Skin Biopsy Detection of Phosphorylated α-Synuclein in Patients With Synucleinopathies.

Importance: Finding a reliable diagnostic biomarker for the disorders collectively known as synucleinopathies (Parkinson disease [PD], dementia with Lewy bodies [DLB], multiple system atrophy [MSA], and pure autonomic failure [PAF]) is an urgent unmet need. Immunohistochemical detection of cutaneous phosphorylated α-synuclein may be a sensitive and specific clinical test for the diagnosis of synucleinopathies. Objective: To evaluate the positivity rate of cutaneous α-synuclein deposition in patients with PD, DLB, MSA, and PAF. Design, Setting, and Participants: This blinded, 30-site, cross-sectional study of academic and community-based neurology practices conducted from February 2021 through March 2023 included patients aged 40 to 99 years with a clinical diagnosis of PD, DLB, MSA, or PAF based on clinical consensus criteria and confirmed by an expert review panel and control participants aged 40 to 99 years with no history of examination findings or symptoms suggestive of a synucleinopathy or neurodegenerative disease. All participants completed detailed neurologic examinations and disease-specific questionnaires and underwent skin biopsy for detection of phosphorylated α-synuclein. An expert review panel blinded to pathologic data determined the final participant diagnosis. Exposure: Skin biopsy for detection of phosphorylated α-synuclein. Main Outcomes: Rates of detection of cutaneous α-synuclein in patients with PD, MSA, DLB, and PAF and controls without synucleinopathy. Results: Of 428 enrolled participants, 343 were included in the primary analysis (mean [SD] age, 69.5 [9.1] years; 175 [51.0%] male); 223 met the consensus criteria for a synucleinopathy and 120 met criteria as controls after expert panel review. The proportions of individuals with cutaneous phosphorylated α-synuclein detected by skin biopsy were 92.7% (89 of 96) with PD, 98.2% (54 of 55) with MSA, 96.0% (48 of 50) with DLB, and 100% (22 of 22) with PAF; 3.3% (4 of 120) of controls had cutaneous phosphorylated α-synuclein detected. Conclusions and Relevance: In this cross-sectional study, a high proportion of individuals meeting clinical consensus criteria for PD, DLB, MSA, and PAF had phosphorylated α-synuclein detected by skin biopsy. Further research is needed in unselected clinical populations to externally validate the findings and fully characterize the potential role of skin biopsy detection of phosphorylated α-synuclein in clinical care.

A neuropsychiatric case of delayed post-hypoxic leukoencephalopathy from opioid intoxication resulting in Anton-Babinski syndrome and quadriplegia.

This is the case of a 26-year-old male who developed Anton Babinski syndrome (ABS), quadriplegia, and delayed post-hypoxic leukoencephalopathy (DPHL) after an opioid overdose. He exhibited cortical blindness, visual anosognosia, and confabulation upon awakening. Several days later, he experienced acute psychosis and agitation. T2-FSE MRI revealed extensive supratentorial leukoencephalopathy involving both cerebral hemispheres, extending to the posterior corpus callosum due to cerebral anoxia. This case report will discuss different types of encephalopathy from opioid abuse, ABS, visual anosognosia, and confabulation's pathogenic mechanisms. It underscores the necessity of researching substance-induced neuropsychiatric disorders and their pathogenic mechanisms for effective treatments.

Clinical Screening for Posterior Cortical Atrophy.

BACKGROUND: Posterior cortical atrophy (PCA) is a progressive neurologic syndrome that presents with complex visual deficits. Although PCA is most commonly a form of Alzheimer disease (AD), its early diagnosis is usually delayed due to a lack of understanding for how best to clinically screen for the syndrome. OBJECTIVE: To identify neurobehavioral screening tasks for PCA-beyond simple visual constructions-that can be administered in clinic or at bedside. METHOD: We compared the performance of 12 individuals who met neuroimaging-supported consensus criteria for PCA with that of 12 matched individuals with typical AD (tAD) and 24 healthy controls (HC) on clinic/bedside tasks measuring (a) complex figure copying, (b) Balint syndrome, (c) visual object agnosia, (d) color identification, (e) figure-ground discrimination, (f) global-local processing, (g) dressing apraxia, (h) ideomotor apraxia, and (i) Gerstmann syndrome. RESULTS: All of the individuals with PCA were impaired on the figure-ground discrimination task compared with half of the tAD group and no HC. Approximately half of the PCA group had Balint syndrome, dressing apraxia, and ideomotor apraxia compared with none in the tAD group. Difficulty copying a complex figure, global-local processing impairment, and Gerstmann syndrome did not distinguish between the two dementia groups. CONCLUSION: The figure-ground discrimination task can be used successfully as an overall screening measure for PCA, followed by specific tasks for Balint syndrome and dressing and limb apraxia. Findings reinforce PCA as a predominant occipitoparietal disorder with dorsal visual stream involvement and parietal signs with spatiomotor impairments.

