PET Imaging of Brain Dysfunction in Alzheimer's Disease and Related Degenerative Conditions





FACTS regarding Alzheimer's : In 2000, there were 4.5 million persons with AD in the US population - by 2050, this number will increase by almost three fold, to 13.2 million. For the 85 years and older age group, this will more than quadruple to 8.0 million, and double to 4.8 million for the 75 to 84 year age group - clearly, more research is needed to develop effective treatments for this large segment of the population. In this regard, PET imaging can play an important role....


PET IMAGING OF ALZHEIMER'S DISEASE by Dr. Mike Meyer, Neurologist and Nuclear Medicine Physician



As shown above, posterior parietal hypo-metabolism is a characteristic finding on PET scans in Alzheimer's disease. At the University of Michigan, Dr. Michael A. Meyer and colleagues studied the pathophysiology of this characteristic change in detail using both 18F-FDG and 11C-Flumazenil in Alzheimer's disease patients with mild, moderate, and severe levels of cognitive impairment, and compared these to normal aged controls. The study, which was published in Archives of Neurology (vol.52, pages 314-317) found a relative preservation benzodiazepine receptors, indicating that nerve cells with receptors for GABA were still preserved in dysfunctional hypometabolic areas of posterior parietal cortex.

For links to an educational teaching site co-authored by Dr. Christopher Neal and Dr. Mike Meyer about Alzheimer's disease and diagnosing dementia, please click on: Tutorial in Dementia



The 11C-Flumazenil (FMZ) PET images from patients with Alzheimer's Disease (left) were compared to age matched elderly controls (right), with the rate of tracer influx, k1 calculated; k1 is very much linked to blood flow and metabolism and is coded in red, FMZ distribution volume in green. Quantitative analysis of the group data confirmed a relative preservation of benzodiazepine receptors (GABA receptors) in areas of hypo-metabolic dysfunctional posterior parietal cortex

Case Example : Progressive Dementia







The illustrated case example of Fronto-Temporal Dementia is evaluated in better detail through the use of the combined modalities of 18F-FDG plus CT to provide a more precise attenuation map. For brain imaging, this becomes important when dealing with focal areas of atrophy,as seen below for the right frontal cortex which has significant degenerative atrophy, as seen typically in Pick's Disease. The corresponding overlay of the color coded PET image dramatically illustrates the preservation of metabolic activity in the occiptal cortex, with major defects in functional activity over the frontal lobes


- NIA AD Video - - Tau AD Video - - MR Brain Atrophy Video - - 3D MR Brain Video - - 3D fMRI Video - - Brain Atlas - - Case Atlas - - AD Project - - MR/PET Video - - Amyloid & Genetic Risk - - 11C PIB - - CSF amyloid - - FTD - - Imaging Dementia - - Lewy Body - - Alzheimer‐type neuropathology in Iatrogenic CJD - - Alzheimer & Prion Disease pathological similarities - - Striatal PIB - - NIA AD Video -

Tutorial in Dementia

Imaging Plaque and Tangle Deposition with PET in AD:

Imaging Alzheimer's Disease with PET:

18F-FDDNP

As shown by Dr. Jorge R. Barrio and colleagues at UCLA, "...[18F]FDDNP is remarkably hydrophobic... and crosses the blood-brain barrier and neuronal membranes readily...and effectively binds to in-vitro amyloid(1-40) fibrils and human brain slices. Also, [18F]FDDNP is the first molecular probe to exhibit localization of NFTs and APs in vivo." (source : Am J Geriatr Psychiatry 10:24-35, February 2002

The molecular strucutre of 18F-FDDNP is shown below, along with recently published 18F-FDDNP PET images of control(left, in adapted format and color coding from original) and mild cognitive impairment (center) with later progression (right). Source : New England Journal of Medicine article by Dr. Gary Small and colleagues at UCLA titled : PET of Brain Amyloid and Tau in Mild Cognitive Impairment, published on December 21, 2006, in Volume 355:2652-2663






NFTs are not sufficient to cause cognitive decline or neuronal death in an animal model of tauopathy
Tau and NF Tangle Formation in AD
Chaperone signalling in AD
Gamma Secretase
Genetics Review
Presenillin Gene
Tau Gene Exon Splicing
Tau Gene
Memory and the Hippocampus : A fascinating case study (video)
Hippocampal Anatomy (video)
Learn more about related Neurodegenerative Diseases through links to free full text articles and videos:

Guamanian Parkinson-ALS-Dementia Complex Video Link (film by Dr. L. Kurland on Guamanian ALS, and preserved by Dr. M. Meyer) ALS in Guam
EVIDENCE supporting a causative role in ABeta in ALZHEIMER'S DISEASE: Irvine et.al. Review:
1. Localization of the APP gene to chromosome 21 and the observation that Alzheimer's disease like neuropathology is invariably seen in Down's syndrome (trisomy 21). This point is further supported by detection of a rare case of Down's syndrome in which the distal location of the chromosome 21q breakpoint left the patient diploid for the APP gene. This individual showed no signs of dementia, and amyloid deposition was essentially absent from the brain upon death at age 78. In addition, duplication of APP is also associated with early-onset Alzheimer's disease.
2. Synthetic Abeta peptides are toxic to hippocampal and cortical neurons, both in culture and in vivo
3. Inherited mutations in the APP gene that immediately flank or localize within the Abeta region and increase the amount or aggregation properties of Abeta are sufficient to precipitate early-onset Alzheimer’s disease. Mutations lying outside the Abeta domain are proximate to the beta- and gamma-cleavage sites and elevate Abeta production or increase the Abeta42/Abeta40 ratio. The five point mutations that lie within the Abeta sequence are clustered around the central hydrophobic core of Abeta and cause an increase in steady-state levels of Abeta and/or an increased propensity of the resultant Abeta to aggregate.
4. Inherited mutations within the presenilin 1 and 2 genes increase the Abeta42/Abeta40 ratio throughout life and cause very early and aggressive forms of Alzheimer's disease. In this regard, presenilin has been found to contribute the active site of the protease (gamma-secretase) that generates the C-terminus of Abeta
5. In humans, Apo E, which codes for apolipoprotein E, has three common alleles, e2, e3, and e4, and genetic epidemiological studies show that the e4 allele is a major risk factor for developing late-onset Alzheimer's disease, whereas the e2 allele appears to be protective. Importantly, e4 is associated with more extensive and fulminant Abeta deposition than is e2
6. Mice transgenic for mutant human APP show a time-dependent increase in extracellular Abeta and develop certain neuropathological and behavioral changes similar to those seen in Alzheimer's disease
7. Finally, injection of synthetic Abeta into the brains of tau transgenic mice accelerates tau hyperphosphorylation and leads to tangle formation reminiscent of the other hallmark that characterizes Alzheimer’s disease whereas reducing endogenous expression of tau ameliorates behavioral deficits in APP transgenic mice (source for above 7 lines of evidence : Irvine et.al. Mol Med. 2008 14(7-8): 451-464)


