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1.  Submandibular Gland Biopsy for the Diagnosis of Parkinson Disease 
The clinical diagnosis of Parkinson disease (PD) is incorrect in 30% or more of subjects, particularly at the time of symptom onset. Because Lewy-type α-synucleinopathy (LTS) is present in the submandibular glands of PD patients, we assessed the feasibility of submandibular gland biopsy for diagnosing PD. We performed immunohistochemical staining for LTS in sections of large segments (simulating open biopsy) and needle cores of submandibular gland from 128 autopsied and neuropathologically classified subjects, including 28 PD, 5 incidental Lewy body disease, 5 progressive supranuclear palsy ([PSP] 3 with concurrent PD), 3 corticobasal degeneration, 2 multiple system atrophy, 22 Alzheimer disease with Lewy bodies (ADLB), 16 Alzheimer disease without Lewy bodies and 50 normal elderly. Immunoreactive nerve fibers were present in large submandibular gland sections of all 28 PD subjects (including 3 that also had PSP); 3 ADLB subjects were also positive, but none of the other subjects were positive. Cores from frozen submandibular glands taken with 18 gauge needles (total length 15–38 mm, between 10 and 118 sections per subject examined) were positive for LTS in 17 of 19 PD patients. These results suggest that biopsy of the submandibular gland may be a feasible means of improving PD clinical diagnostic accuracy. This would be particularly advantageous for subject selection in early-stage clinical trials, for invasive therapies or for verifying other biomarker studies.
doi:10.1097/NEN.0b013e3182805c72
PMCID: PMC3571631  PMID: 23334596
α-Synuclein; Biomarker; Clinical trial; Deep brain stimulation; Gene therapy; Lewy body; Parkinson disease; Surgery; Transplantation
2.  Changes in Properties of Serine 129 Phosphorylated α-Synuclein with Progression of Lewy Type Histopathology in Human Brains 
Experimental neurology  2012;240:190-204.
Modifications of α-synuclein resulting in changes in its conformation are considered to be key pathological events for Lewy body diseases (LBD), which include Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). We have previously described a histopathological Unified Staging System for LBD that classifies the spread of α-synuclein phosphorylated at serine 129 (pS129-α-synuclein) from olfactory bulb to brainstem or limbic regions, and finally neocortex. Lewy bodies and Lewy neurites are highly enriched in pS129-α-synuclein. Increased formation of pS129-α-synuclein changes its solubility properties enhancing its tendency to aggregate and disrupt normal function. As in vitro and animal studies have shown that inhibiting formation of pS129-α-synuclein can prevent toxic consequences, this has become one of the therapeutic targets for LBD. However, detailed biochemical descriptions of the changes in pS129-α-synuclein properties in diseased human brains are needed to further our understanding of how these might contribute to molecular pathogenesis. In this study, we used 130 separate brain samples from cingulate cortex (limbic cortex) and 131 from temporal cortex (neocortex) that had been staged according to our Unified Staging System to examine progressive changes in properties of pS129-α-synuclein with the formation of progressively more severe histological Lewy-type pathology. The brain samples from these staged cases had been separated into cytosol-enriched, membrane-enriched (detergent soluble) and insoluble (ureas/SDS soluble) fractions. We also characterized the nature and appearance of higher molecular weight forms of pS129-α-synuclein. The major species was the 16 kD monomeric form; this accumulated with increasing stage with a large increase in Stage IV samples. By comparing two brain regions, we showed higher accumulation of insoluble pS129-α-synuclein in cingulate cortex, where histological deposits occur first, than in temporal cortex in samples with advanced (Stage IV) LB pathology.
doi:10.1016/j.expneurol.2012.11.020
PMCID: PMC3720241  PMID: 23201181
Western blots; Parkinson’s disease; antibodies; fractionation; post-translational modification; postmortem brain tissue; dementia with Lewy bodies; incidental Lewy body disease; pathogenesis; aggregation
3.  The Distribution of Phosphorylated Tau in Spinal Cords of Alzheimer’s and Non-Demented Individuals 
Abnormal phosphorylation of the microtubule-associated protein tau develops in selected brain regions in normal aging and becomes widespread throughout the brain in Alzheimer’s disease (AD). Braak and others have described the distribution of neurofibrillary tangles and deposition of abnormally phosphorylated tau (p-tau) and correlated this with the progressive cognitive dysfunction in AD. However, to date there have been no comprehensive studies examining abnormally phosphorylated tau deposition in the spinal cord as part of normal aging or AD. We investigated, using immunohistochemical methods, the presence of p-tau in the spinal cord of 46 cases with a clinicopathological diagnosis of AD as well as 37 non-demented (ND) individuals lacking any defined central nervous system-related clinicopathological diagnosis. We found the cervical cord segments to be the most frequently affected subdivision (96% AD vs. 43% ND), followed by thoracic (69% AD vs. 37% ND), lumbar (65% AD vs. 27% ND) and sacral (53% AD vs. 13% ND). The spinal cord was often affected at early-stage brain disease, with p-tau spinal cord immunoreactivity in 40% of subjects at Braak neurofibrillary stage I, however, there were no cases having spinal cord p-tau that did not have p-tau within the brain. As p-tau immunoreactivity is present within the spinal cords of ND as well as AD subjects, it is likely that the phosphorylation of spinal cord tau occurs in the preclinical stage of AD, prior to dementia. The presence of significant spinal cord p-tau-immunoreactive pathology has important implications for both the pathogenesis and clinical manifestations of AD.
