Diagnosis Of Neurodegenerative Disorders Research Articles

Diagnostic and prognostic needs in neurodegenerative disorders: focus on proteomics

Over the past 10 years, the attraction of proteomic approaches for the neurochemical diagnosis of neurodegenerative disorders has increased enormously. Neurodegenerative disorders are characterized...

Non-invasive measurement of vagus activity in the brainstem – a methodological progress towards earlier diagnosis of dementias?

In Alzheimer's disease (AD), mild functional disturbances should precede gross structural damage and even more clinical symptoms, possibly by decades. Moreover, alterations in the brainstem are supposed to occur earlier as cortical affections. Based on these considerations, we developed a new method aiming at the measurement of vagal brainstem functioning by means of evoked potentials after electrical stimulation of the cutaneous representation of the vagus nerve in the external auditory channel. In the current study, a first sample of patients with Alzheimer's disease (n = 7) and mild cognitive impairment (n = 3) were investigated (6m, 4f, range from 57 to 78 y, mean age 68.6 years). Vagus somatosensory evoked potentials (VSEP) were characterized by significantly longer latencies as compared to healthy age- and gender-matched controls (p < 0.05). Future large scale studies - also including preclinical stages of AD - have to assess the value of this non-invasive, fast and cheap method in the early diagnosis of neurodegenerative disorders.

The brain-specific protein TPPP/p25 in pathological protein deposits of neurodegenerative diseases

Immunohistochemical detection of protein components of pathological inclusions is widely used for neuropathological diagnosis of neurodegenerative disorders. However, different antibodies and antigen unmasking methods may account for variability between research studies and thus may affect diagnostic accuracy. Using two different antibodies raised against either a segment (184-200 aa) or the full length of human recombinant brain-specific tubulin polymerization promoting protein TPPP/p25, we immunohistochemically screened neurodegenerative disorders, both with and without pathological alpha-synuclein structures. We tested three different epitope unmasking methods, we applied laser confocal microscopy to evaluate double immunolabelling, and we compared the amount of structures exhibiting TPPP/p25 and alpha-synuclein immunoreactivity. We demonstrate that there are a variety of staining patterns depending on the epitope retrieval method and antibody used. The antibody raised against aa 184-200 segment of TPPP/p25 is better in immunolabelling the majority of alpha-synuclein immunopositive neuronal and glial pathological profiles detectable in Parkinson's disease, diffuse Lewy-body disease, and multiple system atrophy, in addition to immunostaining some extracellular huntingtin immunoreactive structures, lipofuscin, and neuromelanin particles. In contrast, the one raised against the full-length human recombinant TPPP/p25 is more suitable to immunodetect normal oligodendrocytes. Exposition of the segment aa 184-200 of TPPP/p25 in the aggregates of pathological inclusions renders this antibody a reliable marker of all types of alpha-synucleinopathies and suggests a role for TPPP/p25 in the aggregation process of some neurodegenerative conditions.

Positron Emission Tomography and Single-Photon Emission Computed Tomography in Central Nervous System Drug Development

In this review, the value of functional imaging [positron emission tomography (PET)/single-photon emission computed tomography (SPECT)] in drug development is considered. Radionuclide imaging can help establish the diagnosis of neurodegenerative disorders where this is in doubt and provides a potential biomarker for following drug effects on disease progression. PET and SPECT can help understand mechanisms of disease and determine the functional effects of therapeutic approaches on neurotransmission and metabolism. Synthesizing radiotracer analogs of novel drugs can provide proof of principle that these agents reach their enzyme or receptor targets and delineate their regional brain distribution. If such radiotracers do not prove to have ideal properties for imaging, the concept of microdosing potentially allows multiple other drug analogs to be tested with less stringent regulatory requirements than for novel medicinals. Finally, PET tracers can provide receptor and enzyme active site dose occupancy profiles, thereby guiding dosage selection for phase 1 and phase 2 trials. The eventual hope is that radiotracer imaging will provide a surrogate marker for drug efficacy, although this has yet to be realized, and progress the concept of personalized medicine where receptor/enzyme binding profiles help predict therapeutic outcome.

