLB diagnosed using consensus criteria also show amyloid pathology but only 20% of Parkinson's disease patients who develop later dementia (PDD). In frontotemporal dementia patients series have reported between a 0–20% prevalence of raised cortical 11C-PIB binding. Interestingly, while kindred with prion disease showed increased cortical FDDNP binding, PIB uptake was normal. In one series, 10% of elderly normals were reported to have a raised amyloid load. Amyloid deposition is first detected in posterior cingulate in MCIs who later convert to AD. In established AD there appears to be little change in amyloid load over two years suggesting plaque formation occurs years ahead of symptoms. In summary, amyloid imaging is not a specific diagnostic tool for AD but rather allows us to target those dementia subjects who might benefit from emerging anti-amyloid agents. doi:10.1016/j.jns.2009.02.097

Imaging microvascular changes and cognitive function in dementia K. Herholz University of Manchester, Wolfson Molecular Imaging Centre, Manchester, UK Many new imaging methods have been introduced to clinical research in the past decades. Structural imaging based on CT and MRI demonstrates microvascular changes, such as enlarged Robin-Virchow spaces and leukoaraiosis, preferentially in deep brain structures and white matter. They are associated with vascular risk factors, brain atrophy and reduced cognitive performance, but usually do not lead to dementia in absence of other major brain damage. Functional imaging techniques such as PET and SPECT demonstrate reduced regional blood flow and glucose metabolism most clearly in Alzheimer's disease where they indicate synaptic dysfunction and correlate closely with cognitive impairment. In contrast, primary microvascular

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Abstracts / Journal of the Neurological Sciences 283 (2009) 240–320

reduction of blood flow usually shows little regional differences. It is detected only by measurement in absolute physiological units which is rarely being done and is subject to considerable physiological variability. Neurodegenerative and vascular dementia differ in spatial distribution of synaptic impairment, and impairment of association cortex is related to dementia severity in both. Measurements of oxygen extraction rates can detect misery perfusion which is frequently being observed in acute stroke but appears to be relatively rare as a chronic condition. The vascular perfusion reserve is assessed by CBF measurements at rest and after pharmacological vascular dilatation. Its relation to cognitive performance is weak. In conclusion, synaptic dysfunction in association cortices is the main functional correlate of dementia, and microvascular changes may play an important role in dementia when causing such dysfunction. doi:10.1016/j.jns.2009.02.098

Quantitative and functional MRI in aging G. Frisoni Laboratory of Epidemiology Neuroimaging and Telemedicine, IRCCS San Giovanni Di Dio, Fatebenefratelli, Brescia, Italy The extent to which white matter changes affect brain function in elderly individuals is a matter for debate. Clinicopathological studies showed that large confluent white matter lesions (WMLs) can be attributed to small-vessel disease and might denote anatomical damage to axons. Nonconventional MRI techniques such as diffusion tensor imaging, magnetization transfer and spectroscopy, which are sensitive to microstructural and biochemical changes of axons in white matter that are invisible to traditional T2-weighted imaging, provide additional insight into the pathophysiology of WMLs. A number of studies in patients with WMLs have found increased diffusion trace and loss of fractional anisotropy, and spectroscopy has provided evidence for biochemical changes that support the view that WMLs are due to variable degrees of demyelination, axonal loss and gliosis. Moreover, it was found that people with WMLs and cognitive symptoms bear N-acetyl aspartate changes indicative of more-severe axonal damage than people with WMLs of similar volume but no cognitive symptoms, supporting the idea that T2-weighted imaging captures only part of the variability of white matter damage, and diffusion parameters correlated better with cognition-in particular executive function-than did conventional T2-weighted imaging. However, the clinical effect of WMLs with regard to cognitive impairment is uncertain. In this lecture, we argue that WMLs are associated with detectable progressive cognitive deterioration greater than that associated with normal aging, but considerably lower than that associated with other causes of progressive cognitive deterioration such as Alzheimer's disease. In fact, the effect of WMLs on global cognitive performance in crosssectional studies is relatively small even for severe lesions and amounts at most to 0.7 points of MMSE out of a maximum of 30. Moreover, in longitudinal studies, cognitive deterioration attributable to WMLs is, on average, 12 times lower than that attributable to Alzheimer's disease. Only persons with the more severe degrees of WMLs have clinically relevant cognitive decline and might be candidate for drug therapy targeted to small vessel cerebrovascular disease. doi:10.1016/j.jns.2009.02.099