doi:10.3233/JAD-121864
PMCID: PMC3670745  PMID: 23246918
pathology; autopsy; senile dementia; neurofibrillary tangle; aging; systemic disorder; peripheral nervous system
4.  STRIATAL AMYLOID PLAQUE DENSITY PREDICTS BRAAK NEUROFIBRILLARY STAGE AND CLINICOPATHOLOGICAL ALZHEIMER’S DISEASE: IMPLICATIONS FOR AMYLOID IMAGING 
Amyloid imaging may revolutionize Alzheimer’s disease (AD) research and clinical practice but is critically limited by an inadequate correlation between cerebral cortex amyloid plaques and dementia. Also, amyloid imaging does not indicate the extent of neurofibrillary tangle (NFT) spread throughout the brain. Currently, the presence of dementia as well as a minimal brain load of both plaques and NFTs is required for the diagnosis of AD. Autopsy studies suggest that striatal amyloid plaques may be mainly restricted to subjects in higher Braak NFT stages that meet clinicopathological diagnostic criteria for AD. Striatal plaques, which are readily identified by amyloid imaging, might therefore be used to predict the presence of a higher Braak NFT stage and clinicopathological AD in living subjects. This study determined the sensitivity and specificity of striatal plaques for predicting a higher Braak NFT stage and clinicopathological AD in a postmortem series of 211 elderly subjects. Subjects included 87 clinicopathologically classified as non-demented elderly controls and 124 with AD. A higher striatal plaque density score (moderate or frequent) had 95.8% sensitivity, 75.7% specificity for Braak NFT stage V or VI and 85.6% sensitivity, 86.2% specificity for the presence of dementia and clinicopathological AD (National Institute on Aging – Reagan Institute “intermediate” or “high”). Amyloid imaging of the striatum may be useful as a predictor, in living subjects, of Braak NFT stage and the presence or absence of dementia and clinicopathological AD. Validation of this hypothesis will require autopsy studies of subjects that had amyloid imaging during life.
doi:10.3233/JAD-2011-111340
PMCID: PMC3760731  PMID: 22112552
Alzheimer’s disease; amyloid imaging; striatum; amyloid plaques; diagnosis; therapy; asymptomatic; preclinical; autopsy
5.  Parkinson Disease Affects Peripheral Sensory Nerves in the Pharynx 
Dysphagia is very common in patients with Parkinson’s disease (PD) and often leads to aspiration pneumonia, the most common cause of death in PD. Unfortunately, current therapies are largely ineffective for dysphagia. As pharyngeal sensation normally triggers the swallowing reflex, we examined pharyngeal sensory nerves in PD for Lewy pathology. Sensory nerves supplying the pharynx were excised from autopsied pharynges obtained from patients with clinically diagnosed and neuropathologically confirmed PD (n = 10) and healthy age-matched controls (n = 4). We examined: the glossopharyngeal nerve (IX); the pharyngeal sensory branch of the vagus nerve (PSB-X); and the internal superior laryngeal nerve (ISLN) innervating the laryngopharynx. Immunohistochemistry for phosphorylated α-synuclein was used to detect potential Lewy pathology. Axonal α-synuclein aggregates in the pharyngeal sensory nerves were identified in all of the PD subjects but not in the controls. The density of α-synuclein-positive lesions was significantly greater in PD subjects with documented dysphagia compared to those without dysphagia. In addition, α-synuclein-immunoreactive nerve fibers in the ISLN were much more abundant than those in the IX and PSBX. These findings suggest that pharyngeal sensory nerves are directly affected by the pathologic process of PD. This anatomic pathology may decrease pharyngeal sensation impairing swallowing and airway protective reflexes, thereby contributing to dysphagia and aspiration.
doi:10.1097/NEN.0b013e3182965886
PMCID: PMC3695629  PMID: 23771215
Alpha-synuclein aggregates; Dysphagia; Glossopharyngeal nerve; Immunohistochemistry; Internal superior laryngeal nerve; Lewy neurites; Nerve degeneration; Parkinson disease; Peripheral nervous system; Pharyngeal sensory nerves; Pharynx; Swallowing; Vagus nerve
6.  The influence of Apolipoprotein E genotype on regional pathology in Alzheimer’s disease 
BMC Neurology  2013;13:44.
Background
Carriers of the ApoE ϵ4 allele are at a greater risk for developing Alzheimer’s disease (AD) and those who do develop AD tend to have a much greater neuropathological disease burden. Although several studies have shown significant differences in AD pathology among ϵ4 carriers and non-carriers, few have characterized these differences in terms of brain region and neuropathological score frequency.
Methods
566 pathologically-confirmed AD cases who were followed prospectively with antemortem dementia diagnoses (312 ApoE ϵ4 carriers and 254 ApoE ϵ4 non-carriers) were compared on the frequencies of neuropathological frequency scores (none, sparse, moderate, frequent) among several different brain regions (frontal, temporal, parietal, hippocampal, and entorhinal) using the CERAD scoring system. Pathology score frequencies were analyzed by carrier status (ϵ4 carrier vs. ϵ4 non-carrier) and by genotype (2/3, 3/3, 2/4, 3/4, 4/4). Both analyses investigated pathology score frequencies among different brain regions (frontal, temporal, parietal, hippocampal, and entorhinal).
Results
ϵ4 carriers had a significantly lower age at death (p <0.001) and significantly higher Braak scores (p <0.001) than ϵ4 non-carriers. Genotype comparison revealed that plaque and tangle pathologies increased in the following pattern, 2/3<3/3<2/4<3/4<4/4, for several brain regions. When stratified by age and ApoE ϵ4 carrier status, ϵ4 carriers tended to have significantly more frequent scores across most cortical areas. However, non-carriers age 90 and older tended to have greater plaque pathology than carriers. For tangle pathology, ϵ4 carriers tended to have significantly more “frequent” scores than non-carriers, except for the hippocampal and entorhinal areas in individuals age 90 and older.
Conclusions
ApoE ϵ4 carriers had a significantly higher percentage of “frequent” scores for plaques and tangles when compared to ApoE ϵ4 non-carriers for several brain regions. However, ϵ4 non-carriers age 90 and older tended to have less plaque and tangle pathology in certain brain regions. These results demonstrate that AD pathology may manifest itself differently based on ApoE genotype and suggest that ApoE carriers and non-carriers may have different patterns of AD neuropathology location and density.
doi:10.1186/1471-2377-13-44
PMCID: PMC3654892  PMID: 23663404
7.  Brain biochemistry in autopsied patients with essential tremor 
Movement Disorders  2011;27(1):113-117.
