It has been more than 10 years since it was first proposed that the neurodegeneration in Alzheimer9s disease (AD) may be caused by deposition of amyloid β-peptide (Aβ) in plaques in brain tissue. According to the amyloid hypothesis, accumulation of Aβ in the brain is the primary influence driving AD pathogenesis. The rest of the disease process, including formation of neurofibrillary tangles containing tau protein, is proposed to result from an imbalance between Aβ production and Aβ clearance.

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The Amyloid Hypothesis of Alzheimer's Disease: Progress and Problems on the Road to Therapeutics

A consensus panel from the United States and Europe was convened recently to update and revise the 1997 consensus guidelines for the neuropathologic evaluation of Alzheimer's disease (AD) and other diseases of brain that are common in the elderly. The new guidelines recognize the pre-clinical stage of AD, enhance the assessment of AD to include amyloid accumulation as well as neurofibrillary change and neuritic plaques, establish protocols for the neuropathologic assessment of Lewy body disease, vascular brain injury, hippocampal sclerosis, and TDP-43 inclusions, and recommend standard approaches for the workup of cases and their clinico-pathologic correlation.

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National Institute on Aging-Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease

We present a practical guide for the implementation of recently revised National Institute on Aging–Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease (AD). Major revisions from previous consensus criteria are: (1) recognition that AD neuropathologic changes may occur in the apparent absence of cognitive impairment, (2) an “ABC” score for AD neuropathologic change that incorporates histopathologic assessments of amyloid β deposits (A), staging of neurofibrillary tangles (B), and scoring of neuritic plaques (C), and (3) more detailed approaches for assessing commonly co-morbid conditions such as Lewy body disease, vascular brain injury, hippocampal sclerosis, and TAR DNA binding protein (TDP)-43 immunoreactive inclusions. Recommendations also are made for the minimum sampling of brain, preferred staining methods with acceptable alternatives, reporting of results, and clinico-pathologic correlations.

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National Institute on Aging–Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease: a practical approach

Parkinson's disease is characterized by abundant α-synuclein (α-Syn) neuronal inclusions, known as Lewy bodies and Lewy neurites, and the massive loss of midbrain dopamine neurons. However, a cause-and-effect relationship between Lewy inclusion formation and neurodegeneration remains unclear. Here, we found that in wild-type nontransgenic mice, a single intrastriatal inoculation of synthetic α-Syn fibrils led to the cell-to-cell transmission of pathologic α-Syn and Parkinson's-like Lewy pathology in anatomically interconnected regions. Lewy pathology accumulation resulted in progressive loss of dopamine neurons in the substantia nigra pars compacta, but not in the adjacent ventral tegmental area, and was accompanied by reduced dopamine levels culminating in motor deficits. This recapitulation of a neurodegenerative cascade thus establishes a mechanistic link between transmission of pathologic α-Syn and the cardinal features of Parkinson's disease.

/pdf/pathological-a-synuclein-transmission-initiates-parkinson-1zdg64n1in.pdf

Pathological α-Synuclein Transmission Initiates Parkinson-like Neurodegeneration in Nontransgenic Mice

Many neurodegenerative diseases, including Alzheimer's and Parkinson's and the transmissible spongiform encephalopathies (prion diseases), are characterized at autopsy by neuronal loss and protein aggregates that are typically fibrillar. A convergence of evidence strongly suggests that protein aggregation is neurotoxic and not a product of cell death. However, the identity of the neurotoxic aggregate and the mechanism by which it disables and eventually kills a neuron are unknown. Both biophysical studies aimed at elucidating the precise mechanism of in vitro aggregation and animal modeling studies support the emerging notion that an ordered prefibrillar oligomer, or protofibril, may be responsible for cell death and that the fibrillar form that is typically observed at autopsy may actually be neuroprotective. A subpopulation of protofibrils may function as pathogenic amyloid pores. An analogous mechanism may explain the neurotoxicity of the prion protein; recent data demonstrates that the disease-associated, infectious form of the prion protein differs from the neurotoxic species. This review focuses on recent experimental studies aimed at identification and characterization of the neurotoxic protein aggregates.

Protofibrils, pores, fibrils, and neurodegeneration: separating the responsible protein aggregates from the innocent bystanders.

A 73-year·old right-handed man with a history of diabetes, hyperlipidem ia, co ronary artery disease, and asthmatic obstructive lung disease came to our institution beca use of a 2year history of gradual worseoiog of gait aod balaoce. One year previously, he had undergone coronary artery bypass grafting without perioperative complica tions. Subsequently, h is gait worsened, and his fee l felt "glued to the floor." During the 2 years before the curre nt examination, he also noticed urinary urgency, occasional incont inence, and irnpotcnce. His wife noti ced that he had had some mental slo wing and forgetfulness during the precediog 18 months. Review of systems revealed no history of tremo r. speech change, diffi culty with use of his arms, or wea kness . Five months before the current assessment, a neu rol ogist had noted parkin son ism; amantadi oe hydrochlori de and carbidopaIcvodopa were prescribed separate ly but yielded no benefi t. On initi al consultation , the patient had norm al mental status and cranial nerve func tions. Motor examina tion showed generally preserved strength, red uced aokle jerks, and flexor plantar responses bilaterally. Muscle tone was mildly spastic in the legs. Sensory examinat ion showed mild hypoe sthesia 10 pinprick in bot h hands (fingertips) and feet (up 10 the ankles); other sensory modalit ies were normal. His ga it was wide-based , and externa l anal sphincte r tone was mildly reduced . Parkinsoni an signs included shuffl ing gait, slowed walking, and postural instability.

