Objective: To report a case of laryngeal dystonia (LD), parkinsonism and primary progressive aphasia (PPA) with Alzheimer disease (AD) pathology

Background: The presence of 3-4 neurological syndromes typically points to multiple pathologies explaining the heterogeneity. Here, we study one case that argues otherwise.

Method: Case report

Results: A 68-year-old left-handed woman presented with 4 years of tight, forced, tremulous voice with spontaneous voice breaks and mild bilateral hand action tremor. Diagnosed with adductor LD and essential tremor, she responded to thyroarytenoid botulinum toxin injections. At age 71, she developed progressive, dopa-responsive, asymmetric parkinsonism with rest tremor, rigidity, bradykinesia, postural instability (UPDRS 45) and mild word finding difficulty. At age 74, she developed progressive impairment in spontaneous speech, repetition, verbal fluency, abstraction and delayed recall (MOCA 20), consistent with logopenic PPA, that at age 78 involved all cognitive domains (MOCA 4). Post-mortem brain examination [1] following death at age 80 revealed advanced Alzheimer disease neuropathologic change (NIA-AA: High ADNC; A3, B3, C2 [Thal phase 5, Braak stage V]) consistent with the hippocampal-sparing variant [2], including frequent neurofibrillary tangles (NFTs) and severe neuronal loss in the locus coeruleus and moderate-to-frequent NFTs and regionally moderate neuronal loss in the substantia nigra, most pronounced laterally. Immunohistochemistry revealed no α-synuclein, TDP-43 or non-AD tau pathology (except for clinically inconsequential argyrophilic grain disease, Saito stage I).

Conclusion: Although there is a strong association between AD pathology and the logopenic PPA [3], additional clinical and pathological features in this patient are either atypical or exceedingly rare. For instance, only about 10% of AD patients without Lewy body pathology have parkinsonism [4]. Furthermore, the presence of parkinsonism with logopenic PPA is exceedingly rare. In fact, the presence of parkinsonism with PPA (typically agrammatic variant) points to a tauopathy e.g. progressive supranuclear palsy, not AD [5]. Additionally, there is no data suggesting that laryngeal dystonia is associated with either parkinsonism or AD. This case highlights the heterogenous nature of clinicopathologic relationships in neurodegenerative diseases that are increasingly recognized.

References: 1. Perrin RJ, Franklin EE, Bernhardt H, Burns A, Schwetye KE, Cairns NJ, Baxter M, Weiner MW, Morris JC; Alzheimer’s Disease Neuroimaging Initiative. The Alzheimer’s Disease Neuroimaging Initiative Neuropathology Core: An update. Alzheimers Dement. 2024 Nov;20(11):7859-7870. doi: 10.1002/alz.14253. Epub 2024 Oct 1.
PMID: 39351959; PMCID: PMC11567814

2. Murray ME, Graff-Radford NR, Ross OA, Petersen RC, Duara R, Dickson DW. Neuropathologically defined subtypes of Alzheimer’s disease with distinct clinical characteristics: a retrospective study. Lancet Neurol. 2011 Sep;10(9):785-96. doi: 10.1016/S1474-4422(11)70156-9. Epub 2011 Jul 27. PMID: 21802369; PMCID: PMC3175379

3. Watanabe H, Duffy JR, Clark H, Machulda MM, Graff-Radford J, Thu Pham NT, Dickson DW, Lowe VJ, Whitwell JL, Josephs KA. Primary Progressive Aphasia Lacking Core Features of Nonfluent and Semantic Variants: Clinical, Neuroimaging, and Neuropathologic Features. Neurology. 2024 Nov 12;103(9):e209924. doi: 10.1212/WNL.0000000000209924. Epub 2024 Oct 8. PMID: 39656512; PMCID: PMC11474733.

4. Ono D, Sekiya H, Maier AR, Murray ME, Koga S, Dickson DW. Parkinsonism in Alzheimer’s disease without Lewy bodies in association with nigral neuron loss: A data-driven clinicopathologic study. Alzheimers Dement. 2025 Mar;21(3):e14628. doi: 10.1002/alz.14628. PMID: 40042515; PMCID: PMC11881629.

5. Graff-Radford J, Duffy JR, Strand EA, Josephs KA. Parkinsonian motor features distinguish the agrammatic from logopenic variant of primary progressive aphasia. Parkinsonism Relat Disord. 2012 Aug;18(7):890-2. doi: 10.1016/j.parkreldis.2012.04.011. Epub 2012 May 8. PMID: 22575236; PMCID: PMC3424382.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/laryngeal-dystonia-dopa-responsive-parkinsonism-and-primary-progressive-aphasia-with-alzheimer-disease-pathology/