Background
The pathology of essential tremor is increasingly being studied; however, there are limited studies of biochemical changes in this condition.
Methods
We studied several candidate biochemical/anatomical systems in the brainstem, striatum and cerebellum of 23 essential tremor subjects who came to autopsy, comparing them to a control population.
Results
Striatal tyrosine hydroxylase, a marker of dopaminergic neurons, was 91.7 ±113.2 ng/mg versus 96.4±102.7 ng/mg (not significant) in cases and controls. Locus ceruleus dopamine beta-hydroxylase, a marker of noradrenergic neurons, was not significantly different between essential tremor and control groups. Parvalbumin, a marker of GABAergic neurons, was 199.3±42.0 versus 251.4±74.8 ng/mg (p=0.025) in the pons in the region of the locus ceruleus of essential tremor versus controls, while there was no difference in cerebellar parvalbumin.
Conclusion
These results are supportive of a possible role for reduced GABAergic function within the locus ceruleus in essential tremor. The hypothesis that essential tremor represents early Parkinson’s disease was not supported as striatal dopaminergic markers were not reduced compared to control subjects.
doi:10.1002/mds.24004
PMCID: PMC3261329  PMID: 22038525
tremor; pathology; GABA; norepinephrine
8.  Presence of Striatal Amyloid Plaques in Parkinson’s Disease Dementia Predicts Concomitant Alzheimer’s Disease: Usefulness for Amyloid Imaging 
Dementia is a frequent complication of Parkinson’s disease (PD). About half of PD dementia (PDD) is hypothesized to be due to progression of the underlying Lewy body pathology into limbic regions and the cerebral cortex while the other half is thought to be due to coexistent Alzheimer’s disease. Clinically, however, these are indistinguishable. The spread of amyloid plaques to the striatum has been reported to be a sensitive and specific indicator of dementia due to Alzheimer’s disease (AD). The purpose of the present study was to determine if the presence of striatal plaques might also be a useful indicator of the presence of diagnostic levels of AD pathology within PD subjects. We analyzed neuropathologically-confirmed cases of PD without dementia (PDND, N = 31), PDD without AD (PDD, N = 31) and PD with dementia meeting clinicopathological criteria for AD (PDAD, N =40). The minimum diagnostic criterion for AD was defined as including a clinical history of dementia, moderate or frequent CERAD cortical neuritic plaque density and Braak neurofibrillary stage III–VI. Striatal amyloid plaque densities were determined using Campbell-Switzer and Thioflavine S stains. Striatal plaque densities were significantly higher in PDAD compared to PDD (p<0.001). The presence of striatal plaques was approximately 80% sensitive and 80% specific for predicting AD. In comparison, the presence of cerebral cortex plaques alone was highly sensitive (100%) but had poor specificity (48% to 55%). The results suggest that striatal amyloid imaging may be clinically useful for making the distinction between PDD and PDAD.
doi:10.3233/JPD-2012-11073
PMCID: PMC3423968  PMID: 22924088
striatum; Lewy body; diagnosis; autopsy; neuropathology; biomarker
9.  Chemical Characterization of Pro-inflammatory Amyloid-Beta Peptides in Human Atherosclerotic Lesions and Platelets 
Biochimica et biophysica acta  2011;1812(11):1508-1514.
Amyloid-β (Aβ) peptides are intimately involved in the inflammatory pathology of atherosclerotic vascular disease (AVD) and Alzheimer's disease (AD). Although substantial amounts of these peptides are produced in the periphery, their role and significance to vascular disease outside the brain requires further investigation.
Amyloid-β peptides present in the walls of human aorta atherosclerotic lesions as well as activated and non-activated human platelets were isolated using sequential size-exclusion columns and HPLC reverse-phase methods. The Aβ peptide isolates were quantified by ELISA and structurally analyzed using MALDI-TOF mass spectrometry procedures.
Our experiments revealed that both aorta and platelets contained Aβ peptides, predominately Aβ40. The source of the Aβ pool in aortic atherosclerosis lesions is probably the activated platelets and/or vascular wall cells expressing APP/PN2. Significant levels of Aβ42 are present in the plasma, suggesting that this reservoir makes a minor contribution to atherosclerotic plaques.
Our data reveal that although aortic atherosclerosis and AD cerebrovascular amyloidosis exhibit clearly divergent end-stage manifestations, both vascular diseases share some key pathophysiological promoting elements and pathways. Whether they happen to be deposited in vessels of the central nervous system or atherosclerotic plaques in the periphery, Aβ peptides may promote and perhaps synergize chronic inflammatory processes which culminate in the degeneration, malfunction and ultimate destruction of arterial walls.
doi:10.1016/j.bbadis.2011.07.004
PMCID: PMC3185199  PMID: 21784149
atherosclerosis; platelets; amyloid-beta; vascular inflammation; Alzheimer's disease; coagulation cascade
10.  POSTMORTEM INTERVAL EFFECT ON RNA AND GENE EXPRESSION IN HUMAN BRAIN TISSUE 
Cell and Tissue Banking  2010;12(4):311-318.