EVIDENCE supporting a causative role in Alpha-Synuclein in PARKINSON'S DISEASE: Irvine et.al. Review:
1. Solutions of alpha-synuclein, or synthetic peptide fragments derived from it, associate into oligomers that eventually aggregate to produce amyloid fibrils whose morphology resembles that of fibrils purified from Lewy bodies
2. The three mutant forms described above, each involving a single amino acid substitution, are associated with autosomal dominant Parkinson’s disease. The mutations increase the aggregation rate of the resultant α-synuclein
3. Duplication or triplication of the alpha-synuclein gene on one chromosome, giving 50% or 100% increase in expression of protein, causes parkinsonism. Age of onset of disease and its severity are proportional to gene copy number.
4. α-Synuclein is the principal constituent of Lewy bodies. Much of this alpha-synuclein has been posttranslationally modified by sequence truncation at the C-terminus, phosphorylation at Ser129 , or nitration; these modifications have been shown to increase the rate at which oligomers are formed. Dopamine and related catecholamines have been shown to interact with alpha-synuclein and stabilize the protofibril stage of aggregation, providing a possible explanation for the increased susceptibility of dopaminergic neurons. Levels of soluble oligomers of alpha-synuclein are also affected by fatty acids, being upregulated by polyunsaturated fatty acids.
5. alpha-Synuclein aggregation is also increased in the presence of metals and pesticides, which may be environmental risk factors. For example, exposure to paraquat induced increased expression and aggregation of alpha-synuclein in mice. The authors speculate that these increased levels of alpha-synuclein may form part of the neuronal response to toxic insult, but that the increasing protein concentration or its interaction with paraquat may lead to the production of deleterious aggregates. Iron levels are elevated in substantia nigra from Parkinson's disease patients, and in vitro it has been demonstrated that, in the presence of iron, solutions of alpha-synuclein give rise to reactive oxygen species that could be toxic to cells
6. Oligomers of alpha-synuclein are toxic to some cell cultures, including the dopaminergic SH-SY5Y human neuroblastoma cell line. As is the case for Alzheimer's disease, there is mounting evidence that the toxic species is not the final fibril, but early aggregates, which are soluble oligomers on the pathway to fibril formation. A recent study demonstrated that the affinity of α-synuclein for a phospholipid membrane is a function of its degree of aggregation, with tightest binding by an intermediate formed during the conversion from monomeric to fibrillar state
7. Increased human alpha-synuclein expression in transgenic flies and mice is accompanied by neuronal dysfunction and loss of synaptic terminals and/or neurons, the formation of lesions similar to those found in Parkinson's disease brain, and the development of motor abnormalities.
8. Expression of mutant forms of alpha-synuclein in cells promotes mitochondrial defects and cell death and enhances susceptibility to oxidative stress. On the other hand, mice deficient in synuclein are resistant to toxicity induced by MPTP and other mitochondrial toxins (source for above 8 lines of evidence on alpha Synuclein & PD : Irvine et.al. Mol Med. 2008 14(7-8): 451 - 464)

- abnormal protein aggregation in PD and Lewy Body - - Lewy Body Disease Review - - Parkinson's Disease Part 1 - - Parkinson Dis.Part 2 - - Parkinson's Disease Part 3 - - Huntington's Disease - - DRPLA - - ALS - - spinal muscular atrophy (SMA) - - spinal muscular atrophy: Exon Skipping -

EM of Lewy body in PD
Alpha SYNUCLEIN and its relation to LEWY BODY DEMENTIA, PD, and Related Disorders:
- Synuclein Review - - Lewy Body in a SN neuron - - 3D Structure of Alpha Synuclein (SNCA) - - Lewy Body Formation - - Twin pairs discordant for Lewy Body Dementia - - Lewy Body Dementia 1989 study - - Lewy Body Dementia & alpha Synuclein aggregation : 1998 study -
LBD: Trojanowski & Lee As noted by Ikeuchi, et.al., dementia with Lewy bodies (LBs) is clinically characterized by parkinsonism, recurrent visual hallucinations, and fluctuating cognitive impairment. Cognitive impairment is a common symptom of Parkinson disease,2 and this condition is referred to as dementia associated with Parkinson disease. Most cases of dementia associated with Parkinson disease or dementia with LBs are sporadic, but familial cases have been reported. In an Iowa family, triplication of the {alpha}-synuclein gene (SNCA) was found...Pathologically confirmed Lewy body disease clinically characterized by progressive parkinsonism and cognitive dysfunction is caused by SNCA duplication. The homozygous patient demonstrated the most severe phenotype, suggesting that SNCA dosage has a considerable effect on disease phenotype even within a family. SNCA duplication results in the hyperaccumulation of phosphorylated {alpha}-synuclein in the brains of patients.

Regarding the work of Chandra et.al. (Proc. Natl. Acad. Sci. USA 101 (2004), pp. 14966–14971) Bonnini and Glasson note in Cell 4 November 2005, Pages 359-361 that the synucleins are abundant proteins that are predominantly expressed in neurons throughout the mammalian nervous system. They are characterized by their relatively small size (127–140 amino acids) and highly charged composition. The two major synuclein proteins expressed in the central nervous system—α-synuclein and beta-synuclein—are localized predominantly in presynaptic nerve terminals. Although they have been implicated in many cellular activities, the exact physiological function of synucleins has been difficult to pin down. Notably, synucleins are unfolded in solution, but the addition of phospholipids induces α-synuclein to acquire an amphipathic α-helical structure that facilitates interactions with synthetic lipid vesicles. Synucleins can also act as ATP-independent molecular chaperones in vitro, preventing the aggregation of denatured proteins. The discovery that a point mutation (A53T) in the α-synuclein gene (SNCA) can cause autosomal dominant Parkinson’s disease (PD), a neurodegenerative motor disorder, has generated much interest in the synucleins.Subsequently, additional mutations (A30P and E46K) in α-synuclein, including duplications and trisomies of the SNCA genomic region, have been identified. Furthermore, α-synuclein is the major component of fibrillar cellular inclusions called Lewy bodies, a pathological hallmark of PD. Indeed, abnormal accumulation of α-synuclein in Lewy bodies and other types of pathological inclusions is associated with an entire spectrum of neurodegenerative diseases in addition to PD, collectively termed the synucleinopathies....The results reported by Chandra, Sudhof, and colleagues strongly suggest that alpha-synuclein acts as an auxiliary molecular chaperone complementing the chaperone activity of Cysteine string protein (CSPalpha) in vivo. In this way, alpha-synuclein helps to preserve the function and integrity of the synapse. Moreover, alpha-synuclein normally facilitates the function of CSPalpha as reduction of endogenous levels of alpha-synuclein accelerates appearance of the CSPalpha mutant phenotype. However, to compensate for loss of CSPalpha function, high levels of α-synuclein (5 to 10 fold above normal) were typically needed

Cysteine string protein (CSP) is an abundant regulated secretory vesicle protein

RESEARCH FUNDING to investigate Alzheimer's Disease and Related Disorders:
- NIH - - AHAF - - AFAR - - Clinical Trial Index - - Alz.org - - Confrence Grants -

- Duchenne Muscular Dystrophy- - Inclusion Body Myositis - - Micro RNA and Muscle - - Inflammatory Myopathy - - Muscle Apoptosis- - Malignant Hyperthermia- - Ryanodine- - Mitochondria & Gen.Anesthesia- - CoQ10 Deficiency- - Statin Myopathy - - Nemaline Myopathy - - MELAS - - MERRF - - Critical Illness Myopathy - - Amyloid & Inclusion Body - - Duchnne Exon Skip Therapy - - Video Exon Skip Therapy - - Rhabdomyloysis - - Rhabdomyloysis - - WUSTL Muscle Center - - Dystrophinopathy - - Periodic Paralysis - - Anti-Sense Exon Skip - - Muscle Proteins - - Muscle Protein Diagram - - Dystrophin Diagram -

DUCHENNE FACTS: As noted by Drs. Wilton and Fletcher at the University of Western Australia, Duchenne and Becker muscular dystrophy (DMD and BMD) are allelic muscle wasting conditions arising from mutations in the large DMD gene at Xp21, and that The most common, serious and progressive form, DMD, is caused by inactivation of the DMD gene product. Affected individuals appear normal at birth and clinical symptoms may be observed between the ages of two to three years. Approximately 50% of DMD males do not walk until after the age of 18 months, and exhibit signs of retarded motor development, including a waddling gait, difficulty running and jumping and calf enlargement. Muscle wasting is relentlessly progressive in a symmetrical fashion, with joint contractures an important clinical sign. As the process of muscle regeneration becomes overwhelmed, regenerating fibers are less frequent and the replacement with adipose and connective tissue contributes to pseudo-hypertrophy of some muscles. Affected individuals are typically non-ambulant by the age of 12 years, and in some cases as early as seven years...most patients succumb to the disease by the age of 20 years as the result of respiratory and/or cardiac complications.The DMD gene is the largest known and consists of 79 exons spanning some 2.4 Mb...Under the control of multiple promoters, the predominant dystrophin transcript is expressed in skeletal muscle as a mature 14 kb mRNA. It has been estimated that 16 h elapse during the processing of a single dystrophin pre-mRNA, during which time 79 exons must be spliced from the primary gene transcript.