Overview of Binswagner's disease K. Bayülkem Istanbul University, Cerrahpasa Medical Faculty, Department of Neurology, Istanbul, Turkey (BD) which is one of the forms of vascular dementia firstly was described by Otto Binswagner in 1894. It mainly affects elderly hypertensives people with multiple vascular risk factors. There is diffused white matter (WM) loss, often in a patchy and multifocal form in subcortical area, especially such as the basal ganglia and regions. These manifestations are also prominent in normal elderly people as age increases, without any other risk factors. The disease occurs equally in both sexes aging between 55 and 75 years old. The prevalence of BD is not known. The pathophysiological features of

WM changes in BD relate to axonal loss, demyelination, gliosis, and arteriosclerosis of long medullary vessels reach the periventricular regions arising from cortical areas. Principal clinical manifestations of BD include slowly progressive dementia, psedobulber palsy and gait disorder or a combination of them. They had been attributed cumulative effect of degeneration in WM and ischemic changes. Patients with the clinico-pathological diagnosis of BD show bilaterally diffuse periventricular hypodensity on CT (Leucoariosis) and also some degrees of periventricular hyperintensity in MRI. Treatment should be directed toward the control of risk factors such as hypertension, diabetes mellitus, smoking, hyperlipidemia, hyperhomocysteinemia, hypercoagulability and the others. Conclusions: Its etiology is not clear and its clinical characteristics overlap with multi-infarct dementia, dementia of the Alzheimer's type and normal-pressure hydrosephalus making the differential diagnosis. WM periventricular changes in CT and MRI are not specific to BD. Although they seem to be associated with some degree of cognitive impairment, we do not know whether they are a diagnostic marker of future dementia. Finally, it is possible to say that prospective studies of asymptomatic subjects with CT and MRI changes would be required to clarify this issue and assess the importance of the possible risk factors for the development of BD. doi:10.1016/j.jns.2009.02.100

Is arteriosclerotic brain degeneration the most common cause of late-onset dementia? A MR study M.C. Henry Feugeasa, F. Onenb, P. Ravaudc, E. Schouman Claeysa, S. Legrainb Department of Radiology, Bichat Claude Bernard University Hospital AP HP, Paris, France b Department of Geriatry, Bichat Claude Bernard University Hospital AP HP, Paris, France c Department of Epidemiology and Biostatistics, Bichat Claude Bernard University Hospital AP HP, Paris, France

a

Background and aims: Understanding the respective role of AD and cerebrovascular disease is crucial in developing the optimal therapeutic strategy in late life dementia. But cerebrovascular and Alzheimer's type lesions are most often associated in the demented elderly and this key question is still debated. MR examinations, including functional assessment of cerebral perfusion in the early stage of mild cognitive impairment (MCI), may help to identify the main cause of cognitive decline. Methods: Baseline MRI, clinical and neuropsychological follow up for at least 2 years was obtained for 62 community-dwelling older subjects with MCI. Structural sequences allowed entorhinal measurements and assessment of leukoaraïosis, ventricular and sulcal enlargement. Phase contrast sequences allowed MR assessment of the intracranial dynamics. 17 patients (mean age 75 ± 4 years) progressed to dementia so that dementia of the Alzheimer's type was diagnosed in 15 patients. Baseline MR data and predementia neuropsychological performances of these 17 converters are described in the present study. Results: 3 converters showed a MR pattern highly suggestive of AD, with severe and predominantly left atrophy of the whole anteromesial temporal regions but without significant leukoaraiosis. These converters had an amnesic syndrome which contrasted with their high performance on the (BA) Trail Making Test (TMT). The remaining 14 converters lacked similar anteromesial temporal atrophy but were characterized by frequent leukoaraïosis and specific dynamic patterns; with increased intracranial vascular pulsations suggestive of severe vascular windkessel dysfunction (n = 8) or marked cerebral hypoperfusion (n = 6). These 14 converters showed variable memory performance but always worse TMT performance than the 3 other converters. Conclusions: These observations illustrate the pathogenic complexity of late-onset dementia and the deleterious effects of arterial stiffening. They suggest that senile plaques and neurofibrillary tangles may be only indirect markers of chronic cerebral hypoxia in most of the demented elderly. doi:10.1016/j.jns.2009.02.101