Banked tissue is essential to the study of neurological disease but using postmortem tissue introduces a number of possible confounds. Foremost amongst these are factors relating to variation in postmortem interval (PMI). Currently there are conflicting reports on how PMI affects overall RNA integrity, and very few reports of how gene expression is affected by PMI. We analyzed total RNA extracted from frozen cerebellar cortex from 79 deceased human subjects enrolled in the Banner Sun Health Research Institute Brain and Body Donation Program. The PMI, which ranged from 1.5 to 45 hours, correlated with overall RNA quality measures including RNA Integrity Number (RIN) (r = − 0.34, p = 0.002) and RNA quantitative yield (r = − 0.25, p = 0.02). Additionally, we determined the expression of 89 genes using a PCR-based gene expression array (RT2 ProfilerTM PCR Array: Human Alzheimer’s Disease; SABiosciencesTM, Frederick, MD). A greater proportion of genes had decreased rather than increased expression with increasing PMI (65/89 vs 20/89; p < 0.0001). Of these, transcripts from the genes ADAM9, LPL, PRKCG, and SERPINA3 had significantly decreased expression with increasing PMI (p < 0.01). No individual gene transcripts had significantly increased expression with increasing PMI. In conclusion, it is apparent that RNA degrades progressively with increasing PMI and that measurement of gene expression in brain tissue with longer PMI may give artificially low values. For tissue derived from autopsy, a short PMI optimizes its utility for molecular research.
doi:10.1007/s10561-010-9210-8
PMCID: PMC3343031  PMID: 20703815
RIN; RNA; postmortem; brain; gene expression; Alzheimer’s disease; neurological disease; research; methods
11.  Positron Emission Tomography and Neuropathologic Estimates of Fibrillar Amyloid-β in a Patient With Down Syndrome and Alzheimer Disease 
Archives of Neurology  2011;68(11):1461-1466.
Background
Down syndrome appears to be associated with a virtually certain risk of fibrillar amyloid-β (Aβ) pathology by the age of 40 and a very high risk of dementia at older ages. The positron emission tomography (PET) ligand florbetapir F18 has been shown to characterize fibrillar Aβ in the living human brain and to provide a close correlation with subsequent Aβ neuropathology in individuals proximate to and after the end of life. The extent to which the most frequently used PET ligands can be used to detect fibrillar Aβ in patients with Down syndrome remains to be determined.
Objectives
To characterize PET estimates of fibrillar Aβ burden in a Down syndrome patient very close to the end of life and to compare them with neuropathologic assessment made after his death.
Design/Methods
With the family’s informed consent, florbetapir PET was used to study a 55-year-old Down syndrome patient with Alzheimer disease near the end of life; his brain was donated for neuropathologic assessment when he died 14 days later. Visual ratings of cerebral florbetapir uptake were performed by trained readers who were masked to the patient’s diagnosis as part of a larger study, and an automated algorithm was used to characterize regional-to-cerebellar standard uptake value ratios in 6 cerebral regions of interest. Neuropathologic assessments were performed masked to the patient’s diagnosis or PET measurements.
Results
Visual ratings and automated analyses of the PET image revealed a heavy fibrillar Aβ burden in cortical, striatal, and thalamic regions, similar to that reported for patients with late-onset Alzheimer disease. This matched neuropathologic findings of frequent neuritic and diffuse plaques, as well as frequent amyloid angiopathy, except for neuropathologically demonstrated frequent cerebellar diffuse plaques and amyloid angiopathy that were not detected by the PET scan.
Conclusions
Florbetapir PET can be used to detect increased cerebral-to-cerebellar fibrillar Aβ burden in a Down syndrome patient with Alzheimer disease, even in the presence of frequent amyloid angiopathy and diffuse plaques in the cerebellum. Additional studies are needed to determine the extent to which PET could be used to detect and to track fibrillar Aβ and to evaluate investigational Aβ-modifying treatments in the presymptomatic and symptomatic stages of Alzheimer disease.
doi:10.1001/archneurol.2011.535
PMCID: PMC3346179  PMID: 22084131
12.  Induction of Pluripotent Stem Cells from Autopsy Donor-Derived Somatic Cells 
Neuroscience letters  2011;502(3):219-224.
Human induced pluripotent stem cells (iPSCs) have become an intriguing approach for neurological disease modeling, because neural lineage-specific cell types that retain the donors' complex genetics can be established in vitro. The statistical power of these iPSC-based models, however, is dependent on accurate diagnoses of the somatic cell donors; unfortunately, many neurodegenerative diseases are commonly misdiagnosed in live human subjects. Postmortem histopathological examination of a donor's brain, combined with premortem clinical criteria, is often the most robust approach to correctly classify an individual as a disease-specific case or unaffected control. In this study, we describe iPSCs generated from a skin biopsy collected postmortem during the rapid autopsy of a 75-year-old male, whole body donor, defined as an unaffected neurological control by both clinical and histopathological criteria. These iPSCs were established in a feeder-free system by lentiviral transduction of the Yamanaka factors, Oct3/4, Sox2, Klf4, and c-Myc. Selected iPSC clones expressed both nuclear and surface antigens recognized as pluripotency markers of human embryonic stem cells (hESCs) and were able to differentiate in vitro into neurons and glia. Statistical analysis also demonstrated that fibroblast proliferation was significantly affected by biopsy site, but not donor age (within an elderly cohort). These results provide evidence that autopsy donor-derived fibroblasts can be successfully reprogrammed into iPSCs, and may provide an advantageous approach for generating iPSC-based neurological disease models.
doi:10.1016/j.neulet.2011.07.048
PMCID: PMC3195418  PMID: 21839145
induced pluripotent stem cells; genetic disease models; diagnostics; neurodegenerative diseases; postmortem; autopsy; neural differentiation
13.  Frequency of Alzheimer's Disease Pathology at Autopsy in Patients with Clinical Normal Pressure Hydrocephalus 
Background
Normal pressure hydrocephalus (NPH) is considered potentially treatable with the placement of a cerebrospinal fluid (CSF) shunt. Yet, the procedure has had variable success, particularly with respect to improving the cognitive impairment in NPH. The presence of neurologic co-morbidities, particularly Alzheimer's Disease (AD), may contribute to shunt responsiveness. Uncovering the extent to which AD and NPH co-occur has implications for diagnosis and treatment of NPH. Autopsy studies of patients with NPH during life would elucidate the frequency of such co-morbidities.
Methods
We conducted a search of the Sun Health Research Institute Brain Donation Program database between 1/1/1997 and 4/1/09 to identify all cases with neuropathologic evidence of dementia as well as those cases of clinically diagnosed NPH. We reviewed the medical records and brain findings of each NPH case.