MALIGNANT HYPERTHERMIA FACTS: As noted by Dr. H. Rosenberg et.al., malignant hyperthermia (MH) is a hypermetabolic response to potent inhalation agents (such as halothane, sevoflurane, desflurane), the depolarizing muscle relaxant succinylcholine, and rarely, in humans, to stresses such as vigorous exercise and heat. The majority of patients with Central Core Disease (CCD), an inherited myopathy characterized by muscle weakness, are susceptible to MH.....The incidence of MH episodes during anesthesia is between 1:5,000 and 1:50,000�100,000 anesthesias. Even though a MH crisis may develop at first exposure to anesthesia with those agents known to trigger an MH episode, on average, patients require three anesthesias before triggering. Reactions develop more frequently in males than females (2:1). All ethnic groups are affected, in all parts of the world. The highest incidence is in young people, with a mean age of all reactions of 18.3 years. It has been found that children under 15 years age comprised 52.1% of all reactions. Although described in the newborn, the earliest reaction confirmed by testing is six months of age...Genetically, MH is an autosomal dominant condition; the estimated prevalence of the genetic abnormalities may be as great as one in 3,000 individuals...In almost all cases, the MH susceptible patients have a defective calcium channel located in the SR membrane. This channel is termed the ryanodine receptor (RYR). The channel is closely associated with other proteins and structures, such as the dihydropyridine calcium channel that mediates transfer of voltage change to the RYR-1 receptor....The pathophysiologic changes of MH are due to uncontrolled rise of myoplasmic calcium, which activates biochemical processes related to muscle activation. Due to ATP depletion, the muscle membrane integrity is compromised leading to hyperkalemia and rhabdomyolysis. In most cases, the syndrome is caused by a defect in the ryanodine receptor. Over 90 mutations have been identified in the RYR-1 gene located on chromosome 19q13.1, and at least 25 are causal for MH
MG
DISEASES of the Neuro-Muscular Junction
- NMJ Diagram - - NMJ Micrograph - - NMJ WUSTL - - NMJ Proteins - - NMJ AutoImmunine Dis. - - Myasthenia Gravis - - MG review - - MG review 2009 - - Thymoma -

MYASTHENIA GRAVIS FACTS: As noted by Juel and Massey at Duke, Myasthenia gravis (MG) is a rare, autoimmune neuromuscular junction disorder. Contemporary prevalence rates approach 1/5,000. MG presents with painless, fluctuating, fatigable weakness involving specific muscle groups. Ocular weakness with asymmetric ptosis and binocular diplopia is the most typical initial presentation, while early or isolated oropharyngeal or limb weakness is less common. The course is variable, and most patients with initial ocular weakness develop bulbar or limb weakness within three years of initial symptom onset. MG results from antibody-mediated, T cell-dependent immunologic attack on the endplate region of the postsynaptic membrane...Seropositive (SP) MG defines disease with circulating antibodies to the acetylcholine receptor (AChR), while seronegative (SN) patients lack these antibodies. Recently, antibodies to muscle-specific tyrosine kinase (MuSK) have been demonstrated in over 40% of patients with generalized, SN MG...In most cases, antibodies bind to the main immunogenic region of the α-subunit of the AChR, though MG patients with antibodies to MuSK exhibit clinical weakness and electrophysiologic findings that are quite similar to MG patients with AChR antibodies. MuSK initiates aggregation of AChRs at the muscle endplate during development..Antibodies to MuSK have been demonstrated recently in about one third of patients with generalized SN MG. Patients with MuSK MG are predominantly female and may exhibit prominent bulbar, neck, shoulder girdle, and respiratory weakness...Ryanodine antibodies are also associated with late-onset MG. Patients with ryanodine antibodies may exhibit severe, treatment-resistant MG associated with malignant thymomas. In MG, IVIg may provide short-term improvement in strength for MG exacerbations...IVIg is generally administered as 10% solution, and the standard dosage is 2 gm/kg over two to five days...Pretreatment with acetaminophen and diphenhydramine may reduce the frequency and severity of idiosyncratic reactions...Maximum disease severity is reached within the first year in almost two-thirds of patients...Myasthenic crisis, or respiratory failure due to myasthenic weakness occurs in about 20% of patients, usually within the first year of illness..Along with advances in mechanical ventilation and intensive care, immunotherapy has been one of the major factors contributing to improved outcome in MG, and contemporary disease-specific mortality is less than 5%

GBS Axonal Myelin
DISEASES affecting PERIPHERAL NERVE
- Guillain Barre - - Guillain Barre Video - - Neuropathy - - Neuropathy -

GUILLAIN BARRE FACTS: As noted by Dr. Richard Hughes and colleagues, Guillain-Barrw syndrome (GBS) is the major cause of acute neuromuscular paralysis with an annual incidence of 1.3 per 100 000 throughout the world..Experimental evidence implicates autoantibodies to gangliosides as the cause of the axonal subgroups of GBS and of Fisher syndrome. These autoantibodies may be generated by the immune response to an infective organism, such as Campylobacter jejuni, cross-reacting with epitopes on the axon. This systematic review not only confirms that PE hastens recovery from GBS and improves its long-term outcome in severely affected adult patients, but also provides the best quantitative estimates of these effects. In adult patients, the effect of IVIg is equivalent. Because of its greater convenience and availability, IVIg is, appropriately, usually used. Plasma exchange (PE) was introduced as a possible treatment in 1978...Intravenous immunoglobulin (IVIg) was introduced for GBS in 1988 ... In 1992, the first randomized trial comparing IVIg and PE showed similar effects from each treatment. Following PE with IVIg did not produce significant extra benefit. In mildly affected patients, PE may be beneficial but there is no direct evidence about the efficacy of IVIg.
Spinal Cord
DISEASES affecting SPINAL CORD
- Syrinx and Chiari - - Spinal Cord Injury- - Spinal Cord Injury Review- - Anterior Spinal Artery Syndrome- - Cord Herniation- - Friedrich's Ataxia- - HTLV1 myelopathy- - Arachnoid cysts -

Tranverse Myelitis is a Neurologic Emergency: As reviewed by Dr. L. Pandit, acute transverse myelitis (ATM) is an inflammatory demyelinating disorder that affects the spinal cord focally resulting in motor sensory and autonomic dysfunction. Establishing the diagnosis of ATM is not as difficult as determining the possible etiology... multiple sclerosis (MS) is the most common inflammatory disorder of the central nervous system. An attack of ATM may be the beginning of MS.