New chapter in skin biopsy: diagnostic tool for neurodegenerative disorders

The accumulation of the ubiquitous amyloid peptide in the brain is a defining feature of Alzheimer's disease. Consistent with studies demonstrating alterations of various biochemical processes of cells of peripheral tissues and the importance of skin biopsy in the diagnosis of neurodegenerative disorders, we investigated whether differences in the basal intracellular free calcium levels of lymphocytes and cultured cutaneous fibroblasts derived from sporadic Alzheimer patients and from age‐matched control individuals might be present. Calcium levels were measured in Fura‐2AM‐loaded human fibroblasts by dual‐wavelength spectrofluorimetry. Basal calcium levels appeared to be higher in Alzheimer lymphocytes when compared with control ones. Resting calcium concentration of Alzheimer fibroblasts, however, has proved to be lower than that seen with control cells. Exposure of cells to amyloid resulted in the elevation in the Ca2+ level of both control cell types, however, that of Alzheimer lymphocytes and fibroblasts did not differ considerably. Our test could prove useful in supporting the diagnosis of (sporadic) AD in patients suspected of suffering from the disease. Also, this simple finding may serve as a springboard to monitoring Alzheimer pathology in the peripheral systems of the body.

Imaging of central nAChReceptors with 2-[ 18F]F-A85380: optimized synthesis and in vitro evaluation in Alzheimer's disease

In vivo labeling of the nicotinic acetylcholine receptors (nAChR) could be a useful tool for early diagnosis of neurodegenerative disorders. 2-[ 18F]F-A85380 (2-[ 18F]Fluoro-3-[2(S)-2-azetidinylmethoxy]pyridine), a ligand with high affinity to the β2 subunit of the nAChRs, has been shown to label neurons in the nAChR-rich thalamus, cortex and striatum in baboons. We report an optimized synthesis resulting in an uncorrected yield of 58% in 45 min (precursor 2), enabling efficient production intended for clinical use. Incubation of normal rat brain sections with 2-[ 18F]F-A85380 with subsequent autoradiographic analyses showed the expected distribution in nAChR areas. In human brain sections of Alzheimer's disease (AD) a decrease of 2-[ 18F]F-A85380 uptake to 36% of the control group was measured in the thalamus and also in the occipital cortex. These findings suggest that 2-[ 18F]F-A85380 is a promising PET-ligand in the diagnosis of AD.

Tau protein phosphorylated at threonine 181 in CSF as a neurochemical biomarker in Alzheimer's disease: original data and review of the literature.

Cerebrospinal fluid (CSF) concentrations of total Tau and Tau phosphorylated at threonine (position 181 [pTau181]) were studied with ELISA in a group of carefully selected patients with a neurochemically supported diagnosis of Alzheimer's disease (AD, n = 9; age range, 51-89 yr) and in a group of sex- and age-matched nondemented controls (n = 9; age range, 52-81 yr). The concentration of both biomarkers is increased significantly in the AD group (total Tau, p < 0.0008; pTau181, p < 0.008). A significant correlation between CSF concentrations of both biomarkers is observed (R = 0.897; p < 0.001). Neither total Tau nor pTau181 correlates with age or degree of memory impairment, and only a tendency is observed between the concentrations of total Tau and Abeta42 in the CSF. Our results further confirm a possible role of pTau181 as a diagnostic tool in AD. The current literature regarding the physiological and pathological role of phosphorylated Tau proteins is reviewed, as well as the role of these proteins as promising biomarkers in the diagnosis of neurodegenerative disorders.

