Disentangling and quantifying the relative cognitive impact of concurrent mixed neurodegenerative pathologies.

Neurodegenerative pathologies such as Alzheimer disease neuropathologic change (ADNC), Lewy body disease (LBD), limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC), and cerebrovascular disease (CVD) frequently coexist, but little is known about the exact contribution of each pathology to cognitive decline and dementia in subjects with mixed pathologies. We explored the relative cognitive impact of concurrent common and rare neurodegenerative pathologies employing multivariate logistic regression analysis adjusted for age, gender, and level of education. We analyzed a cohort of 6,262 subjects from the National Alzheimer's Coordinating Center database, ranging from 0 to 6 comorbid neuropathologic findings per individual, where 95.7% of individuals had at least 1 neurodegenerative finding at autopsy and 75.5% had at least 2 neurodegenerative findings. We identified which neuropathologic entities correlate most frequently with one another and demonstrated that the total number of pathologies per individual was directly correlated with cognitive performance as assessed by Clinical Dementia Rating (CDR®) and Mini-Mental State Examination (MMSE). We show that ADNC, LBD, LATE-NC, CVD, hippocampal sclerosis, Pick disease, and FTLD-TDP significantly impact overall cognition as independent variables. More specifically, ADNC significantly affected all assessed cognitive domains, LBD affected attention, processing speed, and language, LATE-NC primarily affected tests related to logical memory and language, while CVD and other less common pathologies (including Pick disease, progressive supranuclear palsy, and corticobasal degeneration) had more variable neurocognitive effects. Additionally, ADNC, LBD, and higher numbers of comorbid neuropathologies were associated with the presence of at least one APOE ε4 allele, and ADNC and higher numbers of neuropathologies were inversely correlated with APOE ε2 alleles. Understanding the mechanisms by which individual and concomitant neuropathologies affect cognition and the degree to which each contributes is an imperative step in the development of biomarkers and disease-modifying therapeutics, particularly as these medical interventions become more targeted and personalized.

A Degenerative Form of Mixed Transcortical Aphasia.

Mixed transcortical aphasia (MTA) is characterized by decreased spontaneous speech, impaired naming, and poor comprehension, but with intact repetition. MTA has been reported to be the sequela of left hemisphere watershed infarction that isolates Wernicke's perisylvian arc. We report a 55-year-old right-handed woman who began having word-finding difficulty and then gradually developed impaired spontaneous speech, comprehension, and naming, but with intact repetition. Magnetic resonance imaging showed atrophy in the left frontal, parietal, and temporal lobes. This patient demonstrates that MTA can occur as a result of neurodegenerative disease. Further research is needed to learn whether progressive MTA is a late stage of primary progressive aphasia, examine the neuropathology associated with this syndrome, and identify treatment strategies.

Recent US Case of Variant Creutzfeldt-Jakob Disease-Global Implications.

Variant Creutzfeldt-Jakob disease (vCJD) is a rare, fatal prion disease resulting from transmission to humans of the infectious agent of bovine spongiform encephalopathy. We describe the clinical presentation of a recent case of vCJD in the United States and provide an update on diagnostic testing. The location of this patient's exposure is less clear than those in the 3 previously reported US cases, but strong evidence indicates that exposure to contaminated beef occurred outside the United States more than a decade before illness onset. This case exemplifies the persistent risk for vCJD acquired in unsuspected geographic locations and highlights the need for continued global surveillance and awareness to prevent further dissemination of vCJD.

A pilot study to investigate the safety and feasibility of antiretroviral therapy for Alzheimer's disease (ART-AD).

