Michael Malek-Ahmadi

Arizona Study of Aging and Neurodegenerative Disorders and Brain and Body Donation Program

The Brain and Body Donation Program (BBDP) at Banner Sun Health Research Institute (http://www.brainandbodydonationprogram.org) started in 1987 with brain‐only donations and currently has banked more than 1600 brains. More than 430 whole‐body donations have been received since this service was commenced in 2005. The collective academic output of the BBDP is now described as the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND). Most BBDP subjects are enrolled as cognitively normal volunteers residing in the retirement communities of metropolitan Phoenix, Arizona. Specific recruitment efforts are also directed at subjects with Alzheimers disease, Parkinsons disease and cancer. The median age at death is 82. Subjects receive standardized general medical, neurological, neuropsychological and movement disorders assessments during life and more than 90% receive full pathological examinations by medically licensed pathologists after death. The Program has been funded through a combination of internal, federal and state of Arizona grants as well as user fees and pharmaceutical industry collaborations. Subsets of the Program are utilized by the US National Institute on Aging Arizona Alzheimers Disease Core Center and the US National Institute of Neurological Disorders and Stroke National Brain and Tissue Resource for Parkinsons Disease and Related Disorders. Substantial funding has also been received from the Michael J. Fox Foundation for Parkinsons Research. The Program has made rapid autopsy a priority, with a 3.0‐hour median post‐mortem interval for the entire collection. The median RNA Integrity Number (RIN) for frozen brain and body tissue is 8.9 and 7.4, respectively. More than 2500 tissue requests have been served and currently about 200 are served annually. These requests have been made by more than 400 investigators located in 32 US states and 15 countries. Tissue from the BBDP has contributed to more than 350 publications and more than 200 grant‐funded projects.

Morphological and Pathological Evolution of the Brain Microcirculation in Aging and Alzheimer’s Disease

Key pathological hallmarks of Alzheimer’s disease (AD), including amyloid plaques, cerebral amyloid angiopathy (CAA) and neurofibrillary tangles do not completely account for cognitive impairment, therefore other factors such as cardiovascular and cerebrovascular pathologies, may contribute to AD. In order to elucidate the microvascular changes that contribute to aging and disease, direct neuropathological staining and immunohistochemistry, were used to quantify the structural integrity of the microvasculature and its innervation in three oldest-old cohorts: 1) nonagenarians with AD and a high amyloid plaque load; 2) nonagenarians with no dementia and a high amyloid plaque load; 3) nonagenarians without dementia or amyloid plaques. In addition, a non-demented (ND) group (average age 71 years) with no amyloid plaques was included for comparison. While gray matter thickness and overall brain mass were reduced in AD compared to ND control groups, overall capillary density was not different. However, degenerated string capillaries were elevated in AD, potentially suggesting greater microvascular “dysfunction” compared to ND groups. Intriguingly, apolipoprotein ε4 carriers had significantly higher string vessel counts relative to non-ε4 carriers. Taken together, these data suggest a concomitant loss of functional capillaries and brain volume in AD subjects. We also demonstrated a trend of decreasing vesicular acetylcholine transporter staining, a marker of cortical cholinergic afferents that contribute to arteriolar vasoregulation, in AD compared to ND control groups, suggesting impaired control of vasodilation in AD subjects. In addition, tyrosine hydroxylase, a marker of noradrenergic vascular innervation, was reduced which may also contribute to a loss of control of vasoconstriction. The data highlight the importance of the brain microcirculation in the pathogenesis and evolution of AD.

Cerebral blood flow in Alzheimer's disease.