Results
Of the 761 cases autopsied over the study interval, 563 cases were found to have neuropathological evidence meeting criteria for a dementing illness. AD was found exclusively in 313/563 (56%) cases with 94/563 cases having a secondary diagnosis of dementia.
We identified 9/761 cases with a clinical diagnosis of NPH, all nine cases were among the 563 cases with neuropathology of dementing illness at autopsy, representing 1.6% (9/563). Upon review of brain autopsy reports, 8/9 (89%) cases were found to have AD and 1/9 (11%) had progressive supranuclear palsy. Review of the medical records of the nine NPH cases revealed the following clinical co-morbidities: 5/9 with AD; 1/9 with Parkinson's Disease (PD); 1/9 with Mild Cognitive Impairment (MCI); 1/9 with seizure disorder.
Conclusions
Given the findings of our study, we support the AD-NPH theory and posit that AD is a common pathological co-morbidity in the setting of NPH and may preclude cognitive improvement post-shunt placement. This may have influence on selection of cases for shunting in the future.
doi:10.1016/j.jalz.2010.12.008
PMCID: PMC3166980  PMID: 21723206
normal pressure hydrocephalus; Alzheimer's disease; cerebrospinal fluid shunt; autopsy study; dementia
14.  Intracranial atherosclerosis as a contributing factor to Alzheimer's disease dementia 
Background
A substantial body of evidence amassed from epidemiologic, correlative and experimental studies strongly associates atherosclerotic vascular disease (AVD) with Alzheimer's disease (AD). Depending on the precise interrelationship between AVD and AD, systematic application of interventions to maintain vascular health and function as a component of standard AD therapy offers the prospect of mitigating what is presently the inexorable course of dementia. To assess this hypothesis it is vital to rigorously establish the measures of AVD that are most strongly associated with an AD diagnosis.
Methods
A precise neuropathological diagnosis was established for all subjects using a battery of genetic, clinical, and histological methods. The severity of atherosclerosis in the circle of Willis (CW) was quantified by direct digitized measurement of arterial occlusion in postmortem specimens and compared between AD and non-demented control (NDC) groups by calculating a corresponding index of occlusion.
Results
Atherosclerotic occlusion of the CW arteries was more extensive in the AD group than the NDC group. Statistically significant differences were also observed between control and AD groups with regard to Braak stage, total plaque score, total NFT score, total white matter rarefaction score, brain weight, MMSE scores and apolipoprotein E allelic frequencies.
Conclusions
Our results, combined with a consideration of the multifaceted impacts of impaired cerebral circulation, suggest an immediate need for prospective clinical trials to assess the efficacy of AD prevention using anti-atherosclerotic agents.
doi:10.1016/j.jalz.2010.08.228
PMCID: PMC3117084  PMID: 21388893
Alzheimer's disease; vascular dementia; intracranial atherosclerosis; circle of Willis; brain hypoperfusion
15.  PRE- AND POST-SYNAPTIC CORTICAL CHOLINERGIC DEFICITS ARE PROPORTIONAL TO AMYLOID PLAQUE PRESENCE AND DENSITY AT PRECLINICAL STAGES OF ALZHEIMER’S DISEASE 
Acta Neuropathologica  2011;122(1):49-60.
Amyloid imaging has identified cognitively normal older people with plaques as a group possibly at increased risk for developing Alzheimer’s disease-related dementia. It is important to begin to thoroughly characterize this group so that preventative therapies might be tested. Existing cholinotropic agents are a logical choice for preventative therapy as experimental evidence suggests that they are anti-amyloidogenic and clinical trials have shown that they delay progression of mild cognitive impairment to dementia. A detailed understanding of the status of the cortical cholinergic system in preclinical AD is still lacking, however. For more than 30 years, depletion of the cortical cholinergic system has been known to be one of the characteristic features of AD. Reports to date have suggested that some cholinergic markers are altered prior to cognitive impairment while others may show changes only at later stages of dementia. These studies have generally been limited by relatively small sample sizes, long postmortem intervals and insufficient definition of control and AD subjects by the defining histopathology. We therefore examined pre- and post-synaptic elements of the cortical cholinergic system in frontal and parietal cortex in 87 deceased subjects, including non-demented elderly with and without amyloid plaques as well as demented persons with neuropathologically-confirmed AD. Choline acetyltransferase (ChAT) activity was used as a presynaptic marker while displacement of 3H-pirenzepine binding by oxotremorine-M in the presence and absence of GppNHp was used to assess postsynaptic M1 receptor coupling. The results indicate that cortical ChAT activity as well as M1 receptor coupling are both significantly decreased in non-demented elderly subjects with amyloid plaques and are more pronounced in subjects with AD and dementia. These findings confirm that cortical cholinergic dysfunction in AD begins at the preclinical stage of disease and suggest that cholinotropic agents currently used for AD treatment are a logical choice for preventative therapy.
doi:10.1007/s00401-011-0831-1
PMCID: PMC3362487  PMID: 21533854
Alzheimer’s disease; cholinergic; muscarinic receptor; G-protein; amyloid imaging; preventative therapy; asymptomatic
16.  Neuropathological Findings of PSP in the Elderly Without Clinical PSP: Possible Incidental PSP? 
Parkinsonism & related disorders  2011;17(5):365-371.
Aims
We aimed to describe cases with incidental neuropathological findings of progressive supranuclear palsy (PSP) from the Banner Sun Health Research Institute Brain and Body Donation Program.
Methods
We performed a retrospective review of 277 subjects with longitudinal motor and neuropsychological assessments who came to autopsy. The mean Gallyas-positive PSP features grading for subjects with possible incidental neuropathological PSP was compared to those of subjects with clinically manifest disease.
Results
There were 5 cases with histopathological findings suggestive of PSP, but no parkinsonism, dementia or movement disorder during life. Cognitive evaluation revealed 4 of the 5 cases to be cognitively normal; one case had amnestic mild cognitive impairment (MCI) in her last year of life. The mean age at death of the 5 cases was 88.9 years (range 80-94). All 5 individuals had histopathologic microscopic findings suggestive of PSP. Mean Gallyas-positive PSP features grading was significantly lower in subjects with possible incidental neuropathological PSP than subjects with clinical PSP, particularly in the subthalamic nucleus.