As reviewed by Dr. KK Kim, recurrent transverse myelitis (RTM) usually heralds or is accompanied by lesions producing dysfunction elsewhere in the central nervous system and almost always signifies the presence of multiple sclerosis (MS)....Idiopathic RTM might be a disease entity distinct from MSRTM (multiple sclerosis associated RTM), differing in its male preponderance, absence of oligoclonal bands, frequent multiple relapses, and frequent presentation as acute transverse myelitis.... idiopathic RTM might be a distinct disease entity from MSRTM, with male preponderance, absent OCBs, frequent multiple relapses, and frequently presenting with ATM.


NEOPLASM : Dr. D.A. Shin and colleagues have studied surgical outcomes for patients with tumors at the thoraco-lumbar juncture : The thoracolumbar junction (TLJ) is the transition zone between the thoracic spine and the lumbar spine. The spinal cord transitions to the cauda equina in the TLJ, which contains the upper and lower motor neurons of the spinal cord and the cauda equina. As a result, clinical features of lesions in the TLJ vary...Spinal cord tumors of the TLJ were frequently misdiagnosed as IVDs due to symptomatic similarities. SCTs of the TLJ should be included in differential diagnosis of back and leg pain, and it is highly recommended that routine lumbar magnetic resonance imaging include the TLJ.
ALS FACTS : As reviewed Dr. T. Siddique, roughly 90% of ALS that occurs in individuals with no family history of ALS is called sporadic ALS (SALS), while the remaining 10% of ALS which has at least two affected persons in the same family is concidered familial ALS (FALS).FALS can be transmitted as a dominant or a recessive trait, but is most commonly an adult-onset disorder of autosomal dominant transmission. Autosomal recessive inheritance is rare and appears limited to persons with juvenile onset ALS or persons with a double dose of particular mutations in the SOD1 gene. We have reported a single family with X-linked dominantly inherited ALS, a rarely observed phenomenon in neurogenetics...Mutations in the ALSIN gene, which encodes the protein alsin, produce either a recessive juvenile onset primary lateral sclerosis (PLS) or a juvenile onset upper motor neuron (UMN)-predominant ALS.

ALS FACTS: As reviewed by Wijesekera and Leigh, amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterised by progressive muscular paralysis reflecting degeneration of motor neurones in the primary motor cortex, corticospinal tracts, brainstem and spinal cord. Incidence (average 1.89 per 100,000/year) and prevalence (average 5.2 per100,000) are relatively uniform in Western countries, although foci of higher frequency occur in the Western Pacific. The mean age of onset for sporadic ALS is about 60 years. Overall, there is a slight male prevalence (M:F ratio~1.5:1). Approximately two thirds of patients with typical ALS have a spinal form of the disease (limb onset) and present with symptoms related to focal muscle weakness and wasting, where the symptoms may start either distally or proximally in the upper and lower limbs....Paralysis is progressive and leads to death due to respiratory failure within 2 to 3 years for bulbar onset cases and 3 to 5 years for limb onset ALS cases. Most ALS cases are sporadic but 510% of cases are familial, and of these 20% have a mutation of the SOD1 gene and about 5% have mutations of the TARDBP (TDP-43) gene. Two percent of apparently sporadic patients have SOD1 mutations, and TARDBP mutations also occur in sporadic cases. The diagnosis is based on clinical history, examination, electromyography, and exclusion of 'ALS-mimics' (e.g. cervical spondylotic myelopathies, multifocal motor neuropathy, Kennedy's disease) by appropriate investigations...Geographic loci of the Western Pacific form of ALS, where the prevalence is 50 to 100 times higher than elsewhere world have been reported, although the cause of these aggregations remains elusive. These populations include the Chamorro people of Guam and Marianas island, the Kii peninsula of Honshu Island, and the Auyu and Jakai people of south west New Guinea, in whom ALS is associated with the Parkinsonism and dementia (ALS-PD complex)

Guamanian Parkinson-ALS-Dementia Complex Video Link (film by Dr. L. Kurland on Guamanian ALS, and preserved by Dr. M. Meyer) ALS in Guam
MS
DISEASES affecting CENTRAL MYELINATED AXONS
- MS Video - - MS and T cells- - MS and EB Virus-

MS and EBV : As reviewed by Lunemann et.al., EBV has been a leading candidate trigger for several autoimmune diseases since the initial description of raised EBV-specific antibody titers in patients with SLE in 1971. Although numerous studies have found increased seroprevalence rates, antibody titers, and T-cell reactivity to EBV in patients with major autoimmune diseases, unequivocal evidence for a causative role of the virus in the evolution of MS, SLE, or RA is still lacking...Epidemiological studies first reported a positive association between a history of IM and the occurrence of MS...individuals with a history of IM have a more-than-twofold-increased risk of developing MS compared to subjects who acquired the virus without symptoms.By comparison, a history of IM is associated with a not-higher-than-fourfold-increased risk for EBV-associated Hodgkin's lymphoma... The lack of seronegativity to EBV in adult patients and the substantially increased seroprevalence in children with MS, together with the consistent observation that the risk for developing the disease years before occurrence of the first symptoms increases significantly with the level of EBV antibody titers, suggest a possible involvement of EBV early in the pathogenesis.

EBV Link to MS: As noted by Dr. S Cepok and colleagues, A hallmark of this disease is the occurrence of oligoclonal IgG antibodies in the cerebrospinal fluid (CSF). To assess the specificity of these antibodies, we screened protein expression arrays containing 37,000 tagged proteins. The 2 most frequent MS-specific reactivities were further mapped to identify the underlying high-affinity epitopes. In both cases, we identified peptide sequences derived from EBV proteins expressed in latently infected cells. Immunoreactivities to these EBV proteins, BRRF2 and EBNA-1, were significantly higher in the serum and CSF of MS patients than in those of control donors. Oligoclonal CSF IgG from MS patients specifically bound both EBV proteins....EBV titers in serum are higher in MS patients than in control donors. Almost all MS patients are seropositive whereas between 5 and 10% of the general population are seronegative. Children who develop MS differ from controls by their higher immunoreactivity to EBV but not to other common viral pathogens. MS patients more frequently have a history of mononucleosis than controls. A 2- to 3-fold increased risk of developing MS after late EBV infection has been observed. Studies have demonstrated that immunoreactivity to EBV was higher in donors who later developed MS than in those who did not....Another study found elevated EBV DNA levels in the blood of MS patients during relapses

MR and MS
Meningitis
Prion
INFECTIOUS DISEASES affecting the CENTRAL NERVOUS SYSTEM
- Prion - - Kuru & Prions - - Kuru Video - - Prions : Fatal Familial Insomnia - - Prion Video- - Prion Review - - Kuru & CJD - - Prions InVitro - - Prion : seeded fibrillization - - Encephalitis - - Neoplastic meningitis - - Asceptic and Viral Meningitis - - HIV viral entry - - HIV aniamtion - - HIV Replication - - HIV Cycle - - PML : large T Antigen - - False Negative PCR of CSF : PML - - JC DNA in Normal Brain - - VP1 loop polymorphism and PML - - PML & MS Tx - - PML & Astrocytoma False Positive - - PML and Natalizumab - - PML (NEJM) - - JC virus & Oligodendroglia Apoptosis - - PML intranuclear inclusion - - EM Nucleus in PML - - PML: MRI - - PML pathology - - SSPE - - SSPE & Measles - - Lyme Disease - - CNS Borrelia - - Parasitic CNS Disease (Toxo) - - CNS Fungal Infections - - Bacterial Meningitis - - Bacterial Meningitis -

