https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(06)68880-6.pdf

Mild cognitive impairment

Dementia prevention, intervention, and care

Cerebral small vessel disease (SVD) is a common accompaniment of ageing. Features seen on neuroimaging include recent small subcortical infarcts, lacunes, white matter hyperintensities, perivascular spaces, microbleeds, and brain atrophy. SVD can present as a stroke or cognitive decline, or can have few or no symptoms. SVD frequently coexists with neurodegenerative disease, and can exacerbate cognitive deficits, physical disabilities, and other symptoms of neurodegeneration. Terminology and definitions for imaging the features of SVD vary widely, which is also true for protocols for image acquisition and image analysis. This lack of consistency hampers progress in identifying the contribution of SVD to the pathophysiology and clinical features of common neurodegenerative diseases. We are an international working group from the Centres of Excellence in Neurodegeneration. We completed a structured process to develop definitions and imaging standards for markers and consequences of SVD. We aimed to achieve the following: first, to provide a common advisory about terms and definitions for features visible on MRI; second, to suggest minimum standards for image acquisition and analysis; third, to agree on standards for scientific reporting of changes related to SVD on neuroimaging; and fourth, to review emerging imaging methods for detection and quantification of preclinical manifestations of SVD. Our findings and recommendations apply to research studies, and can be used in the clinical setting to standardise image interpretation, acquisition, and reporting. This Position Paper summarises the main outcomes of this international effort to provide the STandards for ReportIng Vascular changes on nEuroimaging (STRIVE).

https://www.thelancet.com/pdfs/journals/laneur/PIIS1474-4422(13)70124-8.pdf

Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration

Background In cross-sectional studies, elevated plasma homocysteine levels have been associated with poor cognition and dementia. Studies of newly diagnosed dementia are required in order to establish whether the elevated homocysteine levels precede the onset of dementia or result from dementia-related nutritional and vitamin deficiencies. Methods A total of 1092 subjects without dementia (667 women and 425 men; mean age, 76 years) from the Framingham Study constituted our study sample. We examined the relation of the plasma total homocysteine level measured at base line and that measured eight years earlier to the risk of newly diagnosed dementia on follow-up. We used multivariable proportional-hazards regression to adjust for age, sex, apolipoprotein E genotype, vascular risk factors other than homocysteine, and plasma levels of folate and vitamins B12 and B6. Results Over a median follow-up period of eight years, dementia developed in 111 subjects, including 83 given a diagnosis of Alzheimer's disease....

https://www.nejm.org/doi/pdf/10.1056/NEJMoa011613

Plasma Homocysteine as a Risk Factor for Dementia and Alzheimer's Disease

The Blood-Brain Barrier in Health and Chronic Neurodegenerative Disorders

Objective. —To determine the relationship of brain infarction to the clinical expression of Alzheimer disease (AD). Design. —Cognitive function and the prevalence of dementia were determined for participants in the Nun Study who later died. At autopsy, lacunar and larger brain infarcts were identified, and senile plaques and neurofibrillary tangles in the neocortex were quantitated. Participants with abundant senile plaques and some neurofibrillary tangles in the neocortex were classified as having met the neuropathologic criteria for AD. Setting. —Convents in the Midwestern, Eastern, and Southern United States. Participants. —A total of 102 college-educated women aged 76 to 100 years. Main Outcome Measures. —Cognitive function assessed by standard tests and dementia and AD assessed by clinical and neuropathologic criteria. Results. —Among 61 participants who met the neuropathologic criteria for AD, those with brain infarcts had poorer cognitive function and a higher prevalence of dementia than those without infarcts. Participants with lacunar infarcts in the basal ganglia, thalamus, or deep white matter had an especially high prevalence of dementia, compared with those without infarcts (the odds ratio [OR] for dementia was 20.7,95% confidence interval [95% CI], 1.5-288.0). Fewer neuropathologic lesions of AD appeared to result in dementia in those with lacunar infarcts in the basal ganglia, thalamus, or deep white matter than in those without infarcts. In contrast, among 41 participants who did not meet the neuropathologic criteria for AD, brain infarcts were only weakly associated with poor cognitive function and dementia. Among all 102 participants, atherosclerosis of the circle of Willis was strongly associated with lacunar and large brain infarcts. Conclusion. —These findings suggest that cerebrovascular disease may play an important role in determining the presence and severity of the clinical symptoms of AD.

Brain Infarction and the Clinical Expression of Alzheimer Disease: The Nun Study

In Reply. —The analyses of Drs Mirra and Gearing indicate that brain infarcts are not associated with NFTs in the neocortex. Our analyses also indicated that brain infarcts were not associated with the number of NFTs, senile plaques, or neuritic plaques in the neocortex, suggesting that AD lesions and brain infarcts were likely to have occured independently of each other. While AD and brain infarction may represent separate disease processes, their combination may nonetheless increase the likelihood that dementia will occur. Among the participants in our study who met our neuropathologic criteria for AD (ie, abundant senile plaques and some NFTs in the neocortex), those with 1 or 2 lacunar infarcts in the basal ganglia, thalamus, or deep white matter had an especially high prevalence of dementia, compared with those without brain infarcts. The prevalence of dementia was 93% for those with such subcortical lacunar infarcts and 57% in those without infarcts.

https://jamanetwork.com/journals/jama/articlepdf/417387/jama_278_2_024.pdf

Brain Infarction and the Clinical Expression of Alzheimer Disease-Reply

The development of interventions designed to delay the onset of dementia highlights the need to determine the neuropathologic characteristics of individuals whose cognitive function ranges from intact to demented, including those with mild cognitive impairments. We used the Braak method of staging Alzheimer's disease pathology in 130 women ages 76-102 years who were participants in the Nun Study, a longitudinal study of aging and Alzheimer's disease. All participants had complete autopsy data and were free from neuropathologic conditions other than Alzheimer's disease lesions that could affect cognitive function. Findings showed a strong relationship between Braak stage and cognitive state. The presence of memory impairment was associated with more severe Alzheimer's disease pathology and higher incidence of conversion to dementia in the groups classified as having mild or global cognitive impairments. In addition to Braak stage, atrophy of the neocortex was significantly related to the presence of dementia. Our data indicate that Alzheimer's neurofibrillary pathology is one of the neuropathologic substrates of mild cognitive impairments. Additional studies are needed to help explain the variability in neuropathologic findings seen in individuals whose cognitive performance falls between intact function and dementia.

Kathryn P. Riley

Papers

Brain Infarction and the Clinical Expression of Alzheimer Disease: The Nun Study

Brain Infarction and the Clinical Expression of Alzheimer Disease-Reply

Alzheimer's neurofibrillary pathology and the spectrum of cognitive function: Findings from the Nun Study

Serum folate and the severity of atrophy of the neocortex in Alzheimer disease: findings from the Nun Study

Early life linguistic ability, late life cognitive function, and neuropathology: findings from the Nun Study.