The distinctive cortical uptake of the tracer ¹⁸F-FDDNP (2-(1-{6-(2-fluoroethyl(methyl)amino-2-naphthyl}ethylidene)malononitrile) in Alzheimer's disease (AD) is believed to be because of its binding ...to both neurofibrillary tangles (NFTs) and highly fibrillar senile plaques. We therefore investigated the binding of a tracer concentration of ³H-FDDNP to brain sections containing AD hallmark pathologies. Semi-adjacent sections were labelled with ³H-PIB (Pittsburgh compound-B, 2-4'-(methylamino)phenyl-6-hydroxybenzothiazole) and ¹⁴C-SB13 (4-N-methylamino-4'-hydroxystilbene) for comparison. Neocortical sections containing widespread senile plaques and cerebrovascular amyloid angiopathy, produced a sparse and weak labelling following incubation with ³H-FDDNP. Furthermore, in sections containing NFTs, there was no overt labelling of the pathology by ³H-FDDNP. In contrast, sections labelled with ³H-PIB displayed extensive labelling of diffuse plaques, classical plaques, cerebrovascular amyloid angiopathy and NFTs. ¹⁴C-SB13 produced a broadly similar binding pattern to PIB. Radioligand binding assays employing in vitro generated amyloid-β peptide fibrils demonstrated a ~10-fold reduced affinity for ³H-FDDNP (85.0 ± 2.0 nM) compared with ³H-PIB (8.5 ± 1.3 nM). These data provide an alternative mechanistic explanation for the observed low cortical uptake of ¹⁸F-FDDNP in AD; in that the ligand is only weakly retained by the hallmark neuropathology because of its low affinity for amyloid structures.
ABSTRACTCurrently, only presumptive diagnosis of chronic traumatic encephalopathy (CTE) can be made in living patients. We present a modality that may be instrumental to the definitive diagnosis of ...CTE in living patients based on brain autopsy confirmation of F-18FDDNP-PET findings in an American football player with CTE. F-18FDDNP-PET imaging was performed 52 mo before the subjectʼs death. Relative distribution volume parametric images and binding values were determined for cortical and subcortical regions of interest. Upon death, the brain was examined to identify the topographic distribution of neurodegenerative changes. Correlation between neuropathology and F-18FDDNP-PET binding patterns was performed using Spearman rank-order correlation. Mood, behavioral, motor, and cognitive changes were consistent with chronic traumatic myeloencephalopathy with a 22-yr lifetime risk exposure to American football. There were tau, amyloid, and TDP-43 neuropathological substrates in the brain with a differential topographically selective distribution. F-18FDDNP-PET binding levels correlated with brain tau deposition (rs = 0.59, P = .02), with highest relative distribution volumes in the parasagittal and paraventricular regions of the brain and the brain stem. No correlation with amyloid or TDP-43 deposition was observed. F-18FDDNP-PET signals may be consistent with neuropathological patterns of tau deposition in CTE, involving areas that receive the maximal shearing, angular-rotational acceleration-deceleration forces in American football players, consistent with distinctive and differential topographic vulnerability and selectivity of CTE beyond brain cortices, also involving midbrain and limbic areas. Future studies are warranted to determine whether differential and selective F-18FDDNP-PET may be useful in establishing a diagnosis of CTE in at-risk patients.