PRION DISEASE FACTS: As summarized by Dr. R. Linden and colleagues, the prion protein is highly expressed within the nervous system, although its content varies among distinct brain regions, among differing cell types, and among neurons with distinct neurochemical phenotypes. Various cellular components of the immune system, in the bone marrow, blood, and peripheral tissues, also express substantial amounts of the cellular prion protein...PrP-null mice were generated that developed normally but underwent severe ataxia and Purkinje cell degeneration at advanced ages. This was first observed in Prnp-ablated mice now known as Nagasaki (Ngsk)...In fact, it was demonstrated that ataxia in these animals was caused by overexpression of a protein that received the name Doppel, Dpl, coded by the gene Prnd, located 16 kb downstream of Prnp

Cerebellum
DISEASES affecting the CEREBELLUM
- OPCH - - OPCH - - Cerebellum - Cerebellum diagram Cerebellar Degeneration Purkinje Cell Video Purkinje Cell 3D


ALD
DISEASES affecting the WHITE MATTER (Leukodystrophies)
- Leukodystrophy links - - Leukodystophy: ALD - - Lyelin Project: ALD - - Leukodystophy: MLD - - Leukodystophy: Adult Onset Alexander's Disease -


- Cajal and HIppocampal Circuitry -
DISEASES affecting the HIPPOCAMPUS

- Famous Case of HM - - UCSD Brain Observatory - - Stem Cells and Aging - - Entorhinal Cortex - - New Neurons - - CA3 - - Molecular Mechanisms (PDF) - - spatial vs. contextual memory - - Epilepsy & Cell loss - - Major Depression - - Temporal sequence recall - - unfolded protein - - Abeta and memory - - 7 Tesla MR Hippocampus - - CA1 and CA2 lesions - - CA1 injury : case of RB (Zola-Morgan et.al.) - - CA1 & memory - - CA1 vs. CA3 - - synaptic vesicle release rates - - Long term potentiation - - NMDA and Phosphorylation - - NMDA review -

HIPPOCAMPAL CA1: Central Role of CA1 in Memory, Epilepsy, Ischemia, AD and Related Disorders
- Hippocampal Pathways - - Dentate Dendritic Spine - - Dendritic Spine video - - Axonal Transport video - - Afferents/Efferents - - Synaptic Plasticity - - Calcyon - - p38 mitogen activated Kinase - - Enkephalin -GABAergic - - Musc/adrenergic Kinase - - Neonatal Isolation - - Neurotensin - - Nackground Firing Rates - - LIM Kinase - - Chronic Hypoxia - - BDNF and ERK - - kainate receptors & glutamatergic synapses - - Glutamate - - Cyclin - - Acitvity Dependent change - - Spatial representation - - Glutamate - - p38 MAPK - - CCK Basket Cell - - Dopamine Transporter Blockade - - Growth Hormone - - A3 adenosine receptor angtagonist - - Sleep deprivation - - Theta frequency stimulation - - Arc/Arg3.1 - - SLM inter-neuron electric coupling - - D3 Disinhibition - - Astrocytes - - INsulin-Like Growth Factor - - Beta-adrenergic - - Adensoine A1 deficient - - Theta stimualtion - - Epilepsy - - ischemia and GABA release - - sging - - GABA release : developmental factors - - Potassium channels -

- Brain Development Video -
DEVELOPMENTAL AND INHERITED CNS disorders affecting CHILDREN

- Absence of the Septum Pellucidum - - Acid Lipase Disease - - Acid Maltase Deficiency - - Acid Maltase Deficiency - - Acute Disseminated Encephalomyelitis - - ADHD - - ADHD - - Adrenoleukodystrophy - - Agenesis of the Corpus Callosum - - Aicardi Syndrome - - Aicardi Syndrome - - Alexander Disease - - Alpers' Disease - - Anencephaly - - Anencephaly - - Angelman Syndrome - - Angelman Syndrome - - Arachnoid Cysts - - Arnold-Chiari Malformation - - Arnold-Chiari Malformation - - Asperger Syndrome - - Asperger Syndrome - - Ataxia Telangiectasia - - Ataxia Telangiectasia - - Barth Syndrome - - Batten Disease - - Batten Disease - - Becker's Myotonia - - Bulbospinal Muscular Atrophy - - Bulbospinal Muscular Atrophy - - Canavan Disease - - Canavan Disease - - Ceramidase Deficiency - - Cerebellar Degeneration - - Cerebellar Degeneration - - Cerebellar Hypoplasia - - Cerebral Palsy - - Cerebral Palsy - - Cerebro-Oculo-Facio-Skeletal Syndrome - - Charcot-Marie-Tooth Disease - - Charcot-Marie-Tooth Disease - - Chiari Malformation - - Choreoacanthocytosis - - Chronic Inflam. Demyel. Polyneuropathy (CIDP) - - (CIDP) - - Coffin Lowry Syndrome - - Coffin Lowry Syndrome - - Colpocephaly - - Congenital Facial Diplegia - - Congenital Myasthenia - - Congenital Myasthenia - - Congenital Myopathy - - Congenital Vascular Cavernous Malformations - - Congenital Vascular Cavernous Malformations - - Craniosynostosis - - Craniosynostosis - - Cytomegalovirus Infection - - Dandy-Walker Syndrome - - Dandy-Walker Syndrome - - Dawson Disease - - Dejerine-Klumpke Palsy - - Dejerine-Klumpke Palsy - - Dermatomyositis - - Dermatomyositis - - Devic's Syndrome - - Diabetic Neuropathy - - Dysautonomia - - Dysautonomia - - Dystonias - - Dystonias - - Empty Sella Syndrome - - Encephalitis - - Encephaloceles - - Epilepsy - - Epilepsy - - Erb-Duchenne Palsy - - Essential Tremor - - Fabry Disease - - Fabry Disease - - Fahr's Syndrome - - Fam. Basal Ganglia Calcifctn - - Farber's Disease - - Febrile Seizures - - Fibromuscular Dysplasia - - Fisher Syndrome - - Friedreich's Ataxia - - Friedreich's Ataxia - - Gangliosidoses - - Gaucher's Disease - - Giant Axonal Neuropathy - - Globoid Cell Leukodystrophy - - Guillain-Barre Syndrome - - Guillain-Barre Syndrome - - IRON: NBIA - - Hereditary Neuropathies - - Hereditary Neuropathies - - Hereditary Spastic Paraplegia - - Hereditary Spastic Paraplegia - - Herpes Zoster - - Herpes Zoster - - Holoprosencephaly - - Holoprosencephaly - - Hydranencephaly - - Hydranencephaly - - Hydromyelia - - Infantile Neuroaxonal Dystrophy - - Isaac's Syndrome - - Joubert Syndrome - - Joubert Syndrome - - Kearns-Sayre Syndrome - - Kennedy's Disease - - Kennedy's Disease - - Kleine-Levin Syndrome - - Kleine-Levin Syndrome - - Klippel-Feil Syndrome - - Klippel-Trenaunay Syndrome (KTS) - - Krabbe Disease - - Krabbe Disease - - Kugelberg-Welander Disease - - Landau-Kleffner Syndrome - - Leigh's Disease - - Leigh's Disease - - Lennox-Gastaut Syndrome - - Lennox-Gastaut Syndrome - - Meningitis and Encephalitis - - Menkes Disease - - Metachromatic Leukodystrophy - - Migraine - - Migraine video - - Migraine : NHF - - Mitochondrial Myopathies - - Mitochondrial Myopathies - - Moebius Syndrome - - Moyamoya Disease - - Moyamoya Disease - - Multifocal Motor Neuropathy - - Muscular Dystrophy - - Narcolepsy - - Narcolepsy - - Narcolepsy - - Narcolepsy video - - Neurofibromatosis - - Neurofibromatosis - - Neuroleptic Malignant Syndrome - - Neuronal Ceroid Lipofuscinosis - - Neuronal Ceroid Lipofuscinosis - - Neuronal Migration Disorders - - Neuronal Migration Disorders - - Neuropathy - Hereditary - - Niemann-Pick Disease - - Niemann-Pick Disease - - Pelizaeus-Merzbacher Disease - - Pelizaeus-Merzbacher Disease - - Pituitary Tumors - - Pompe Disease - - Rett Syndrome - - Rett Syndrome - - Reye's Syndrome - - Reye's Syndrome - - Spina Bifida - - Spinal Cord Infarction - - Spinal Cord Injury - - Spinal Cord Tumors - - Spinal Muscular Atrophy - - Spinocerebellar Atrophy - - Spinocerebellar Degeneration - - Stiff-Person Syndrome - - Sturge-Weber Syndrome - - Sturge-Weber Syndrome - - Subacute Sclerosing Panencephalitis - - Sydenham Chorea - - Syringomyelia - - Tethered Spinal Cord Syndrome - - Transverse Myelitis - - Transverse Myelitis - - Tuberous Sclerosis - - Tuberous Sclerosis - - Von Hippel-Lindau Disease (VHL) - - Von Hippel-Lindau Disease (VHL) - - NF-1: von Recklinghausen Dis - - NF-2: von Recklinghausen Dis - - von Recklinghausen's Disease - - Werdnig-Hoffman Disease - - Wilson's Disease - - Zellweger Syndrome - - KF ring of Wilson Dis. - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
For additional links to Neurologic Diseases, please connect to : :
BrainChill.info