Conclusions
We present 5 patients with histopathological findings suggestive of PSP, without clinical PSP, dementia or parkinsonism during life. These incidental neuropathological PSP findings may represent the early or pre-symptomatic stage of PSP. The mean Gallyas-positive PSP features grading was significantly lower in possible incidental PSP than in clinical PSP, thus suggesting that a threshold of pathological burden needs to be reached within the typically affected areas in PSP before clinical signs and symptoms appear.
doi:10.1016/j.parkreldis.2011.02.017
PMCID: PMC3109165  PMID: 21420891
progressive supranuclear palsy; PSP; incidental; autopsy; parkinsonism; neuropathology
17.  Multi-organ distribution of phosphorylated α-synuclein histopathology in subjects with Lewy body disorders 
Acta neuropathologica  2010;119(6):689-702.
A sensitive immunohistochemical method for phosphorylated α-synuclein was used to stain sets of sections of spinal cord and tissue from 41 different sites in the bodies of 92 subjects, including 23 normal elderly, 7 with incidental Lewy body disease (ILBD), 17 with Parkinson’s disease (PD), 9 with dementia with Lewy bodies (DLB), 19 with Alzheimer’s disease with Lewy bodies (ADLB) and 17 with Alzheimer’s disease with no Lewy bodies (AD-NLB). The relative densities and frequencies of occurrence of phosphorylated α-synuclein histopathology (PASH) were tabulated and correlated with diagnostic category. The greatest densities and frequencies of PASH occurred in the spinal cord, followed by the paraspinal sympathetic ganglia, the vagus nerve, the gastrointestinal tract and endocrine organs. The frequency of PASH within other organs and tissue types was much lower. Spinal cord and peripheral PASH was most common in subjects with PD and DLB, where it appears likely that it is universally widespread. Subjects with ILBD had lesser densities of PASH within all regions, but had frequent involvement of the spinal cord and paraspinal sympathetic ganglia, with less-frequent involvement of end-organs. Subjects with ADLB had infrequent involvement of the spinal cord and paraspinal sympathetic ganglia with rare involvement of end-organs. Within the gastrointestinal tract, there was a rostrocaudal gradient of decreasing PASH frequency and density, with the lower esophagus and submandibular gland having the greatest involvement and the colon and rectum the lowest.
doi:10.1007/s00401-010-0664-3
PMCID: PMC2866090  PMID: 20306269
Parkinson’s disease; Parkinsonism; Dementia with Lewy bodies; Alzheimer’s disease; Incidental Lewy bodies; α-Synuclein; Spinal cord; Sympathetic nervous system; Peripheral nervous system; Autonomic nervous system; Enteric nervous system; Submandibular gland; Esophagus; Adrenal gland; Heart; Stomach; Gastrointestinal system
18.  Reduced clinical and postmortem measures of cardiac pathology in subjects with advanced Alzheimer's Disease 
BMC Geriatrics  2011;11:3.
Background
Epidemiological studies indicate a statistical linkage between atherosclerotic vascular disease (ATH) and Alzheimer's disease (AD). Autopsy studies of cardiac disease in AD have been few and inconclusive. In this report, clinical and gross anatomic measures of cardiac disease were compared in deceased human subjects with and without AD.
Methods
Clinically documented cardiovascular conditions from AD (n = 35) and elderly non-demented control subjects (n = 22) were obtained by review of medical records. Coronary artery stenosis and other gross anatomical measures, including heart weight, ventricular wall thickness, valvular circumferences, valvular calcifications and myocardial infarct number and volume were determined at autopsy.
Results
Compared to non-demented age-similar control subjects, those with AD had significantly fewer total diagnosed clinical conditions (2.91 vs 4.18), decreased coronary artery stenosis (70.8 vs 74.8%), heart weight (402 vs 489 g for males; 319 vs 412 g for females) and valvular circumferences. Carriage of the Apolipoprotein E-ε4 allele did not influence the degree of coronary stenosis. Group differences in heart weight remained significant after adjustment for age, gender, body mass index and apolipoprotein E genotype while differences in coronary artery stenosis were significantly associated with body mass index alone.
Conclusions
The results are in agreement with an emerging understanding that, while midlife risk factors for ATH increase the risk for the later development of AD, once dementia begins, both risk factors and manifest disease diminish, possibly due to progressive weight loss with increasing dementia as well as disease involvement of the brain's vasomotor centers.
doi:10.1186/1471-2318-11-3
PMCID: PMC3039594  PMID: 21266042
19.  Proteomics-Derived Cerebrospinal Fluid Markers of Autopsy-Confirmed Alzheimer’s Disease 
The diagnostic performance of several candidate cerebrospinal fluid (CSF) protein biomarkers of neuropathologically-confirmed Alzheimer’s disease (AD), non-demented (ND) elderly controls and non-AD dementias (NADD) was assessed. Candidate markers were selected on the basis of initial 2-dimensional gel electrophoresis studies or by literature review. Markers selected by the former method included apolipoprotein A-1 (ApoA1), hemopexin (HPX), transthyretin (TTR) and pigment epithelium-derived factor (PEDF) while markers identified from the literature included Aβ1–40, Aβ1–42, total tau, phosphorylated tau, α-1 acid glycoprotein (A1GP), haptoglobin, zinc α-2 glycoprotein (Z2GP) and apolipoprotein E (ApoE). Ventricular CSF concentrations of the markers were measured by ELISA. The concentrations of Aβ1–42, ApoA1, A1GP, ApoE, HPX and Z2GP differed significantly among AD, ND and NADD subjects. Logistic regression analysis for the diagnostic discrimination of AD from ND found that Aβ1–42, ApoA1 and HPX each had significant and independent associations with diagnosis. The CSF concentrations of these three markers distinguished AD from ND subjects with 84% sensitivity and 72% specificity, with 78% of subjects correctly classified. By comparison, using Aβ1–42 alone gave 79% sensitivity and 61% specificity, with 68% of subjects correctly classified. For the diagnostic discrimination of AD from NADD, only the concentration of Aβ1–42 was significantly related to diagnosis, with a sensitivity of 58%, specificity of 86% and 86% correctly classified. The results indicate that for the discrimination of AD from ND control subjects, measurement of a set of markers including Aβ1–42, ApoA1 and HPX improved diagnostic performance over that obtained by measurement of Aβ1–42 alone. For the discrimination of AD from NADD subjects, measurement of Aβ1–42 alone was superior.