Retrotransposons are viral-like DNA sequences that constitute approximately 41% of the human genome. Studies in Drosophila, mice, cultured cells, and human brain indicate that retrotransposons are activated in settings of tauopathy, including Alzheimer's disease, and causally drive neurodegeneration. The anti-retroviral medication 3TC (lamivudine), a nucleoside analog reverse transcriptase inhibitor, limits retrotransposon activation and suppresses neurodegeneration in tau transgenic Drosophila, two mouse models of tauopathy, and in brain assembloids derived from patients with sporadic Alzheimer's disease. We performed a 24-week phase 2a open-label clinical trial of 300 mg daily oral 3TC (NCT04552795) in 12 participants aged 52-83 years with a diagnosis of mild cognitive impairment due to suspected Alzheimer's disease. Primary outcomes included feasibility, blood brain barrier penetration, effects of 3TC on reverse transcriptase activity in the periphery, and safety. Secondary outcomes included changes in cognition and fluid-based biomarkers of neurodegeneration and neuroinflammation. All participants completed the six-month trial; one event of gastrointestinal bleeding due to a peptic ulcer was reported. 3TC was detected in blood and cerebrospinal fluid (CSF) of all participants, suggestive of adherence to study drug and effective brain penetration. Cognitive measures remained stable throughout the study. Glial fibrillary acidic protein (GFAP) (P=0.03) and Flt1 (P=0.05) were significantly reduced in CSF over the treatment period; Aß42/40 (P=0.009) and IL-15 (P=0.006) were significantly elevated in plasma. While this is an open label study of small sample size, the significant decrease of some neurodegeneration- and neuroinflammation-related biomarkers in CSF, significantly elevated levels of plasma Aß42/40, and a trending decrease of CSF NfL after six months of 3TC exposure suggest a beneficial effect on subjects with mild cognitive impairment due to suspected Alzheimer's disease. Feasibility, safety, tolerability, and central nervous system (CNS) penetration assessments further support clinical evaluation of 3TC in a larger placebo-controlled, multi-dose clinical trial.

Posterior Cortical Atrophy with Right Lower Egocentric Quadrantic Neglect and Lower Vertical Allocentric Neglect.

BACKGROUND/OBJECTIVES: Whereas rare cases of hemispatial visual neglect have been reported in patients with a neurodegenerative disease, quadrantic visuospatial neglect has not been described. We report a patient with probable posterior cortical atrophy who demonstrated lower right-sided quadrantic visuospatial neglect, together with allocentric vertical neglect. METHODS/RESULTS: A 68-year-old man initially noted deficits in reading and writing. Subsequently, he developed other cognitive deficits. On vertical line bisections, he deviated upward, and on horizontal line bisections, he deviated to the left. These deviations together suggest that this man's neglect might be most severe in his right (head/body-centered) lower (below eye level) visual space. When attempting to perform vertical line bisections in all four egocentric quadrants, his upward deviations were largest in the right lower quadrant. On a cancelation test, he revealed bilateral lower (ventral) allocentric neglect but not egocentric neglect. This patient's magnetic resonance imaging revealed cortical atrophy, most prominent in the left parietal lobe. DISCUSSION: Previous research in stroke patients has demonstrated that the parietal lobes are important in mediating attention to contralateral and inferior visual space. The presence of left parietal atrophy may have induced this right lower (ventral) egocentric inattention as well as bilateral ventral allocentric inattention. Although to our knowledge there have been no prior reports of a patient with right lower quadrantic and lower vertical allocentric visuospatial neglect, patients are rarely tested for these forms of neglect, and this patient illustrates the importance of evaluating patients for these and other forms of neglect.

Spontaneous Regeneration of Human Photoreceptor Outer Segments.

Photoreceptors are damaged in many common eye diseases, such as macular degeneration, retinal detachment, and retinitis pigmentosa. The development of methods to promote the repair or replacement of affected photoreceptors is a major goal of vision research. In this context, it would be useful to know whether photoreceptors are capable of undergoing some degree of spontaneous regeneration after injury. We report a subject who lost retinal function in a wide zone around the optic disc, giving rise to massive enlargement of the physiological blind spot. Imaging with an adaptive optics scanning laser ophthalmoscope (AOSLO) showed depletion of cone outer segments in the affected retina. A year later visual function had improved, with shrinkage of the enlarged blind spot. AOSLO imaging showed repopulation of cone outer segments, although their density remained below normal. There was a one-to-one match between sites of formerly missing outer segments and new outer segments that had appeared over the course of the year's recovery. This correspondence provided direct morphological evidence that damaged cones are capable, under some circumstances, of generating new outer segments.