PET and CANCER


Case Example : BURKITT'S LYMPHOMA




The 18F-FDG PET scan of the lower extremities helped properly stage Burkitt's lymphoma presenting as leg pain with rectal bleeding from a primary colonic lymphomatous mass: Although bone marrow biopsy and aspirate was negative for malignancy, the whole body PET scan clearly showed marrow involvement within both femurs. The PET information led to treatment with aggressive chemotherapy protocol for advanced stage four metastatic disease, leading to a successful cure for the patient with no evidence of recurrence by repeat PET examinations and close follow-up over the subsequent three years


PET Imaging Center

For more information on Positron Emission Tomography (PET), please visit an informational web site by University of Buffalo Neurologist and Nuclear Medicine physician Dr. Mike Meyer regarding the development of 18F-FDG for use in cancer detection : cureglioma.info





PET & Psychiatry Grand Rounds Lecture: Click Here-> Teaching Web Site on PET Imaging of CNS Receptors

PET Web Site Link : Click Here-> Teaching Web Site on PET by Michael A. Meyer, MD and Steven G. Meyer


WNY PET/CT Web Site Link : Click Here-> Teaching Web Site on Time of Flight PET by Michael A. Meyer

PET scanning begins with an initial transmission scan to help correct for soft tissue attenuation of photons leaving the body from various depths:


The EMISSION PET Scan:


18F-FDG PET Scan, axial slice, after attenuation correction:


Whole Body PET : Projection Image

Example : The above whole body 18F-FDG PET scan of a patient with lung cancer involving right supraclavicular nodes displays other complex findings : 1) Diffuse cerebral hypometabolism in relation to prominent cerebellar tracer uptake, 2) Absent left renal activity with a photopenic adjacent cyst 3) Prominent and diffuse large bowel uptake 4) Metastatic disease to a right lateral rib, 5) Prominent vertebral body marrow uptake
For a three dimensional rotating PET scan, please see: 3-D PET/CT 3D rotating view


In order to properly interpret PET scans for oncology patients, normal variants must be appreciated : Normal Variant Review article
PET and Cancer: For a recent review on PET in Oncology by Kumar R, Bhargava P, Bozkurt MF, Zhuang H, Potenta S, Alavi A (Positron Emission Tomography imaging in Evaluation of Cancer Patients), please see : PET Oncology Review Article


PET and PEDIATRIC ONCOLOGY
For a review on PET and Cancer in Pediatric patients, please see : Assessment of therapy response by FDG PET in pediatric patients
Additional links for pediatric nuclear medicine:
Patient preparation
JNMT - Procedures, Technical Considerations
Pediatric Radiology
Society Nuclear Medicine Interactive CME
Radiology.info
Sedation Guidelines for Pediatric Nuc. Med.
Pediatric Epilepsy PET Case
Lymphoma PET Case

PET can help detect LYMPHOMA:

Links to New England Journal of Medicine articles on Lymphoma and Leukemia: New England Journal of Medicine

To review an article on PET and lymphoma by Friedberg & Chengazi, please see: PET & Lymphoma article
To view PET images of a diffuse large B cell lymphoma, please click on this link to the publication by Friedberg and Chengazi Diffuse Large B Cell Lymphoma To review another similar case, before and after chemotherapy, click on: Diffuse Large B Cell Lymphoma, before and after Chemotherapy
18F-FDG PET imaging can help assess prognosis in lymphoma, as noted in a 2003 publication in Quarterly J. Nuclear Medicine (link to journal via Radiolgia e Medicina Nucleare, with search under 2003 articles in QJNM): Quarterly Journal of Nuclear Medicine
Marrow involvment in Lymphoma has been studied by PET (please see article in the journal, Blood : Marrow
The efficacy of chemotherapy in NHL has been studied by PET (click on : NHL and Chemotherapy ). To learn more about PET versus CT in evaluating lymphoma, click on : PET & CT

Other important Lymhpoma links include :
National Cancer Institute
The Leukemia & Lymphoma Society
For more information on other studies by Dr. Meyer on lymphoma, please see CNS Lymphoma


- primary Hodgkin's disease of liver - - classic Hodkins - - T Cell Lymphoma - - Primary CNS Lymphoma - - NHL Radiotherapy - - HD and NHL review -


PET IMAGING of Neoplasms arising within GASTRIC MUCOSA

- FDG Coronal - - Endoscopy screen - - Multi-Center Screen - - Post-Op. follow-up - - Chemosensitivity - - Fluid distention -

PET can help evaluate MYELOMA



As discussed in a April 1, 2004 New England Journal of Medicine letter from the PET Imaging Center at Buffalo Cardiology and Pulmonary Associates, PET can help in evaluating marrow involvement by multiple myeloma. As proposed by Dr. Mike Meyer, PET could be helpful not only clinically, but assist in the advancement of basic science research on gene microarray analysis of myeloma cells. To view a whole body PET scan depicting marrow involvement in myeloma, please see
Myeloma PET Scan
To view other published data on the use of PET in myeloma, please see Journal of Nuclear Medicine


PET can help detect BREAST CANCER
Dr. Mike Meyer, PET Nuclear Medicine physician at Buffalo Cardiology & Pulmonary Associates, was part of the intial team of researchers at Brookhaven National Lab to confirm that 18F-FDG would be of potential use in studying breast cancer; for links to view his 1980 autoradiograph, please click here to go to fdgpetscans.info, and follow the Breast Cancer link: fdgpetscan.info web site on PET and Breast Cancer
For New England Journal of Medicine articles on Breast Cancer, click on: NEJM Breast Cancer Articles
For more information on PET and occult Breast Cancer, please see an article written by Dr. Meyer with Dr. Ernest Block: American Surgeon 1998, vol 64, pages 906-908

For more information on the combined use of FDG PET imaging and MRI in recurrent breast cancer, please see: Univ. Washington Radiology journal article
To learn about the combined use of PET with intra-operative isosulphan blue dye for sentinel lymphadenectomy, please see : Seoul National Univ. Hospital study
The basis for elevated uptake in breast cancer is elucidated in the following NIH article that compares breast cancer cell line T47D versus other neoplams, and shows better correlation of FDG uptake to mitochondrial phosphoryaltion of glucose than to Glut-1 glucose transport protein expression : NIH study on 18F-FDG uptake in-vitro