Impaired visual search in posterior cortical atrophy vs. typical Alzheimer's disease.

BACKGROUND: Posterior cortical atrophy (PCA) is a neurocognitive disorder characterized by difficulty localizing in space. Recognizing PCA is important because it is usually missed early in its course and may result from a number of neurological disorders other than Alzheimer's disease (AD). OBJECTIVE: This study aimed to clarify whether impaired visual search tasks of spatial localization distinguished patients with PCA from those with other more typical dementias as well as from healthy control (HC) subjects. METHODS: Twelve patients meeting neuroimaging-supported Consensus Criteria for PCA, 12 comparably advanced patients with amnestic-predominant typical AD (tAD), and 24 HC participants were compared on tests of untimed and timed visual search, spatial neglect, mental rotation, environmental orientation, visuospatial construction, and face recognition. RESULTS: Only abnormalities in untimed and timed visual search and environmental orientation distinguished the PCA patients from both the tAD group and the HC group without also distinguishing the tAD patients from HC's. The PCA patients also had a tendency to greater difficulty scanning left hemispace compared to HC's. Visuospatial constructions, although worse in PCA, and face recognition were impaired in both dementia groups. CONCLUSIONS: These findings support the concept of PCA as a disorder of spatial processing and localization, indicating that visual search tasks are particularly sensitive and specific for detecting PCA and distinguishing it from more typical dementia syndromes.

Benson's Disease or Posterior Cortical Atrophy, Revisited.

BACKGROUND: D. Frank Benson and colleagues first described the clinical and neuropathological features of posterior cortical atrophy (PCA) from patients in the UCLA Neurobehavior Program. OBJECTIVE: We reviewed the Program's subsequent clinical experience with PCA, and its potential for clarifying this relatively rare syndrome in comparison to the accumulated literature on PCA. METHODS: Using the original criteria derived from this clinic, 65 patients with neuroimaging-supported PCA were diagnosed between 1995 and 2020. RESULTS: On presentation, most had visual localization complaints and related visuospatial symptoms, but nearly half had memory complaints followed by symptoms of depression. Neurobehavioral testing showed predominant difficulty with visuospatial constructions, Gerstmann's syndrome, and Balint's syndrome, but also impaired memory and naming. On retrospective application of the current Consensus Criteria for PCA, 59 (91%) met PCA criteria with a modification allowing for "significantly greater visuospatial over memory and naming deficits." There were 37 deaths (56.9%) with the median overall survival of 10.3 years (95% CI: 9.6-13.6 years), consistent with a slow neurodegenerative disorder in most patients. CONCLUSION: Together, these findings recommend modifying the PCA criteria for "relatively spared" memory, language, and behavior to include secondary memory and naming difficulty and depression, with increased emphasis on the presence of Gerstmann's and Balint's syndromes.

Clinical Features of Late-onset Semantic Dementia.