Background Alzheimer’s disease (AD) dementia is a consequence of heterogeneous and complex interactions of age-related neurodegeneration and vascular-associated pathologies. Evidence has accumulated that there is increased atherosclerosis/arteriosclerosis of the intracranial arteries in AD and that this may be additive or synergistic with respect to the generation of hypoxia/ischemia and cognitive dysfunction. The effectiveness of pharmacologic therapies and lifestyle modification in reducing cardiovascular disease has prompted a reconsideration of the roles that cardiovascular disease and cerebrovascular function play in the pathogenesis of dementia. Methods Using two-dimensional phase-contrast magnetic resonance imaging, we quantified cerebral blood flow within the internal carotid, basilar, and middle cerebral arteries in a group of individuals with mild to moderate AD (n = 8) and compared the results with those from a group of age-matched nondemented control (NDC) subjects (n = 9). Clinical and psychometric testing was performed on all individuals, as well as obtaining their magnetic resonance imaging-based hippocampal volumes. Results Our experiments reveal that total cerebral blood flow was 20% lower in the AD group than in the NDC group, and that these values were directly correlated with pulse pressure and cognitive measures. The AD group had a significantly lower pulse pressure (mean AD 48, mean NDC 71; P = 0.0004). A significant group difference was also observed in their hippocampal volumes. Composite z-scores for clinical, psychometric, hippocampal volume, and hemodynamic data differed between the AD and NDC subjects, with values in the former being significantly lower (t = 12.00, df = 1, P = 0.001) than in the latter. Conclusion These results indicate an association between brain hypoperfusion and the dementia of AD. Cardiovascular disease combined with brain hypoperfusion may participate in the pathogenesis/pathophysiology of neurodegenerative diseases. Future longitudinal and larger-scale confirmatory investigations measuring multidomain parameters are warranted.

Increased Alzheimer’s Disease Neuropathology is Associated with Type 2 Diabetes and ApoE ε4 Carrier Status

BACKGROUND Past studies investigating the association between Alzheimers disease (AD) pathology and diabetes mellitus type 2 (DM2) have provided conflicting results. While several studies indicate that subjects with comorbid AD and DM2 have less AD pathology, others have found no significant differences in AD pathology between the two groups. Other studies have indicated that individuals with AD and DM2 have significantly greater neuropathology than AD individuals who do not have DM2. Additional research has demonstrated that ApoE ε4 carriers with AD and DM2 have significantly greater pathology than ApoE ε4 non-carriers. METHODS Data on clinically and pathologically diagnosed Alzheimers disease cases (NINDS-ADRDA clinically and NIA Reagan intermediate or high pathologically) with DM2 (n= 40) and those without DM2 (n= 322) from the Banner Sun Health Research Institute Brain and Body Donation Program were obtained for this study. Plaque and tangle scores from the frontal, parietal, temporal, entorhinal and hippocampal regions were compared between the DM2+ and DM2 - groups. In addition, total plaque count, total tangle count, and Braak scores were also compared between groups. Similar analyses were conducted to determine the effect of ApoE ε4 carrier status on the neuropathological variables while also accounting for and DM2 status. RESULTS The DM2+ and DM2 - groups showed no significant differences on plaque and tangle pathology. Logistic regression analyses, which accounted for the effects of ApoE .ε4 carrier status and age at death, found no association between total plaque [OR 1.05 (0.87, 1.27), p = 0.60] or total tangle [OR 0.97 (0.89, 1.07) p = 0.58] counts and DM2 status. ApoE ε4 carrier status was not significantly associated with DM2 status [.Χ2 = 0.30 (df = 1), p = 0.58]. Within the DM2+ group, significantly greater plaque and tangle pathology was found for ApoE ε4 carriers in relation to DM2+ ApoE ε4 non-carriers. CONCLUSION Overall, the presence of DM2 does not affect plaque and tangle burden in a sample of clinically and pathologically confirmed AD cases. Among AD individuals with DM2, those who are ApoE ε4 carriers had significantly greater neuropathology than those who do not carry an ApoE ε4 allele. Positive DM2 status appears to exacerbate AD neuropathology in the presence of ApoE ε4.

Reversion From Mild Cognitive Impairment to Normal Cognition: A Meta-Analysis.

The initiation of Alzheimer disease (AD) prevention studies has placed greater emphasis on the need to accurately detect individuals with amnestic mild cognitive impairment (aMCI) given their increased risk for developing AD. Several studies reporting on the incidence and prevalence of aMCI have also found that a substantial number of aMCI cases at baseline assessments revert to normal cognition at subsequent assessments. This instability presents a major challenge to intervention studies aimed at preventing the onset of clinical symptoms associated with aMCI. Reversion rates from 25 studies were used for this meta-analysis which found an overall reversion rate of approximately 24%. When the studies were separated by their setting (community vs. clinic), substantial differences in reversion rates were noted with clinic-based studies having a much lower reversion rate (14%) than community-based studies (31%). North American and European studies had high heterogeneity of reversion rates, whereas Asian studies had moderate levels of heterogeneity and significantly lower rates of reversion. Continued improvement in diagnostic and classification methodologies may help in more accurately identifying aMCI cases which are less likely to revert to normal cognition.