CANCER of the LUNG
PET can help evaluate Solitary Pulmonary Nodules , as well as help in the diagnosis of Lung Cancer and assess response to therapy. Note : low recovery coefficients for small emission sources under 5 mm lead to limited ability to resolve small solitary nodules; furthermore, respiratory motion is technical consideration that become significant for scanners that combine CT with PET, leading to misregistration of the CT performed in seconds versus the emission acquisition that averages activity over many respiratory cycles over minutes
1) For a general review on PET with specific references and illustrations on the use in Lung Cancer, please see : PET Oncology Review Article

Squamous Cell CA Lung


Brain Metastasis from Lung Cancer

2) If one uses a lesion to background count ratio of 5 as a cut-off marker for benign versus malignant solitary pulmonary lung lesions, a sensitivity of 95% is noted, with specificity of 50% yet accuracy of 86%; the positive predictive value was 75% with a negative predictive value of 85% (please see : Japan PET Pulmonary Oncology Study

3) Proliferative scores as assessed by use of Ki-67 histochemical staining intensity, correlates to the SUVmax (please see : Ki-67 and FDG PET scans of SPN and Lung Cancer

4) Duke University review of lung abnormalities seen by PET : Lung PET review
5) Pulmonary Tuberculosis can simulate neoplasm as a hot spot on the PET scan; mean peak SUV by one study was 4.2 Please see : FDG PET in TB
6) Stage One Non-Small lung cancer was studied by PET, which showed a 82% sensitivity and 86% specificity for accurate diagnosis; the positive predictive value was 47% but negative predictive value was at an impressively high rate of 97% Stage One NSC Lung CA


Literature Update : PET and Cancer
An udpated set of links to full text articles from 2000 onward on FDG and PET arranged anatomically by organ system:
Tumors of the Nervous System

PET Imaging of Glioblastoma:



Electron Microscopy of Glioblastoma:



Glioblastoma Pathology:



Standard Treatments for Glioblastoma:



Mechanism of Action for Temodar in Glioblastoma Treatment:



The Normal Astrocyte:


Malignant Transformation into Glioblastoma:



Experimental Radiotherapy of Glioblastoma:



Positron Radiotherapy for Cancer:



Glioblastoma Information Links Brain Tumor Organization TBTS
Brain Tumor Organization ABTA
Brain Tumor Foundation MTG
Brain Tumor Clinical Trials
NBTF
Children with Brain Tumors
BT Organization for Children
Pediatric BT Foundation
SouthEastern BT Foundation

Proton Beam Therapy for Malignant Neoplasms : Potential for development of research applications in the treatment of Glioblastoma
Although proton beam therapy protocols for brain tumor treatment are not typically used at the major treatment facility sites, there is great potential to explore this further for glioblastoma treatment ( a 1999 study concluded that "...The median survival time was extended to 20 months, likely as a result of central control.." ) Click here for Fitzek, et.al. Journal of Neurosurgery, August 1999:
Web Site Link to Learn About Proton Beam Therapy Loma Linda University Medical Center

Neutron Capture Therapy for Glioma : Alternative approaches developed by Dr. Mike Meyer that do not depend on a reactor and boron based tumor avid agents Click here for book chapter by Dr. Mike Meyer and colleagues in : Frontiers in Neutron Capture Therapy

To review a rare CNS tumor (Pleomorphic Xanthoastrocytoma) please see: Pleomorphic Xanthoastrocytoma
To learn about PET in studying plexiform neurofibromas in neurofibromatosis, please see : neurofibromatosis
A rare primary CNS tumor involves the spinal cord : please see a PET FDG study on : Primary diffuse leptomeningeal gliomatosis Spinal Cord
Autonomic Nervous System tissue can form neoplastic lesions as well (metastatic paraganglioma). For a PET study on this rare tumor,which can also be visualized by MIBG scanning, please see : paraganglioma

Tumors of the THYROID and HEAD & NECK region
Positron emission tomography with F-18-FDG: a new tool in the evaluation of patients with head and neck tumors Spanish article on PET in Head and Neck Cancers
Thyroid Cancer is very well delineated by PET FDG imaging, and can reveal underlying tumor when conventional radioiodine scans are negative
Thyroid Cancer

Tumors of the STOMACH and ESOPHAGUS
Primary and Recurrent Esophageal Cancer is well revealed by PET FDG imaging : Esophagus
An overall update on gastrointestinal imaging puts FDG PET imaging in perspective : GI Imaging review

LYMPHOMA For an update on lymphoma imaging with FDG PET, please see : PET Scans in the Staging of Lymphoma: Current Status by Jonathan W. Friedberg, Vaseem Chengazi

Prognostic value of FDG-PET in malignant lymphoma, by Becherer A, Jaeger U, Szabo M, Kletter K. Prognostic value

Can 18F-fluorodeoxyglucose position emission tomography after first cycle chemotherapy predict the efficacy of therapy in Hodgkin's disease? Hodgkin's disease

Staging patients with Hodgkin's disease Staging

Management of Lymphomas FDG PET aiding management decisions

Treatment failure in non-Hodgkin's lymphoma Treatment failure


COLORECTAL CANCER
Is an FDG-PET Scan the New Imaging Standard for Colon Cancer? Imaging Standard

Detecting Colon Cancer Recurrence in Patients With Increasing Carcinoembryonic Antigen Levels Increasing Carcinoembryonic Antigen

PET-FDG as predictor of therapy response in patients with colorectal carcinoma by Dimitrakopoulou-Strauss A, Strauss LG, Rudi J. FDG as predictor


The Solitary Pulmonay Nodule and CANCER of the LUNG
Small (<1 cm), Intermediate (1 to 3 cm), and Large (>3 cm) Lymph Node Lesions Recovery Coefficients
Solitary Pulmonary Nodules SPN
Indeterminate Solitary Pulmonary Nodules Indeterminate SPN
Non-Small Cell Lung Cancer NSCL Ca
Pulmonary Tuberculoma TB


Renal Cell Carcinoma and PROSTATE Cancer, and other urologic malignancies
Clinical role of F-18 fluorodeoxyglucose positron emission tomography for detection and management of renal cell carcinoma Renal Cancer

Untreated Prostate Cancer Prostate
Positron emission tomography in urologic oncology Urologic Cancers


SARCOMAS
Images of Sarcomatous neoplasms : Bone and Soft Tissue Sarcoma


PANCREATIC CANCER
18F-fluorodeoxyglucose positron emission tomography for characterization and initial staging of pancreatic tumors Pancreas



Canadian PET Centers:

As of November 2007, there were 22 centres performing publicly funded PET scans in seven Canadian provinces:

Ontario Cancer Treatment Centers:
For further information on diagnosis and treatment of cancer, the following links to Ontario Cancer Centers may be helpful:
Grand River Regional Cancer Center
Hamilton Regional Cancer Center
London Regional Cancer Center
Princess Margaret Hospital
Toronto-Sunnybrook Regional Cancer Center
Pediatric Oncology Group of Ontario



PET has additional uses in Neurology:

PET has also been shown to be of value in confirmation of brain death(please see: PET Study by Dr. Meyer (Dynamic 18F-FDG PET)


PET has also been shown to be helpful in studying the pathophysiology of the persistent vegetative state after head trauma (please see: PET Study by Dr. Schiff and colleagues

