Distinct amyloid and tau PET signatures are associated with diverging clinical and imaging trajectories in patients with amnestic syndrome of the hippocampal type

We aimed to investigate the amyloid and tau PET imaging signatures of patients with amnestic syndrome of the hippocampal type (ASHT) and study their clinical and imaging progression according to their initial PET imaging status. Thirty-six patients with a progressive ASHT and 30 controls underwent a complete neuropsychological assessment, 3 T brain MRI, [11C]-PiB and [18F]-Flortaucipir PET imaging. Subjects were clinically followed-up annually over 2 years, with a second 3 T MRI (n = 27 ASHT patients, n = 28 controls) and tau-PET (n = 20 ASHT patients) at the last visit. At baseline, in accordance with the recent biological definition of Alzheimer’s disease (AD), the AD PET signature was defined as the combination of (i) positive cortical amyloid load, and (ii) increased tau tracer binding in the entorhinal cortices and at least one of the following regions: amygdala, parahippocampal gyri, fusiform gyri. Patients who did not meet these criteria were considered to have a non-AD pathology (SNAP). Twenty-one patients were classified as AD and 15 as SNAP. We found a circumscribed tau tracer retention in the entorhinal cortices and/or amygdala in 5 amyloid-negative SNAP patients. At baseline, the SNAP patients were older and had lower ApoE ε4 allele frequency than the AD patients, but both groups did not differ regarding the neuropsychological testing and medial temporal lobe atrophy. During the 2-year follow-up, the episodic memory and language decline, as well as the temporo-parietal atrophy progression, were more pronounced in the AD sub-group, while the SNAP patients had a more pronounced progression of atrophy in the frontal lobes. Longitudinal tau tracer binding increased in AD patients but remained stable in SNAP patients. At baseline, distinct amyloid and tau PET signatures differentiated early AD and SNAP patients despite identical cognitive profiles characterized by an isolated ASHT and a similar degree of medial temporal atrophy. During the longitudinal follow-up, AD and SNAP patients diverged regarding clinical and imaging progression. Among SNAP patients, tau PET imaging could detect a tauopathy restricted to the medial temporal lobes, which was possibly explained by primary age-related tauopathy.

Rapidly progressive amnestic syndrome with psychiatric and autonomic features: extending the spectrum of GFAP-astrocytopathies and autoimmune dementias?

Objective Autoimmune glial fibrillary acidic protein astrocytopathy (GFAP-A) is a steroid-responsive meningoencephalomyelitis, sometimes presenting with atypical clinical signs such as movement disorders or psychiatric and autonomic features. Diagnosis relies on clinical presentation, detection of GFAP autoantibodies in CSF as well as ancillary MRI biomarkers. We aimed to characterize two patients seropositive for GFAP antibodies in CSF presenting with a highly atypical clinical picture of isolated neurocognitive and autonomic features resembling neurodegenerative dementia in absence of cranial MRI abnormalities.Methods Semiquantitative, clinicoradiological, serologic and immunohistochemical analysis of two cases with longitudinal observation over a time course of 18–24 months.Results Both patients had rapidly progressive amnestic syndromes in absence of other focal neurologic signs. Cranial MRI was grossly unremarkable while functional neuroimaging showed cortical and subcortical metabolic changes. Tissue-based assays (TBA) of CSF confirmed GFAP-specific astrocytic binding patterns in rat corpus callosum and hippocampus in both cases. Incomplete steroid response prompted therapy escalation to B-cell depletion, which improved or stabilized disease courses over the observation time.Conclusions These cases suggest that rapidly progressive amnestic syndromes with psychiatric and autonomic features may be a novel phenotype of GFAP astrocytopathy as well as a potentially underrecognized mimic of neurodegenerative dementia amenable to immunomodulation. We recommend including GFAP-AB screening using TBA in the work-up of rapidly progressive dementias especially when autoimmune etiologies are suspected.

Seronegative limbic encephalitis manifesting as subacute amnestic syndrome: a case report and review of the literature

Background Limbic encephalitis (LE), a variant of autoimmune encephalitis, is inflammation of the limbic system of the brain. The disorder presents with subacute impairment of short-term memory, psychiatric manifestations, confusion and seizures. “Seronegative LE” is a challenging diagnosis in the absence of well-characterized autoantibodies. Case presentation A 33-year-old Kuwaiti woman with no relevant past history presented with subacute progressive amnesia of 6-month duration. Magnetic resonance imaging (MRI) showed bilateral hyperintensity of the limbic structures. An extensive workup of the blood and cerebrospinal fluid (CSF) failed to identify paraneoplastic or autoimmune antibodies. The diagnosis of seronegative LE was made, and immunotherapy was initiated, with improvement in cognitive function. Conclusion Seronegative LE is a challenging diagnosis. Inability to detect autoantibodies, especially early in the disease course, should not rule out the diagnosis of autoimmune encephalitis. Early diagnosis and treatment with immunotherapy may prevent irreversible brain damage.