Chronic traumatic encephalopathy (CTE) is an acquired primary tauopathy with a variety of cognitive, behavioral, and motor symptoms linked to cumulative brain damage sustained from single, episodic, ...or repetitive traumatic brain injury (TBI). No definitive clinical diagnosis for this condition exists. In this work, we used F-18FDDNP PET to detect brain patterns of neuropathology distribution in retired professional American football players with suspected CTE ( n = 14) and compared results with those of cognitively intact controls ( n = 28) and patients with Alzheimer’s dementia (AD) ( n = 24), a disease that has been cognitively associated with CTE. F-18FDDNP PET imaging results in the retired players suggested the presence of neuropathological patterns consistent with models of concussion wherein brainstem white matter tracts undergo early axonal damage and cumulative axonal injuries along subcortical, limbic, and cortical brain circuitries supporting mood, emotions, and behavior. This deposition pattern is distinctively different from the progressive pattern of neuropathology paired helical filament (PHF)-tau and amyloid-β in AD, which typically begins in the medial temporal lobe progressing along the cortical default mode network, with no or minimal involvement of subcortical structures. This particular F-18FDDNP PET imaging pattern in cases of suspected CTE also is primarily consistent with PHF-tau distribution observed at autopsy in subjects with a history of mild TBI and autopsy-confirmed diagnosis of CTE.
Significance Mild traumatic brain injuries are frequent events in the general population and are associated with a severe neurodegenerative disease, chronic traumatic encephalopathy (CTE). This disease is characterized by abnormal accumulation of protein aggregates, primarily tau proteins, which accumulate in brain areas responsible for mood, fear, stress, and cognition. There is no definitive clinical diagnosis of CTE at the present time, and this new work shows how a tau-sensitive brain imaging agent, F-18FDDNP, may be able to detect the disease in living people with varying degrees of symptoms. Early detection would facilitate the most effective management strategies and provide a baseline to measure the effectiveness of treatments.
Mild traumatic brain injury due to contact sports may cause chronic behavioral, mood, and cognitive disturbances associated with pathological deposition of tau protein found at brain autopsy. To ...explore whether brain tau deposits can be detected in living retired players, we used positron emission tomography (PET) scans after intravenous injections of 2-(1-{6-(2-F-18fluoroethyl)(methyl)amino-2-naphthyl}ethylidene)malononitrile (FDDNP).
Five retired National Football League players (age range: 45 to 73 years) with histories of mood and cognitive symptoms received neuropsychiatric evaluations and FDDNP-PET. PET signals in subcortical (caudate, putamen, thalamus, subthalamus, midbrain, cerebellar white matter) and cortical (amygdala, frontal, parietal, posterior cingulate, medial and lateral temporal) regions were compared with those of five male controls of comparable age, education, and body mass index.
FDDNP signals were higher in players compared with controls in all subcortical regions and the amygdala, areas that produce tau deposits following trauma.
The small sample size and lack of autopsy confirmation warrant larger, more definitive studies, but if future research confirms these initial findings, FDDNP-PET may offer a means for premorbid identification of neurodegeneration in contact-sports athletes.
Purpose
Caution is warranted when
in vitro
results of biomarkers labeled with tritium were perfunctorily used to criticize
in vivo
data and conclusions derived with the same tracers labeled with ...positron emitters and positron emission tomography (PET). This concept is illustrated herein with the PET utilization of
18
FFDDNP, a biomarker used for
in vivo
visualization of β-amyloid and tau protein neuroaggregates in humans, later contradicted by
in vitro
data reported with
3
HFDDNP. In this investigation, we analyze the multiple factors involved in the experimental design of the
3
HFDDNP
in vitro
study that led to the erroneous interpretation of results.
Procedure
The present work describes full details on the synthesis, characterization, purity, and kinetics of radiolytic stability of
3
HFDDNP. The optimal
in vitro
conditions for detecting tau and β-amyloid protein aggregates using macroscopic and microscopic autoradiography with both
18
FFDDNP and
3
HFDDNP are also presented. Macroscopic autoradiography determinations were performed with
3
HFDDNP of verified purity using established methods described previously in the literature.
Results
The autoradiographic results using phosphate buffered saline (PBS) with less than 1 % EtOH and pure, freshly prepared
3
HFDDNP compared with the earlier reported data using
3
HFDDNP of undetermined purity and PBS in 10 % EtOH demonstrate the critical importance of rigorous experimental design for meaningful
in vitro
determinations.