doi:10.3109/13547500903108423
PMCID: PMC2824250  PMID: 19863188
Alzheimer’s disease; non-Alzheimer’s disease dementias; cerebrospinal fluid; biomarkers; ELISA; Aβ; tau; apolipoprotein A-1; α-1 acid glycoprotein; haptoglobin; hemopexin; transthyretin; pigment epithelium-derived factor; zinc α-2 glycoprotein and apolipoprotein E
20.  Proteomic Analysis of Alzheimer’s Disease Cerebrospinal Fluid from Neuropathologically Diagnosed Subjects 
Current Alzheimer research  2009;6(4):399-406.
A crucial need exists for reliable Alzheimer’s disease (AD) diagnostic and prognostic tests. Given its intimate communication with the brain, the cerebrospinal fluid (CSF) has been surveyed intensively for reliable AD biomarkers. The heterogeneity of AD pathology and the unavoidable difficulties associated with the clinical diagnosis and differentiation of this dementia from other pathologies have confounded biomarker studies in antemortem CSF samples. Using postmortem ventricular CSF (V-CSF) pools, two-dimensional difference gel electrophoresis (2D DIGE) analyses revealed a set of proteins that showed significant differences between neuropathologically-diagnosed AD and elderly non-demented controls (NDC), as well as subjects with non-AD dementias. The 2D DIGE system identified a set of 21 different protein biomarkers. This panel of proteins probably reflects fundamental pathological changes that are divergent from both normal aging and non-AD dementias.
PMCID: PMC2832860  PMID: 19689240
Alzheimer’s disease; cerebrospinal fluid; proteomics; DIGE; biomarkers
21.  Parkinson's disease with dementia: comparing patients with and without Alzheimer pathology 
Subjects with Parkinson's disease (PD) frequently develop dementia with greater than one-third meeting neuropathologic diagnostic criteria for Alzheimer's disease (AD). The objective is to identify clinical and neuropathological differences between PDD (PD with dementia) subjects, with and without coexistent AD pathology. Neuropathologic examination was available on subjects diagnosed by clinicopathologic criteria with PDD-AD (N = 23) and PDD+AD (N = 28). A small subset of subjects with PDD-AD and PDD+AD had received at least one standardized neuropsychological assessment. PDD+AD subjects were significantly older at age of PD onset and death, progressed to onset of dementia in less time, and had a shorter duration of PD symptoms prior to the onset of dementia. Education, responsiveness of L-Dopa and dopaminergic medications, presence of cognitive fluctuations and hallucinations, mean MMSE, GDS, FAST and UPDRS scores did not differ significantly between the two groups. The PDD+AD group had significantly greater total plaques, neuritic plaques, total tangles, and Braak stages compared to PDD-AD. This study suggests that it is difficult to distinguish PDD+AD and PDD-AD on the basis of movement, clinical, and neuropsychological assessment. PDD-AD and PDD+AD have similar degrees of dementia and approximately half of PDD subjects have enough AD pathology to attain a neuropathological diagnosis of AD. PDD can develop in the absence of significant Alzheimer pathology.
doi:10.1097/WAD.0b013e31819c5ef4
PMCID: PMC2760034  PMID: 19812474
Parkinson' disease with dementia; Alzheimer's Disease; Dementia with Lewy Bodies; assessment of dementia
22.  Unified Staging System for Lewy Body Disorders: Correlation with Nigrostriatal Degeneration, Cognitive Impairment and Motor Dysfunction 
Acta neuropathologica  2009;117(6):613-634.
The two current major staging systems in use for Lewy body disorders fail to classify up to 50% of subjects. Both systems do not allow for large numbers of subjects who have Lewy-type α-synucleinopathy (LTS) confined to the olfactory bulb or who pass through a limbic-predominant pathway that at least initially bypasses the brainstem. The results of the current study, based on examination of a standard set of 10 brain regions from 417 subjects stained immunohistochemically for α-synuclein, suggest a new staging system that, in this study, allows for the classification of all subjects with Lewy body disorders. The autopsied subjects included elderly subjects with Parkinson’s disease, dementia with Lewy bodies, incidental Lewy body disease and Alzheimer’s disease with Lewy bodies, as well as comparison groups without Lewy bodies. All subjects were classifiable into one of the following stages: I. Olfactory Bulb Only; IIa Brainstem Predominant; IIb Limbic Predominant; III Brainstem and Limbic; IV Neocortical. Progression of subjects through these stages was accompanied by a generally stepwise worsening in terms of striatal tyrosine hydroxylase concentration, substantia nigra pigmented neuron loss score, Mini Mental State Examination score and score on the Unified Parkinson’s Disease Rating Scale Part 3. Additionally there were significant correlations between these measures and LTS density scores. It is suggested that the proposed staging system would improve on its predecessors by allowing classification of a much greater proportion of cases.
doi:10.1007/s00401-009-0538-8
PMCID: PMC2757320  PMID: 19399512
Parkinson’s disease; parkinsonism; dementia with Lewy bodies; Alzheimer’s disease; incidental Lewy bodies; α-synuclein; olfactory bulb; amgydala; limbic; brainstem; neocortex
23.  Olfactory bulb α-synucleinopathy has high specificity and sensitivity for Lewy body disorders 
Acta neuropathologica  2008;117(2):169-174.