73-year-old man with gait disturbance and imbalance.

Objective: To advance discovery of biomarkers towards improving the efficiency and outcome of Phase II clinical trials for Parkinson9s Disease (PD).
Background: Parkinson’s Disease (PD) affects > one-half million patients in the US. Current treatments provide some symptomatic relief, but do not impact progression. The National Institute of Neurological Disorders and Stroke (NINDS) Parkinson9s Disease Biomarkers Program (PDBP) was established to advance discovery of biomarkers that will improve the efficiency and outcome of Phase II and III clinical trials PD and advance therapeutic development.
Design/Methods: The PDBP is a longitudinal program gathering clinical data and biospecimens in subjects who span the range of PD course, as well as from control subjects. Six of the ten projects supported under the PDBP are clinical. PDBP has enrolled >1000 well-characterized participants. Each clinical site follows a standardized protocol for subject visits and biospecimen collection.
Results: There are >250 cerebrospinal fluid samples and collectively more than 3800 RNA, DNA, plasma and serum samples available for analysis. These biospecimens and associated quality control data are available for PD research by academics and industry researchers.
Conclusions: The PDBP is a resource with a collection of detailed clinical data and extensive associated biospecimens on subjects with PD and controls. Researchers gain access to the PDBP DMR data by requesting an account. They can subsequently request biospecimens through a straightforward process. More information about requesting an account, ordering biospecimens and more generally, the NINDS PDBP, can be found on the PDBP website (https://pdbp.ninds.nih.gov). For grant mechanisms associated with PDBP, please refer to the following funding opportunity announcements: PAR-14-259 Parkinson9s Disease Biomarker Program (PDBP) Discovery Projects (U01) and PAR-14-340 Request to Access Parkinson9s Disease Related-Biospecimens (X01).
Supported by: National Institute of Neurological Disorders and Stroke. Disclosure: Dr. Gwinn has nothing to disclose. Dr. David has nothing to disclose. Dr. Hillaire-Clarke has nothing to disclose. Dr. Matt has nothing to disclose. Dr. Babcock has nothing to disclose. Dr. Sieber has nothing to disclose. Dr. Sutherland has nothing to disclose.

The NINDS Parkinson’s Disease Biomarkers Program (P1.194)

80-Year-Old Woman With Dementia and Parkinsonism

Deletion at ITPR1 underlies ataxia in mice and humans (SCA15)

Clinical trials provide the ‘evidence’ in evidence-based medicine. Despite their cost and complexity, clinical trials save society billions of dollars [1]. Recent advances have enabled genome-wide analyses of single nucleotide polymorphisms in complex diseases. Such analyses require large sample sizes and thus depend on collaborative efforts. Genetics ancillary to clinical trials benefit from recruitment by numerous investigators at diverse institutions. Additionally, clinical trial subjects are well characterized via trial eligibility screening, and baseline characteristics and outcomes are collected via validated, standardized measures. This allows genotype-phenotype, genotype-outcome and treatment-response analyses. Banking DNA only marginally increases costs relative to the cost of the trial itself.

The disadvantages to ancillary genetic studies in clinical trials are also clear. Typically, trials do not recruit disease-free individuals necessary for genetic controls. As a result, historical control subjects, who may have incomplete, differentially acquired phenotypes, are frequently used. Trial eligibility criteria result in collections that are not representative of the disease-affected population. For example, PROACT II, a study of intra-arterial thrombolysis, randomized subjects representing 1.5% of those screened [2]. Such small samples can render subcollections useless, even in the absence of recruitment bias.

Although pharmacogenetics is subject to hyperbole, the underlying concepts are traditional. Clinicians consider treatment based on ethnicity, gender and other factors, all of which are the result of gene expression. Malignant hyperthermia [3], long QT syndrome [4], venous thromboembolic disease [5] and tardive dyskinesia [6], among others, have associated underlying genetic risk factors. New tools including microarray technology [7], high-throughput screening and bioinformatics, when combined with large simple trial infrastructure, allow a better understanding of pharmacogenetics.

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Katrina Gwinn

Papers

73-year-old man with gait disturbance and imbalance.

The NINDS Parkinson’s Disease Biomarkers Program (P1.194)

80-Year-Old Woman With Dementia and Parkinsonism

Deletion at ITPR1 underlies ataxia in mice and humans (SCA15)

Genetics in clinical trials.