18
FFDDNP binding to both amyloid plaques and neurofibrillary tangles was confirmed by amyloid and tau immunohistochemical stains of adjacent tissues.
Conclusions
This work illustrates the sensitivity of
in vitro
techniques to various experimental conditions and underscores that conclusions obtained from translational
in vitro
to
in vivo
determinations must always be performed with extreme care to avoid wrong interpretations that can be perpetuated and assumed without further analysis.
Exercise and diet impact body composition, but their age-related brain effects are unclear at the molecular imaging level. To address these issues, the authors determined whether body mass index ...(BMI), physical activity, and diet relate to brain positron emission tomography (PET) of amyloid plaques and tau tangles using 2-(1-(6-(2-F-18fluoroethyl)(methyl)amino-2-naphthyl)ethylidene)malononitrile (FDDNP).
Volunteers (N = 44; mean age: 62.6 ± 10.7 years) with subjective memory impairment (N = 24) or mild cognitive impairment (MCI; N = 20) were recruited by soliciting for memory complaints. Levels of physical activity and extent of following a Mediterranean-type diet were self-reported. FDDNP-PET scans assessed plaque/tangle binding in Alzheimer disease-associated regions (frontal, parietal, medial and lateral temporal, posterior cingulate). Mixed models controlling for known covariates examined BMI, physical activity, and diet in relation to FDDNP-PET.
MCI subjects with above normal BMI (>25) had higher FDDNP-PET binding compared with those with normal BMI (1.11(0.03) versus 1.08(0.03), ES = 1.04, t(35) = 3.3, p = 0.002). Greater physical activity was associated with lower FDDNP-PET binding in MCI subjects (1.07(0.03) versus 1.11(0.03), ES = 1.13, t(35) = -3.1, p = 0.004) but not in subjects with subjective memory impairment (1.07(0.03) versus 1.07(0.03), ES = 0.02, t(35) = -0.1, p = 0.9). Healthier diet related to lower FDDNP-PET binding, regardless of cognitive status (1.07(0.03) versus 1.09(0.02), ES = 0.72, t(35) = -2.1, p = 0.04).
These preliminary findings are consistent with a relationship between risk modifiersand brain plaque/tangle deposition in nondemented individuals and supports maintenance of normal body weight, regular physical activity, and healthy diet to protect the brain during aging. (clinicaltrials.gov; NCT00355498).
Currently 18FFDDNP is the only PET imaging probe with the ability to visualize hyperphosphorylated tau fibrillar aggregates in living subjects. In this work, we evaluate in vivo 18FFDDNP labeling of ...brain neuropathology, primarily tau fibrillar aggregates, in patients with progressive supranuclear palsy (PSP), a human tauopathy usually lacking amyloid-β deposits.
Fifteen patients with PSP received 18FFDDNP PET scanning. 18FFDDNP distribution volume ratios, in reference to cerebellar gray matter, were determined for cortical and subcortical areas and compared with those of patients with Parkinson's disease with short disease duration, and age-matched control subjects without neurodegenerative disorders.
18FFDDNP binding was present in subcortical areas (e.g., striatum, thalamus, subthalamic region, midbrain, and cerebellar white matter) regardless of disease severity, with progressive subcortical and cortical involvement as disease severity increased. Brain patterns of 18FFDDNP binding were entirely consistent with the known pathology distribution for PSP. High midbrain and subthalamic region 18FFDDNP binding was distinctive for PSP subjects and separated them from controls and patients with Parkinson's disease.
These results provide evidence that 18FFDDNP is a sensitive in vivo PET imaging probe to map and quantify the dynamic regional localization of tau fibrillar aggregates in PSP. Furthermore, 18FFDDNP PET may provide a tool to detect changes in tau pathology distribution either associated with disease progression or as a treatment biomarker for future tau-specific therapies. Patterns of 18FFDDNP binding may also be useful in diagnosis early in disease presentation when clinical distinction among neurodegenerative disorders is often difficult.