Positron emission tomography: quantitative measurement of brain acetylcholinesterase activity using radiolabeled substrates

A new method for quantitative measurement of brain acetylcholinesterase (AChE) activity in living human brain using positron emission tomography (PET) is described. We tested several radiolabeled lipophilic acetylcholine analogs, e.g., N-methylpiperidyl esters, which readily entered the brain via the blood–brain barrier, were hydrolyzed selectively by AChE, and were then trapped in the brain. Among them, and tested and N-[ 11C]methylpiperidin-4-yl acetate ([ 11C]MP4A) was chosen as the tracer for PET. Quantitative measurement of cortical AChE was accomplished by fitting the time course of cerebral radioactivity concentration measured by PET and the metabolite-corrected arterial plasma input function using a nonlinear least-squares fitting method. Normal control studies of subjects with a wide range in age (24–89 years) showed no decrease in AChE activity in the cerebral cortex with age. Studies on patients with Alzheimer's disease demonstrated a widespread reduction of AChE activity in the cerebral cortex (more profound in early-onset than in late-onset Alzheimer's disease). Parkinson's disease and progressive supranuclear palsy, clinically similar disorders, could be differentiated with [ 11C]MP4A/PET studies. Simple methods without using an arterial input function are also proposed. The method provides a quantitative measure of the cholinergic aspect of brain function and proved to be useful in diagnosis of neurodegenerative disorders including Alzheimer's disease.

Neuropathological diagnosis of neurodegenerative and dementia diseases

Neurodegenerative and dementing disorders such as Parkinson disease and Alzheimer disease are among the most common diseases of advanced age. Despite progress in the clinical diagnosis of neurodegenerative disorders, definite diagnosis for most of these disorders is still possible only by neuropathological examination of the brain. The neuropathological diagnosis and classification of neurodegenerative disorders has made clear advances in recent years, particularly due to the results of genetic and biochemical studies, resulting in the development of new disease-specific antibodies. Internationally recognized consensus criteria for most neurodegenerative disorders allow a definite and standardized diagnosis to be made. To obtain further knowledge about the etiopathogenesis, particularly with regard to new therapeutic strategies, studies with clinically and neuropathologically well-documented cases are needed. The project "Brain-Net" has therefore been established with the aim of setting up a German Brain and Tissue Bank for Diseases of the Central Nervous System. The project is funded by the Federal Ministry of Education and Research.

Usefulness of follow-up regional cerebral blood flow measurements by single-photon emission computed tomography in the differential diagnosis of dementia.

The aim of this study was to evaluate whether follow-up measurements of regional cerebral blood flow (rCBF) by single-photon emission computed tomography (SPECT) provide additional information in the differential diagnosis of dementia. Thirty-six patients (70 +/- 14 yr) with suspected dementia who had two technetium 99m-hexamethylpropyleneamineoxime SPECT scans over 18 +/- 7 months were included in this retrospective study. The patients comprised three groups based on the final clinical diagnosis: (1) neurodegenerative disorder (NDD) including Alzheimer's disease (AD) (n = 13), frontotemporal lobe dementia (n = 2), progressive supranuclear palsy (n = 1), and mixed dementia (AD plus multiinfarct dementia [MID]) (n = 3); (2) MID (n = 8); and (3) psychiatric disorders (depression [n = 7], psychosis [n = 1], and anxiety [n = 1]). Blinded to the clinical diagnosis and using visual analysis, the nuclear medicine physicians compared the second scan with the first scan for each patient to characterize temporal changes in rCBF. SPECT findings were categorized into three patterns of rCBF change: worsened, improved, and unchanged. Of the worsened rCBF group, 17 (85%) belonged to the NDD group whereas 2 (10%) and 1 (5%) belonged to the MID and psychiatric disorders groups, respectively. All 5 (100%) of the improved rCBF patients belonged to the psychiatric disorders group. Thus, worsening of rCBF favors the diagnosis of NDD whereas improvement in rCBF may mitigate against the diagnosis of NDD or MID. Follow-up rCBF measurements by SPECT thus provided additional information on the possible cause of dementia. A prospective study to further evaluate the usefulness of follow-up rCBF measurements by SPECT appears warranted.