Involvement of the olfactory bulb by Lewy-type α-synucleinopathy (LTS) is known to occur at an early stage of Parkinson's disease (PD) and Lewy body disorders and is therefore of potential usefulness diagnostically. An accurate estimate of the specificity and sensitivity of this change has not previously been available. We performed immunohistochemical α-synuclein staining of the olfactory bulb in 328 deceased individuals. All cases had received an initial neuropathological examination that included α-synuclein immunohistochemical staining on sections from brainstem, limbic and neocortical regions, but excluded olfactory bulb. These cases had been classified based on their clinical characteristics and brain regional distribution and density of LTS, as PD, dementia with Lewy bodies (DLB), Alzheimer's disease with LTS (ADLS), Alzheimer's disease without LTS (ADNLS), incidental Lewy body disease (ILBD) and elderly control subjects. The numbers of cases found to be positive and negative, respectively, for olfactory bulb LTS were: PD 55/3; DLB 34/1; ADLS 37/5; ADNLS 19/84; ILBD 14/7; elderly control subjects 5/64. The sensitivities and specificities were, respectively: 95 and 91% for PD versus elderly control; 97 and 91% for DLB versus elderly control; 88 and 91% for ADLS versus elderly control; 88 and 81% for ADLS versus ADNLS; 67 and 91% for ILBD versus elderly control. Olfactory bulb synucleinopathy density scores correlated significantly with synucleinopathy scores in all other brain regions (Spearman R values between 0.46 and 0.78) as well as with scores on the Mini-Mental State Examination and Part 3 of the unified Parkinson's Disease Rating Scale (Spearman R −0.27, 0.35, respectively). It is concluded that olfactory bulb LTS accurately predicts the presence of LTS in other brain regions. It is suggested that olfactory bulb biopsy be considered to confirm the diagnosis in PD subjects being assessed for surgical therapy.
doi:10.1007/s00401-008-0450-7
PMCID: PMC2631085  PMID: 18982334
Parkinson's disease, surgery; Deep brain stimulation; Gene therapy; Transplantation; Dementia with Lewy bodies, diagnosis, therapy, clinical trial; α-Synuclein, Lewy bodies, incidental Lewy body disease; Biopsy; Olfactory bulb
24.  Reduced striatal tyrosine hydroxylase in incidental Lewy body disease 
Acta neuropathologica  2007;115(4):445-451.
Incidental Lewy body disease (ILBD) is the term used when Lewy bodies are found in the nervous system of subjects without clinically documented parkinsonism or dementia. The prevalence of ILBD in the elderly population has been estimated at between 3.8 and 30%, depending on subject age and anatomical site of sampling. It has been speculated that ILBD represents the preclinical stage of Parkinson’s disease (PD) and/or dementia with Lewy bodies (DLB). Studies of ILBD could potentially identify early diagnostic signs of these disorders. At present, however, it is impossible to know whether ILBD is a precursor to PD or DLB or is just a benign finding of normal aging. We hypothesized that, if ILBD represents an early stage of PD or DLB, it should be associated with depletion of striatal dopaminergic markers. Eleven subjects with ILBD and 27 control subjects were studied. The ILBD subjects ranged in age from 74 to 96 years (mean 86.5) while the control subjects’ age ranged from 75 to 102 years (mean 86.7). Controls and subjects did not differ in terms of age, postmortem interval, gender distribution, medical history conditions, brain weight, neuritic plaque density or Braak neurofibrillary stage. Quantitative ELISA measurement of striatal tyrosine hydroxylase (TH), the principal enzyme for dopamine synthesis, showed a 49.8% (P = 0.01) reduction in ILBD cases, as compared with control cases. The finding suggests that ILBD is not a benign condition but is likely a precursor to PD and/or DLB.
doi:10.1007/s00401-007-0313-7
PMCID: PMC2724592  PMID: 17985144
Striatum; Dopamine; Parkinson’s disease; Lewy bodies; Pathogenesis; Aging
25.  Cholesterol retention in Alzheimer’s brain is responsible for high β- and γ-secretase activities and Aβ production 
Neurobiology of disease  2007;29(3):422-437.
Alzheimer’s disease (AD) is characterized by overproduction of Aβ derived from APP cleavage via β- and γ-secretase pathway. Recent evidence has linked altered cholesterol metabolism to AD pathogenesis. In this study, we show that AD brain had significant cholesterol retention and high β- and γ-secretase activities as compared to age-matched non-demented controls (ND). Over one-half of AD patients had an apoE4 allele but none of the ND. β- and γ-secretase activities were significantly stimulated in vitro by 40 and 80 µm cholesterol in AD and ND brains, respectively. Both secretase activities in AD brain were more sensitive to cholesterol (40 µm) than those of ND (80 µm). Filipin-stained cholesterol overlapped with BACE and Aβ in AD brain sections. Cholesterol (10–80 µM) added to N2a cultures significantly increased cellular cholesterol, β- and γ-secretase activities and Aβ secretion. Similarly, addition of cholesterol (20–80 µM) to cell lysates stimulated both in vitro secretase activities. Ergosterol slightly decreased β-secretase activity at 20–80 µM, but strongly inhibited γ-secretase activity at 40 µM. Cholesterol depletion reduced cellular cholesterol, β-secretase activity and Aβ secretion. Transcription factor profiling shows that several key nuclear receptors involving cholesterol metabolism were significantly altered in AD brain, including decreased LXR-β, PPAR and TR, and increased RXR. Treatment of N2a cells with LXR, RXR or PPAR agonists strongly stimulated cellular cholesterol efflux to HDL and reduced cellular cholesterol and β-/γ-secretase activities. This study provides direct evidence that cholesterol homeostasis is impaired in AD brain and suggests that altered levels or activities of nuclear receptors may contribute to cholesterol retention which likely enhances β- and γ-secretase activities and Aβ production in human brain.
doi:10.1016/j.nbd.2007.10.005
PMCID: PMC2720683  PMID: 18086530
Alzheimer’disease; Cholesterol retention; Nuclear receptors; β- and γ-secretases; Aβ- production

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