Sossi, Vesna

ImportanceIncreased white matter hyperintensity (WMH) volume is a common magnetic resonance imaging (MRI) finding in both autosomal dominant Alzheimer disease (ADAD) and late-onset Alzheimer disease (LOAD), but it remains unclear whether increased WMH along the AD continuum is reflective of AD-intrinsic processes or secondary to elevated systemic vascular risk factors.ObjectiveTo estimate the associations of neurodegeneration and parenchymal and vessel amyloidosis with WMH accumulation and investigate whether systemic vascular risk is associated with WMH beyond these AD-intrinsic processes.Design, Setting, and ParticipantsThis cohort study used data from 3 longitudinal cohort studies conducted in tertiary and community-based medical centers—the Dominantly Inherited Alzheimer Network (DIAN; February 2010 to March 2020), the Alzheimer’s Disease Neuroimaging Initiative (ADNI; July 2007 to September 2021), and the Harvard Aging Brain Study (HABS; September 2010 to December 2019).Main Outcome and MeasuresThe main outcomes were the independent associations of neurodegeneration (decreases in gray matter volume), parenchymal amyloidosis (assessed by amyloid positron emission tomography), and vessel amyloidosis (evidenced by cerebral microbleeds [CMBs]) with cross-sectional and longitudinal WMH.ResultsData from 3960 MRI sessions among 1141 participants were included: 252 pathogenic variant carriers from DIAN (mean [SD] age, 38.4 [11.2] years; 137 [54%] female), 571 older adults from ADNI (mean [SD] age, 72.8 [7.3] years; 274 [48%] female), and 318 older adults from HABS (mean [SD] age, 72.4 [7.6] years; 194 [61%] female). Longitudinal increases in WMH volume were greater in individuals with CMBs compared with those without (DIAN: t = 3.2 [P = .001]; ADNI: t = 2.7 [P = .008]), associated with longitudinal decreases in gray matter volume (DIAN: t = −3.1 [P = .002]; ADNI: t = −5.6 [P < .001]; HABS: t = −2.2 [P = .03]), greater in older individuals (DIAN: t = 6.8 [P < .001]; ADNI: t = 9.1 [P < .001]; HABS: t = 5.4 [P < .001]), and not associated with systemic vascular risk (DIAN: t = 0.7 [P = .40]; ADNI: t = 0.6 [P = .50]; HABS: t = 1.8 [P = .06]) in individuals with ADAD and LOAD after accounting for age, gray matter volume, CMB presence, and amyloid burden. In older adults without CMBs at baseline, greater WMH volume was associated with CMB development during longitudinal follow-up (Cox proportional hazards regression model hazard ratio, 2.63; 95% CI, 1.72-4.03; P < .001).Conclusions and RelevanceThe findings suggest that increased WMH volume in AD is associated with neurodegeneration and parenchymal and vessel amyloidosis but not with elevated systemic vascular risk. Additionally, increased WMH volume may represent an early sign of vessel amyloidosis preceding the emergence of CMBs.

ABSTRACTBackground and Objectives: To study selective regional binding for tau pathology in vivo, using PET with [11C]PBB3 in PSP patients, and other conditions not typically associated with tauopathy.Methods: Dynamic PET scans were obtained for 70 minutes after the bolus injection of [11C]PBB3 in 5 PSP subjects, 1 subject with DCTN1 mutation and PSP phenotype, 3 asymptomatic SNCA duplication carriers, 1 MSA subject, and 6 healthy controls of similar age. Tissue reference Logan analysis was applied to each region of interest using a cerebellar white matter reference region.Results: In comparison to the control group, PSP subjects showed specific uptake of [11C]PBB3 in putamen, midbrain, GP, and SN. Longer disease duration and more advanced clinical severity were generally associated with higher tracer retention. A DCTN1/PSP phenotype case showed increased binding in putamen, parietal lobe, and GP. In SNCA duplication carriers, there was a significant increase of [11C] PBB3 binding in GP, putamen, thalamus, ventral striatum, SN, and pedunculopontine nucleus. The MSA case showed increased binding in frontal lobe, GP, midbrain, parietal lobe, putamen, temporal lobe, SN, thalamus, and ventral striatum.Conclusions: All PSP patients showed increased retention of the tracer in the basal ganglia, as expected. Binding was also present in asymptomatic SNCA duplication carriers and in an MSA case, which are not typically associated with pathological tau deposition. This suggests the possibility that [11C]PBB3 binds to alpha‐synuclein. © 2017 International Parkinson and Movement Disorder Society

AbstractBackgroundFamilies of Dutch‐German‐Russian Mennonite descent with multi‐incident parkinsonism have been identified as harboring a pathogenic DNAJC13 p.N855S mutation and are awaiting clinical and pathophysiological characterization.MethodsFamily members were examined clinically longitudinally, and 5 underwent dopaminergic PET imaging. Four family members came to autopsy.ResultsOf the 16 symptomatic DNAJC13 mutation carriers, 12 had clinically definite, 3 probable, and 1 possible Parkinson's disease (PD). Symptoms included bradykinesia, tremor, rigidity, and postural instability, with a mean onset of 63 years (range, 40‐85) and slow progression. Eight of ten subjects who required treatment had a good levodopa response; motor complications and nonmotor symptoms were observed. Dopaminergic PET imaging revealed rostrocaudal striatal deficits typical for idiopathic PD in established disease and subtle abnormalities in incipient disease. Pathological examinations revealed Lewy body pathology.ConclusionPD associated with a DNAJC13 p.N855S mutation presents as late‐onset, often slowly progressive, usually dopamine‐responsive typical PD. © 2014 International Parkinson and Movement Disorder Society

ABSTRACTIntroductionWe used positron emission tomography (PET) to assess dopaminergic and serotonergic terminal density in three subjects carrying a mutation in the DCT1 gene, two clinically affected with Perry syndrome.MethodsAll subjects had brain imaging using 18F‐6‐fluoro‐l‐dopa (FDOPA, dopamine synthesis and storage), (+)‐11C‐dihydrotetrabenazine (DTBZ, vesicular monoamine transporter type 2), and 11C‐raclopride (RAC, dopamine D2/D3 receptors). One subject also underwent PET with 11C‐3‐amino‐4‐(2‐dimethylaminomethyl‐phenylsulfanyl)‐benzonitrile (DASB, serotonin transporter).ResultsFDOPA‐PET and DTBZ‐PET in the affected individuals showed a reduction of striatal tracer uptake. Also, RAC‐PET showed higher uptake in these area. DASB‐PET showed significant uptake changes in left orbitofrontal cortex, bilateral anterior insula, left dorsolateral prefrontal cortex, left orbitofrontal cortex, left posterior cingulate cortex, left caudate, and left ventral striatum.ConclusionsOur data showed evidence of both striatal dopaminergic and widespread cortical/subcortical serotonergic dysfunctions in individuals carrying a mutation in the DCTN1 gene. © 2014 International Parkinson and Movement Disorder Society