ALZHEIMER'S DISEASE
PET has additional uses in diagnosing Alzheimer's Disease, where posterior parietal hypo-metabolism is a characteristic finding on PET scans. While at the University of Michigan, Dr. Michael A. Meyer studied this characteristic change in detail using both 18F-FDG and 11C-Flumazenil in Alzheimer's disease patients with mild, moderate, and severe levels of cognitive impairment, and compared these to normal aged controls. The study, which was published in Archives of Neurology (vol.52, pages 314-317) found a relative preservation benzodiazepine receptors, indicating that nerve cells with receptors for GABA were still preserved in dysfunctional hypometabolic areas of posterior parietal cortex.
(For links to an educational teaching site co-authored by Dr. Christopher Neal and Dr. Mike Meyer about Alzheimer's disease and diagnosing dementia, please click on: Tutorial in Dementia

The 11C-Flumazenil (FMZ) PET images from patients with Alzheimer's Disease (left) were compared to age matched elderly controls (right), with the rate of tracer influx, k1 calculated; k1 is very much linked to blood flow and metabolism and is coded in red, FMZ distribution volume in green. Quantitative analysis of the group data confirmed a relative preservation of benzodiazepine receptors (GABA receptors) in areas of hypo-metabolic dysfunctional posterior parietal cortex


Learn more about other Neurologic Diseases through links to free full text articles


ALS Video Link (film by Dr. L. Kurland on Guamanian ALS) ALS in Guam



PET-CT:

A Major Advance in Medical Imaging


The below illustrated case example of Fronto-Temporal Dementia is evaluated in better detail through the use of the combined modalities of 18F-FDG plus CT to provide a more precise attenuation map. For brain imaging, this becomes important when dealing with focal areas of atrophy,as seen below for the right frontal cortex which has significant degenerative atrophy, as seen typically in Pick's Disease. The corresponding overlay of the color coded PET image dramatically illustrates the preservation of metabolic activity in the occiptal cortex, with major defects in functional activity over the frontal lobes





Imaging Alzheimer's Disease with PET:

18F-FDDNP

As shown by Dr. Jorge R. Barrio and colleagues at UCLA, "...[18F]FDDNP is remarkably hydrophobic... and crosses the blood-brain barrier and neuronal membranes readily...and effectively binds to in-vitro amyloid(1-40) fibrils and human brain slices. Also, [18F]FDDNP is the first molecular probe to exhibit localization of NFTs and APs in vivo." (source : Am J Geriatr Psychiatry 10:24-35, February 2002

The molecular strucutre of 18F-FDDNP is shown below, along with recently published 18F-FDDNP PET images of control(left, in adapted format and color coding from original) and mild cognitive impairment (center) with later progression (right). Source : New England Journal of Medicine article by Dr. Gary Small and colleagues at UCLA titled : PET of Brain Amyloid and Tau in Mild Cognitive Impairment, published on December 21, 2006, in Volume 355:2652-2663






PET-CT: Literature review
Color Images showing PET-CT Fusion with Review on PET-CT Technology

A new development in PET-CT to enhance image quality is the introduction of time of flight data For original publications on the use of time of flight data to enhance image quality for PET-CT, please see : 1980 publication on : Feasibility of time-of-flight reconstruction in positron emission tomography


J Nucl Med. 2003 Feb;44(2):240-3 Clinically significant inaccurate localization of lesions with PET/CT: frequency in 300 patients.Osman MM, Cohade C, Nakamoto Y, Marshall LT, Leal JP, Wahl RL.Division of Nuclear Medicine, Department of Internal Medicine, School of Medicine, St. Louis University, St. Louis, Missouri, USA. These authors noted that : Six of 300 patients (2%) had lesion mislocalization when CT was used for AC or fusion.... "....Serious lesion mislocalization on PET/CT studies may occur, albeit very infrequently, when CT is used for either AC or fusion"

Eur J Nucl Med Mol Imaging. 2004 Jan;31(1):38-43. Epub 2003 Radiation exposure during transmission measurements: comparison between CT- and germanium-based techniques with a current PET scanner. Wu TH, Huang YH, Lee JJ, Wang SY, Wang SC, Su CT, Chen LK, Chu TC. The authors noted something important to consider, particularly in studying children : ".....doses absorbed during germanium-based transmission scans were almost negligible. On the other hand, absorbed doses from CT-based transmission scans were significantly higher.... the radiation doses represent a limitation to the generalised use of CT-based transmission measurements with current PET/CT scanner systems"


J Nucl Med. 2004 Jan;45 Suppl 1:15S-24S. PET/CT: panacea, redundancy, or something in between? Vogel WV, Oyen WJ, Barentsz JO, Kaanders JH, Corstens FH. In 2004, These authors from the Netherlands reviewed PET/CT : "....Because scientific data that unequivocally show that state-of-the-art software fusion is less accurate than hardware fusion (as provided in hybrid PET/CT scanners) are unavailable, the primacy of a combined PET/CT scanner over stand-alone PET and CT is more a matter of belief than of science". However, much data has accumulated since that time to show that PET-CT has a definite role and can increase accuracy of diagnosis









Development of new Cancer imaging methods and therapies:


Free links to full text journal articles:
November 2006 through 2007 - Selected articles:
Gliadel wafers in the treatment of malignant glioma: a systematic review
Regulation and function of aquaporin-1 in glioma cells
central regulator of glioma invasion
intensity modulated radiation therapy
recommendations for the treatment of GBM
DNA methyltransferase
vascular endothelial growth factor
Necrosis induction
A novel small molecule that selectively inhibits GBM
IGF2 signaling
prognostic marker for survival
Notch signaling enhances nestin expression in gliomas
HEDGEHOG-GLI1 signaling
Epidermal growth factor receptor activation
chemoresistance of CD133+ cancer stem cells in glioblastoma
HIV protease inhibitors and GBM



To offer suggestions for new links, or for web site improvements, please e-mail : cureglioma@cureglioma.info

Long Term Survival after GBM Diagnosis:
Long Term Survival is a well described phenomenon - click below to find out more details:

Six cases of GBM with LTS with an average survival of 9 years (range 5-15 years) were identified
intermediate fibrillary elements were more common in LTS
MIB-1 and topoisomerase II alpha LIs were related significantly to survival
Loss of 19q may be a marker of long-term survival
LTS were more likely to have p53-overexpressing tumors
A patient's plea--breaking the news
interferon-beta and radiation: case report



The link between the JC Virus and Glioma:
Fatal Astrocytoma Autopsy Diagnsois at a major European University Hospital later re-classified as PML
argues against the association of JC and BT
T-antigen expression was detected in the nuclei of tumor cells
The JCV early gene product, T antigen, in medulloblastoma
JCV and medulloblastoma
primitive tumors originating from the cerebellum
immunocompetent patient with an oligoastrocytoma
medulloblastoma induction by JC viral strain Tokyo-1
JCV-induced owl monkey glioblastoma
neurooncogenicity of strains of JC virus

New Advances in Glioma Research:
CD133 cells from human GBM may be novel targets for therapeutics
high-capacity helper-dependent adenoviral vectors
Targets for GBM Tx
cytotoxic and immune mediated gene-based therapies
treatment with hsFlt3L leads to inhibition of tumor growth
laminin-8 may facilitate tumor invasion and tumor regrowth after therapy
With the ability to label molecules that are active within the human body, PET Imaging technology will continue to have great potential to make new and unforeseen advances in modern molecular medicine.....

For more information, please contact : Dr. Mike Meyer, Professor of Clinical Neurology and Nuclear Medicine, ECMC Chief of Neurology, Attending Neurologist for SUNY Dept Neurology and Jacobs Neurological Institute, SUNY Buffalo