Florbetapir PET, FDG PET, and MRI in Down syndrome individuals with and without Alzheimer's dementia

Down syndrome (DS) is associated with amyloid b (Ab) deposition.

Neurochemical Profile of Dementia Pugilistica

Dementia pugilistica (DP), a suite of neuropathological and cognitive function declines after chronic traumatic brain injury (TBI), is present in approximately 20% of retired boxers. Epidemiological studies indicate TBI is a risk factor for neurodegenerative disorders including Alzheimer disease (AD) and Parkinson disease (PD). Some biochemical alterations observed in AD and PD may be recapitulated in DP and other TBI persons. In this report, we investigate long-term biochemical changes in the brains of former boxers with neuropathologically confirmed DP. Our experiments revealed biochemical and cellular alterations in DP that are complementary to and extend information already provided by histological methods. ELISA and one-dimensional and two dimensional Western blot techniques revealed differential expression of select molecules between three patients with DP and three age-matched non-demented control (NDC) persons without a history of TBI. Structural changes such as disturbances in the expression and processing of glial fibrillary acidic protein, tau, and α-synuclein were evident. The levels of the Aβ-degrading enzyme neprilysin were reduced in the patients with DP. Amyloid-β levels were elevated in the DP participant with the concomitant diagnosis of AD. In addition, the levels of brain-derived neurotrophic factor and the axonal transport proteins kinesin and dynein were substantially decreased in DP relative to NDC participants. Traumatic brain injury is a risk factor for dementia development, and our findings are consistent with permanent structural and functional damage in the cerebral cortex and white matter of boxers. Understanding the precise threshold of damage needed for the induction of pathology in DP and TBI is vital.

The Alzheimer's Questionnaire: A Proof of Concept Study for a New Informant-Based Dementia Assessment

The aim of this pilot study is to determine the feasibility and clinical utility of a brief, informant-based screening questionnaire for Alzheimers disease (AD) that can be administered in a primary care setting. The Alzheimers Questionnaire (AQ) was administered to the informants of 188 patients in 3 dementia clinics (50 cognitively normal, 69 mild cognitive impairment (MCI), 69 AD). Total score for the AQ is based upon the sum of clinical symptom items in which the informant responds as being present. Clinical symptoms which are known to be highly predictive of the clinical AD diagnosis are given greater weight in the total AQ score. The mean time of administration of the AQ was 2.6 ± 0.6 minutes. Sensitivity and specificity were found to be high for detecting both AD (98.55, 96.00) and MCI (86.96, 94.00) with ROC curves yielding AUC values of 0.99 and 0.95, respectively. This pilot study indicates that the AQ is a brief, sensitive measure for detecting both MCI and AD and could be easily implemented in a primary care setting.

Age- and education-adjusted normative data for the Montreal Cognitive Assessment (MoCA) in older adults age 70–99

The original validation study for the Montreal Cognitive Assessment (MoCA) suggests a cutoff score of 26; however, this may be too stringent for older adults, particularly for those with less education. Given the rapidly increasing number of older adults and associated risk of dementia, this study aims to provide appropriate age- and education-adjusted norms for the MoCA. Data from 205 participants in an ongoing longevity study were used to derive normative data. Individuals were grouped based on age (70–79, 80–89, 90–99) and education level (≤12 Years, 13–15, ≥16 Years). There were significant differences between age and education groups with younger and more educated participants outperforming their counterparts. Forty-six percent of our sample scored below the suggested cutoff of 26. These normative data may provide a more accurate representation of MoCA performance in older adults for specific age and education stratifications.

Braak staging, plaque pathology, and APOE status in elderly persons without cognitive impairment

Clinico-pathological studies reveal that some elderly people with no cognitive impairment have high burdens of neurofibrillary tangles (NFTs), a pathology associated with Alzheimers disease. We examined a total of 123 elderly participants without dementia and free of other neurological disorders or pathologies who at autopsy were classified as Braak NFT stages of I-V. We found that women were significantly more likely to have a high Braak score. Significant associations were found between high Braak scores and entorhinal cortex amyloid load, combined hippocampal and entorhinal cortex amyloid loads with perceptual speed in the low Braak group after adjusting for age, gender and apolipoprotein E ε4 status. Elderly with preserved cognitive function show a wide range of Braak scores and plaque pathology similar to that seen in prodromal and frank Alzheimers disease at death. These data suggest that some older people with extensive NFT and plaque pathology demonstrate brain resilience or reserve leading to preserved cognitive function.