Purpose
11
CPIB and
18
FFDDNP are PET tracers for in vivo detection of the neuropathology underlying Alzheimer’s disease (AD).
18
FFDG is a glucose analogue and its uptake reflects metabolic ...activity. The purpose of this study was to examine longitudinal changes in these tracers in patients with AD or mild cognitive impairment (MCI) and in healthy controls.
Methods
Longitudinal, paired, dynamic
11
CPIB and
18
FFDDNP (90 min each) and static
18
FFDG (15 min) PET scans were obtained in 11 controls, 12 MCI patients and 8 AD patients. The mean interval between baseline and follow-up was 2.5 years (range 2.0–4.0 years). Parametric
11
CPIB and
18
FFDDNP images of binding potential (BP
ND
) and
18
FFDG standardized uptake value ratio (SUVr) images were generated.
Results
A significant increase in global cortical
11
CPIB BP
ND
was found in MCI patients, but no changes were observed in AD patients or controls. Subsequent regional analysis revealed that this increase in
11
CPIB BP
ND
in MCI patients was most prominent in the lateral temporal lobe (
p
< 0.05). For
18
FFDDNP, no changes in global BP
ND
were found.
18
FFDG uptake was reduced at follow-up in the AD group only, especially in frontal, parietal and lateral temporal lobes (all
p
< 0.01). Changes in global
11
CPIB binding (ρ = −0.42,
p
< 0.05) and posterior cingulate
18
FFDG uptake (ρ = 0.54,
p
< 0.01) were correlated with changes in Mini-Mental-State Examination score over time across groups, whilst changes in
18
FFDDNP binding (ρ = −0.18,
p
= 0.35) were not.
Conclusion
11
CPIB and
18
FFDG track molecular changes in different stages of AD. We found increased amyloid load in MCI patients and progressive metabolic impairment in AD patients.
18
FFDDNP seems to be less useful for examining disease progression.
Background
Neurotoxicity associated with amyloid and tau protein aggregation could represent a pathophysiological cascade that, along with vascular compromise, may predispose individuals to late‐life ...depression (LLD). In LLD, apathy is common, leads to worsening of functioning, and responds poorly to antidepressant treatment. Better understanding of the pathophysiological mechanisms of apathy in LLD would facilitate development of more effective diagnostic and treatment approaches. In this cross‐sectional pilot study, we performed positron emission tomography scans after injection of 2‐(1‐{6‐(2‐18
Ffluoroethyl)(methyl)‐amino‐2‐naphthyl}ethylidene) malononitrile (18
FFDDNP), an in vivo amyloid and tau neuroimaging study, in patients with LLD to explore neural correlates of apathy.
Methods
Sixteen depressed elderly volunteers received clinical assessments and 18
FFDDNP positron emission tomography scans. The cross‐sectional relationship of 18FFDDNP binding levels with depression (Hamilton Depression Rating Scale) and apathy (Apathy Evaluation Scale) were studied using Spearman's correlation analyses because of the relatively small sample size. Age, sex, and years of education were partialed out. Significance levels were set at P ≤ 0.05.
Results
18
FFDDNP binding in the anterior cingulate cortex was negatively associated with the Apathy Evaluation Scale total (r = −0.62, P = 0.02; where low Apathy Evaluation Scale score equals greater severity of apathy). This suggests that apathy in LLD is associated with higher amyloid and/or tau levels in the anterior cingulate cortex. None of the regional 18
FFDDNP binding levels was significantly associated with the Hamilton Depression Rating Scale total.
Conclusion
This pilot study suggests that increased apathy in subjects with LLD may be associated with greater amyloid and/or tau burden in certain brain regions. Future studies in larger samples would elucidate the generalizability of these results, which eventually could lead to improved diagnostic and treatment methods in LLD.
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