BACKGROUND: Semantic dementia (SD) is characterized by progressive semantic anomia extending to a multimodal loss of semantic knowledge. Although often considered an early-onset dementia, SD also occurs in later life, when it may be misdiagnosed as Alzheimer disease (AD). OBJECTIVE: To evaluate late-onset SD in comparison to early-onset SD and to AD. METHODS: We identified 74 individuals with SD and then compared those with late-onset SD (≥65 years of age) to those with early-onset SD (<65) on demographic and clinical features. We also compared a subgroup of 23 of the late-onset SD individuals with an equal number of individuals with clinically probable AD. RESULTS: Twenty-six (35.1%) of the SD individuals were late onset, and 48 (64.9%) were early onset. There were no differences between the two groups on clinical measures, although greater asymmetry of temporal involvement trended to significance in the late-onset SD group. Compared to the 23 AD individuals, the subgroup of 23 late-onset SD individuals had worse performance on confrontational naming, irregular word reading, and face recognition; however, this subgroup displayed better verbal delayed recall and constructions. The late-onset SD individuals also experienced early personality changes at a time when most individuals with AD had not yet developed behavioral changes. CONCLUSIONS: Approximately one-third of SD individuals may be late onset, and the differentiation of late-onset SD from AD can lead to better disease management, education, and prognosis. SD may be distinguished by screening for disproportionate changes in reading, face recognition, and personality.

Dietary recommendations for patients with dementia.

With the emergence of support for diet in the maintenance of cognition, clinicians have been justifiably eager to promote diet recommendations for their older patients. But popular diets, such as the Mediterranean diet, Dietary Approaches to Stop Hypertension (DASH), and the Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND), have not been shown to benefit cognition among patients who already have dementia or cognitive decline. In our experience, promoting these restrictive diets can be detrimental to patients with dementia who are already prone to eating disturbance; vulnerable to malnutrition; and, if underweight, demonstrate increased mortality. Moreover, we have seen both patient and caregiver satisfaction negatively affected by dietary modification. Clinicians need to be aware that any dietary recommendations for patients with dementia should be mitigated by the lack of evidence for improvement in cognition, the risks for exacerbating poor nutrition, and the potential for further limiting their quality of life.

Neuropsychiatric Effects on Decision-Making in Early Alzheimer Disease.

BACKGROUND: Neuropsychiatric symptoms can impact decision-making in patients with Alzheimer disease (AD). METHODS: Using a simple decision-making task, a variant of the ultimatum game (UG) modified to control feelings of unfairness, this study investigated rejection responses among responders to unfair offers. The UG was administered to 11 patients with AD, 10 comparably demented patients with behavioral variant frontotemporal dementia (bvFTD), and 9 healthy controls (HC). The results were further compared with differences on the caregiver Neuropsychiatric Inventory (NPI). RESULTS: Overall, patients with AD significantly rejected more total offers than did the patients with bvFTD and the HC (P < .01). On the NPI, the only domain that was significantly worse among the patients with AD compared to the other groups was dysphoria/depression. CONCLUSIONS: These results suggest that early AD can be distinguished based on increased rejections of offers in decision-making, possibly consequent to a heightened sense of unfairness from dysphoria/depression.

Vicarious Embarrassment or "Fremdscham": Overendorsement in Frontotemporal Dementia.

OBJECTIVE: The experience of embarrassment signals violations in social norms, and impairment in this social emotion may underlie much of the social dysfunction in behavioral variant frontotemporal dementia (bvFTD). The authors investigated whether impaired self-awareness of embarrassment may distinguish patients with bvFTD early in the course of disease from healthy control subjects (HCs). METHODS: Self-reported embarrassment was examined among 18 patients with early bvFTD and 23 HCs by using the 36-item Embarrassability Scale, which includes items of situations eliciting embarrassment for oneself ("self-embarrassment") and embarrassment for others ("vicarious embarrassment"). The two study groups were also compared with the Social Norms Questionnaire (SNQ). The analyses included correlations of SNQ results (total score, violations or "break" errors, and overendorsement of social rules or "overadhere" errors) with Embarrassability Scale scores. RESULTS: Patients with bvFTD did not differ from HCs on total or self-embarrassment scores but did have significantly higher vicarious embarrassment scores. Unlike in the HC group, reports of vicarious embarrassment did not differ from reports of self-embarrassment among patients in the bvFTD group. The Embarrassability Score further correlated with overadherence to norms on the SNQ. CONCLUSIONS: In the presence of social dysfunction and emotional blunting, these findings suggest that patients with bvFTD rely on their own perspective for a rule-based application of social norms in reporting vicarious embarrassment. The assessment of reports of embarrassment for others may indicate an early and previously unrecognized clinical measure for detecting bvFTD.