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. 2024 Sep 1;81(9):977-984.
doi: 10.1001/jamaneurol.2024.2213.

Itching Frequency and Neuroanatomic Correlates in Frontotemporal Lobar Degeneration

Rafi Hadad  1   2 , Maria Luisa Mandelli  2   3 , Katherine P Rankin  2   3 , Charlie Toohey  3 , Virginia E Sturm  2   3   4 , Shireen Javandel  2   3 , Andjelika Milicic  2   3 , Marguerite Knudtson  3 , Isabel Elaine Allen  2   5 , Nathalia Hoffmann  6 , Adit Friedberg  2   3 , Katherine Possin  2   3 , Victor Valcour  2   3 , Bruce L Miller  2   3
Affiliations

Itching Frequency and Neuroanatomic Correlates in Frontotemporal Lobar Degeneration

Rafi Hadad et al. JAMA Neurol. .

Abstract

Importance: Itching is common in geriatric populations and is frequently linked to dermatological or systemic conditions. Itching engages specific brain regions that are implicated in the pathogenesis of frontotemporal lobar degeneration spectrum disorders (FTLD-SD). Thus, itching of undetermined origin (IUO) may indicate the presence of a neurodegenerative process.

Objective: To compare the frequency of itching in FTLD-SD and Alzheimer disease (AD) and to determine the neuroanatomical underpinnings of IUO.

Design, setting, and participants: This case-control study evaluated data and brain magnetic resonance images (MRIs) for participants with FTLD-SD or AD. Participants of a research study on FTLD-SD at the University of California, San Francisco, Memory and Aging Center were evaluated from May 1, 2002, to December 31, 2021. The exposure group underwent structural brain MRI within 6 months of initial diagnosis. Research visit summaries were reviewed to validate qualitative details and accurately identify itching with undetermined origin (IUO).

Exposures: Symptoms suggestive of FTLD-SD or AD.

Main outcomes and measures: Frequency of itching in FTLD-SD and AD and neuroanatomic correlates.

Results: A total of 2091 research visit summaries were reviewed for 1112 patients exhibiting symptoms indicative of FTLD-SD or AD. From 795 records where itching or a related phrase was endorsed, 137 had IUO. A total of 454 participants were included in the study: 137 in the itching group (mean [SD] age, 62.7 [9.9] years; 74 [54%] females and 63 males [46%]) and 317 in the nonitching group (mean [SD] age, 60.7 [10.8] years; 154 [49%] females and 163 males [51%]). Groups were similar in age, sex, and disease severity. More frequent itching was found in FTLD-SD (95/248 patients [38%], of which 44 [46%] had behavioral variant frontotemporal dementia [bvFTD]) compared with the AD group (14/77 patients [18%]; P = .001). The odds of itching were 2.4 (95% CI, 1.48-3.97) times higher for FTLD-SD compared with all other cases of dementia. Compared with healthy controls, the group with IUO exhibited greater gray matter atrophy bilaterally in the amygdala, insula, precentral gyrus, and cingulum, as well as in the right frontal superior gyrus and thalamus. Among patients with bvFTD and itching vs bvFTD without itching, itching was associated with right-lateralized gray matter atrophy affecting the insula, thalamus, superior frontal gyrus, and cingulum.

Conclusions and relevance: Among individuals with IUO, FTLD-SD was disproportionately represented compared with AD. In FTLD-SD, dysfunction in the right anterior insula and its connected regions, including the right precentral gyrus, cingulum, and bilateral amygdala, contribute to dysregulation of the itching-scratching networks, resulting in uncontrollable itching or skin picking. Awareness among physicians about the relationship between neurodegeneration and itching may help in the management of itch in older individuals. Further studies are needed to determine the best treatments for these symptoms in patients with neurodegenerative disorders.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Rankin reported grants from the National Institutes of Health (NIH) during the conduct of the study. Dr Miller reported serving on the scientific advisory boards of the Bluefield Project to Cure FTD, John Douglas French Alzheimer’s Foundation, Genworth, Larry L. Hillblom Foundation, Kissick Family Foundation, and Tau Consortium of the Rainwater Charitable Foundation; serving on the external scientific advisory committees of the Arizona Alzheimer’s Consortium, Massachusetts General Brigham Alzheimer’s Disease Research Center (ADRC), and Stanford ADRC; receiving royalties from Elsevier, Guilford Press, Cambridge University Press, Johns Hopkins Press, and Oxford University Press; serving as editor for Neurocase; serving as section editor for Frontiers in Neurology; and receiving grants from the NIH (P01 AG019724 and R01 AG057234) and Bluefield Project to Cure FTD (P0544014). No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Selection Approach for Itching and Nonitching Groups
For image analysis, the subset within the itching group (n = 43) was paired in a 1:2 fashion with a nonitching counterpart (n = 86). This matching was executed by selecting individuals seen most recently, along with congruence in age range, Clinical Dementia Rating global score, and diagnosis. Subsequently, after magnetic resonance image (MRI) quality control, a total of 6 individuals from the itching group and 9 from the nonitching group were excluded from the analysis because of a low-quality MRI or movement artifacts noted. AD indicates Alzheimer disease; IUO, itching of undetermined origin; FTLD, frontotemporal lobar degeneration spectrum disorder.
Figure 2.
Figure 2.. Gray Matter Volume Comparison of the Itching Group vs the Nonitching Group
This figure demonstrates greater right-lateralized gray matter atrophy in the anterior insula and precentral gyrus and bilaterally in the amygdala when comparing the itching with the nonitching group within preselected regions of interest (ROIs).
Figure 3.
Figure 3.. Gray Matter Volume Comparison Between the Behavioral Variant Frontotemporal Dementia (bvFTD) Patient Subgroups (Itching vs Nonitching)
This figure demonstrates gray matter atrophy observed in the right anterior and posterior insula, thalamus, and precentral gyrus when comparing the bvFTD itching group with the bvFTD nonitching group within preselected regions of interest (ROIs).
See this image and copyright information in PMC

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